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Sample records for prognostic chromosome instability

  1. HDAC4, a prognostic and chromosomal instability marker, refines the predictive value of MGMT promoter methylation.

    PubMed

    Cheng, Wen; Li, Mingyang; Cai, Jinquan; Wang, Kuanyu; Zhang, Chuanbao; Bao, Zhaoshi; Liu, Yanwei; Wu, Anhua

    2015-04-01

    Chromosomal instability is a hallmark of human cancers and is closely linked to tumorigenesis. The prognostic value of molecular signatures of chromosomal instability (CIN) has been validated in various cancers. However, few studies have examined the relationship between CIN and glioma. Histone deacetylases (HDACs) regulate chromosome structure and are linked to the loss of genomic integrity in cancer cells. In this study, the prognostic value of HDAC4 expression and its association with markers of CIN were investigated by analyzing data from our own and four other large sample databases. The results showed that HDAC4 expression is downregulated in high- as compared to low-grade glioma and is associated with a favorable clinical outcome. HDAC4 expression and CIN were closely related in glioma from both functional and statistical standpoints. Moreover, the predictive value of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status-a widely used glioma marker-was refined by HDAC4 expression level, which was significantly related to CIN in our study. In conclusion, we propose that HDAC4 expression, a prognostic and CIN marker, enhances the predictive value of MGMT promoter methylation status for identifying patients who will most benefit from radiochemotherapy.

  2. Chromosome instability syndromes

    SciTech Connect

    1993-12-31

    Chapter 11, discusses chromosome instability syndromes. The focus is on the most extensively studied genotypic chromosomal aberrations which include Bloom syndrome, Fanconi anemia, ataxia telangiectasia, and xeroderma pigmentosum. The great interest in these syndromes is out of proportion to their rare occurrence; however, studies of genotypic chromosome breakage have been inspired by the hope of throwing light on chromosome structure and behavior. A table is given which relates chromosomal aberrations in Bloom syndrome which may cause or promote cancer. 34 refs., 3 figs., 1 tab.

  3. Chromosomal instability induced by heavy ion irradiation

    NASA Technical Reports Server (NTRS)

    Limoli, C. L.; Ponnaiya, B.; Corcoran, J. J.; Giedzinski, E.; Morgan, W. F.

    2000-01-01

    PURPOSE: To establish the dose-response relationship for the induction of chromosomal instability in GM10115 cells exposed to high-energy iron ions (1 GeV/nucleon, mean LET 146 keV/microm) and gold ions (11 GeV/nucleon, mean LET 1450 keV/microm). Past work has established that sparsely ionizing X-rays can induce a long-lived destabilization of chromosomes in a dose-dependent manner at an incidence of approximately 3% per gray. The present investigation assesses the capacity of High-Z and High-energy (HZE) particles to elicit this same endpoint. MATERIALS AND METHODS: Clonal populations derived from single progenitor cells surviving heavy-ion irradiation were analyzed cytogenetically to identify those clones showing a persistent destablization of chromosomes. RESULTS: Dose-response data, with a particular emphasis at low dose (< 1.0 Gy), indicate a frequency of approximately 4% per gray for the induction of chromosomal instability in clones derived from single progenitor cells surviving exposure to iron ions. The induction of chromosomal instability by gold ions was, however, less responsive to applied dose, as the observed incidence of this phenotype varied from 0 to 10% over 1-8 Gy. Both iron and gold ions gave dose-dependent increases in the yield of chromosomal aberrations (both chromosome- and chromatid-type) measured at the first mitosis following irradiation, as well as shoulderless survival curves having D0=0.87 and 1.1 Gy respectively. CONCLUSIONS: Based on the present dose-response data, the relative biological effectiveness of iron ions is 1.3 for the induction of chromosomal instability, and this indicates that heavy ions are only slightly more efficient than X-rays at eliciting this delayed phenotype.

  4. A computer simulation of chromosomal instability

    NASA Astrophysics Data System (ADS)

    Goodwin, E.; Cornforth, M.

    The transformation of a normal cell into a cancerous growth can be described as a process of mutation and selection occurring within the context of clonal expansion. Radiation, in addition to initial DNA damage, induces a persistent and still poorly understood genomic instability process that contributes to the mutational burden. It will be essential to include a quantitative description of this phenomenon in any attempt at science-based risk assessment. Monte Carlo computer simulations are a relatively simple way to model processes that are characterized by an element of randomness. A properly constructed simulation can capture the essence of a phenomenon that, as is often the case in biology, can be extraordinarily complex, and can do so even though the phenomenon itself is incompletely understood. A simple computer simulation of one manifestation of genomic instability known as chromosomal instability will be presented. The model simulates clonal expansion of a single chromosomally unstable cell into a colony. Instability is characterized by a single parameter, the rate of chromosomal rearrangement. With each new chromosome aberration, a unique subclone arises (subclones are defined as having a unique karyotype). The subclone initially has just one cell, but it can expand with cell division if the aberration is not lethal. The computer program automatically keeps track of the number of subclones within the expanding colony, and the number of cells within each subclone. Because chromosome aberrations kill some cells during colony growth, colonies arising from unstable cells tend to be smaller than those arising from stable cells. For any chosen level of instability, the computer program calculates the mean number of cells per colony averaged over many runs. These output should prove useful for investigating how such radiobiological phenomena as slow growth colonies, increased doubling time, and delayed cell death depend on chromosomal instability. Also of

  5. Evidence of chromosomal instability in neurofibromatosis

    SciTech Connect

    Hafez, M.; Sharaf, L.; Abd el-Nabi, S.M.; el-Wehedy, G.

    1985-05-15

    Blood lymphocytes from six unrelated patients with neurofibromatosis and three normal controls were examined for their response to different doses (0, 75, 150, 300, 400 rad) of x-radiation, as measured by chromosome aberrations (gaps, breaks, dicentrics, centric rings, acentric ring, fragments, and minutes). Cytogenetic studies on phytohemagglutinin-stimulated cells revealed chromosomal instability in the neurofibromatosis lymphocytes as shown by the significant increase in the in the incidence of gaps, breaks and dicentrics. This increase paralleled the increase in the dose of irradiation. The significance of these findings is discussed.

  6. Chromosomal instability causes sensitivity to metabolic stress.

    PubMed

    Shaukat, Z; Liu, D; Choo, A; Hussain, R; O'Keefe, L; Richards, R; Saint, R; Gregory, S L

    2015-07-30

    Chromosomal INstability (CIN), a hallmark of cancer, refers to cells with an increased rate of gain or loss of whole chromosomes or chromosome parts. CIN is linked to the progression of tumors with poor clinical outcomes such as drug resistance. CIN can give tumors the diversity to resist therapy, but it comes at the cost of significant stress to tumor cells. To tolerate this, cancer cells must modify their energy use to provide adaptation against genetic changes as well as to promote their survival and growth. In this study, we have demonstrated that CIN induction causes sensitivity to metabolic stress. We show that mild metabolic disruption that does not affect normal cells, can lead to high levels of oxidative stress and subsequent cell death in CIN cells because they are already managing elevated stress levels. Altered metabolism is a differential characteristic of cancer cells, so our identification of key regulators that can exploit these changes to cause cell death may provide cancer-specific potential drug targets, especially for advanced cancers that exhibit CIN.

  7. Chromosome instability in a patient with recurrent abortions.

    PubMed

    Bobadilla-Morales, L; Cervantes-Luna, M I; García-Cobián, T A; Gómez-Meda, B C; de la Torre, C Ortega; Corona-Rivera, J R; Corona-Rivera, A

    2009-01-01

    Chromosomal aberrations are one of the recognized possible etiologic genetic causes of recurrent spontaneous abortions. Increased chromosome instability without constitutional chromosome abnormalities is uncommon in these couples. In this work we present a non consanguineous healthy couple with recurrent abortions without constitutional chromosome aberrations in which spontaneous and induced chromosome aberrations were observed in the female. Chromosome analysis was performed in the presence of different chromosome damage inductors such as gamma radiation, Uv light, and mitomycin-C. Alterations observed only in the female were: spontaneous and induced tetraradial chromosomes and increased chromosomal damage induced only by gamma radiation. Oral mucosa micronuclei were moderately increased in the female. Chromosome instability associated to abortion is proposed.

  8. Chromosomal Instability in the progeny of human irradiated cells

    NASA Astrophysics Data System (ADS)

    Testard, I.; Boissière, A.; Martins, L. M.; Sabatier, L.

    Manned space missions recently increased in number and duration, thus it became important to estimate the biological risks encountered by astronauts. They are exposed to cosmic and galactic rays, a complex mixture of different radiations. In addition to the measurements realized by physical dosimeters, it becomes essential to estimate real biologically effective doses and compare them to physical doses. Biological dosimetry of radiation exposures has been widely performed using cytogenetic analysis of chromosomes. This approach has been used for many years in order to estimate absorbed doses in accidental or chronic overexposures of humans. Recent studies show that some alterations can appear many cell generations after the initial radiation exposure as a delayed genomic instability. This delayed instability is characterized by the accumulation of cell alterations leading to cell transformation, delayed cell death and mutations. Chromosome instability was shown in vitro in different model systems (Sabatier et al., 1992; Marder and Morgan, 1993; Kadhim et al., 1994 and Holmberg et al., 1993, 1995). All types of radiation used induce chromosome instability; however, heavy ions cause the most damage. The period of chromosome instability followed by the formation of clones with unbalanced karyotypes seems to be shared by cancer cells. The shortening of telomere sequences leading to the formation of telomere fusions is an important factor in the appearance of this chromosome instability.

  9. The presence of extra chromosomes leads to genomic instability.

    PubMed

    Passerini, Verena; Ozeri-Galai, Efrat; de Pagter, Mirjam S; Donnelly, Neysan; Schmalbrock, Sarah; Kloosterman, Wigard P; Kerem, Batsheva; Storchová, Zuzana

    2016-02-15

    Aneuploidy is a hallmark of cancer and underlies genetic disorders characterized by severe developmental defects, yet the molecular mechanisms explaining its effects on cellular physiology remain elusive. Here we show, using a series of human cells with defined aneuploid karyotypes, that gain of a single chromosome increases genomic instability. Next-generation sequencing and SNP-array analysis reveal accumulation of chromosomal rearrangements in aneuploids, with break point junction patterns suggestive of replication defects. Trisomic and tetrasomic cells also show increased DNA damage and sensitivity to replication stress. Strikingly, we find that aneuploidy-induced genomic instability can be explained by the reduced expression of the replicative helicase MCM2-7. Accordingly, restoring near-wild-type levels of chromatin-bound MCM helicase partly rescues the genomic instability phenotypes. Thus, gain of chromosomes triggers replication stress, thereby promoting genomic instability and possibly contributing to tumorigenesis.

  10. The presence of extra chromosomes leads to genomic instability

    PubMed Central

    Passerini, Verena; Ozeri-Galai, Efrat; de Pagter, Mirjam S.; Donnelly, Neysan; Schmalbrock, Sarah; Kloosterman, Wigard P.; Kerem, Batsheva; Storchová, Zuzana

    2016-01-01

    Aneuploidy is a hallmark of cancer and underlies genetic disorders characterized by severe developmental defects, yet the molecular mechanisms explaining its effects on cellular physiology remain elusive. Here we show, using a series of human cells with defined aneuploid karyotypes, that gain of a single chromosome increases genomic instability. Next-generation sequencing and SNP-array analysis reveal accumulation of chromosomal rearrangements in aneuploids, with break point junction patterns suggestive of replication defects. Trisomic and tetrasomic cells also show increased DNA damage and sensitivity to replication stress. Strikingly, we find that aneuploidy-induced genomic instability can be explained by the reduced expression of the replicative helicase MCM2-7. Accordingly, restoring near-wild-type levels of chromatin-bound MCM helicase partly rescues the genomic instability phenotypes. Thus, gain of chromosomes triggers replication stress, thereby promoting genomic instability and possibly contributing to tumorigenesis. PMID:26876972

  11. Somatic Instability of a Drosophila Chromosome

    PubMed Central

    Wines, D. R.; Henikoff, S.

    1992-01-01

    A mitotically unstable chromosome, detectable because of mosaic expression of marker genes, was generated by X-ray mutagenesis in Drosophila. Nondisjunction of this chromosome is evident in mitotic chromosome preparations, and premature sister chromatid separation is frequent. The mosaic phenotype is modified by genetic elements that are thought to alter chromatin structure. We hypothesize that the mitotic defects result from a breakpoint deep in the pericentric heterochromatin, within or very near to the DNA sequences essential for centromere function. This unique chromosome may provide a tool for the genetic and molecular dissection of a higher eukaryotic centromere. PMID:1628811

  12. [Chromosomal instability in carcinogenesis of cervical cancer.

    PubMed

    de Los Santos-Munive, Victoria; Alonso-Avelino, Juan Angel

    2013-01-01

    In order to spot common chromosomal imbalances in early and late lesions of cervical cancer that might be used as progression biomarkers, we made a search of literature in PubMed from 1996 to 2011. The medical subject headings employed were chromosomal alterations, loss of heterozygosis, cervical cancer, cervical tumorigenesis, chromosomal aberrations, cervical intraepithelial neoplasm and low-grade squamous intraepithelial lesion. The common chromosomal imbalances were gains in 8q24 (77.7 %), 20q13 (66.9 %), 3q26 (47.1 %), Xp22 (43.8 %), and 5p15 (60 %), principally. On the other hand, integration of the high-risk human papillomavirus genome into the host chromosome has been associated with the development of neoplasia, but the chromosomal imbalances seem to precede and promote such integration. Chromosomal imbalances in 8q24, 20q13, 3q21-26 and 5p15-Xp22, determined by fluorescent in situ hybridization assay or comparative genomic hybridization assay for early detection of the presence of high-risk human papillomavirus, are promising markers of cervical cancer progression.

  13. Whole chromosome gain does not in itself confer cancer-like chromosomal instability.

    PubMed

    Valind, Anders; Jin, Yuesheng; Baldetorp, Bo; Gisselsson, David

    2013-12-24

    Constitutional aneuploidy is typically caused by a single-event meiotic or early mitotic error. In contrast, somatic aneuploidy, found mainly in neoplastic tissue, is attributed to continuous chromosomal instability. More debated as a cause of aneuploidy is aneuploidy itself; that is, whether aneuploidy per se causes chromosomal instability, for example, in patients with inborn aneuploidy. We have addressed this issue by quantifying the level of somatic mosaicism, a proxy marker of chromosomal instability, in patients with constitutional aneuploidy by precise background-filtered dual-color FISH. In contrast to previous studies that used less precise methods, we find that constitutional trisomy, even for large chromosomes that are often trisomic in cancer, does not confer a significantly elevated rate of somatic chromosomal mosaicism in individual cases. Constitutional triploidy was associated with an increased level of somatic mosaicism, but this consisted mostly of reversion from trisomy to disomy and did not correspond to a proportionally elevated level of chromosome mis-segregation in triploids, indicating that the observed mosaicism resulted from a specific accumulation of cells with a hypotriploid chromosome number. In no case did the rate of somatic mosaicism in constitutional aneuploidy exceed that of "chromosomally stable" cancer cells. Our findings show that even though constitutional aneuploidy was in some cases associated with low-level somatic mosaicism, it was insufficient to generate the cancer-like levels expected if aneuploidy single-handedly triggered cancer-like chromosomal instability.

  14. Chromosomal instability and aneuploidy in cancer: from yeast to man

    PubMed Central

    Pfau, Sarah J; Amon, Angelika

    2012-01-01

    Aneuploidy is frequently associated with disease and developmental abnormalities. It is also a key characteristic of cancer. Several model systems have been developed to study the role of chromosomal instability and aneuploidy in tumorigenesis. The results are surprisingly complex, with the conditions sometimes promoting and sometimes inhibiting tumour formation. Here, we review the effects of aneuploidy and chromosomal instability in cells and model systems of cancer, propose a model that could explain these complex findings and discuss how the aneuploid condition could be exploited in cancer therapy. PMID:22614003

  15. Radiation-induced chromosomal instability in human mammary epithelial cells

    NASA Astrophysics Data System (ADS)

    Durante, M.; Grossi, G. F.; Yang, T. C.

    Karyotypes of human cells surviving X- and alpha-irradiation have been studied. Human mammary epithelial cells of the immortal, non-tumorigenic cell line H184B5 F5-1 M/10 were irradiated and surviving clones isolated and expanded in culture. Cytogenetic analysis was performed using dedicated software with an image analyzer. We have found that both high- and low-LET radiation induced chromosomal instability in long-term cultures, but with different characteristics. Complex chromosomal rearrangements were observed after X-rays, while chromosome loss predominated after alpha-particles. Deletions were observed in both cases. In clones derived from cells exposed to alpha-particles, some cells showed extensive chromosome breaking and double minutes. Genomic instability was correlated to delayed reproductive death and neoplastic transformation. These results indicate that chromosomal instability is a radiation-quality-dependent effect which could determine late genetic effects, and should therefore be carefully considered in the evaluation of risk for space missions.

  16. Radiation-induced chromosomal instability in human mammary epithelial cells

    NASA Technical Reports Server (NTRS)

    Durante, M.; Grossi, G. F.; Yang, T. C.

    1996-01-01

    Karyotypes of human cells surviving X- and alpha-irradiation have been studied. Human mammary epithelial cells of the immortal, non-tumorigenic cell line H184B5 F5-1 M/10 were irradiated and surviving clones isolated and expanded in culture. Cytogenetic analysis was performed using dedicated software with an image analyzer. We have found that both high- and low-LET radiation induced chromosomal instability in long-term cultures, but with different characteristics. Complex chromosomal rearrangements were observed after X-rays, while chromosome loss predominated after alpha-particles. Deletions were observed in both cases. In clones derived from cells exposed to alpha-particles, some cells showed extensive chromosome breaking and double minutes. Genomic instability was correlated to delayed reproductive death and neoplastic transformation. These results indicate that chromosomal instability is a radiation-quality-dependent effect which could determine late genetic effects, and should therefore be carefully considered in the evaluation of risk for space missions.

  17. Autophagy regulates the survival of cells with chromosomal instability

    PubMed Central

    Liu, Dawei; Shaukat, Zeeshan; Xu, Tianqi; Denton, Donna; Saint, Robert; Gregory, Stephen

    2016-01-01

    Chromosomal instability (CIN) refers to genomic instability in which cells have gained or lost chromosomes or chromosomal fragments. A high level of CIN is common in solid tumours and is associated with cancer drug resistance and poor prognosis. The impact of CIN-induced stress and the resulting cellular responses are only just beginning to emerge. Using proliferating tissue in Drosophila as a model, we found that autophagy is activated in CIN cells and is necessary for their survival. Specifically, increasing the removal of defective mitochondria by mitophagy is able to lower levels of reactive oxygen species and the resultant cellular damage that is normally seen in CIN cells. In response to DNA damage, CIN is increased in a positive feedback loop, and we found that increasing autophagy by Tor depletion could decrease the level of CIN in proliferating cells. These findings underline the importance of autophagy control in the development of CIN tumours. PMID:27590505

  18. Evaluation of Chromosomal Instability in Diabetic Rats Treated with Naringin

    PubMed Central

    A. Bakheet, Saleh; M. Attia, Sabry

    2011-01-01

    We used the bone marrow DNA strand breaks, micronucleus formations, spermatocyte chromosomal aberrations, and sperm characteristic assays to investigate the chromosomal instability in somatic and germinal cells of diabetic rats treated with multiple doses of naringin. The obtained results revealed that naringin was neither cytotoxic nor genotoxic for the rats at all tested doses. Moreover, naringin significantly reduced the diabetes-induced chromosomal instability in somatic and germinal cells in a dose-dependent manner. In addition, diabetes induced marked biochemical alterations characteristic of oxidative stress including enhanced lipid peroxidation, accumulation of oxidized glutathione, reduction in reduced glutathione, and accumulation of intracellular reactive oxygen species. Treatment with naringin ameliorated these biochemical markers dose-dependently. In conclusion, naringin confers an appealing protective effect against diabetes-induced chromosomal instability towards rat somatic and germinal cells which might be explained partially via diminishing the de novo free radical generation induced by hyperglycemia. Thus, naringin might be a good candidate to reduce genotoxic risk associated with hyperglycemia and may provide decreases in the development of secondary malignancy and abnormal reproductive outcomes risks, which seems especially important for diabetic patients. PMID:21941606

  19. Studying chromosome instability in the mouse

    PubMed Central

    Foijer, Floris; Draviam, Viji M.; Sorger, Peter K.

    2010-01-01

    Aneuploidy has long been recognized as one of the hallmarks of cancer. It nonetheless remains uncertain whether aneuploidy occurring early in the development of a cancer is a primary cause of oncogenic transformation, or whether it is an epiphenomenon that arises from a general breakdown in cell cycle control late in tumorigenesis. The accuracy of chromosome segregation is ensured both by the intrinsic mechanics of mitosis and by an error-checking spindle assembly checkpoint. Many cancers show altered expression of proteins involved in the spindle checkpoint or in proteins implicated in other mitotic processes. To understand the role of aneuploidy in the initiation and progression of cancer, a number of spindle checkpoint genes have been disrupted in mice, most through conventional gene targeting (to create germ-line knockouts). We describe the consequence of these mutations with respect to embryonic development, tumor progression and an unexpected link to premature aging; readers are referred elsewhere [1] for a discussion of other cell cycle regulators. PMID:18706976

  20. Chromosomal Instability as a Driver of Tumor Heterogeneity and Evolution.

    PubMed

    Bakhoum, Samuel F; Landau, Dan Avi

    2017-02-17

    Large-scale, massively parallel sequencing of human cancer samples has revealed tremendous genetic heterogeneity within individual tumors. Indeed, tumors are composed of an admixture of diverse subpopulations-subclones-that vary in space and time. Here, we discuss a principal driver of clonal diversification in cancer known as chromosomal instability (CIN), which complements other modes of genetic diversification creating the multilayered genomic instability often seen in human cancer. Cancer cells have evolved to fine-tune chromosome missegregation rates to balance the acquisition of heterogeneity while preserving favorable genotypes, a dependence that can be exploited for a therapeutic benefit. We discuss how whole-genome doubling events accelerate clonal evolution in a subset of tumors by providing a viable path toward favorable near-triploid karyotypes and present evidence for CIN-induced clonal speciation that can overcome the dependence on truncal initiating events.

  1. JNK signaling is needed to tolerate chromosomal instability

    PubMed Central

    Wong, Heidi W-S; Shaukat, Zeeshan; Wang, Jianbin; Saint, Robert; Gregory, Stephen L

    2014-01-01

    Chromosomal instability (CIN), as a common feature of tumors, represents a potential therapeutic target if ways can be found to specifically cause apoptosis in unstably dividing cells. We have previously shown that if signaling through the JNK pathway is reduced, apoptosis is triggered in models of chromosomal instability induced by loss of the spindle checkpoint. Here we identify components upstream and downstream of JNK that are able to mediate this effect, and test the involvement of p53 and DNA damage in causing apoptosis when JNK signaling is reduced in CIN cells. We show that cell cycle progression timing has a strong effect on the apoptosis seen when JNK signaling is reduced in genetically unstable cells: a shortened G2 phase enhances the apoptosis, while lengthening G2 rescues the JNK-deficient CIN cell death phenotype. Our findings suggest that chromosomal instability represents a significant stress to dividing cells, and that without JNK signaling, cells undergo apoptosis because they lack a timely and effective response to DNA damage. PMID:24335260

  2. The nucleus is the target for radiation-induced chromosomal instability

    NASA Technical Reports Server (NTRS)

    Kaplan, M. I.; Morgan, W. F.

    1998-01-01

    We have previously described chromosomal instability in cells of a human-hamster hybrid cell line after exposure to X rays. Chromosomal instability in these cells is characterized by the appearance of novel chromosomal rearrangements multiple generations after exposure to ionizing radiation. To identify the cellular target(s) for radiation-induced chromosomal instability, cells were treated with 125I-labeled compounds and frozen. Radioactive decays from 125I cause damage to the cell primarily at the site of their decay, and freezing the cells allows damage to accumulate in the absence of other cellular processes. We found that the decay of 125I-iododeoxyuridine, which is incorporated into the DNA, caused chromosomal instability. While cell killing and first-division chromosomal rearrangements increased with increasing numbers of 125I decays, the frequency of chromosomal instability was independent of dose. Chromosomal instability could also be induced from incorporation of 125I-iododeoxyuridine without freezing the cells for accumulation of decays. This indicates that DNA double-strand breaks in frozen cells resulting from 125I decays failed to lead to instability. Incorporation of an 125I-labeled protein (125I-succinyl-concanavalin A), which was internalized into the cell and/or bound to the plasma membrane, neither caused chromosomal instability nor potentiated chromosomal instability induced by 125I-iododeoxyuridine. These results show that the target for radiation-induced chromosomal instability in these cells is the nucleus.

  3. Chromosome instabilities and programmed cell death in tapetal cells of maize with B chromosomes and effects on pollen viability.

    PubMed Central

    González-Sánchez, Mónica; Rosato, Marcela; Chiavarino, Mauricio; Puertas, María J

    2004-01-01

    B chromosomes (B's), knobbed chromosomes, and chromosome 6 (NOR) of maize undergo nondisjunction and micronucleus formation in binucleate tapetal cells. These chromosome instabilities are regular events in the program of tapetal cell death, but the B's strongly increase A chromosome instability. We studied 1B and 0B plants belonging to selected lines for high or low B transmission rate and their F1 hybrids. These lines are characterized by meiotic conservation or loss of B chromosomes, respectively. The female B transmission (fBtl) allele(s) for low B transmission is dominant, inducing micronucleus formation and B nondisjunction. We hypothesize that the fBtl allele(s) induces knob instability. This instability would be sufficient to produce B loss in both meiocytes and binucleate tapetal cells. B instability could, in turn, produce instabilities in all chromosomes of maize complement. To establish whether the chromosomal instabilities are related to the tapetal programmed cell death (PCD) process, we applied the TUNEL technique. PCD, estimated as the frequency of binucleate tapetal cells with TUNEL label, was significantly correlated with the formation of micronuclei and the frequency of pollen abortion. It can be concluded that the observed chromosome instabilities are important to the PCD process and to the development of microspores to form viable pollen grains. PMID:15020483

  4. Non-meiotic chromosome instability in human immature oocytes

    PubMed Central

    Daina, Gemma; Ramos, Laia; Rius, Mariona; Obradors, Albert; del Rey, Javier; Giralt, Magda; Campillo, Mercedes; Velilla, Esther; Pujol, Aïda; Martinez-Pasarell, Olga; Benet, Jordi; Navarro, Joaquima

    2014-01-01

    Aneuploidy has been a major issue in human gametes and is closely related to fertility problems, as it is known to be present in cleavage stage embryos and gestational losses. Pre-meiotic chromosome abnormalities in women have been previously described. The aim of this study is to assess the whole-chromosome complement in immature oocytes to find those abnormalities caused by mitotic instability. For this purpose, a total of 157 oocytes at the germinal vesicle or metaphase I stage, and discarded from IVF cycles, were analysed by CGH. Fifty-six women, between 18 and 45 years old (mean 32.5 years), including 32 IVF patients (25–45 years of age) and 24 IVF oocyte donors (18–33 years of age), were included in the study. A total of 25/157 (15.9%) of the oocytes analysed, obtained from three IVF clinics, contained chromosome abnormalities, including both aneuploidy (24/157) and structural aberrations (9/157). Independently of the maternal age, the incidence of abnormal oocytes which originated before meiosis is 15.9%, and these imbalances were found in 33.9% of the females studied. This work sheds light on the relevance of mitotic instability responsible for the generation of the abnormalities present in human oocytes. PMID:23695274

  5. Non-meiotic chromosome instability in human immature oocytes.

    PubMed

    Daina, Gemma; Ramos, Laia; Rius, Mariona; Obradors, Albert; Del Rey, Javier; Giralt, Magda; Campillo, Mercedes; Velilla, Esther; Pujol, Aïda; Martinez-Pasarell, Olga; Benet, Jordi; Navarro, Joaquima

    2014-02-01

    Aneuploidy has been a major issue in human gametes and is closely related to fertility problems, as it is known to be present in cleavage stage embryos and gestational losses. Pre-meiotic chromosome abnormalities in women have been previously described. The aim of this study is to assess the whole-chromosome complement in immature oocytes to find those abnormalities caused by mitotic instability. For this purpose, a total of 157 oocytes at the germinal vesicle or metaphase I stage, and discarded from IVF cycles, were analysed by CGH. Fifty-six women, between 18 and 45 years old (mean 32.5 years), including 32 IVF patients (25-45 years of age) and 24 IVF oocyte donors (18-33 years of age), were included in the study. A total of 25/157 (15.9%) of the oocytes analysed, obtained from three IVF clinics, contained chromosome abnormalities, including both aneuploidy (24/157) and structural aberrations (9/157). Independently of the maternal age, the incidence of abnormal oocytes which originated before meiosis is 15.9%, and these imbalances were found in 33.9% of the females studied. This work sheds light on the relevance of mitotic instability responsible for the generation of the abnormalities present in human oocytes.

  6. Aurora-A Expression Is Independently Associated with Chromosomal Instability in Colorectal Cancer1

    PubMed Central

    Baba, Yoshifumi; Nosho, Katsuhiko; Shima, Kaori; Irahara, Natsumi; Kure, Shoko; Toyoda, Saori; Kirkner, Gregory J; Goel, Ajay; Fuchs, Charles S; Ogino, Shuji

    2009-01-01

    AURKA (the official symbol for Aurora-A, STK15, or BTAK) regulates the function of centrosomes, spindles, and kinetochores for proper mitotic progression. AURKA overexpression is observed in various cancers including colon cancer, and a link between AURKA and chromosomal instability (CIN) has been proposed. However, no study has comprehensively examined AURKA expression in relation to CIN or prognosis using a large number of tumors. Using 517 colorectal cancers in two prospective cohort studies, we detected AURKA overexpression (by immunohistochemistry) in 98 tumors (19%). We assessed other molecular events including loss of heterozygosity (LOH) in 2p, 5q, 17q, and 18q, the CpG island methylation phenotype (CIMP), and microsatellite instability (MSI). Prognostic significance of AURKA was evaluated by Cox regression and Kaplan-Meier method. In both univariate and multivariate logistic regressions, AURKA overexpression was significantly associated with CIN (defined as the presence of LOH in any of the chromosomal segments; multivariate odds ratio, 2.97; 95% confidence interval, 1.40–6.29; P = .0045). In multivariate analysis, AURKA was associated with cyclin D1 expression (P = .010) and inversely with PIK3CA mutation (P=.014), fatty acid synthase expression (P=.028), and family history of colorectal cancer (P = .050), but not with sex, age, body mass index, tumor location, stage, CIMP, MSI, KRAS, BRAF, BMI, LINE-1 hypomethylation, p53, p21, β-catenin, or cyclooxygenase 2. AURKA was not significantly associated with clinical outcome or survival. In conclusion, AURKA overexpression is independently associated with CIN in colorectal cancer, supporting a potential role of Aurora kinase-A in colorectal carcinogenesis through genomic instability (rather than epigenomic instability). PMID:19412426

  7. Original CIN: reviewing roles for APC in chromosome instability.

    PubMed

    Rusan, Nasser M; Peifer, Mark

    2008-06-02

    You may have seen the bumper sticker "Eve was framed." Thousands of years of being blamed for original sin and still many wonder, where's the evidence? Today, the tumor suppressor adenomatous polyposis coli (APC) may have the same complaint about accusations of a different type of CIN, chromosome instability. A series of recent papers, including three in this journal, propose that loss of APC function plays an important role in the CIN seen in many colon cancer cells. However, a closer look reveals a complex story that raises more questions than answers.

  8. Hexavalent chromium induces chromosome instability in human urothelial cells.

    PubMed

    Wise, Sandra S; Holmes, Amie L; Liou, Louis; Adam, Rosalyn M; Wise, John Pierce

    2016-04-01

    Numerous metals are well-known human bladder carcinogens. Despite the significant occupational and public health concern of metals and bladder cancer, the carcinogenic mechanisms remain largely unknown. Chromium, in particular, is a metal of concern as incidences of bladder cancer have been found elevated in chromate workers, and there is an increasing concern for patients with metal hip implants. However, the impact of hexavalent chromium (Cr(VI)) on bladder cells has not been studied. We compared chromate toxicity in two bladder cell lines; primary human urothelial cells and hTERT-immortalized human urothelial cells. Cr(VI) induced a concentration- and time-dependent increase in chromosome damage in both cell lines, with the hTERT-immortalized cells exhibiting more chromosome damage than the primary cells. Chronic exposure to Cr(VI) also induced a concentration-dependent increase in aneuploid metaphases in both cell lines which was not observed after a 24h exposure. Aneuploidy induction was higher in the hTERT-immortalized cells. When we correct for uptake, Cr(VI) induces a similar amount of chromosome damage and aneuploidy suggesting that the differences in Cr(VI) sensitivity between the two cells lines were due to differences in uptake. The increase in chromosome instability after chronic chromate treatment suggests this may be a mechanism for chromate-induced bladder cancer, specifically, and may be a mechanism for metal-induced bladder cancer, in general.

  9. Role of chromosome instability in long term effect of manned-space missions

    NASA Astrophysics Data System (ADS)

    Ducray, C.; Sabatier, L.

    Astronauts are exposed to heavy ions during space missions and heavy ion induced-chromosome damages have been observed in their lymphocytes. This raises the problem of the consequence of longer space flights. Recent studies show that some alterations can appear many cell generations after the initial radiation exposure as a delayed genomic instability. This delayed instability is characterized by the accumulation of cell alterations leading to cell transformation, delayed cell death and mutations. Chromosome instability was shown in vitro in different model systems. All types of radiation used induce a chromosome instability, however, heavy ions cause the most damage. The period of chromosome instability followed by the formation of clones with unbalanced karyotypes seems to be shared by cancer cells. The shortening of telomere sequences leading to the formation of telomere fusions is an important factor in the appearance of this chromosome instability.

  10. Centromeric instability of chromosomes 1, 9, and 16 associated with combined immunodeficiency.

    PubMed

    Fryns, J P; Azou, M; Jaeken, J; Eggermont, E; Pedersen, J C; Van den Berghe, H

    1981-01-01

    Instability of the centromeric regions of chromosomes 1, 9, and 16 in cultured lymphocytes of an 8-month-old girl with malabsorption and combined immunodeficiency is reported. Together with the two previous reports on this condition, the present report seems to confirm the specific association of combined immunodeficiency and centromeric instability of chromosomes 1, 9, and 16 with multibranching.

  11. Mechanism of Suppression of Chromosomal Instability by DNA Polymerase POLQ

    PubMed Central

    Yousefzadeh, Matthew J.; Wyatt, David W.; Takata, Kei-ichi; Mu, Yunxiang; Hensley, Sean C.; Tomida, Junya; Bylund, Göran O.; Doublié, Sylvie; Johansson, Erik; Ramsden, Dale A.; McBride, Kevin M.; Wood, Richard D.

    2014-01-01

    Although a defect in the DNA polymerase POLQ leads to ionizing radiation sensitivity in mammalian cells, the relevant enzymatic pathway has not been identified. Here we define the specific mechanism by which POLQ restricts harmful DNA instability. Our experiments show that Polq-null murine cells are selectively hypersensitive to DNA strand breaking agents, and that damage resistance requires the DNA polymerase activity of POLQ. Using a DNA break end joining assay in cells, we monitored repair of DNA ends with long 3′ single-stranded overhangs. End joining events retaining much of the overhang were dependent on POLQ, and independent of Ku70. To analyze the repair function in more detail, we examined immunoglobulin class switch joining between DNA segments in antibody genes. POLQ participates in end joining of a DNA break during immunoglobulin class-switching, producing insertions of base pairs at the joins with homology to IgH switch-region sequences. Biochemical experiments with purified human POLQ protein revealed the mechanism generating the insertions during DNA end joining, relying on the unique ability of POLQ to extend DNA from minimally paired primers. DNA breaks at the IgH locus can sometimes join with breaks in Myc, creating a chromosome translocation. We found a marked increase in Myc/IgH translocations in Polq-defective mice, showing that POLQ suppresses genomic instability and genome rearrangements originating at DNA double-strand breaks. This work clearly defines a role and mechanism for mammalian POLQ in an alternative end joining pathway that suppresses the formation of chromosomal translocations. Our findings depart from the prevailing view that alternative end joining processes are generically translocation-prone. PMID:25275444

  12. Characteristics of chromosome instability in the human lymphoblast cell line WTK1

    NASA Technical Reports Server (NTRS)

    Schwartz, J. L.; Jordan, R.; Evans, H. H.

    2001-01-01

    The characteristics of spontaneous and radiation-induced chromosome instability were determined in each of 50 individual clones isolated from control populations of human lymphoblasts (WTK1), as well as from populations of these cells previously exposed to two different types of ionizing radiation, Fe-56 and Cs-137. The types of chromosome instability did not appear to change in clones surviving radiation exposure. Aneuploidy, polyploidy, chromosome dicentrics and translocations, and chromatid breaks and gaps were found in both control and irradiated clones. The primary effect of radiation exposure was to increase the number of cells within any one clone that had chromosome alterations. Chromosome instability was associated with telomere shortening and elevated levels of apoptosis. The results suggest that the proximal cause of chromosome instability is telomere shortening.

  13. Whole Chromosome Instability induces senescence and promotes SASP

    PubMed Central

    Andriani, Grasiella Angelina; Almeida, Vinnycius Pereira; Faggioli, Francesca; Mauro, Maurizio; Tsai, Wanxia Li; Santambrogio, Laura; Maslov, Alexander; Gadina, Massimo; Campisi, Judith; Vijg, Jan; Montagna, Cristina

    2016-01-01

    Age-related accumulation of ploidy changes is associated with decreased expression of genes controlling chromosome segregation and cohesin functions. To determine the consequences of whole chromosome instability (W-CIN) we down-regulated the spindle assembly checkpoint component BUB1 and the mitotic cohesin SMC1A, and used four-color-interphase-FISH coupled with BrdU incorporation and analyses of senescence features to reveal the fate of W-CIN cells. We observed significant correlations between levels of not-diploid cells and senescence-associated features (SAFs). W-CIN induced DNA double strand breaks and elevated oxidative stress, but caused low apoptosis. SAFs of W-CIN cells were remarkably similar to those induced by replicative senescence but occurred in only 13 days versus 4 months. Cultures enriched with not-diploid cells acquired a senescence-associated secretory phenotype (SASP) characterized by IL1B, CXCL8, CCL2, TNF, CCL27 and other pro-inflammatory factors including a novel SASP component CLEC11A. These findings suggest that W-CIN triggers premature senescence, presumably to prevent the propagation of cells with an abnormal DNA content. Cells deviating from diploidy have the ability to communicate with their microenvironment by secretion of an array of signaling factors. Our results suggest that aneuploid cells that accumulate during aging in some mammalian tissues potentially contribute to age-related pathologies and inflammation through SASP secretion. PMID:27731420

  14. The TP53 dependence of radiation-induced chromosome instability in human lymphoblastoid cells

    NASA Technical Reports Server (NTRS)

    Schwartz, Jeffrey L.; Jordan, Robert; Evans, Helen H.; Lenarczyk, Marek; Liber, Howard

    2003-01-01

    The dose and TP53 dependence for the induction of chromosome instability were examined in cells of three human lymphoblastoid cell lines derived from WIL2 cells: TK6, a TP53-normal cell line, NH32, a TP53-knockout created from TK6, and WTK1, a WIL2-derived cell line that spontaneously developed a TP53 mutation. Cells of each cell line were exposed to (137)Cs gamma rays, and then surviving clones were isolated and expanded in culture for approximately 35 generations before the frequency and characteristics of the instability were analyzed. The presence of dicentric chromosomes, formed by end-to-end fusions, served as a marker of chromosomal instability. Unexposed TK6 cells had low levels of chromosomal instability (0.002 +/- 0.001 dicentrics/cell). Exposure of TK6 cells to doses as low as 5 cGy gamma rays increased chromosome instability levels nearly 10-fold to 0.019 +/- 0.008 dicentrics/cell. There was no further increase in instability levels beyond 5 cGy. In contrast to TK6 cells, unexposed cultures of WTK1 and NH32 cells had much higher levels of chromosome instability of 0.034 +/- 0.007 and 0.041 +/- 0.009, respectively, but showed little if any effect of radiation on levels of chromosome instability. The results suggest that radiation exposure alters the normal TP53-dependent cell cycle checkpoint controls that recognize alterations in telomere structure and activate apoptosis.

  15. Hypo-methylation mediates chromosomal instability in pancreatic NET.

    PubMed

    Marinoni, I; Wiederkeher, A; Wiedmer, T; Pantasis, S; Di Domenico, A; Frank, R; Vassella, E; Schmitt, A; Perren, A

    2017-03-01

    DAXX and or ATRX loss occur in 40% of pancreatic neuroendocrine tumors (PanNETs). PanNETs negative for DAXX or ATRX show an increased risk of relapse. The tumor-associated pathways activated upon DAXX or ATRX loss and how this event may induce chromosomal instability (CIN) and alternative lengthening telomeres (ALT) are still unknown. Both DAXX and ATRX are involved in DNA methylation regulation. DNA methylation of heterochromatin and of non-coding sequences is extremely important for the maintenance of genomic stability. We analyzed the association of DAXX and/or ATRX loss and CIN with global DNA methylation in human PanNET samples and the effect of DAXX knock-down on methylation and cell proliferation. We assessed LINE1 as well as global DNA methylation in 167 PanNETs, and we found that DAXX and or ATRX-negative tumors and tumors with CIN were hypomethylated. DAXX knock-down in PanNET cell lines blocked cells in G1/G0 phase and seemed to increase CIN in QGP-1 cells. However, no direct changes in DNA methylation were observed after DAXX knock-down in vitro In conclusion, our data indicate that epigenetic changes are crucial steps in the progression of PanNETs loss and suggest that DNA methylation is the mechanism via which CIN is induced, allowing clonal expansion and selection.

  16. Genomic Instability in Human Pluripotent Stem Cells Arises from Replicative Stress and Chromosome Condensation Defects.

    PubMed

    Lamm, Noa; Ben-David, Uri; Golan-Lev, Tamar; Storchová, Zuzana; Benvenisty, Nissim; Kerem, Batsheva

    2016-02-04

    Human pluripotent stem cells (hPSCs) frequently acquire chromosomal aberrations such as aneuploidy in culture. These aberrations progressively increase over time and may compromise the properties and clinical utility of the cells. The underlying mechanisms that drive initial genomic instability and its continued progression are largely unknown. Here, we show that aneuploid hPSCs undergo DNA replication stress, resulting in defective chromosome condensation and segregation. Aneuploid hPSCs show altered levels of actin cytoskeletal genes controlled by the transcription factor SRF, and overexpression of SRF rescues impaired chromosome condensation and segregation defects in aneuploid hPSCs. Furthermore, SRF downregulation in diploid hPSCs induces replication stress and perturbed condensation similar to that seen in aneuploid cells. Together, these results suggest that decreased SRF expression induces replicative stress and chromosomal condensation defects that underlie the ongoing chromosomal instability seen in aneuploid hPSCs. A similar mechanism may also operate during initiation of instability in diploid cells.

  17. Response to chemotherapy is not related to chromosome instability in synovial sarcoma

    PubMed Central

    Chakiba, C.; Lagarde, P.; Pissaloux, D.; Neuville, A.; Brulard, C.; Pérot, G.; Coindre, J. M.; Terrier, P.; Ranchere-Vince, D.; Ferrari, A.; Collini, P.; Suurmeijer, A. J. H.; Blay, J. Y.; Terrisse, S. A.; Piperno-Neumann, S.; Averous, G.; Bui, B.; Orbach, D.; Italiano, A.; Chibon, F.

    2014-01-01

    Background Synovial sarcoma (SS) is an aggressive soft-tissue tumor. Despite being considered as a chemosensitive disease, the real impact of perioperative chemotherapy on metastasis-free survival (MFS) is controversial. We have shown that metastatic relapse of SS is strongly associated with genomic complexity. There are no data regarding the potential correlation between genomic complexity and response to chemotherapy. Patients and methods The study population included 65 SS patients diagnosed between 1991 and 2013 and with available tissue material. Genomic profiling was carried out by using array-CGH. Forty-five SS out of the 65 patients were treated with neoadjuvant anthracycline/ifosfamide-based chemotherapy. Radiological response was assessed according to RECIST criteria. Histological response was defined by the percentage of recognizable tumor cells on the surgical specimen. Results Genomic complexity was significantly associated with MFS. However, there was no statistically significant association between radiological or histological response and genomic complexity. Conclusion The absence of significant association between response to chemotherapy and genomic complexity suggests that the prognostic value of chromosome instability in SS is independent of response to chemotherapy; mechanisms leading to metastatic relapse of SS are intrinsic to the biology of the tumor and current cytotoxic drugs are only poorly efficient to prevent it. PMID:25070544

  18. In vitro and in silico modeling of chromosomal instability

    NASA Astrophysics Data System (ADS)

    Andreev, Sergey; Eidelman, Yuri; Krasavin, Eugene; Govorun, Raisa; Koshlan, Igor; Pyatenko, Valentina; Korovchuk, Olga; Khvostunov, Igor; Sevankaev, Alexander

    Exposure to ionizing radiation increases cancer risk in human population. Cancer is thought to originate from an altered expression of certain number of specific genes. It is widely recognized that chromosome aberrations (CA) are involved in stable change in expression of genes by gain or loss of their functions. Thus CA can contribute to initiation or progression of cancer. Radiation induces CA immediately after exposure (in first cell cycle) and results in formation of delayed CA in descendants of irradiated cells, or chromosomal instability phenotype (CI). Therefore quantification of CI is a prerequisite of any mechanistic model of radiation induced cancer risks. To quantify CI we designed a set of in vitr o and in silico experiments. Two experimental models for study of CI in vitro, CHO-K1 wild-type and V79 HPRT-mutant cells, were exploited. Chromosome and chromatid type aberrations (Giemsa staining) were scored following exposure to gamma-radiation and accelerated ions (protons, LET=0.22 keV/µm, 7 Li3+ , LET=20 keV/µm, 14 7+ N , LET=77 keV/µm). The obtained results suggested that slowly growing colonies of HPRT mutant cells originating from lowand high-LET irradiated wt V79 cells were formed. After 14 N7+ ions irradiation about 50-100% of colonies had the decreased growth rate and CI phenotype was observed mainly in slowly growing colonies. High, compared to control, level of unstable CA (dicentrics) was observed in the progeny of gamma-irradiated CHO-K1 cells at different time points up to 30 cell generations. CA frequency, the number of cells with aberrations and the shape of a CA-vs-time curve were found to be dependent on the cell culture state (stationary or logarithmic phase) in which they were irradiated. Inhibition of replication and repair DNA synthesis by ara-C and hydroxyurea resulted in small modification of CA dynamics for stat-phase cells. For log-phase cell culture, in contrast, DNA synthesis inhibitors drastically impacted CA dynamics. In

  19. The evolution of chromosomal instability in Chinese hamster cells: a changing picture?

    NASA Technical Reports Server (NTRS)

    Ponnaiya, B.; Limoli, C. L.; Corcoran, J.; Kaplan, M. I.; Hartmann, A.; Morgan, W. F.

    1998-01-01

    PURPOSE: To investigate the kinetics of chromosomal instability induced in clones of Chinese hamster cells following X-irradiation. MATERIALS AND METHODS: X-irradiated clones of GM10115, human-hamster hybrid cells containing a single human chromosome 4 (HC4), have been previously established. These clones were defined as unstable if they contained > or = three subpopulations of cells with unique rearrangements of HC4 as detected by FISH. Stable and unstable clones were analysed by FISH and Giemsa staining at various times post-irradiation. RESULTS: While most of the stable clones continued to show chromosomal stability of HC4 over time, one became marginally unstable at approximately 45 population doublings post-irradiation. Clones exhibiting chromosomal instability had one of several fates. Many of the unstable clones were showed similar levels of instability over time. However, one unstable clone became stable with time in culture, while another became even more unstable over time. Cytogenetic analyses of all clones after Giemsa staining indicated that in some clones the hamster chromosomes were rearranged independent of HC4, demonstrating increased frequencies of chromatid breaks and dicentric chromosomes. The majority of the unstable clones also had higher yields of chromatid gaps. CONCLUSIONS: These data demonstrate the dynamic nature of chromosomal instability as measured by two different cytogenetic assays.

  20. A role for chromosomal instability in the development of and selection for radioresistant cell variants

    NASA Technical Reports Server (NTRS)

    Limoli, C. L.; Corcoran, J. J.; Jordan, R.; Morgan, W. F.; Schwartz, J. L.

    2001-01-01

    Chromosome instability is a common occurrence in tumour cells. We examined the hypothesis that the elevated rate of mutation formation in unstable cells can lead to the development of clones of cells that are resistant to the cancer therapy. To test this hypothesis, we compared chromosome instability to radiation sensitivity in 30 independently isolated clones of GM10115 human-hamster hybrid cells. There was a broader distribution of radiosensitivity and a higher mean SF(2)in chromosomally unstable clones. Cytogenetic and DNA double-strand break rejoining assays suggest that sensitivity was a function of DNA repair efficiency. In the unstable population, the more radioresistant clones also had significantly lower plating efficiencies. These observations suggest that chromosome instability in GM10115 cells can lead to the development of cell variants that are more resistant to radiation. In addition, these results suggest that the process of chromosome breakage and recombination that accompanies chromosome instability might provide some selective pressure for more radioresistant variants. Copyright 2001 Cancer Research Campaign.

  1. Immunodeficiency, centromeric heterochromatin instability of chromosomes 1, 9, and 16, and facial anomalies: the ICF syndrome.

    PubMed Central

    Maraschio, P; Zuffardi, O; Dalla Fior, T; Tiepolo, L

    1988-01-01

    Instability of the heterochromatic centromeric regions of chromosomes 1, 9, and 16 associated with immunodeficiency was found in a four year old girl. Similar phenotypic and chromosomal abnormalities were described in a previous patient studied by us and in four other published cases. All these patients have facial anomalies in addition to combined immunodeficiency and chromosomal instability. Stretching of the heterochromatic centromeric regions of chromosomes 1, 16, and to a lesser extent, 9 and homologous and non-homologous associations of these regions were the most common cytogenetic findings in all the patients. Multi-branched configurations and whole arm deletions of chromosomes 1 or 16 or both were also found. Comparing clinical and chromosomal data we conclude that immunodeficiency, centromeric heterochromatin instability, and facial anomalies form a new syndrome, for which we propose the acronym ICF. A mutation interfering with the normal process of condensation of part of the centromeric heterochromatin is postulated as the basic chromosome defect in this syndrome. Images PMID:3351904

  2. Evidence that both genetic instability and selection contribute to the accumulation of chromosome alterations in cancer.

    PubMed

    Gorringe, Kylie L; Chin, Suet-Feung; Pharoah, Paul; Staines, Joanne M; Oliveira, Carla; Edwards, Paul A W; Caldas, Carlos

    2005-05-01

    Cancer cells contain many genetic alterations, and genetic instability may be important in tumourigenesis. We evaluated 58 breast and ovarian cancer cell lines for microsatellite instability (MSI) and chromosomal instability (CIN). MSI was identified in 3/33 breast and 5/25 ovarian cell lines, and 7/8 MSI lines showed an inactivation of mismatch repair. Average ploidy by centromeric fluorescence in situ hybridization (FISH) of MSI (n = 8, average ploidy = 2.65) and microsatellite stable (MSS; n = 7, average ploidy = 3.01) cell lines was not different, due to the presence of three aneuploid MSI lines, and two near-diploid MSS lines. However, the variability of the centromeric FISH data was different between MSI and MSS (P = 0.049). The complexity of structural chromosomal rearrangements was not different between MSI and MSS. Thus, MSI and numerical CIN are not mutually exclusive, and structural CIN occurs independently of MSI or numerical CIN. Dynamic genetic instability was evaluated in three cell lines-MSI diploid (MT-3), MSS diploid (SUM159) and MSS aneuploid (MT-1). Ten clones of each of these cell lines were analysed by centromeric FISH and six-colour chromosome painting. The variation in chromosome number was different among all three cell lines (P < 0.001). MT-3 appeared numerically constant (94% of centromeric FISH signals matched the mode). SUM159 was 88% constant; however, 7% of cells had duplicated chromosomes. MT-1 was 82% constant; most changes were chromosomal losses. The six-colour FISH data showed that SUM159 had more stable structural chromosomal alterations (e.g. chromosomal translocations) compared with MT-3 and MT-1, but had no increase in unstable changes (e.g. chromatid breaks) when compared with MT-3. MT-1 had fewer unstable changes than both MT-3 and SUM159. These data suggest that numerical CIN may contribute to aneuploidy, but that selection plays an important role, particularly for the accumulation of structural chromosomal changes.

  3. Polysomy of chromosomes 1 and 19: an underestimated prognostic factor in oligodendroglial tumors.

    PubMed

    Jiang, Haihui; Ren, Xiaohui; Zhang, Zhe; Zeng, Wei; Wang, Junmei; Lin, Song

    2014-10-01

    The clinical significance of chromosomes 1 and 19 deletion was well established in oligodendroglial tumors (ODGs). This study was designed to evaluate the prognostic implication of chromosomes 1 and 19 polysomy in gliomas. 584 patients with histological diagnosis of primary gliomas enrolled in the study. Chromosomes 1 and 19 status was detected with fluorescence in situ hybridization (FISH). Of the 584 cases, the frequency of 1q and 19p polysomy in mixed gliomas was significantly higher than ODGs or astrocytic tumors (1q P = 0.032 and P = 0.044; 19p P = 0.024 and P = 0.027); the frequency of 1q and 19p polysomy in low-grade gliomas (WHO II) was relatively lower compared with WHO III or WHO IV (1q P = 0.097 and P = 0.026; 19p P = 0.04 and P = 0.002). 1q, 19p and co-polysomy were confirmed as risk factors conveyed unfavorable outcomes, which has been further validated in both anaplastic oligodendroglial tumors (AOGs) (P = 0.07, P = 0.028 and P = 0.054 for PFS; P = 0.007, P = 0.001 and P = 0.002 for OS, respectively) and glioblastomas with oligodendroglioma component (GBMOs) (P = 0.005, P < 0.001 and P < 0.001 for PFS; P = 0.136, P = 0.006 and P = 0.051 for OS, respectively). Based on chromosomes 1/19 co-deletion and co-polysomy, AOGs and GBMOs could be divided into three subgroups which harbored distinct prognosis (AOGs P < 0.001 for PFS and P < 0.001 for OS; GBMOs P < 0.001 for PFS and P = 0.012 for OS). Chromosomes 1/19 polysomy are potential prognostic factors which confer unfavorable outcomes. The molecular prognostic grouping model based on chromosomes 1/19 co-polysomy and co-deletion better predicts prognosis and provides a more reliable information for treatment decision-making.

  4. Micronucleus assay in human fibroblasts: a measure of spontaneous chromosomal instability and mutagen hypersensitivity

    SciTech Connect

    Rudd, N.L.; Hoar, D.I.; Greentree, C.L.; Dimnik, L.S.; Hennig, U.S.S.

    1988-01-01

    By comparing fibroblast strains derived from individuals exhibiting chromosome instability and/or mutagen hypersensitivity (Cockayne syndrome, ataxia telangiectasia, and Fanconi anemia) with strains derived from health donors, the fibroblast micronucleus assay has been established as a reproducible measure of the genotypic variation in spontaneous or mitomycin C (MMC)-induced chromosomal instability. The patient strains that were moderately or exquisitely sensitive to MMC could be distinguished readily from the control strains, both in levels of spontaneous micronuclei and in sensitivity to MMC, whereas the mildly sensitive strain (Cockayne syndrome) overlapped with the control range. The reproducibility of the assay was evaluated within and between experiments. In addition to its value as a test system for genotoxins, the fibroblast micronucleus assay may be useful for investigating genetically determined hypersensitivity to mutagens, elevated spontaneous chromosomal breakage, and chromosome segregation errors.

  5. Genetic disruption of cytosine DNA methyltransferase enzymes induces chromosomal instability in human cancer cells.

    PubMed

    Karpf, Adam R; Matsui, Sei-ichi

    2005-10-01

    DNA methyltransferase 1 (DNMT1)-deficient mice are tumor-prone, and this has been proposed to result from the induction of genomic instability. To address whether loss of DNMT1, or the related protein DNMT3b, results in genomic instability in human cancer cells, we used a near-diploid human colorectal cancer cell line, HCT116, in which one or both DNMT genes were disrupted by homologous recombination. Array-based comparative genomic hybridization analyses indicated that double, but not single, DNMT knock-out cells display two specific alterations in regional DNA copy number, suggesting that DNMT deficiency and genomic DNA hypomethylation are not associated with widespread genomic amplifications or deletions in human cancer cells. However, spectral karyotype analyses revealed that DNMT-deficient HCT116 cells are highly unstable with respect to large-scale chromosomal alterations; furthermore, this effect is characterized by a high degree of individual cell heterogeneity. The induction of chromosomal alterations in DNMT-deficient cells was evidenced both by aneuploidy and by large increases in the number of novel chromosomal translocations. Studies of double knock-out cells indicated that the generation of chromosomal alterations is spontaneous and persistent in vitro, meeting the formal definition of genomic instability. In summary, we show that DNMT deficiency in human cancer cells results in constitutive genomic instability manifested by chromosomal translocations.

  6. Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy

    PubMed Central

    2012-01-01

    Background Between 8% and 22% of female carriers of DMD mutations exhibit clinical symptoms of variable severity. Development of symptoms in DMD mutation carriers without chromosomal rearrangements has been attributed to skewed X-chromosome inactivation (XCI) favouring predominant expression of the DMD mutant allele. However the prognostic use of XCI analysis is controversial. We aimed to evaluate the correlation between X-chromosome inactivation and development of clinical symptoms in a series of symptomatic female carriers of dystrophinopathy. Methods We reviewed the clinical, pathological and genetic features of twenty-four symptomatic carriers covering a wide spectrum of clinical phenotypes. DMD gene analysis was performed using MLPA and whole gene sequencing in blood DNA and muscle cDNA. Blood and muscle DNA was used for X-chromosome inactivation (XCI) analysis thought the AR methylation assay in symptomatic carriers and their female relatives, asymptomatic carriers as well as non-carrier females. Results Symptomatic carriers exhibited 49.2% more skewed XCI profiles than asymptomatic carriers. The extent of XCI skewing in blood tended to increase in line with the severity of muscle symptoms. Skewed XCI patterns were found in at least one first-degree female relative in 78.6% of symptomatic carrier families. No mutations altering XCI in the XIST gene promoter were found. Conclusions Skewed XCI is in many cases familial inherited. The extent of XCI skewing is related to phenotype severity. However, the assessment of XCI by means of the AR methylation assay has a poor prognostic value, probably because the methylation status of the AR gene in muscle may not reflect in all cases the methylation status of the DMD gene. PMID:23092449

  7. Chromosome instability induced in vitro with mitomycin C in five Seckel syndrome patients.

    PubMed

    Bobabilla-Morales, Lucina; Corona-Rivera, Alfredo; Corona-Rivera, J Román; Buenrostro, C; García-Cobián, Teresa A; Corona-Rivera, Enrique; Cantú-Garza, José María; García-Cruz, Diana

    2003-12-01

    Seckel syndrome (SS) is an autosomal recessive entity characterized by proportionate pre- and post-natal growth retardation, microcephaly, typical facial appearance with beak-like protrusion, and severe mental retardation. A heterogeneous basis for SS was proposed since around 25% of SS patients have hematological anomalies, suggesting a subgroup of SS with chromosome instability and hematological disorders. Chromosome instability induced by mitomycin C (MMC) has been observed in previous reports. The purpose of this study is to report cytogenetic features in five patients with SS. The patients had low birth weight (mean 1,870 g), short stature (SD = 6.36), microcephaly (OFC, SD = 8.1), typical facial appearance, and multiple articular dislocations. None of them had anemia at the time of examination. In all cases their parents were healthy and non-consanguineous. Lymphocytes of SS patients and a control group (n = 9) matched by age and sex were cultured with and without MMC, and harvested at 72 and 96 hr. Chromosomal aberrations (chromatid and chromosomal gaps and breaks, deletions, fragments, and exchanges) were scored in 100 metaphases per culture. A statistical increase of chromosomal aberrations was observed in 96 hr MMC cultures in all patients (40.2% vs. 2.8%). Sister chromatid exchanges were also performed with no differences between groups. Clinical and cytogenetic findings support the idea that SS may correspond to a chromosome instability syndrome.

  8. miR-214-mediated downregulation of RNF8 induces chromosomal instability in ovarian cancer cells.

    PubMed

    Wang, Zheng; Yin, Hao; Zhang, Yuanwei; Feng, Yukun; Yan, Zhaofeng; Jiang, Xiaohua; Bukhari, Ihtisham; Iqbal, Furhan; Cooke, Howard J; Shi, Qinghua

    2014-01-01

    Defective DNA damage response (DDR) is frequently associated with carcinogenesis. Abrogation of DDR leads to chromosomal instability, a most common characteristic of tumors. However, the molecular mechanisms underlying regulation of DDR are still elusive. The ubiquitin ligase RNF8 mediates the ubiquitination of γH2AX and recruits 53BP1 and BRCA1 to DNA damage sites which promotes DDR and inhibits chromosomal instability. Though RNF8 is a key player involved in DDR, regulation of its expression is still poorly understood. Here, we show that miR-214 could abrogate DDR by repressing RNF8 expression through direct binding to 3'-untranslated region (3' UTR) of RNF8 mRNA in human ovarian cancer cells. Antagonizing miR-214 by expressing its inhibitors in A2780 cells significantly increased RNF8 expression and thus promoted DNA damage repair. Consistent with the role of miR-214 in regulating RNF8 expression, the impaired DNA repair induced by miR-214 overexpression can be rescued by overexpressing RNF8 mRNA lacking the 3' UTR. Together, our results indicate that down-regulation of RNF8 mediated by miR-214 impedes DNA damage response to induce chromosomal instability in ovarian cancers, which may facilitate the understanding of mechanisms underlying chromosomal instability.

  9. Centrosome dynamics as a source of chromosomal instability

    PubMed Central

    Nam, Hyun-Ja; Naylor, Ryan; van Deursen, Jan M.

    2014-01-01

    Accurate segregation of duplicated chromosomes between two daughter cells depends on bi-polar spindle formation, a metaphase state in which sister kinetochores are attached to microtubules emanating from opposite spindle poles. To ensure bi-orientation, cells possess surveillance systems that safeguard against microtubule-kinetochore attachment defects, including the spindle assembly checkpoint and the error correction machinery. However, recent developments have identified centrosome dynamics – that is, centrosome disjunction and poleward movement of duplicated centrosomes – as a central target for deregulation of bi-orientation in cancer cells. Here we review novel insights into the mechanisms that underlie centrosome dynamics and discuss how these mechanisms are perturbed in cancer cells to drive chromosome missegregation and advance neoplastic transformation. PMID:25455111

  10. Chromosomal instability in rodents caused by pollution from Baikonur cosmodrome.

    PubMed

    Kolumbayeva, Saule; Begimbetova, Dinara; Shalakhmetova, Tamara; Saliev, Timur; Lovinskaya, Anna; Zhunusbekova, Benazir

    2014-09-01

    An assessment of the health status of ecosystems exposed to man-made pollution is a vital issue for many countries. Particularly it concerns the consequences of contamination caused by the activity of the space industry. Each rocket launch is accompanied by the introduction of parts of the rocket propellant into the environment. This study aims to scrutinize the effect of the components of rocket fuel on the induction of lipid peroxidation and chromosomal aberrations on rodents inhabiting the area exposed to pollution from Baikonur cosmodrome. The results showed the increase of the level of lipid hydroperoxide and malondialdehyde in the livers of Citellus pygmaeus Pallas and Mus musculus L., which indicates an augmentation of free radical activity and DNA damage. The cytogenetic analysis of bone marrow cells revealed that the frequency of chromosomal aberrations was a few times higher in the rodents from contaminated territory. The signs of oxidative stress and high level of chromosomal aberrations indicate the environmental impact of the cosmodrome, and its possible toxic and mutagenic effects on ecosystems.

  11. Isolation of molecular probes associated with the chromosome 15 instability in the Prader-Willi syndrome.

    PubMed Central

    Donlon, T A; Lalande, M; Wyman, A; Bruns, G; Latt, S A

    1986-01-01

    Flow cytometry and recombinant DNA techniques have been used to obtain reagents for a molecular analysis of the Prader-Willi syndrome (PWS). HindIII total-digest libraries were prepared in lambda phage Charon 21A from flow-sorted inverted duplicated no. 15 human chromosomes and propagated on recombination-proficient (LE392) and recBC-, sbcB- (DB1257) bacteria. Twelve distinct chromosome 15-specific probes have been isolated. Eight localized to the region 15q11----13. Four of these eight sublocalized to band 15q11.2 and are shown to be deleted in DNA of one of two patients examined with the PWS. Heteroduplex analysis of two of these clones, which grew on DB1257 but not on LE392, revealed stem-loop structures in the inserts, indicative of inverted, repeated DNA elements. Such DNA repeats might account for some of the cloning instability of DNA segments from proximal 15q. Analysis of the genetic and physical instability associated with the repeated sequences we have isolated from band 15q11.2 may elucidate the molecular basis for the instability of this chromosomal region in patients with the PWS or other diseases associated with chromosomal abnormalities in the proximal long arm of human chromosome 15. Images PMID:3012567

  12. Transient ALT activation protects human primary cells from chromosome instability induced by low chronic oxidative stress

    PubMed Central

    Coluzzi, Elisa; Buonsante, Rossella; Leone, Stefano; Asmar, Anthony J.; Miller, Kelley L.; Cimini, Daniela; Sgura, Antonella

    2017-01-01

    Cells are often subjected to the effect of reactive oxygen species (ROS) as a result of both intracellular metabolism and exposure to exogenous factors. ROS-dependent oxidative stress can induce 8-oxodG within the GGG triplet found in the G-rich human telomeric sequence (TTAGGG), making telomeres highly susceptible to ROS-induced oxidative damage. Telomeres are nucleoprotein complexes that protect the ends of linear chromosomes and their dysfunction is believed to affect a wide range of cellular and/or organismal processes. Acute oxidative stress was shown to affect telomere integrity, but how prolonged low level oxidative stress, which may be more physiologically relevant, affects telomeres is still poorly investigated. Here, we explored this issue by chronically exposing human primary fibroblasts to a low dose of hydrogen peroxide. We observed fluctuating changes in telomere length and fluctuations in the rates of chromosome instability phenotypes, such that when telomeres shortened, chromosome instability increased and when telomeres lengthened, chromosome instability decreased. We found that telomere length fluctuation is associated with transient activation of an alternative lengthening of telomere (ALT) pathway, but found no evidence of cell death, impaired proliferation, or cell cycle arrest, suggesting that ALT activation may prevent oxidative damage from reaching levels that threaten cell survival. PMID:28240303

  13. Genomic Instability and Copy-Number Heterogeneity of Chromosome 19q, Including the Kallikrein Locus, in Ovarian Carcinomas

    PubMed Central

    Bayani, Jane; Marrano, Paula; Graham, Cassandra; Zheng, Yingye; Li, Lin; Katsaros, Dionyssios; Lassus, Heini; Butzow, Ralf; Squire, Jeremy A.; Diamandis, Eleftherios P.

    2011-01-01

    Many tissue kallikrein (KLK) genes and proteins are candidate diagnostic, prognostic and predictive biomarkers for ovarian cancer (OCa). We previously demonstrated that the KLK locus (19q13.3/4) is subject to copy-number gains and structural rearrangements in a pilot study of cell lines and ovarian cancer primary tissues, shown to overexpress KLK gene family members. To determine the overall frequency of genomic instability and copy-number changes, a retrospective study was conducted using formalin-fixed paraffin embedded (FFPE) tissues. Eighty-one chemotherapy naïve serous OCas were examined using 3-colour fluorescence in situ hybridization (FISH) to identify structural and numerical changes on 19q, including the KLK locus; in addition to immunohistochemistry (IHC) for KLK6, which has been shown to be overexpressed in OCa. The KLK locus was subject to copy-number changes in ~83% of cases: net gain in 51%, net loss in 30% and amplified in 2%; and found to be chromosomally unstable (p<0.001). All cases showed a wide range of immuoreactivity for KLK6 by IHC. Although no strong correlation could be found with copy number, the latter was contributing factor to the observed KLK6 protein overexpression. Moreover, univariate and multivariate analyses showed an association between the net loss of the KLK locus with longer disease-free survival. Interestingly, FISH analyses indicated that chromosome 19q was subject to structural rearrangement in 62% of cases and was significantly correlated to tumor grade (p<0.001). We conclude that numerical and structural aberrations of chromosome 19q, affect genes including the KLK gene members, may contributing to ovarian carcinoma progression and aggressiveness. PMID:20800559

  14. TP53-dependent chromosome instability is associated with transient reductions in telomere length in immortal telomerase-positive cell lines

    NASA Technical Reports Server (NTRS)

    Schwartz, J. L.; Jordan, R.; Liber, H.; Murnane, J. P.; Evans, H. H.

    2001-01-01

    Telomere shortening in telomerase-negative somatic cells leads to the activation of the TP53 protein and the elimination of potentially unstable cells. We examined the effect of TP53 gene expression on both telomere metabolism and chromosome stability in immortal, telomerase-positive cell lines. Telomere length, telomerase activity, and chromosome instability were measured in multiple clones isolated from three related human B-lymphoblast cell lines that vary in TP53 expression; TK6 cells express wild-type TP53, WTK1 cells overexpress a mutant form of TP53, and NH32 cells express no TP53 protein. Clonal variations in both telomere length and chromosome stability were observed, and shorter telomeres were associated with higher levels of chromosome instability. The shortest telomeres were found in WTK1- and NH32-derived cells, and these cells had 5- to 10-fold higher levels of chromosome instability. The primary marker of instability was the presence of dicentric chromosomes. Aneuploidy and other stable chromosome alterations were also found in clones showing high levels of dicentrics. Polyploidy was found only in WTK1-derived cells. Both telomere length and chromosome instability fluctuated in the different cell populations with time in culture, presumably as unstable cells and cells with short telomeres were eliminated from the growing population. Our results suggest that transient reductions in telomere lengths may be common in immortal cell lines and that these alterations in telomere metabolism can have a profound effect on chromosome stability. Copyright 2000 Wiley-Liss, Inc.

  15. Palindromic GOLGA8 core duplicons promote chromosome 15q13.3 microdeletion and evolutionary instability

    PubMed Central

    Antonacci, Francesca; Dennis, Megan Y.; Huddleston, John; Sudmant, Peter H.; Steinberg, Karyn Meltz; Rosenfeld, Jill A.; Miroballo, Mattia; Graves, Tina A.; Vives, Laura; Malig, Maika; Denman, Laura; Raja, Archana; Stuart, Andrew; Tang, Joyce; Munson, Brenton; Shaffer, Lisa G.; Amemiya, Chris T.; Wilson, Richard K.; Eichler, Evan E.

    2014-01-01

    Recurrent deletions of chromosome 15q13.3 associate with intellectual disability, schizophrenia, autism and epilepsy. To gain insight into its instability, we sequenced the region in patients, normal individuals and nonhuman primates. We discovered five structural configurations of the human chromosome 15q13.3 region ranging in size from 2 to 3 Mbp. These configurations arose recently (~0.5–0.9 million years ago) as a result of human-specific expansions of segmental duplications and two independent inversion events. All inversion breakpoints map near GOLGA8 core duplicons—a ~14 kbp primate-specific chromosome 15 repeat that became organized into larger palindromic structures. GOLGA8-flanked palindromes also demarcate the breakpoints of recurrent 15q13.3 microdeletions, the expansion of chromosome 15 segmental duplications in the human lineage, and independent structural changes in apes. The significant clustering (p=0.002) of breakpoints provides mechanistic evidence for the role of this core duplicon and its palindromic architecture in promoting evolutionary and disease-related instability of chromosome 15. PMID:25326701

  16. Epstein–Barr virus particles induce centrosome amplification and chromosomal instability

    PubMed Central

    Shumilov, Anatoliy; Tsai, Ming-Han; Schlosser, Yvonne T.; Kratz, Anne-Sophie; Bernhardt, Katharina; Fink, Susanne; Mizani, Tuba; Lin, Xiaochen; Jauch, Anna; Mautner, Josef; Kopp-Schneider, Annette; Feederle, Regina; Hoffmann, Ingrid; Delecluse, Henri-Jacques

    2017-01-01

    Infections with Epstein–Barr virus (EBV) are associated with cancer development, and EBV lytic replication (the process that generates virus progeny) is a strong risk factor for some cancer types. Here we report that EBV infection of B-lymphocytes (in vitro and in a mouse model) leads to an increased rate of centrosome amplification, associated with chromosomal instability. This effect can be reproduced with virus-like particles devoid of EBV DNA, but not with defective virus-like particles that cannot infect host cells. Viral protein BNRF1 induces centrosome amplification, and BNRF1-deficient viruses largely lose this property. These findings identify a new mechanism by which EBV particles can induce chromosomal instability without establishing a chronic infection, thereby conferring a risk for development of tumours that do not necessarily carry the viral genome. PMID:28186092

  17. Chromosomal Replication Complexity: A Novel DNA Metrics and Genome Instability Factor

    PubMed Central

    Kuzminov, Andrei

    2016-01-01

    As the ratio of the copy number of the most replicated to the unreplicated regions in the same chromosome, the definition of chromosomal replication complexity (CRC) appears to leave little room for variation, being either two during S-phase or one otherwise. However, bacteria dividing faster than they replicate their chromosome spike CRC to four and even eight. A recent experimental inquiry about the limits of CRC in Escherichia coli revealed two major reasons to avoid elevating it further: (i) increased chromosomal fragmentation and (ii) complications with subsequent double-strand break repair. Remarkably, examples of stable elevated CRC in eukaryotic chromosomes are well known under various terms like "differential replication," "underreplication," "DNA puffs," "onion-skin replication," or "re-replication" and highlight the phenomenon of static replication fork (sRF). To accurately describe the resulting "amplification by overinitiation," I propose a new term: "replification" (subchromosomal overreplication). In both prokaryotes and eukaryotes, replification, via sRF processing, causes double-strand DNA breaks and, with their repair elevating chromosomal rearrangements, represents a novel genome instability factor. I suggest how static replication bubbles could be stabilized and speculate that some tandem duplications represent such persistent static bubbles. Moreover, I propose how static replication bubbles could be transformed into tandem duplications, double minutes, or inverted triplications. Possible experimental tests of these models are discussed. PMID:27711112

  18. Tolerance whole of genome doubling propagates chromosomal instability and accelerates cancer genome evolution

    PubMed Central

    Burrell, Rebecca A; Rowan, Andrew J; Grönroos, Eva; Endesfelder, David; Joshi, Tejal; Mouradov, Dmitri; Gibbs, Peter; Ward, Robyn L.; Hawkins, Nicholas J.; Szallasi, Zoltan; Sieber, Oliver M.; Swanton, Charles

    2015-01-01

    The contribution of whole genome doubling to chromosomal instability (CIN) and tumour evolution is unclear. We use long-term culture of isogenic tetraploid cells from a stable diploid colon cancer progenitor to investigate how a genome-doubling event affects genome stability over time. Rare cells that survive genome doubling demonstrate increased tolerance to chromosome aberrations. Tetraploid cells do not exhibit increased frequencies of structural or numerical CIN per chromosome. However, the tolerant phenotype in tetraploid cells, coupled with a doubling of chromosome aberrations per cell, allows chromosome abnormalities to evolve specifically in tetraploids, recapitulating chromosomal changes in genomically complex colorectal tumours. Finally, a genome-doubling event is independently predictive of poor relapse-free survival in early stage disease in two independent cohorts in multivariate analyses (discovery data: HR=4.70, 95% CI 1.04-21.37, validation data: HR=1.59, 95% CI 1.05-2.42). These data highlight an important role for the tolerance of genome doubling in driving cancer genome evolution. PMID:24436049

  19. Evolution of Chromosomal Instability in Chinese Hamster Cells: aChanging Picture?

    SciTech Connect

    Ponnaiya, Brian; Limoli, Charles L.; Corcoran, James; Kaplan,Mark I.; Hartmann, Andreas; Morgan, William F.

    1998-07-14

    Purpose: To investigate the kinetics of chromosomalinstability induced in clones of Chinese hamster cells followingX-irradiation. Materials and methods: X-irradiated clones of GM10115,human hamster hybrid cells containing a single human chromosome 4 (HC4),have been previously established. These clones were defined as unstableif they contained three sub-populations of cells with uniquerearrangements of HC4 as detected by FISH. Stable and unstable cloneswere analysed by FISH and Giemsa staining at various timespost-irradiation. Results: While most of the stable clones continued toshow chromosomal stability of HC4 over time, one became marginallyunstable at approximately 45 population doublings postirradiation. Clonesexhibiting chromosomal instability had one of several fates. Many of theunstable clones were showed similar levels of instability over time.However, one unstable clone became stable with time in culture, whileanother became even more unstable over time. Cytogenetic analyses of allclones after Giemsa staining indicated that in some clones the hamsterchromosomes were rearranged independent of HC4, demonstrating increasedfrequencies of chromatid breaks and dicentric chromosomes. The majorityof the unstable clones also had higher yields of chromatid gaps.Conclusions: These data demonstrate the dynamic nature of chromosomalinstability as measured by two different cytogenetic assays.

  20. Chromosome Instability and Oxidative Stress Markers in Patients with Ataxia Telangiectasia and Their Parents

    PubMed Central

    Bitelo Ludwig, Luciane; Valiati, Victor Hugo; Palazzo, Roberta Passos; Jardim, Laura Bannach; da Rosa, Darlan Pase; Bona, Silvia; Rodrigues, Graziela; Marroni, Norma Possa; Prá, Daniel; Maluf, Sharbel Weidner

    2013-01-01

    Ataxia telangiectasia (AT) is a rare neurodegenerative disorder, inherited in an autosomal recessive manner. Total blood samples were collected from 20 patients with AT, 13 parents of patients, and 17 healthy volunteers. This study aimed at evaluating the frequency of chromosomal breaks in spontaneous cultures, induced by bleomycin and ionizing radiation, and further evaluated the rates of oxidative stress in AT patients and in their parents, compared to a control group. Three cell cultures were performed to each individual: the first culture did not receive induction to chromosomal instability, the second was exposed to bleomycin, and the last culture was exposed to ionizing radiation. To evaluate the rates of oxidative stress, the markers superoxide dismutase (SOD), catalase (CAT), and thiobarbituric acid (TBARS) were utilized. Significant differences were observed between the three kinds of culture treatments (spontaneous, bleomycin, and radiation induced) and the breaks and chromosomal aberrations in the different groups. The oxidative stress showed no significant differences between the markers. This study showed that techniques of chromosomal instability after the induction of ionizing radiation and bleomycin are efficient in the identification of syndrome patients, with the ionizing radiation being the most effective. PMID:23936845

  1. DNA Double-Strand Breaks, Chromosomal Rearrangements, and GenomicInstability

    SciTech Connect

    Morgan, W.F.; Corcoran, J.; Hartmann, A.; Kaplan, M.I.; Limoli,C.L.; Ponnaiya, B.

    1998-03-09

    DNA double-strand breaks can lead to chromosomalrearrangements at the first mitosis after exposure to the DNAstrand-breaking agent. The evidence suggests a number of differentpathways for DNA double-strand break rejoining in mammalian cells, but itis unclear what factors determine the fate of the induced break andwhether or not it will lead to chromosomal rearrangement. If a cell doessurvive and proliferate after DNA cleavage, delayed chromosomalinstability can be observedin the clonal descendants of the exposedcell. Most, but not all DNA double-strand breaking agents are effectiveat inducing this delayed chromosomal instability. In this paper, wereview the evidence for the role of the DNA double-strand break indirectly induced and delayed chromosomal rearrangements. Copyright 1998Elsevier Science B.V.

  2. Critical target and dose and dose-rate responses for the induction of chromosomal instability by ionizing radiation

    NASA Technical Reports Server (NTRS)

    Limoli, C. L.; Corcoran, J. J.; Milligan, J. R.; Ward, J. F.; Morgan, W. F.

    1999-01-01

    To investigate the critical target, dose response and dose-rate response for the induction of chromosomal instability by ionizing radiation, bromodeoxyuridine (BrdU)-substituted and unsubstituted GM10115 cells were exposed to a range of doses (0.1-10 Gy) and different dose rates (0.092-17.45 Gy min(-1)). The status of chromosomal stability was determined by fluorescence in situ hybridization approximately 20 generations after irradiation in clonal populations derived from single progenitor cells surviving acute exposure. Overall, nearly 700 individual clones representing over 140,000 metaphases were analyzed. In cells unsubstituted with BrdU, a dose response was found, where the probability of observing delayed chromosomal instability in any given clone was 3% per gray of X rays. For cells substituted with 25-66% BrdU, however, a dose response was observed only at low doses (<1.0 Gy); at higher doses (>1.0 Gy), the incidence of chromosomal instability leveled off. There was an increase in the frequency and complexity of chromosomal instability per unit dose compared to cells unsubstituted with BrdU. The frequency of chromosomal instability appeared to saturate around approximately 30%, an effect which occurred at much lower doses in the presence of BrdU. Changing the gamma-ray dose rate by a factor of 190 (0.092 to 17.45 Gy min(-1)) produced no significant differences in the frequency of chromosomal instability. The enhancement of chromosomal instability promoted by the presence of the BrdU argues that DNA comprises at least one of the critical targets important for the induction of this end point of genomic instability.

  3. Role of ATRX in chromatin structure and function: implications for chromosome instability and human disease

    PubMed Central

    De La Fuente, Rabindranath; Baumann, Claudia; Viveiros, Maria M

    2011-01-01

    Functional differentiation of chromatin structure is essential for the control of gene expression, nuclear architecture, and chromosome stability. Compelling evidence indicates that alterations in chromatin remodeling proteins play an important role in the pathogenesis of human disease. Among these, α-thalassemia mental retardation X-linked protein (ATRX) has recently emerged as a critical factor involved in heterochromatin formation at mammalian centromeres and telomeres as well as facultative heterochromatin on the murine inactive X chromosome. Mutations in human ATRX result in an X-linked neurodevelopmental condition with various degrees of gonadal dysgenesis (ATRX syndrome). Patients with ATRX syndrome may exhibit skewed X chromosome inactivation (XCI) patterns, and ATRX-deficient mice exhibit abnormal imprinted XCI in the trophoblast cell line. Non-random or skewed XCI can potentially affect both the onset and severity of X-linked disease. Notably, failure to establish epigenetic modifications associated with the inactive X chromosome (Xi) results in several conditions that exhibit genomic and chromosome instability such as fragile X syndrome as well as cancer development. Insight into the molecular mechanisms of ATRX function and its interacting partners in different tissues will no doubt contribute to our understanding of the pathogenesis of ATRX syndrome as well as the epigenetic origins of aneuploidy. In turn, this knowledge will be essential for the identification of novel drug targets and diagnostic tools for cancer progression as well as the therapeutic management of global epigenetic changes commonly associated with malignant neoplastic transformation. PMID:21653732

  4. Ataxia telangiectasia derived iPS cells show preserved x-ray sensitivity and decreased chromosomal instability

    PubMed Central

    Fukawatase, Yoshihiro; Toyoda, Masashi; Okamura, Kohji; Nakamura, Ken-ichi; Nakabayashi, Kazuhiko; Takada, Shuji; Yamazaki-Inoue, Mayu; Masuda, Akira; Nasu, Michiyo; Hata, Kenichiro; Hanaoka, Kazunori; Higuchi, Akon; Takubo, Kaiyo; Umezawa, Akihiro

    2014-01-01

    Ataxia telangiectasia is a neurodegenerative inherited disease with chromosomal instability and hypersensitivity to ionizing radiation. iPS cells lacking ATM (AT-iPS cells) exhibited hypersensitivity to X-ray irradiation, one of the characteristics of the disease. While parental ataxia telangiectasia cells exhibited significant chromosomal abnormalities, AT-iPS cells did not show any chromosomal instability in vitro for at least 80 passages (560 days). Whole exome analysis also showed a comparable nucleotide substitution rate in AT-iPS cells. Taken together, these data show that ATM is involved in protection from irradiation-induced cell death. PMID:24970375

  5. Prognostic Impact of IPSS-R and Chromosomal Translocations in 751 Korean Patients with Primary Myelodysplastic Syndrome

    PubMed Central

    Kim, Inho; Kim, Hyeoung-Joon; Shin, Dong-Yeop; Koh, Youngil; Yoon, Sung-Soo; Min, Yoo Hong; Ahn, Jae-Sook; Kim, Yeo-Kyeoung; Lee, Yun-Gyoo; Lee, Jeong-Ok; Bang, Soo-Mee; Mun, Yeung-Chul; Seong, Chu-Myoung; Park, Yong; Kim, Byung-Soo; Hong, Junshik; Park, Jinny; Lee, Jae Hoon; Kim, Sung-Yong; Lee, Hong Ghi

    2016-01-01

    Chromosomal translocations are rare in myelodysplastic syndrome (MDS) and their impact on overall survival (OS) and response to hypomethylating agents (HMA) is unknown. The prognostic impact of the revised International Prognostic Scoring System (IPSS-R) and for chromosomal translocations was assessed in 751 patients from the Korea MDS Registry. IPSS-R effectively discriminated patients according to leukaemia evolution risk and OS. We identified 40 patients (5.3%) carrying translocations, 30 (75%) of whom also fulfilled complex karyotype criteria. Translocation presence was associated with a shorter OS (median, 12.0 versus 79.7 months, P < 0.01). Multivariate analysis demonstrated that translocations (hazard ratio [HR] 1.64 [1.06–2.63]; P = 0.03) as well as age, sex, IPSS-R, and CK were independent predictors of OS. In the IPSS-R high and very high risk subgroup (n = 260), translocations remained independently associated with OS (HR 1.68 [1.06–2.69], P = 0.03) whereas HMA treatment was not associated with improved survival (median OS, 20.9 versus 21.2 months, P = 0.43). However, translocation carriers exhibited enhanced survival following HMA treatment (median 2.1 versus 12.4 months, P = 0.03). Our data suggest that chromosomal translocation is an independent predictor of adverse outcome and has an additional prognostic value in discriminating patients with MDS having higher risk IPSS-R who could benefit from HMA treatment. PMID:27824923

  6. Occurrence of deletions, associated with genetic instability in Streptomyces ambofaciens, is independent of the linearity of the chromosomal DNA.

    PubMed Central

    Fischer, G; Decaris, B; Leblond, P

    1997-01-01

    The chromosomal structures of mutant strains of Streptomyces ambofaciens which have arisen from genetic instability were investigated by using pulsed-field gel electrophoresis and probing with sequences cloned from the unstable region which maps near the ends of the linear chromosomal DNA. The chromosomal structures of seven mutant strains harboring large deletions were classified into three types. (i) Deletions internal to one chromosomal arm were characterized in two of the mutant strains. In these strains, a linear chromosomal structure was retained, as were parts of the terminal inverted repeats sequences (TIRs) and the proteins bound to them. (ii) Four of the mutants presented a deletion including all sequences from the TIRs. A junction fragment homologous to sequences originating from internal region of both arms was characterized. Consequently, the chromosomal DNA of these strains was deduced to be circularized. Furthermore, chromosomal stability was assessed in the progeny of these circular DNA mutants. Additional deletion events were detected in 11 mutants among the 13 strains isolated, demonstrating that circular chromosomes do not correspond to a stabilization of the chromosome structure and that the occurrence of deletion could be independent of the presence of chromosomal ends. (iii) A mutant with DNA amplification was shown to have a linear chromosome with a deletion of all sequences between the amplified region and the end of the chromosome. The other chromosomal arm remained unaffected by deletion and associated with protein. PMID:9226265

  7. Progesterone facilitates chromosome instability (aneuploidy) in p53 null normal mammary epithelial cells

    NASA Technical Reports Server (NTRS)

    Goepfert, T. M.; McCarthy, M.; Kittrell, F. S.; Stephens, C.; Ullrich, R. L.; Brinkley, B. R.; Medina, D.

    2000-01-01

    Mammary epithelial cells from p53 null mice have been shown recently to exhibit an increased risk for tumor development. Hormonal stimulation markedly increased tumor development in p53 null mammary cells. Here we demonstrate that mammary tumors arising in p53 null mammary cells are highly aneuploid, with greater than 70% of the tumor cells containing altered chromosome number and a mean chromosome number of 56. Normal mammary cells of p53 null genotype and aged less than 14 wk do not exhibit aneuploidy in primary cell culture. Significantly, the hormone progesterone, but not estrogen, increases the incidence of aneuploidy in morphologically normal p53 null mammary epithelial cells. Such cells exhibited 40% aneuploidy and a mean chromosome number of 54. The increase in aneuploidy measured in p53 null tumor cells or hormonally stimulated normal p53 null cells was not accompanied by centrosome amplification. These results suggest that normal levels of progesterone can facilitate chromosomal instability in the absence of the tumor suppressor gene, p53. The results support the emerging hypothesis based both on human epidemiological and animal model studies that progesterone markedly enhances mammary tumorigenesis.

  8. Prognostics

    NASA Technical Reports Server (NTRS)

    Goebel, Kai; Vachtsevanos, George; Orchard, Marcos E.

    2013-01-01

    Knowledge discovery, statistical learning, and more specifically an understanding of the system evolution in time when it undergoes undesirable fault conditions, are critical for an adequate implementation of successful prognostic systems. Prognosis may be understood as the generation of long-term predictions describing the evolution in time of a particular signal of interest or fault indicator, with the purpose of estimating the remaining useful life (RUL) of a failing component/subsystem. Predictions are made using a thorough understanding of the underlying processes and factor in the anticipated future usage.

  9. Are chromosomal instabilities induced by exposure of cultured normal human cells to low- or high-LET radiation?

    NASA Technical Reports Server (NTRS)

    Dugan, Lawrence C.; Bedford, Joel S.

    2003-01-01

    Radiation-induced genomic instability has been proposed as a very early, if not an initiating, step in radiation carcinogenesis. Numerous studies have established the occurrence of radiation-induced chromosomal instability in various cells of both human and rodent origin. In many of these studies, however, the cells were not "normal" initially, and in many cases they involved tumor-derived cell lines. The phenomenon clearly would be of even greater interest if it were shown to occur generally in cells that are normal at the outset, rather than cells that may have been "selected" because of a pre-existing susceptibility to induced instability. As a test of the generality of the phenomenon, we studied low-passage normal diploid human fibroblasts (AG1521A) to determine whether they are susceptible to the induction of chromosomal instability in the progeny of surviving cells after exposure in G(0) to low- and high-LET radiation. Cytogenetic assays for instability were performed on both mixed populations of cells and clones of cells surviving exposure. We found no evidence for the induction of such instability as a result of radiation exposure, though we observed a senescence-related chromosomal instability in the progeny of both irradiated and unirradiated cell populations. Copyright 2003 by Radiation Research Society.

  10. Carcinogens induce genome-wide loss of heterozygosity in normal stem cells without persistent chromosomal instability.

    PubMed

    Donahue, Sarah L; Lin, Qing; Cao, Shang; Ruley, H Earl

    2006-08-01

    Widespread losses of heterozygosity (LOH) in human cancer have been thought to result from chromosomal instability caused by mutations affecting DNA repair/genome maintenance. However, the origin of LOH in most tumors is unknown. The present study examined the ability of carcinogenic agents to induce LOH at 53 sites throughout the genome of normal diploid mouse ES cells. Brief exposures to nontoxic levels of methylnitrosourea, diepoxybutane, mitomycin C, hydroxyurea, doxorubicin, and UV light stimulated LOH at all loci at frequencies ranging from 1-8 x 10(-3) per cell (10-123 times higher than in untreated cells). This greatly exceeds the frequencies at which these agents have been reported to induce point mutations and is comparable to the rates of LOH observed in ES cells lacking the gene responsible for Bloom syndrome, an inherited DNA repair defect that results in greatly increased risk of cancer. These results suggest that LOH contributes significantly to the carcinogenicity of a variety of mutagens and raises the possibility that genome-wide LOH observed in some human cancers may reflect prior exposure to genotoxic agents rather than a state of chromosomal instability during the carcinogenic process. Finally, as a practical matter, chemically induced LOH is expected to enhance the recovery of homozygous recessive mutants from phenotype-based genetic screens in mammalian cells.

  11. Carcinogens induce genome-wide loss of heterozygosity in normal stem cells without persistent chromosomal instability

    PubMed Central

    Donahue, Sarah L.; Lin, Qing; Cao, Shang; Ruley, H. Earl

    2006-01-01

    Widespread losses of heterozygosity (LOH) in human cancer have been thought to result from chromosomal instability caused by mutations affecting DNA repair/genome maintenance. However, the origin of LOH in most tumors is unknown. The present study examined the ability of carcinogenic agents to induce LOH at 53 sites throughout the genome of normal diploid mouse ES cells. Brief exposures to nontoxic levels of methylnitrosourea, diepoxybutane, mitomycin C, hydroxyurea, doxorubicin, and UV light stimulated LOH at all loci at frequencies ranging from 1–8 × 10−3 per cell (10–123 times higher than in untreated cells). This greatly exceeds the frequencies at which these agents have been reported to induce point mutations and is comparable to the rates of LOH observed in ES cells lacking the gene responsible for Bloom syndrome, an inherited DNA repair defect that results in greatly increased risk of cancer. These results suggest that LOH contributes significantly to the carcinogenicity of a variety of mutagens and raises the possibility that genome-wide LOH observed in some human cancers may reflect prior exposure to genotoxic agents rather than a state of chromosomal instability during the carcinogenic process. Finally, as a practical matter, chemically induced LOH is expected to enhance the recovery of homozygous recessive mutants from phenotype-based genetic screens in mammalian cells. PMID:16868089

  12. Chromosome instability of HPRT-mutant subclones induced by ionising radiation of various let

    NASA Astrophysics Data System (ADS)

    Govorun, R. D.; Koshlan, I. V.; Koshlan, N. A.; Krasavin, E. A.; Shmakova, N. L.

    The induction of HPRT-mutations and survival of Chinese hamster cells (line B11ii-FAF28, clone 431) were studied after irradiation by 4He and 12C-ions of various LET (20 - 360 keV/μm), produced by the U-200 heavy ion accelerator. The RBE increases with LET up to the maximum at 100-200 keV/μm and then decreases. Cytogenetic analysis was performed on the HPRT-mutant subclones selected from unirradiated Chinese hamster V-79 cells and from HPRT- mutant subclones that arose after exposure to γ-rays, 1GeV protons and 14N-ions (LET - 77 keV/μm), produced by the synchrophasotron and the U-400M heavy ion accelerator. Slow growing mutant subclones were observed. The cytogenetic properties of individual clones were highly heterogeneous and chromosome instability was observed in both spontaneous and radiation-induced mutants. Chromosome instability was highest among spontaneous mutants and decreased with increasing LET.

  13. Chromosome instability of HPRT-mutant subclones induced by ionising radiation of various LET.

    PubMed

    Govorun, R D; Koshlan, I V; Koshlan, N A; Krasavin, E A; Shmakova, N L

    2002-01-01

    The induction of HPRT-mutations and survival of Chinese hamster cells (line B11ii-FAF28, clone 431) were studied after irradiation by 4He and 12C-ions of various LET (20-360 keV/micrometers), produced by the U-200 heavy ion accelerator. The RBE increases with LET up to the maximum at 100-200 keV/micrometers and then decreases. Cytogenetic analysis was performed on the HPRT-mutant subclones selected from unirradiated Chinese hamster V-79 cells and from HPRT-mutant subclones that arose after exposure to gamma-rays, 1 GeV protons and 14N-ions (LET-77 keV/micrometers), produced by the synchrophasotron and the U-400M heavy ion accelerator. Slow growing mutant subclones were observed. The cytogenetic properties of individual clones were highly heterogeneous and chromosome instability was observed in both spontaneous and radiation-induced mutants. Chromosome instability was highest among spontaneous mutants and decreased with increasing LET.

  14. Quantitative assessment of chromosome instability induced through chemical disruption of mitotic progression

    PubMed Central

    Markossian, Sarine; Arnaoutov, Alexei; Saba, Nakhle S.; Larionov, Vladimir; Dasso, Mary

    2016-01-01

    ABSTRACT Most solid tumors are aneuploid, carrying an abnormal number of chromosomes, and they frequently missegregate whole chromosomes in a phenomenon termed chromosome instability (CIN). While CIN can be provoked through disruption of numerous mitotic pathways, it is not clear which of these mechanisms are most critical, or whether alternative mechanisms could also contribute significantly in vivo. One difficulty in determining the relative importance of candidate CIN regulators has been the lack of a straightforward, quantitative assay for CIN in live human cells: While gross mitotic abnormalities can be detected visually, moderate levels of CIN may not be obvious, and are thus problematic to measure. To address this issue, we have developed the first Human Artificial Chromosome (HAC)-based quantitative live-cell assay for mitotic chromosome segregation in human cells. We have produced U2OS-Phoenix cells carrying the alphoidtetO-HAC encoding copies of eGFP fused to the destruction box (DB) of anaphase promoting complex/cyclosome (APC/C) substrate hSecurin and sequences encoding the tetracycline repressor fused to mCherry (TetR-mCherry). Upon HAC missegregation, daughter cells that do not obtain a copy of the HAC are GFP negative in the subsequent interphase. The HAC can also be monitored live following the TetR-mCherry signal. U2OS-Phoenix cells show low inherent levels of CIN, which can be enhanced by agents that target mitotic progression through distinct mechanisms. This assay allows direct detection of CIN induced by clinically important agents without conspicuous mitotic defects, allowing us to score increased levels of CIN that fall below the threshold required for discernable morphological disruption. PMID:27104376

  15. Arsenic-induced Aurora-A activation contributes to chromosome instability and tumorigenesis

    NASA Astrophysics Data System (ADS)

    Wu, Chin-Han; Tseng, Ya-Shih; Yang, Chao-Chun; Kao, Yu-Ting; Sheu, Hamm-Ming; Liu, Hsiao-Sheng

    2013-11-01

    Arsenic may cause serious environmental pollution and is a serious industrial problem. Depending on the dosage, arsenic may trigger the cells undergoing either proliferation or apoptosis-related cell death. Because of lack of the proper animal model to study arsenic induced tumorigenesis, the accurate risk level of arsenic exposure has not been determined. Arsenic shows genotoxic effect on human beings who uptake water contaminated by arsenic. Chromosome aberration is frequently detected in arsenic exposure-related diseases and is associated with increased oxidative stress and decreased DNA repairing activity, but the underlying mechanism remains elusive. Aurora-A is a mitotic kinase, over-expression of Aurora-A leads to centrosome amplification, chromosomal instability and cell transformation. We revealed that Aurora-A is over-expressed in the skin and bladder cancer patients from blackfoot-disease endemic areas. Our cell line studies reveal that arsenic exposure between 0.5 μM and 1 μM for 2-7 days are able to induce Aurora-A expression and activation based on promoter activity, RNA and protein analysis. Aurora-A overexpression further increases the frequency of unsymmetrical chromosome segregation through centrosome amplification followed by cell population accumulated at S phase in immortalized keratinocyte (HaCaT) and uroepithelial cells (E7). Furthermore, Aurora-A over-expression was sustained for 1-4 weeks by chronic treatment of immortalized bladder and skin cells with NaAsO2. Aurora-A promoter methylation and gene amplification was not detected in the long-term arsenic treated E7 cells. Furthermore, the expression level of E2F1 transcription factor (E2F1) is increased in the presence of arsenic, and arsenic-related Aurora-A over-expression is transcriptionally regulated by E2F1. We further demonstrated that overexpression of Aurora-A and mutant Ha-ras or Aurora-A and mutant p53 may act additively to trigger arsenic-related bladder and skin cancer

  16. Chromosomal instability in mouse embryonic fibroblasts null for the transcriptional co-repressor Ski.

    PubMed

    Marcelain, Katherine; Armisen, Ricardo; Aguirre, Adam; Ueki, Nobuhide; Toro, Jessica; Colmenares, Clemencia; Hayman, Michael J

    2012-01-01

    Ski is a transcriptional regulator that has been considered an oncoprotein given its ability to induce oncogenic transformation in avian model systems. However, studies in mouse and in some human tumor cells have also indicated a tumor suppressor activity for this protein. We found that Ski-/- mouse embryo fibroblasts exhibit high levels of genome instability, namely aneuploidy, consistent with a tumor suppressor function for Ski. Time-lapse microscopy revealed lagging chromosomes and chromatin/chromosome bridges as the major cause of micronuclei (MN) formation and the subsequent aneuploidy. Although these cells arrested in mitosis after treatment with spindle disrupting drugs and exhibited a delayed metaphase/anaphase transition, spindle assembly checkpoint (SAC) was not sufficient to prevent chromosome missegregation, consistent with a weakened SAC. Our in vivo analysis also showed dynamic metaphase plate rearrangements with switches in polarity in cells arrested in metaphase. Importantly, after ectopic expression of Ski the cells that displayed this metaphase arrest died directly during metaphase or after aberrant cell division, relating SAC activation and mitotic cell death. This increased susceptibility to undergo mitosis-associated cell death reduced the number of MN-containing cells. The presented data support a new role for Ski in the mitotic process and in maintenance of genetic stability, providing insights into the mechanism of tumor suppression mediated by this protein.

  17. Chromosomal instability in mouse embryonic fibroblasts null for the transcriptional co-repressor Ski

    PubMed Central

    Marcelain, Katherine; Armisen, Ricardo; Aguirre, Adam; Ueki, Nobuhide; Toro, Jessica; Colmenares, Clemencia; Hayman, Michael J

    2011-01-01

    Ski is a transcriptional regulator that has been considered an oncoprotein, given its ability to induce oncogenic transformation in avian model systems. However, studies in mouse and in some human tumor cells have also indicated a tumor suppressor activity for this protein. We found that Ski−/− mouse embryo fibroblasts exhibit high levels of genome instability, namely aneuploidy, consistent with a tumor suppressor function for Ski. Time-lapse microscopy revealed lagging chromosomes and chromatin/chromosome bridges as the major cause of micronuclei formation and the subsequent aneuploidy. Although these cells arrested in mitosis after treatment with spindle disrupting drugs and exhibited a delayed metaphase/anaphase transition, Spindle Assembly Checkpoint (SAC) was not sufficient to prevent chromosome missegregation, consistent with a weakened SAC. Our in vivo analysis also showed dynamic metaphase plate rearrangements with switches in polarity in cells arrested in metaphase. Importantly, after ectopic expression of Ski the cells that displayed this metaphase arrest died directly during metaphase or after aberrant cell division, relating SAC activation and mitotic cell death. This increased susceptibility to undergo mitosis-associated cell death reduced the number of micronuclei-containing cells. The presented data support a new role for Ski in the mitotic process and in maintenance of genetic stability, providing insights into the mechanism of tumor suppression mediated by this protein. PMID:21412778

  18. Chromosome analysis in childhood cancer survivors and their offspring—No evidence for radiotherapy-induced persistent genomic instability

    PubMed Central

    Tawn, E. Janet; Whitehouse, Caroline A.; Winther, Jeanette F.; Curwen, Gillian B.; Rees, Gwen S.; Stovall, Marilyn; Olsen, Jørgen H.; Guldberg, Per; Rechnitzer, Catherine; Schrøder, Henrik; Boice, John D.

    2009-01-01

    Suggestions that the induction of genomic instability could play a role in radiation-induced carcinogenesis and heritable disease prompted the investigation of chromosome instability in relation to radiotherapy for childhood cancer. Chromosome analysis of peripheral blood lymphocytes at their first in vitro division was undertaken on 25 adult survivors of childhood cancer treated with radiation, 26 partners who acted as the non-irradiated control group and 43 offspring. A statistically significant increase in the frequency of dicentrics in the cancer survivor group compared with the partner control group was attributed to the residual effect of past radiation therapy. However, chromatid aberrations plus chromosome gaps, the aberrations most associated with persistent instability, were not increased. Therefore, there was no evidence that irradiation of the bone marrow had resulted in instability being transmitted to descendant cells. Frequencies of all aberration categories were significantly lower in the offspring group, compared to the partner group, apart from dicentrics for which the decrease did not reach statistical significance. The lower frequencies in the offspring provide no indication of transmissible instability being passed through the germline to the somatic cells of the offspring. Thus, in this study, genomic instability was not associated with radiotherapy in those who had received such treatment, nor was it found to be a transgenerational radiation effect. PMID:15914077

  19. Amplifications of chromosomal region 20q13 as a prognostic indicator breast cancer

    DOEpatents

    Gray, Joe W.; Collins, Colin; Pinkel, Daniel; Kallioniemi, Olli-Pekka; Tanner, Minna M.

    2001-01-01

    The present invention relates to in situ hybridization methods for the identification of new chromosomal abnormalities associated with various diseases. In particular, it provides probes which are specific to a region of amplification in chromosome 20.

  20. Amplifications of chromosomal region 20q13 as a prognostic indicator in breast cancer

    DOEpatents

    Gray, Joe W.; Collins, Colin; Pinkel, Daniel; Kallioniemi, Olli-Pekka; Tanner, Minna M.

    1998-01-01

    The present invention relates to in situ hybridization methods for the identification of new chromosomal abnormalities associated with various diseases. In particular, it provides probes which are specific to a region of amplification in chromosome 20.

  1. The Relationship between the Presence of Chromosomal Instability and Prognosis of Squamous Cell Carcinoma of the Lung: Fluorescence in situ Hybridization Analysis of Paraffin-embedded Tissue from 47 Korean Patients

    PubMed Central

    Yoo, Jung-Wan; Seo, Kwang Won; Jang, Se Jin; Oh, Yeon-Mock; Shim, Tae Sun; Kim, Woo Sung; Lee, Dong-Soon; Lee, Sang-Do

    2010-01-01

    To evaluate the prognostic importance of chromosomal instability (CIN) in squamous cell carcinoma (SCC) of the lung, the relationship between CIN detected by fluorescence in situ hybridization (FISH) and survival in SCC patients was examined. Forty-seven surgical specimens of lung SCC were analyzed. To identify tumors with CIN, p16 and multi-target DNA FISH assays for c-myc, chromosome 6, EGFR, and chromosome 5 (LAVysion, Vysis) were performed on nuclei extracted from paraffin-embedded tumor tissues. Survival rates were compared in terms of age, T factor, N factor, CIN, and smoking status. A sample was defined as CIN-positive if at least four of the five chromosomes were positive. Among the 47 specimens, 9 (19%) were CIN-positive. The overall survival rate was 66%. Overall survival rates were estimated as 33.3% for CIN-positive patients and 76.7% for CIN-negative patients (Hazard ratio 3.47; 95% Confidence interval, 1.25-9.67; P=0.017). In multivariate analysis, the presence of CIN was a predictive factor for survival. CIN-positive based on FISH can be prognostic factor of lung SCC. PMID:20514306

  2. Instability of Multiple Sex Chromosomes Systems in Fish: The Case of Erythrinus erythrinus (Bloch & Schneider, 1801) (Characiformes, Erythrinidae).

    PubMed

    Bueno, Vanessa; Moresco, Rafaela Maria; Konerat, Jocicléia Thums; Moreira-Filho, Orlando; Margarido, Vladimir Pavan

    2016-02-01

    The fish species Erythrinus erythrinus belongs to the family Erythrinidae (order Characiformes, superorder Teleostei) and is considered a species complex because of the considerable differences between the karyotypes of analyzed populations. Whereas some populations present a sex chromosome system with male heterogamety, others do not show differentiated sex chromosomes. In this article, two novel karyotypes of E. erythrinus with the occurrence of male and female heterogamety are described, and a discussion of the stability of multiple sex chromosome systems is provided. A possible cause for sex chromosomes instability is that the Robertsonian rearrangements that originated the multiple systems did not prevent recombination with ancestral chromosomes, which also did not pass through a heterochromatinization process, the opposite of what usually happens with simple systems, especially of the ZZ/ZW or XX/XY type. It is suggested that multiple sex chromosome systems would not act as an effective postzygotic barrier, especially when there are hybridization zones between distinct karyomorphs that bear and that do not bear sex chromosome systems, allowing the generation of hybrids. This finding is important both for the comprehension of sex chromosomes evolution in fish and for conservation biology since the contact between populations with and without multiple sex chromosomes may compromise the regional biodiversity.

  3. Upregulated Op18/stathmin activity causes chromosomal instability through a mechanism that evades the spindle assembly checkpoint

    SciTech Connect

    Holmfeldt, Per; Sellin, Mikael E.; Gullberg, Martin

    2010-07-15

    Op18/stathmin (Op18) is a microtubule-destabilizing protein that is phosphorylation-inactivated during mitosis and its normal function is to govern tubulin subunit partitioning during interphase. Human tumors frequently overexpress Op18 and a tumor-associated Q18{yields}E mutation has been identified that confers hyperactivity, destabilizes spindle microtubules, and causes mitotic aberrancies, polyploidization, and chromosome loss in K562 leukemia cells. Here we determined whether wild-type and mutant Op18 have the potential to cause chromosomal instability by some means other than interference with spindle assembly, and thereby bypassing the spindle assembly checkpoint. Our approach was based on Op18 derivatives with distinct temporal order of activity during mitosis, conferred either by differential phosphorylation inactivation or by anaphase-specific degradation through fusion with the destruction box of cyclin B1. We present evidence that excessive Op18 activity generates chromosomal instability through interference occurring subsequent to the metaphase-to-anaphase transition, which reduces the fidelity of chromosome segregation to spindle poles during anaphase. Similar to uncorrected merotelic attachment, this mechanism evades detection by the spindle assembly checkpoint and thus provides an additional route to chromosomal instability.

  4. Immortalization capacity of HPV types is inversely related to chromosomal instability.

    PubMed

    Schütze, Denise M; Krijgsman, Oscar; Snijders, Peter J F; Ylstra, Bauke; Weischenfeldt, Joachim; Mardin, Balca R; Stütz, Adrian M; Korbel, Jan O; de Winter, Johan P; Meijer, Chris J L M; Quint, Wim G V; Bosch, Leontien; Wilting, Saskia M; Steenbergen, Renske D M

    2016-06-21

    High-risk human papillomavirus (hrHPV) types induce immortalization of primary human epithelial cells. Previously we demonstrated that immortalization of human foreskin keratinocytes (HFKs) is HPV type dependent, as reflected by the presence or absence of a crisis period before reaching immortality. This study determined how the immortalization capacity of ten hrHPV types relates to DNA damage induction and overall genomic instability in HFKs.Twenty five cell cultures obtained by transduction of ten hrHPV types (i.e. HPV16/18/31/33/35/45/51/59/66/70 E6E7) in two or three HFK donors each were studied.All hrHPV-transduced HFKs showed an increased number of double strand DNA breaks compared to controls, without exhibiting significant differences between types. However, immortal descendants of HPV-transduced HFKs that underwent a prior crisis period (HPV45/51/59/66/70-transduced HFKs) showed significantly more chromosomal aberrations compared to those without crisis (HPV16/18/31/33/35-transduced HFKs). Notably, the hTERT locus at 5p was exclusively gained in cells with a history of crisis and coincided with increased expression. Chromothripsis was detected in one cell line in which multiple rearrangements within chromosome 8 resulted in a gain of MYC.Together we demonstrated that upon HPV-induced immortalization, the number of chromosomal aberrations is inversely related to the viral immortalization capacity. We propose that hrHPV types with reduced immortalization capacity in vitro, reflected by a crisis period, require more genetic host cell aberrations to facilitate immortalization than types that can immortalize without crisis. This may in part explain the observed differences in HPV-type prevalence in cervical cancers and emphasizes that changes in the host cell genome contribute to HPV-induced carcinogenesis.

  5. Detection of dicentric chromosome (9;20) in paediatric B-cell acute lymphoblastic leukaemia: prognostic significance.

    PubMed

    Letouzey, Mathilde; Penther, Dominique; Roche-Lestienne, Catherine; Nelken, Brigitte; Devoldère, Catherine; Vannier, Jean-Pierre; Schneider, Pascale

    2015-02-01

    The dicentric chromosome (9;20) (dic(9;20)) is described in 2 % of childhood B-acute lymphoblastic leukaemia. Fluorescence in situ hybridization (FISH) is the most reliable method to identify dic(9;20) when compared with conventional cytogenetics. To define the prognostic importance of dic(9;20), we evaluated treatment response and patient survival. This was a retrospective study in three French university centres. Patients' clinical and laboratory characteristics and treatment response are described. Nine children with dic(9;20) have been identified since 1995. All patients had at least one poor prognostic feature either among the clinical features, the initial laboratory results or in the initial treatment response: central nervous system involvement (2/9), high median leucocyte count (≥50 G/L) (8/9) and poor response to prednisone (2/9). All patients were in complete cytological remission after induction therapy but only three had a good molecular response with minimal residual disease (MRD) <10(-3). Five out of nine patients relapsed and two died, 4 and 12 months after diagnosis, respectively. The event-free survival rate in this population was 44 % (95 % confidence interval (CI) = 0.09-0.79) and overall survival 78 % (95 % CI = 0.51-1.05). In this population, dic(9;20) is associated with a relatively poor prognosis. Patients showing dic(9;20), whether this cytogenetic abnormality is associated with other poor prognostic factors or not, should be identified at the outset in order to be offered a more intensive treatment protocol.

  6. Ultraviolet-induced chromosomal instability in cultured fibroblasts of heterozygote carriers for xeroderma pigmentosum

    SciTech Connect

    Bielfeld, V.; Weichenthal, M.; Roser, M.; Breitbart, E.; Berger, J.; Seemanova, E.; Ruediger, H.W. )

    1989-12-01

    Fibroblast cultures of seven patients with xeroderma pigmentosum (XP), 19 healthy sibs or parents of XP patients (XP-heterozygotes), and 24 healthy normal controls were studied for chromosome instability induced by ultraviolet rays (UV). We used a UV source that contained predominantly UV-A and UV-B at an intensity of 500 J/m2 and evaluated the induction of micronuclei (MN) and sister chromatid exchange (SCE). the XP homozygotes had a UV sensitivity that was clearly above that of all heterozygotes and normal controls. Heterozygotes had an increased rate of UV-induced MN (4.76 {plus minus} 1.96 vs. 1.82 {plus minus} 2.05, p less than 0.0001) and increased UV induction of SCE (13.21 {plus minus} 3.49 vs. 9.01 {plus minus} 1.25, p less than 0.001), as compared to normal controls. These data support epidemiologic findings that suggest that XP heterozygotes are particularly cancer prone. In addition, the determination of the UV sensitivity in vitro as described may be used for genetic counseling of asymptomatic relatives of XP patients.

  7. A single mutation in Securin induces chromosomal instability and enhances cell invasion.

    PubMed

    Mora-Santos, Mar; Castilla, Carolina; Herrero-Ruiz, Joaquín; Giráldez, Servando; Limón-Mortés, M Cristina; Sáez, Carmen; Japón, Miguel Á; Tortolero, Maria; Romero, Francisco

    2013-01-01

    Pituitary tumour transforming gene (pttg1) encodes Securin, a protein involved in the inhibition of sister chromatid separation binding to Separase until the onset of anaphase. Separase is a cysteine-protease that degrades cohesin to segregate the sister chromatids to opposite poles of the cell. The amount of Securin is strongly regulated because it should allow Separase activation when it is degraded by the anaphase promoting complex/cyclosome, should arrest the cell cycle after DNA damage, when it is degraded through SKP1-CUL1-βTrCP ubiquitin ligase, and its overexpression induces tumour formation and correlates with metastasis in multiple tumours. Securin is a phosphoprotein that contains 32 potentially phosphorylatable residues. We mutated and analysed most of them, and found a single mutant, hSecT60A, that showed enhanced oncogenic properties. Our fluorescence activated cell sorting analysis, fluorescence in situ hybridisation assays, tumour cell migration and invasion experiments and gene expression by microarrays analysis clearly involved hSecT60A in chromosomal instability and cell invasion. These results show, for the first time, that a single mutation in pttg1 is sufficient to trigger the oncogenic properties of Securin. The finding of this point mutation in patients might be used as an effective strategy for early detection of cancer.

  8. MCM9 Mutations Are Associated with Ovarian Failure, Short Stature, and Chromosomal Instability

    PubMed Central

    Wood-Trageser, Michelle A.; Gurbuz, Fatih; Yatsenko, Svetlana A.; Jeffries, Elizabeth P.; Kotan, L. Damla; Surti, Urvashi; Ketterer, Deborah M.; Matic, Jelena; Chipkin, Jacqueline; Jiang, Huaiyang; Trakselis, Michael A.; Topaloglu, A. Kemal; Rajkovic, Aleksandar

    2014-01-01

    Premature ovarian failure (POF) is genetically heterogeneous and manifests as hypergonadotropic hypogonadism either as part of a syndrome or in isolation. We studied two unrelated consanguineous families with daughters exhibiting primary amenorrhea, short stature, and a 46,XX karyotype. A combination of SNP arrays, comparative genomic hybridization arrays, and whole-exome sequencing analyses identified homozygous pathogenic variants in MCM9, a gene implicated in homologous recombination and repair of double-stranded DNA breaks. In one family, the MCM9 c.1732+2T>C variant alters a splice donor site, resulting in abnormal alternative splicing and truncated forms of MCM9 that are unable to be recruited to sites of DNA damage. In the second family, MCM9 c.394C>T (p.Arg132∗) results in a predicted loss of functional MCM9. Repair of chromosome breaks was impaired in lymphocytes from affected, but not unaffected, females in both families, consistent with MCM9 function in homologous recombination. Autosomal-recessive variants in MCM9 cause a genomic-instability syndrome associated with hypergonadotropic hypogonadism and short stature. Preferential sensitivity of germline meiosis to MCM9 functional deficiency and compromised DNA repair in the somatic component most likely account for the ovarian failure and short stature. PMID:25480036

  9. Phyllanthus emblica L. fruit extract induces chromosomal instability and suppresses necrosis in human colon cancer cells.

    PubMed

    Guo, Xihan; Ni, Juan; Liu, Xuemin; Xue, Jinglun; Wang, Xu

    2013-01-01

    Phyllanthus emblica L. (PE) is an edible fruit indigenous to Southeast Asia. It has been considered as a potent functional food due to its numerous pharmacological applications, such as anti-oxidant, antimicrobial, anti-diabetic and protection for multiple organs. The aim of this study was to evaluate the effects of a water extract of PE fruit on genomic damage and cell death in the human colon adenocarcinoma cell line COLO320 using the cytokinesis-block micronucleus cytome assay. Cells were exposed to RPMI-1640 medium containing 0, 20, 40, 80, or 160 μg/mL PE for 24, 48, 72, or 96 hours. The results showed that PE induced a significant decrease in necrosis (p < 0.001) and nuclear division index (NDI) (p < 0.001) in a dose- and time-dependent manner, and there was a highly significant correlation between the reduction of necrosis and NDI (r = 0.820, p < 0.001). Dose- and time-dependent increases (p < 0.001) in the frequency of chromosomal instability (CIN) were observed after PE exposure, and the frequency of CIN was negatively correlated with NDI (r = - 0.640, p < 0.001). PE also significantly increased apoptosis (p < 0.001), and there was a significant correlation of apoptosis with CIN (r = 0.566, p < 0.001). In conclusion, PE suppresses necrosis and delays mitotic progression, which results in massive CIN followed by apoptosis in COLO320 cells.

  10. Prognostic value of replication errors on chromosomes 2p and 3p in non-small-cell lung cancer.

    PubMed Central

    Pifarré, A.; Rosell, R.; Monzó, M.; De Anta, J. M.; Moreno, I.; Sánchez, J. J.; Ariza, A.; Mate, J. L.; Martińez, E.; Sánchez, M.

    1997-01-01

    As chromosomes 2p and 3p are frequent targets for genomic instability in lung cancer, we have addressed whether alterations of simple (CA)n DNA repeats occur in non-small-cell lung cancer (NSCLC) at early stages. We have analysed by polymerase chain reaction (PCR) assay replication errors (RER) and loss of heterozygosity (LOH) at microsatellites mapped on chromosomes 2p and 3p in 64 paired tumour-normal DNA samples from consecutively resected stage I, II or IIIA NSCLC. DNA samples were also examined for K-ras and p53 gene mutations by PCR-single-stranded conformational polymorphism (PCR-SSCP) analysis and cyclic sequencing, as well as their relationship with clinical outcome. Forty-two of the 64 (66%) NSCLC patients showed RER at single or multiple loci. LOH was detected in 23 tumours (36%). Among patients with stage I disease, the 5-year survival rate was 80% in those whose tumours had no evidence of RER and 26% in those with RER (P = 0.005). No correlation was established between RER phenotype and LOH, K-ras or p53 mutations. RER remained a strong predictive factor (hazard ratio for death, 2.89; 95% confidence interval, 2.23-3.79; P = 0.002) after adjustment for all other evaluated factors, including p53, K-ras, LOH, histological type, tumour differentiation and TNM stage, suggesting that microsatellite instability on chromosomes 2p and 3p may play a role in NSCLC progression through a different pathway from the traditional tumour mechanisms of oncogene activation and/or tumour-suppressor gene inactivation. Images Figure 1 PMID:9010024

  11. Clinical Significance and Prognostic Relevance of Microsatellite Instability in Sporadic Colorectal Cancer Patients

    PubMed Central

    Copija, Angelika; Waniczek, Dariusz; Witkoś, Andrzej; Walkiewicz, Katarzyna; Nowakowska-Zajdel, Ewa

    2017-01-01

    Microsatellite instability (MSI) is a marker of the replication error phenotype. It is caused by impaired DNA mismatch repair processes (MMR), resulting in ineffectiveness of the mechanisms responsible for the DNA replication precision and postreplicative DNA repair. MSI underlies the pathogenesis of 10%–20% of colorectal cancer (CRC) cases. The data about the potential value of MMR status as a predictive factor for 5-fluorouracil (FU)-based chemotherapy remain unclear. According to National Comprehensive Cancer Network updated guidelines, MSI testing is recommended for all patients with stage II CRC because patients with MSI-H (high-frequency MSI) tumour may have a good prognosis and obtain no benefit from 5-FU-based adjuvant chemotherapy. The significance of the MSI status as a predictive factor for patients with metastatic disease was not confirmed. The association between the MSI status and the efficacy of the therapy based on anti-programmed death-1 receptor inhibitors requires further studies. PMID:28067827

  12. Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer

    PubMed Central

    Duffy, Supipi; Fam, Hok Khim; Wang, Yi Kan; Styles, Erin B.; Kim, Jung-Hyun; Ang, J. Sidney; Singh, Tejomayee; Larionov, Vladimir; Shah, Sohrab P.; Andrews, Brenda; Boerkoel, Cornelius F.; Hieter, Philip

    2016-01-01

    Somatic copy number amplification and gene overexpression are common features of many cancers. To determine the role of gene overexpression on chromosome instability (CIN), we performed genome-wide screens in the budding yeast for yeast genes that cause CIN when overexpressed, a phenotype we refer to as dosage CIN (dCIN), and identified 245 dCIN genes. This catalog of genes reveals human orthologs known to be recurrently overexpressed and/or amplified in tumors. We show that two genes, TDP1, a tyrosyl-DNA-phosphdiesterase, and TAF12, an RNA polymerase II TATA-box binding factor, cause CIN when overexpressed in human cells. Rhabdomyosarcoma lines with elevated human Tdp1 levels also exhibit CIN that can be partially rescued by siRNA-mediated knockdown of TDP1. Overexpression of dCIN genes represents a genetic vulnerability that could be leveraged for selective killing of cancer cells through targeting of an unlinked synthetic dosage lethal (SDL) partner. Using SDL screens in yeast, we identified a set of genes that when deleted specifically kill cells with high levels of Tdp1. One gene was the histone deacetylase RPD3, for which there are known inhibitors. Both HT1080 cells overexpressing hTDP1 and rhabdomyosarcoma cells with elevated levels of hTdp1 were more sensitive to histone deacetylase inhibitors valproic acid (VPA) and trichostatin A (TSA), recapitulating the SDL interaction in human cells and suggesting VPA and TSA as potential therapeutic agents for tumors with elevated levels of hTdp1. The catalog of dCIN genes presented here provides a candidate list to identify genes that cause CIN when overexpressed in cancer, which can then be leveraged through SDL to selectively target tumors. PMID:27551064

  13. Effects of Anticancer Drug on Chromosome Instability (CIN) and New Clinical Implications for Tumor-Suppressing Therapies

    PubMed Central

    Lee, Hee-Sheung; Lee, Nicholas CO; Kouprina, Natalay; Kim, Jung-Hyun; Kagansky, Alex; Bates, Susan; Trepel, Jane B.; Pommier, Yves; Sackett, Dan; Larionov, Vladimir

    2016-01-01

    Whole-chromosomal instability (CIN), manifested as unequal chromosome distribution during cell division, is a distinguishing feature of most cancer types. CIN is generally considered to drive tumorigenesis, but a threshold level exists whereby further increases in CIN frequency in fact hinder tumor growth. While this attribute is appealing for therapeutic exploitation, drugs that increase CIN beyond this therapeutic threshold are currently limited. In our previous work, we developed a quantitative assay for measuring CIN based on the use of a non-essential human artificial chromosome (HAC) carrying a constitutively expressed EGFP transgene. Here, we used this assay to rank 62 different anticancer drugs with respect to their effects on chromosome transmission fidelity. Drugs with various mechanisms of action such as antimicrotubule activity, histone deacetylase (HDAC) inhibition, mitotic checkpoint inhibition, and targeting of DNA replication and damage responses were included in the analysis. Ranking of the drugs based on their ability to induce HAC loss revealed that paclitaxel, gemcitabine, dactylolide, LMP400, talazoparib, olaparib, peloruside A, GW843682, VX-680, and cisplatin were the top ten drugs demonstrating HAC loss at a high frequency. Therefore, identification of currently used compounds that greatly increase chromosome mis-segregation rates should expedite the development of new therapeutic strategies to target and leverage the CIN phenotype in cancer cells. PMID:26837770

  14. Telomeric fusion and chromosome instability in multiple tissues of a patient with mosaic Ullrich-Turner syndrome

    SciTech Connect

    Sawyer, J.R.; North, P.E.; Hassed, S.J.

    1997-04-14

    We describe the cytogenetic evolution of multiple cell lines in the gonadal tissue of a 10-year-old girl with mosaic Ullrich-Turner syndrome (UTS) involving clonal telomeric associations (tas) of the Y chromosome. G-band analysis of all tissues showed at least 2 cell lines; 45,X and 46,X,tas(Y;21)(q12;p13). However, analysis of left gonadal tissue of this patient showed the evolution of 2 additional cell lines, one designated 45,X,tas(Y;21)(q12;p13),-22 and the other 46,X,tas(Y;21)(q12;p13),+tas(Y;14)(q12;p13),-22. Fluorescence in situ hybridization (FISH) analysis of interphase nuclei from uncultured gonadal tissue confirmed the findings of aneuploidy in the left gonadal tissue and extended the findings of aneuploidy to the tissue of the right gonad. The chromosome findings in the gonadal tissue of this patient suggest a preneoplastic karyotype relating to several distinct tumor associations. The clonal evolution of telomeric fusions indicates chromosome instability and suggests the extra copy of the Y chromosome may have resulted from a fusion-related malsegregation. In addition, the extra Y suggests low-level amplification of a putative gonadoblastoma gene, while the loss of chromosome 22 suggests the loss of heterozygosity for genes on chromosome 22. This case demonstrates the utility of the study of gonadal tissue in 45X46,XY UTS patients, and provides evidence that clonal telomeric fusions may, in rare cases, be associated with chromosomal malsegregation and with the subsequent evolution of unstable karyotypes. 27 refs., 3 figs.

  15. Chromosome

    MedlinePlus

    Chromosomes are structures found in the center (nucleus) of cells that carry long pieces of DNA. DNA ... is the building block of the human body. Chromosomes also contain proteins that help DNA exist in ...

  16. Growth inhibition and chromosomal instability of cultured marsupial (opossum) cells after treatment with DNA polymerase α inhibitor.

    PubMed

    Takemura, Masaharu; Kazama, Tomoko; Sakuma, Kurumi; Mizushina, Yoshiyuki; Oshima, Teruyoshi

    2011-01-01

    The DNA replication mechanism has been well established for eutherian mammals (placental mammals such as humans, mice, and cattle), but not, to date, for metatherian mammals (marsupials such as kangaroos, koalas, and opossums). In this study, we found that dehydroaltenusin, a selective inhibitor of mammalian (eutherian) DNA polymerase α, clearly suppressed the growth of metatherian (opossum and rat kangaroo) cultured cells. In cultured opossum (OK) cells, dehydroaltenusin also suppressed the progression of DNA replication. These results suggest that dehydroaltenusin inhibits metatherian as well as eutherian DNA replication. Dehydroaltenusin treatment of OK cells engendered fluctuations in the numbers of chromosomes in the OK cells as well as inhibition of cell growth and DNA replication. This suggests that partial inhibition of DNA replication by dehydroaltenusin causes chromosomal instability in cultured cells.

  17. The role of telomere length modulation in delayed chromosome instability induced by ionizing radiation in human primary fibroblasts.

    PubMed

    Berardinelli, Francesco; Antoccia, Antonio; Buonsante, Rossella; Gerardi, Silvia; Cherubini, Roberto; De Nadal, Viviana; Tanzarella, Caterina; Sgura, Antonella

    2013-04-01

    Telomere integrity is important for chromosome stability. The main objective of our study was to investigate the relationship between telomere length modulation and mitotic chromosome segregation induced by ionizing radiation in human primary fibroblasts. We used X-rays and low-energy protons because of their ability to induce different telomeric responses. Samples irradiated with 4 Gy were fixed at different times up to 6 days from exposure and telomere length, anaphase abnormalities, and chromosome aberrations were analyzed. We observed that X-rays induced telomere shortening in cells harvested at 96 hrs, whereas protons induced a significant increase in telomere length at short as well as at long harvesting times (24 and 96 hrs). Consistent with this, the analysis of anaphase bridges at 96 hrs showed a fourfold increase in X-ray- compared with proton-irradiated samples, suggesting a correlation between telomere length/dysfunction and chromosome missegregation. In line with these findings, the frequency of dicentrics and rings decreased with time for protons whereas it remained stable after X-rays irradiation. Telomeric FISH staining on anaphases revealed a higher percentage of bridges with telomere signals in X-ray-treated samples than that observed after proton irradiation, thus suggesting that the aberrations observed after X-ray irradiation originated from telomere attrition and consequent chromosome end-to-end fusion. This study shows that, beside an expected "early" chromosome instability induced shortly after irradiation, a delayed one occurs as a result of alterations in telomere metabolism and that this mechanism may play an important role in genomic stability.

  18. DNA tandem repeat instability in the Escherichia coli chromosome is stimulated by mismatch repair at an adjacent CAG·CTG trinucleotide repeat

    PubMed Central

    Blackwood, John K.; Okely, Ewa A.; Zahra, Rabaab; Eykelenboom, John K.; Leach, David R. F.

    2010-01-01

    Approximately half the human genome is composed of repetitive DNA sequences classified into microsatellites, minisatellites, tandem repeats, and dispersed repeats. These repetitive sequences have coevolved within the genome but little is known about their potential interactions. Trinucleotide repeats (TNRs) are a subclass of microsatellites that are implicated in human disease. Expansion of CAG·CTG TNRs is responsible for Huntington disease, myotonic dystrophy, and a number of spinocerebellar ataxias. In yeast DNA double-strand break (DSB) formation has been proposed to be associated with instability and chromosome fragility at these sites and replication fork reversal (RFR) to be involved either in promoting or in preventing instability. However, the molecular basis for chromosome fragility of repetitive DNA remains poorly understood. Here we show that a CAG·CTG TNR array stimulates instability at a 275-bp tandem repeat located 6.3 kb away on the Escherichia coli chromosome. Remarkably, this stimulation is independent of both DNA double-strand break repair (DSBR) and RFR but is dependent on a functional mismatch repair (MMR) system. Our results provide a demonstration, in a simple model system, that MMR at one type of repetitive DNA has the potential to influence the stability of another. Furthermore, the mechanism of this stimulation places a limit on the universality of DSBR or RFR models of instability and chromosome fragility at CAG·CTG TNR sequences. Instead, our data suggest that explanations of chromosome fragility should encompass the possibility of chromosome gaps formed during MMR. PMID:21149728

  19. The Role of Chromosomal Instability and Epigenetics in Colorectal Cancers Lacking β-Catenin/TCF Regulated Transcription.

    PubMed

    Abdel-Rahman, Wael M; Lotsari-Salomaa, Johanna E; Kaur, Sippy; Niskakoski, Anni; Knuutila, Sakari; Järvinen, Heikki; Mecklin, Jukka-Pekka; Peltomäki, Päivi

    2016-01-01

    All colorectal cancer cell lines except RKO displayed active β-catenin/TCF regulated transcription. This feature of RKO was noted in familial colon cancers; hence our aim was to dissect its carcinogenic mechanism. MFISH and CGH revealed distinct instability of chromosome structure in RKO. Gene expression microarray of RKO versus 7 colon cancer lines (with active Wnt signaling) and 3 normal specimens revealed 611 differentially expressed genes. The majority of the tested gene loci were susceptible to LOH in primary tumors with various β-catenin localizations as a surrogate marker for β-catenin activation. The immunohistochemistry of selected genes (IFI16, RGS4, MCTP1, DGKI, OBCAM/OPCML, and GLIPR1) confirmed that they were differentially expressed in clinical specimens. Since epigenetic mechanisms can contribute to expression changes, selected target genes were evaluated for promoter methylation in patient specimens from sporadic and hereditary colorectal cancers. CMTM3, DGKI, and OPCML were frequently hypermethylated in both groups, whereas KLK10, EPCAM, and DLC1 displayed subgroup specificity. The overall fraction of hypermethylated genes was higher in tumors with membranous β-catenin. We identified novel genes in colorectal carcinogenesis that might be useful in personalized tumor profiling. Tumors with inactive Wnt signaling are a heterogeneous group displaying interaction of chromosomal instability, Wnt signaling, and epigenetics.

  20. The Role of Chromosomal Instability and Epigenetics in Colorectal Cancers Lacking β-Catenin/TCF Regulated Transcription

    PubMed Central

    Lotsari-Salomaa, Johanna E.; Kaur, Sippy; Niskakoski, Anni; Mecklin, Jukka-Pekka

    2016-01-01

    All colorectal cancer cell lines except RKO displayed active β-catenin/TCF regulated transcription. This feature of RKO was noted in familial colon cancers; hence our aim was to dissect its carcinogenic mechanism. MFISH and CGH revealed distinct instability of chromosome structure in RKO. Gene expression microarray of RKO versus 7 colon cancer lines (with active Wnt signaling) and 3 normal specimens revealed 611 differentially expressed genes. The majority of the tested gene loci were susceptible to LOH in primary tumors with various β-catenin localizations as a surrogate marker for β-catenin activation. The immunohistochemistry of selected genes (IFI16, RGS4, MCTP1, DGKI, OBCAM/OPCML, and GLIPR1) confirmed that they were differentially expressed in clinical specimens. Since epigenetic mechanisms can contribute to expression changes, selected target genes were evaluated for promoter methylation in patient specimens from sporadic and hereditary colorectal cancers. CMTM3, DGKI, and OPCML were frequently hypermethylated in both groups, whereas KLK10, EPCAM, and DLC1 displayed subgroup specificity. The overall fraction of hypermethylated genes was higher in tumors with membranous β-catenin. We identified novel genes in colorectal carcinogenesis that might be useful in personalized tumor profiling. Tumors with inactive Wnt signaling are a heterogeneous group displaying interaction of chromosomal instability, Wnt signaling, and epigenetics. PMID:27047543

  1. A Novel Multiplexed, Image-Based Approach to Detect Phenotypes That Underlie Chromosome Instability in Human Cells

    PubMed Central

    Thompson, Laura L.; McManus, Kirk J.

    2015-01-01

    Chromosome instability (CIN) is characterized by a progressive change in chromosome numbers. It is a characteristic common to virtually all tumor types, and is commonly observed in highly aggressive and drug resistant tumors. Despite this information, the majority of human CIN genes have yet to be elucidated. In this study, we developed and validated a multiplexed, image-based screen capable of detecting three different phenotypes associated with CIN. Large-scale chromosome content changes were detected by quantifying changes in nuclear volumes following RNAi-based gene silencing. Using a DsRED-LacI reporter system to fluorescently label chromosome 11 within a human fibrosarcoma cell line, we were able to detect deviations from the expected number of two foci per nucleus (one focus/labelled chromosome) that occurred following CIN gene silencing. Finally, micronucleus enumeration was performed, as an increase in micronucleus formation is a classic hallmark of CIN. To validate the ability of each assay to detect phenotypes that underlie CIN, we silenced the established CIN gene, SMC1A. Following SMC1A silencing we detected an increase in nuclear volumes, a decrease in the number of nuclei harboring two DsRED-LacI foci, and an increase in micronucleus formation relative to controls (untreated and siGAPDH). Similar results were obtained in an unrelated human fibroblast cell line. The results of this study indicate that each assay is capable of detecting CIN-associated phenotypes, and can be utilized in future experiments to uncover novel human CIN genes, which will provide novel insight into the pathogenesis of cancer. PMID:25893404

  2. Re-replication of a Centromere Induces Chromosomal Instability and Aneuploidy

    PubMed Central

    Hanlon, Stacey L.; Li, Joachim J.

    2015-01-01

    The faithful inheritance of chromosomes during cell division requires their precise replication and segregation. Numerous mechanisms ensure that each of these fundamental cell cycle events is performed with a high degree of fidelity. The fidelity of chromosomal replication is maintained in part by re-replication controls that ensure there are no more than two copies of every genomic segment to distribute to the two daughter cells. This control is enforced by inhibiting replication initiation proteins from reinitiating replication origins within a single cell cycle. Here we show in Saccharomyces cerevisiae that re-replication control is important for the fidelity of chromosome segregation. In particular, we demonstrate that transient re-replication of centromeric DNA due to disruption of re-replication control greatly induces aneuploidy of the re-replicated chromosome. Some of this aneuploidy arises from missegregation of both sister chromatids to one daughter cell. Aneuploidy can also arise from the generation of an extra sister chromatid via homologous recombination, suggesting that centromeric re-replication can trigger breakage and repair events that expand chromosome number without causing chromosomal rearrangements. Thus, we have identified a potential new non-mitotic source of aneuploidy that can arise from a defect in re-replication control. Given the emerging connections between the deregulation of replication initiation proteins and oncogenesis, this finding may be relevant to the aneuploidy that is prevalent in cancer. PMID:25901968

  3. Loss of BRCA1 impairs centromeric cohesion and triggers chromosomal instability.

    PubMed

    Di Paolo, Aurélie; Racca, Carine; Calsou, Patrick; Larminat, Florence

    2014-12-01

    In contrast to its well-known role in the DNA damage response during interphase, the function of BRCA1 in the maintenance of chromosomal stability during mitosis remains to be defined. In this study, we uncover a novel role of BRCA1 in preserving centromere integrity in mitotic human cells. Using immunofluorescence and chromatin immunoprecipitation approaches, we report BRCA1 association with centromeric chromatin during mitosis. BRCA1 depletion impairs centromeric cohesion, leading to an increase in interkinetochore distance and in unpaired sister-chromatids frequency during prometaphase. Moreover, BRCA1 loss partially decreased accumulation of the Aurora B kinase at the centromere. We found that proper recruitment of the DNMT3b DNA methyltransferase to satellite sequences is BRCA1-dependent during mitosis, suggesting that DNA hypomethylation contributes to Aurora B mislocalization. BRCA1-deficient cells exhibited decreased ability to correct improper Aurora B-dependent chromosome-spindle attachments and to align chromosomes at metaphase. Finally, we show that BRCA1 disruption promotes merotelic kinetochore attachments that represent a major mechanism of aneuploidy in human cells. In summary, we report here a novel function of BRCA1 in maintaining chromosomal stability through its contribution to the mitotic centromere integrity necessary for faithful segregation of sister-chromatids during cell division.

  4. Instability in X chromosome inactivation patterns in AMD: a new risk factor?

    PubMed Central

    Vladan, Bajic; Biljana, Spremo-Potparevic; Mandusic, Vesna; Zorana, Milicevic; Zivkovic, Lada

    2013-01-01

    Years ago, it was thought that a genetic component was the fundamental cause of a number retinopathy diseases including age related macular degeneration (AMD). Since then, information has emerged about novel genes that contribute to various forms of AMD and other retinopathies that have been eluding researchers for years. In the genetic sense, only the APOE 2 and 4 genes have been found to be a risk factor for sporadic AMD. But, a recent Genome wide association study (GWAS) revealed that an alteration of five SNIPs on the X chromosome in a gene named DIAPH2 may be a susceptibility gene for AMD. Furthermore, the gene DIAPH2 showed to have a polygenic pleiotropy for premature ovarian failure (POF) and AMD in a cohort of women. POF is highly associated with X chromosome skewing, an epigenetic alteration of the inactivation process of the X chromosome. These findings suggest a hypothesis that an epigenetic alteration on the inactivation centres of the X chromosome (or skewing) relates not only to aging, but might be a novel property that affects women with AMD more often than men. PMID:24600647

  5. Deletion of Brca2 exon 27 causes hypersensitivity to DNA crosslinks, chromosomal instability, and reduced life span in mice

    NASA Technical Reports Server (NTRS)

    Donoho, Greg; Brenneman, Mark A.; Cui, Tracy X.; Donoviel, Dorit; Vogel, Hannes; Goodwin, Edwin H.; Chen, David J.; Hasty, Paul

    2003-01-01

    The Brca2 tumor-suppressor gene contributes to genomic stability, at least in part by a role in homologous recombinational repair. BRCA2 protein is presumed to function in homologous recombination through interactions with RAD51. Both exons 11 and 27 of Brca2 code for domains that interact with RAD51; exon 11 encodes eight BRC motifs, whereas exon 27 encodes a single, distinct interaction domain. Deletion of all RAD51-interacting domains causes embryonic lethality in mice. A less severe phenotype is seen with BRAC2 truncations that preserve some, but not all, of the BRC motifs. These mice can survive beyond weaning, but are runted and infertile, and die very young from cancer. Cells from such mice show hypersensitivity to some genotoxic agents and chromosomal instability. Here, we have analyzed mice and cells with a deletion of only the RAD51-interacting region encoded by exon 27. Mice homozygous for this mutation (called brca2(lex1)) have a shorter life span than that of control littermates, possibly because of early onsets of cancer and sepsis. No other phenotype was observed in these animals; therefore, the brca2(lex1) mutation is less severe than truncations that delete some BRC motifs. However, at the cellular level, the brca2(lex1) mutation causes reduced viability, hypersensitivity to the DNA interstrand crosslinking agent mitomycin C, and gross chromosomal instability, much like more severe truncations. Thus, the extreme carboxy-terminal region encoded by exon 27 is important for BRCA2 function, probably because it is required for a fully functional interaction between BRCA2 and RAD51. Copyright 2003 Wiley-Liss, Inc.

  6. Relative telomere lengths in tumor and normal mucosa are related to disease progression and chromosome instability profiles in colorectal cancer

    PubMed Central

    Jorissen, Robert N.; Hampson, Debbie; Ghosh, Anil; Sengupta, Neel; Thaha, Mohamed; Ahmed, Shafi; Kirwan, Michael; Aleva, Floor; Propper, David; Feakins, Roger M.; Vulliamy, Tom; Elwood, Ngaire J.; Tian, Pei; Ward, Robyn L.; Hawkins, Nicholas J.; Xu, Zheng-Zhou; Molloy, Peter L.; Jones, Ian T.; Croxford, Matthew; Gibbs, Peter; Silver, Andrew; Sieber, Oliver M.

    2016-01-01

    Telomeric dysfunction is linked to colorectal cancer (CRC) initiation. However, the relationship of normal tissue and tumor telomere lengths with CRC progression, molecular features and prognosis is unclear. Here, we measured relative telomere length (RTL) by real-time quantitative PCR in 90 adenomas (aRTL), 419 stage I-IV CRCs (cRTL) and adjacent normal mucosa (nRTL). Age-adjusted RTL was analyzed against germline variants in telomere biology genes, chromosome instability (CIN), microsatellite instability (MSI), CpG island methylator phenotype (CIMP), TP53, KRAS, BRAF mutations and clinical outcomes. In 509 adenoma or CRC patients, nRTL decreased with advancing age. Female gender, proximal location and the TERT rs2736100 G allele were independently associated with longer age-adjusted nRTL. Adenomas and carcinomas exhibited telomere shortening in 79% and 67% and lengthening in 7% and 15% of cases. Age-adjusted nRTL and cRTL were independently associated with tumor stage, decreasing from adenoma to stage III and leveling out or increasing from stage III to IV, respectively. Cancer MSI, CIMP, TP53, KRAS and BRAF status were not related to nRTL or cRTL. Near-tetraploid CRCs exhibited significantly longer cRTLs than CIN- and aneuploidy CRCs, while cRTL was significantly shorter in CRCs with larger numbers of chromosome breaks. Age-adjusted nRTL, cRTL or cRTL:nRTL ratios were not associated with disease-free or overall survival in stage II/III CRC. Taken together, our data show that both normal mucosa and tumor RTL are independently associated with CRC progression, and highlight divergent associations of CRC telomere length with tumor CIN profiles. PMID:27167335

  7. Relative telomere lengths in tumor and normal mucosa are related to disease progression and chromosome instability profiles in colorectal cancer.

    PubMed

    Suraweera, Nirosha; Mouradov, Dmitri; Li, Shan; Jorissen, Robert N; Hampson, Debbie; Ghosh, Anil; Sengupta, Neel; Thaha, Mohamed; Ahmed, Shafi; Kirwan, Michael; Aleva, Floor; Propper, David; Feakins, Roger M; Vulliamy, Tom; Elwood, Ngaire J; Tian, Pei; Ward, Robyn L; Hawkins, Nicholas J; Xu, Zheng-Zhou; Molloy, Peter L; Jones, Ian T; Croxford, Matthew; Gibbs, Peter; Silver, Andrew; Sieber, Oliver M

    2016-06-14

    Telomeric dysfunction is linked to colorectal cancer (CRC) initiation. However, the relationship of normal tissue and tumor telomere lengths with CRC progression, molecular features and prognosis is unclear. Here, we measured relative telomere length (RTL) by real-time quantitative PCR in 90 adenomas (aRTL), 419 stage I-IV CRCs (cRTL) and adjacent normal mucosa (nRTL). Age-adjusted RTL was analyzed against germline variants in telomere biology genes, chromosome instability (CIN), microsatellite instability (MSI), CpG island methylator phenotype (CIMP), TP53, KRAS, BRAF mutations and clinical outcomes. In 509 adenoma or CRC patients, nRTL decreased with advancing age. Female gender, proximal location and the TERT rs2736100 G allele were independently associated with longer age-adjusted nRTL. Adenomas and carcinomas exhibited telomere shortening in 79% and 67% and lengthening in 7% and 15% of cases. Age-adjusted nRTL and cRTL were independently associated with tumor stage, decreasing from adenoma to stage III and leveling out or increasing from stage III to IV, respectively. Cancer MSI, CIMP, TP53, KRAS and BRAF status were not related to nRTL or cRTL. Near-tetraploid CRCs exhibited significantly longer cRTLs than CIN- and aneuploidy CRCs, while cRTL was significantly shorter in CRCs with larger numbers of chromosome breaks. Age-adjusted nRTL, cRTL or cRTL:nRTL ratios were not associated with disease-free or overall survival in stage II/III CRC. Taken together, our data show that both normal mucosa and tumor RTL are independently associated with CRC progression, and highlight divergent associations of CRC telomere length with tumor CIN profiles.

  8. Chromosomal instability in Afrotheria: fragile sites, evolutionary breakpoints and phylogenetic inference from genome sequence assemblies

    PubMed Central

    Ruiz-Herrera, Aurora; Robinson, Terence J

    2007-01-01

    Background Extant placental mammals are divided into four major clades (Laurasiatheria, Supraprimates, Xenarthra and Afrotheria). Given that Afrotheria is generally thought to root the eutherian tree in phylogenetic analysis of large nuclear gene data sets, the study of the organization of the genomes of afrotherian species provides new insights into the dynamics of mammalian chromosomal evolution. Here we test if there are chromosomal bands with a high tendency to break and reorganize in Afrotheria, and by analyzing the expression of aphidicolin-induced common fragile sites in three afrotherian species, whether these are coincidental with recognized evolutionary breakpoints. Results We described 29 fragile sites in the aardvark (OAF) genome, 27 in the golden mole (CAS), and 35 in the elephant-shrew (EED) genome. We show that fragile sites are conserved among afrotherian species and these are correlated with evolutionary breakpoints when compared to the human (HSA) genome. Inddition, by computationally scanning the newly released opossum (Monodelphis domestica) and chicken sequence assemblies for use as outgroups to Placentalia, we validate the HSA 3/21/5 chromosomal synteny as a rare genomic change that defines the monophyly of this ancient African clade of mammals. On the other hand, support for HSA 1/19p, which is also thought to underpin Afrotheria, is currently ambiguous. Conclusion We provide evidence that (i) the evolutionary breakpoints that characterise human syntenies detected in the basal Afrotheria correspond at the chromosomal band level with fragile sites, (ii) that HSA 3p/21 was in the amniote ancestor (i.e., common to turtles, lepidosaurs, crocodilians, birds and mammals) and was subsequently disrupted in the lineage leading to marsupials. Its expansion to include HSA 5 in Afrotheria is unique and (iii) that its fragmentation to HSA 3p/21 + HSA 5/21 in elephant and manatee was due to a fission within HSA 21 that is probably shared by all

  9. Loss of Ewing sarcoma EWS allele promotes tumorigenesis by inducing chromosomal instability in zebrafish

    PubMed Central

    Park, Hyewon; Galbraith, Richard; Turner, Thaddeus; Mehojah, Justin; Azuma, Mizuki

    2016-01-01

    The Ewing sarcoma family of tumors expresses aberrant EWSR1- (EWS) fusion genes that are derived from chromosomal translocation. Although these fusion genes are well characterized as transcription factors, their formation leaves a single EWS allele in the sarcoma cells, and the contribution that the loss of EWS makes towards disease pathogenesis is unknown. To address this question, we utilized zebrafish mutants for ewsa and tp53. The zebrafish tp53(M214K)w/m line and the ewsaw/m, zygotic ewsam/m, and Maternal-Zygotic (MZ) ewsam/m lines all displayed zero to low incidence of tumorigenesis. However, when the ewsa and tp53 mutant lines were crossed with each other, the incidence of tumorigenesis drastically increased. Furthermore, 27 hour post fertilization (hpf) MZ ewsam/m mutant embryos displayed a higher incidence of aberrant chromosome numbers and mitotic dysfunction compared to wildtype zebrafish embryos. Consistent with this finding, tumor samples obtained from ewsam/m;tp53w/m zebrafish displayed loss of heterozygosity (LOH) for the wildtype tp53 locus. These results suggest that wildtype Ewsa inhibits LOH induction, possibly by maintaining chromosomal stability. We propose that the loss of ewsa promotes tumorigenesis, and EWS deficiency may contribute to the pathogenesis of EWS-fusion-expressing sarcomas. PMID:27557633

  10. 5-bp Classical Satellite DNA Loci from Chromosome-1 Instability in Cervical Neoplasia Detected by DNA Breakage Detection/Fluorescence in Situ Hybridization (DBD-FISH).

    PubMed

    Cortés-Gutiérrez, Elva I; Ortíz-Hernández, Brenda L; Dávila-Rodríguez, Martha I; Cerda-Flores, Ricardo M; Fernández, José Luis; López-Fernández, Carmen; Gosálvez, Jaime

    2013-02-19

    We aimed to evaluate the association between the progressive stages of cervical neoplasia and DNA damage in 5-bp classical satellite DNA sequences from chromosome-1 in cervical epithelium and in peripheral blood lymphocytes using DNA breakage detection/fluorescence in situ hybridization (DBD-FISH). A hospital-based unmatched case-control study was conducted in 2011 with a sample of 30 women grouped according to disease stage and selected according to histological diagnosis; 10 with low-grade squamous intraepithelial lesions (LG-SIL), 10 with high-grade SIL (HG-SIL), and 10 with no cervical lesions, from the Unidad Medica de Alta Especialidad of The Mexican Social Security Institute, IMSS, Mexico. Specific chromosome damage levels in 5-bp classical satellite DNA sequences from chromosome-1 were evaluated in cervical epithelium and peripheral blood lymphocytes using the DBD-FISH technique. Whole-genome DNA hybridization was used as a reference for the level of damage. Results of Kruskal-Wallis test showed a significant increase according to neoplastic development in both tissues. The instability of 5-bp classical satellite DNA sequences from chromosome-1 was evidenced using chromosome-orientation FISH. In conclusion, we suggest that the progression to malignant transformation involves an increase in the instability of 5-bp classical satellite DNA sequences from chromosome-1.

  11. Chromosomal Abnormalities Are Major Prognostic Factors in Elderly Patients With Multiple Myeloma: The Intergroupe Francophone du Myélome Experience

    PubMed Central

    Avet-Loiseau, Hervé; Hulin, Cyrille; Campion, Loic; Rodon, Philippe; Marit, Gerald; Attal, Michel; Royer, Bruno; Dib, Mamoun; Voillat, Laurent; Bouscary, Didier; Caillot, Denis; Wetterwald, Marc; Pegourie, Brigitte; Lepeu, Gerard; Corront, Bernadette; Karlin, Lionel; Stoppa, Anne-Marie; Fuzibet, Jean-Gabriel; Delbrel, Xavier; Guilhot, Francois; Kolb, Brigitte; Decaux, Olivier; Lamy, Thierry; Garderet, Laurent; Allangba, Olivier; Lifermann, Francois; Anglaret, Bruno; Moreau, Philippe; Harousseau, Jean-Luc; Facon, Thierry

    2013-01-01

    Purpose Chromosomal abnormalities, especially t(4;14) and del(17p), are major prognostic factors in patients with multiple myeloma (MM). However, this has been especially demonstrated in patients age < 66 years treated with intensive approaches. The goal of this study was to address this issue in elderly patients treated with conventional-dose chemotherapy. Patients and Methods To answer this important question, we retrospectively analyzed a series of 1,890 patients (median age, 72 years; range, 66 to 94 years), including 1,095 with updated data on treatment modalities and survival. Results This large study first showed that the incidence of t(4;14) was not uniform over age, with a marked decrease in the oldest patients. Second, it showed that both t(4;14) and del(17p) retained their prognostic value in elderly patients treated with melphalan and prednisone–based chemotherapy. Conclusion t(4;14) and del(17p) are major prognostic factors in elderly patients with MM, both for progression-free and overall survival, indicating that these two abnormalities should be investigated at diagnosis of MM, regardless of age. PMID:23796999

  12. Eleven Polish patients with microcephaly, immunodeficiency, and chromosomal instability: The Nijmegan breakage syndrome

    SciTech Connect

    Chrzanowska, K.H.; Krajewska-Walasek, M.; Gutkowska, A.

    1995-07-03

    We report on 11 patients with 8 independent families (3 pairs of sibs) with a complex clinical pattern including microcephaly, peculiar {open_quotes}bird-like{close_quotes} face, growth retardation, and, in some cases, mild-to-moderate mental deficiency. Most of the patients have recurring respiratory tract infections. One girl has developed B-cell lymphoma. A detailed anthropometric study of 15 physical parameters, including 3 cephalic traits, was performed. It was possible to study the chromosomes of PHA-stimulated lymphocytes in all of the patients. We found structural aberrations with multiple rearrangements, preferentially involving chromosomes 7 and 14 in a proportion of metaphases in all individuals. Profound humoral and cellular immune defects were observed. Serum AFP levels were within normal range. Radioresistant DNA synthesis was strongly increased in all 8 patients who were hitherto studied in this respect. Our patients fulfill the criteria of the Nijmegen breakage syndrome, which belongs to the growing category of ataxia telangiectasia-related genetic disorders. In light of the increased predisposition to malignancy in this syndrome, an accurate diagnosis is important for the patient. 27 refs., 5 figs., 4 tabs.

  13. Cortisol Is Not Associated with Telomere Shortening or Chromosomal Instability in Human Lymphocytes Cultured under Low and High Folate Conditions

    PubMed Central

    Bull, Caroline; Christensen, Helen; Fenech, Michael

    2015-01-01

    Chronic psychological stress and nutritional deficiencies are factors that impact negatively on human health and disease risk. Chronic stress has been associated with accelerated leukocyte telomere shortening in numerous cohorts, however, a mechanistic link has proven elusive. This study tested the hypotheses that chronic exposure to the stress hormone, cortisol, causes telomere shortening and chromosome instability (CIN) in vitro, and that these effects would be further exacerbated by folate (vitamin B9) deficiency. Primary human lymphocytes were maintained in vitro for 12 days in medium containing either 25 nM folic acid (FA(low)) or 100 nM FA (FA(high)), together with either 0, 400, 1000 or 3500 nM cortisol. The interactive effects of cortisol and FA were examined by comparing telomere length (TL), biomarkers of DNA damage, and cytostasis. At day 12 TL was 5-17% longer in lymphocytes cultured in FA(low) conditions (mean ± SD;10.2% ± 1.6), compared with those in FA(high) medium (9.1% ± 1, p = 0.02). Refuting the hypothesis, TL was consistently greater in the presence of cortisol. The effect of FA deficiency on the frequency of DNA damage was significant for nucleoplasmic bridges, circular nuclei, micronuclei and nuclear buds, (p < 0.0001 – 0.001). The effect of cortisol, however, was negligible, only reaching statistical significance for the frequency of fused nuclei (p = 0.04). Cortisol was significantly associated with reduced cell division and growth and had an apparent protective effect on cell viability in the FA(low) conditions. Conclusions: Both chronic cortisol exposure, and folate deficiency, resulted in telomere elongation, however, the effect of cortisol was marginal relative to that of folate. Cortisol was not associated with increased chromosomal instability, but caused a significant reduction in cell division and growth. Together these results indicate that cortisol is not directly genotoxic and that the telomere shortening associated with

  14. Cortisol is not associated with telomere shortening or chromosomal instability in human lymphocytes cultured under low and high folate conditions.

    PubMed

    Bull, Caroline; Christensen, Helen; Fenech, Michael

    2015-01-01

    Chronic psychological stress and nutritional deficiencies are factors that impact negatively on human health and disease risk. Chronic stress has been associated with accelerated leukocyte telomere shortening in numerous cohorts, however, a mechanistic link has proven elusive. This study tested the hypotheses that chronic exposure to the stress hormone, cortisol, causes telomere shortening and chromosome instability (CIN) in vitro, and that these effects would be further exacerbated by folate (vitamin B9) deficiency. Primary human lymphocytes were maintained in vitro for 12 days in medium containing either 25 nM folic acid (FA(low)) or 100 nM FA (FA(high)), together with either 0, 400, 1000 or 3500 nM cortisol. The interactive effects of cortisol and FA were examined by comparing telomere length (TL), biomarkers of DNA damage, and cytostasis. At day 12 TL was 5-17% longer in lymphocytes cultured in FA(low) conditions (mean ± SD;10.2% ± 1.6), compared with those in FA(high) medium (9.1% ± 1, p = 0.02). Refuting the hypothesis, TL was consistently greater in the presence of cortisol. The effect of FA deficiency on the frequency of DNA damage was significant for nucleoplasmic bridges, circular nuclei, micronuclei and nuclear buds, (p < 0.0001-0.001). The effect of cortisol, however, was negligible, only reaching statistical significance for the frequency of fused nuclei (p = 0.04). Cortisol was significantly associated with reduced cell division and growth and had an apparent protective effect on cell viability in the FA(low) conditions. Conclusions: Both chronic cortisol exposure, and folate deficiency, resulted in telomere elongation, however, the effect of cortisol was marginal relative to that of folate. Cortisol was not associated with increased chromosomal instability, but caused a significant reduction in cell division and growth. Together these results indicate that cortisol is not directly genotoxic and that the telomere shortening associated with

  15. Zinc chromate induces chromosome instability and DNA double strand breaks in human lung cells

    SciTech Connect

    Xie Hong; Holmes, Amie L.; Young, Jamie L.; Qin Qin; Joyce, Kellie; Pelsue, Stephen C.; Peng Cheng; Wise, Sandra S.; Jeevarajan, Antony S.; Wallace, William T.; Hammond, Dianne; Wise, John Pierce E-mail: John.Wise@usm.maine.edu

    2009-02-01

    Hexavalent chromium Cr(VI) is a respiratory toxicant and carcinogen, with solubility playing an important role in its carcinogenic potential. Zinc chromate, a water insoluble or 'particulate' Cr(VI) compound, has been shown to be carcinogenic in epidemiology studies and to induce tumors in experimental animals, but its genotoxicity is poorly understood. Our study shows that zinc chromate induced concentration-dependent increases in cytotoxicity, chromosome damage and DNA double strand breaks in human lung cells. In response to zinc chromate-induced breaks, MRE11 expression was increased and ATM and ATR were phosphorylated, indicating that the DNA double strand break repair system was initiated in the cells. In addition, our data show that zinc chromate-induced double strand breaks were only observed in the G2/M phase population, with no significant amount of double strand breaks observed in G1 and S phase cells. These data will aid in understanding the mechanisms of zinc chromate toxicity and carcinogenesis.

  16. Fork rotation and DNA precatenation are restricted during DNA replication to prevent chromosomal instability.

    PubMed

    Schalbetter, Stephanie A; Mansoubi, Sahar; Chambers, Anna L; Downs, Jessica A; Baxter, Jonathan

    2015-08-18

    Faithful genome duplication and inheritance require the complete resolution of all intertwines within the parental DNA duplex. This is achieved by topoisomerase action ahead of the replication fork or by fork rotation and subsequent resolution of the DNA precatenation formed. Although fork rotation predominates at replication termination, in vitro studies have suggested that it also occurs frequently during elongation. However, the factors that influence fork rotation and how rotation and precatenation may influence other replication-associated processes are unknown. Here we analyze the causes and consequences of fork rotation in budding yeast. We find that fork rotation and precatenation preferentially occur in contexts that inhibit topoisomerase action ahead of the fork, including stable protein-DNA fragile sites and termination. However, generally, fork rotation and precatenation are actively inhibited by Timeless/Tof1 and Tipin/Csm3. In the absence of Tof1/Timeless, excessive fork rotation and precatenation cause extensive DNA damage following DNA replication. With Tof1, damage related to precatenation is focused on the fragile protein-DNA sites where fork rotation is induced. We conclude that although fork rotation and precatenation facilitate unwinding in hard-to-replicate contexts, they intrinsically disrupt normal chromosome duplication and are therefore restricted by Timeless/Tipin.

  17. Allelic imbalance and instability of microsatellite loci on chromosome 1p in human non-small-cell lung cancer.

    PubMed Central

    Gasparian, A. V.; Laktionov, K. K.; Belialova, M. S.; Pirogova, N. A.; Tatosyan, A. G.; Zborovskaya, I. B.

    1998-01-01

    The mapping of allelic loss on the short arm of chromosome 1 has been performed in non-small-cell lung cancer. We used a set of 11 microsatellite loci spanning 1p to examine the frequency of allelic imbalance in a panel of 58 tumours. Fifty-one of 58 (87.9%) cases have shown somatic allelic loss at one or more loci tested. The two shortest regions of the overlap (SRO) of the deletions have been identified: SRO 1 at 1p13.1 and SRO 2 at 1p32-pter. Allelic losses at these regions have been compared among adenocarcinoma and squamous cell carcinoma and no difference has been found. In contrast to SRO 1, deletions at SRO 2 significantly correlated with advanced stage of the disease as well as post-operative metastasizing and relapse. These data may suggest that SRO 1 and SRO 2 can harbour tumour-supressor genes (TSGs) involved in different stages of NSCLC development. SRO 2 is still quite large and its refined mapping should help attempts to clone and identify the putative TSG(s). Microsatellite instability (replication errors) affecting only 6 (10.3%) of 58 tumour samples is an infrequent genetic alteration at the loci tested. Images Figure 2 PMID:9635835

  18. Personalised pathway analysis reveals association between DNA repair pathway dysregulation and chromosomal instability in sporadic breast cancer.

    PubMed

    Liu, Chao; Srihari, Sriganesh; Lal, Samir; Gautier, Benoît; Simpson, Peter T; Khanna, Kum Kum; Ragan, Mark A; Lê Cao, Kim-Anh

    2016-01-01

    The Homologous Recombination (HR) pathway is crucial for the repair of DNA double-strand breaks (DSBs) generated during DNA replication. Defects in HR repair have been linked to the initiation and development of a wide variety of human malignancies, and exploited in chemical, radiological and targeted therapies. In this study, we performed a personalised pathway analysis independently for four large sporadic breast cancer cohorts to investigate the status of HR pathway dysregulation in individual sporadic breast tumours, its association with HR repair deficiency and its impact on tumour characteristics. Specifically, we first manually curated a list of HR genes according to our recent review on this pathway (Liu et al., 2014), and then applied a personalised pathway analysis method named Pathifier (Drier et al., 2013) on the expression levels of the curated genes to obtain an HR score quantifying HR pathway dysregulation in individual tumours. Based on the score, we observed a great diversity in HR dysregulation between and within gene expression-based breast cancer subtypes, and by using two published HR-defect signatures, we found HR pathway dysregulation reflects HR repair deficiency. Furthermore, we identified a novel association between HR pathway dysregulation and chromosomal instability (CIN) in sporadic breast cancer. Although CIN has long been considered as a hallmark of most solid tumours, with recent extensive studies highlighting its importance in tumour evolution and drug resistance, the molecular basis of CIN in sporadic cancers remains poorly understood. Our results imply that HR pathway dysregulation might contribute to CIN in sporadic breast cancer.

  19. CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer.

    PubMed

    Ling, Hui; Spizzo, Riccardo; Atlasi, Yaser; Nicoloso, Milena; Shimizu, Masayoshi; Redis, Roxana S; Nishida, Naohiro; Gafà, Roberta; Song, Jian; Guo, Zhiyi; Ivan, Cristina; Barbarotto, Elisa; De Vries, Ingrid; Zhang, Xinna; Ferracin, Manuela; Churchman, Mike; van Galen, Janneke F; Beverloo, Berna H; Shariati, Maryam; Haderk, Franziska; Estecio, Marcos R; Garcia-Manero, Guillermo; Patijn, Gijs A; Gotley, David C; Bhardwaj, Vikas; Shureiqi, Imad; Sen, Subrata; Multani, Asha S; Welsh, James; Yamamoto, Ken; Taniguchi, Itsuki; Song, Min-Ae; Gallinger, Steven; Casey, Graham; Thibodeau, Stephen N; Le Marchand, Loïc; Tiirikainen, Maarit; Mani, Sendurai A; Zhang, Wei; Davuluri, Ramana V; Mimori, Koshi; Mori, Masaki; Sieuwerts, Anieta M; Martens, John W M; Tomlinson, Ian; Negrini, Massimo; Berindan-Neagoe, Ioana; Foekens, John A; Hamilton, Stanley R; Lanza, Giovanni; Kopetz, Scott; Fodde, Riccardo; Calin, George A

    2013-09-01

    The functional roles of SNPs within the 8q24 gene desert in the cancer phenotype are not yet well understood. Here, we report that CCAT2, a novel long noncoding RNA transcript (lncRNA) encompassing the rs6983267 SNP, is highly overexpressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis, and chromosomal instability. We demonstrate that MYC, miR-17-5p, and miR-20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CCAT2 and TCF7L2 resulting in an enhancement of WNT signaling activity. We show that CCAT2 is itself a WNT downstream target, which suggests the existence of a feedback loop. Finally, we demonstrate that the SNP status affects CCAT2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel lncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation of the SNP-conferred cancer risk.

  20. CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer

    PubMed Central

    Ling, Hui; Spizzo, Riccardo; Atlasi, Yaser; Nicoloso, Milena; Shimizu, Masayoshi; Redis, Roxana S.; Nishida, Naohiro; Gafà, Roberta; Song, Jian; Guo, Zhiyi; Ivan, Cristina; Barbarotto, Elisa; De Vries, Ingrid; Zhang, Xinna; Ferracin, Manuela; Churchman, Mike; van Galen, Janneke F.; Beverloo, Berna H.; Shariati, Maryam; Haderk, Franziska; Estecio, Marcos R.; Garcia-Manero, Guillermo; Patijn, Gijs A.; Gotley, David C.; Bhardwaj, Vikas; Shureiqi, Imad; Sen, Subrata; Multani, Asha S.; Welsh, James; Yamamoto, Ken; Taniguchi, Itsuki; Song, Min-Ae; Gallinger, Steven; Casey, Graham; Thibodeau, Stephen N.; Le Marchand, Loïc; Tiirikainen, Maarit; Mani, Sendurai A.; Zhang, Wei; Davuluri, Ramana V.; Mimori, Koshi; Mori, Masaki; Sieuwerts, Anieta M.; Martens, John W.M.; Tomlinson, Ian; Negrini, Massimo; Berindan-Neagoe, Ioana; Foekens, John A.; Hamilton, Stanley R.; Lanza, Giovanni; Kopetz, Scott; Fodde, Riccardo; Calin, George A.

    2013-01-01

    The functional roles of SNPs within the 8q24 gene desert in the cancer phenotype are not yet well understood. Here, we report that CCAT2, a novel long noncoding RNA transcript (lncRNA) encompassing the rs6983267 SNP, is highly overexpressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis, and chromosomal instability. We demonstrate that MYC, miR–17–5p, and miR–20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CCAT2 and TCF7L2 resulting in an enhancement of WNT signaling activity. We show that CCAT2 is itself a WNT downstream target, which suggests the existence of a feedback loop. Finally, we demonstrate that the SNP status affects CCAT2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel lncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation of the SNP-conferred cancer risk. PMID:23796952

  1. Non integrative strategy decreases chromosome instability and improves endogenous pluripotency genes reactivation in porcine induced pluripotent-like stem cells

    PubMed Central

    Congras, Annabelle; Barasc, Harmonie; Canale-Tabet, Kamila; Plisson-Petit, Florence; Delcros, Chantal; Feraud, Olivier; Oudrhiri, Noufissa; Hadadi, Eva; Griscelli, Franck; Bennaceur-Griscelli, Annelise; Turhan, Ali; Afanassieff, Marielle; Ferchaud, Stéphane; Pinton, Alain; Yerle-Bouissou, Martine; Acloque, Hervé

    2016-01-01

    The pig is an emerging animal model, complementary to rodents for basic research and for biomedical and agronomical purposes. However despite the progress made on mouse and rat models to produce genuine pluripotent cells, it remains impossible to produce porcine pluripotent cell lines with germline transmission. Reprogramming of pig somatic cells using conventional integrative strategies remains also unsatisfactory. In the present study, we compared the outcome of both integrative and non-integrative reprogramming strategies on pluripotency and chromosome stability during pig somatic cell reprogramming. The porcine cell lines produced with integrative strategies express several pluripotency genes but they do not silence the integrated exogenes and present a high genomic instability upon passaging. In contrast, pig induced pluripotent-like stem cells produced with non-integrative reprogramming system (NI-iPSLCs) exhibit a normal karyotype after more than 12 months in culture and reactivate endogenous pluripotency markers. Despite the persistent expression of exogenous OCT4 and MYC, these cells can differentiate into derivatives expressing markers of the three embryonic germ layers and we propose that these NI-iPSLCs can be used as a model to bring new insights into the molecular factors controlling and maintaining pluripotency in the pig and other non-rodent mammalians. PMID:27245508

  2. Unexpected rates of chromosomal instabilities and alterations of hormone levels in Namibian uranium miners

    SciTech Connect

    Zaire, R.; Notter, M.; Thiel, E.

    1997-05-01

    A common problem in determining the health consequences of radiation exposure is factoring out other carcinogenic influences. The conditions in Namibia provide a test case for distinguishing the effects of long-term low-dose exposure to uranium from the other environmental factors because of good air quality and the lack of other industries with negative health effects. Present records indicate a much higher prevalence of cancer among male workers in the open-pit uranium mine in Namibia compared with the general population. The objective of the present study was to determine whether long-term exposure to low doses of uranium increases the risk of a biological radiation damage which would lead to malignant diseases and to derive a dose-response model for these miners. To investigate this risk, we measured uranium excretion in urine, neutrophil counts and the serum level of FSH, LH and testosterone and analyzed chromosome aberrations in whole blood cells using fluorescence in situ hybridization. A representative cohort of 75 non-smoking, HIV-negative miners was compared to a control group of 31 individuals with no occupational history in mining. A sixfold increase in uranium excretion among the miners compared to the controls was recorded (P < 0.001). Furthermore, we determined a significant reduction in testosterone levels (P < 0.008) and neutrophil count (P < 0.0001). Most remarkably, cells with multiple aberrations such as {open_quotes}rogue{close_quotes} cells were observed for the first time in miners; these cells had previously been found only after short-term high-dose radiation exposure, e.g. from the Hiroshima atomic bomb or the Chernobyl accident. 19 refs., 1 fig., 3 tabs.

  3. Gradual telomere shortening and increasing chromosomal instability among PanIN grades and normal ductal epithelia with and without cancer in the pancreas.

    PubMed

    Matsuda, Yoko; Ishiwata, Toshiyuki; Izumiyama-Shimomura, Naotaka; Hamayasu, Hideki; Fujiwara, Mutsunori; Tomita, Ken-Ichiro; Hiraishi, Naoki; Nakamura, Ken-Ichi; Ishikawa, Naoshi; Aida, Junko; Takubo, Kaiyo; Arai, Tomio

    2015-01-01

    A large body of evidence supports a key role for telomere dysfunction in carcinogenesis due to the induction of chromosomal instability. To study telomere shortening in precancerous pancreatic lesions, we measured telomere lengths using quantitative fluorescence in situ hybridization in the normal pancreatic duct epithelium, pancreatic intraepithelial neoplasias (PanINs), and cancers. The materials employed included surgically resected pancreatic specimens without cancer (n = 33) and with invasive ductal carcinoma (n = 36), as well as control autopsy cases (n = 150). In comparison with normal ducts, telomere length was decreased in PanIN-1, -2 and -3 and cancer. Furthermore, telomeres were shorter in cancer than in PanIN-1 and -2. Telomere length in cancer was not associated with histological type, lesion location, or cancer stage. PanINs with or without cancer showed similar telomere lengths. The incidences of atypical mitosis and anaphase bridges, which are morphological characteristics of chromosomal instability, were negatively correlated with telomere length. The telomeres in normal duct epithelium became shorter with aging, and those in PanINs or cancers were shorter than in age-matched controls, suggesting that telomere shortening occurs even when histological changes are absent. Our data strongly suggest that telomere shortening occurs in the early stages of pancreatic carcinogenesis and progresses with precancerous development. Telomere shortening and chromosomal instability in the duct epithelium might be associated with carcinogenesis of the pancreas. Determination of telomere length in pancreatic ductal lesions may be valuable for accurate detection and risk assessment of pancreatic cancer.

  4. CD38+ CD58- is an independent adverse prognostic factor in paediatric Philadelphia chromosome negative B cell acute lymphoblastic leukaemia patients.

    PubMed

    Li, Xu-Mian; Zhang, Le-Ping; Wang, Ya-Zhe; Lu, Ai-Dong; Chang, Yan; Zhu, Hong-Hu; Qin, Ya-Zhen; Lai, Yue-Yun; Kong, Yuan; Huang, Xiao-Jun; Liu, Yan-Rong

    2016-04-01

    To explore new risk predictors for a high risk of relapse in Philadelphia chromosome negative (Ph-) B cell acute lymphoblastic leukaemia (B-ALL) patients, 196 paediatric Ph- B-ALL patients (≤ 18 years) were retrospectively analysed. We mainly focus on investigating the prognostic value of CD38 and CD58 expression in leukemic blasts in these patients by four colour flow cytometry. The CD38+ CD58- group (n=16) had a higher relapse rate, a shorter 3-year event-free survival (EFS) and overall survival (OS) than the CD38+ CD58+ group (n=157; 31.3% vs 10.2%, P=0.04; 52.4% vs 92.3%, P<0.01; 32.5% vs 91.0%, P=0.01); CD38+ CD58- was an independent adverse prognostic predictor for relapse (hazard ratio [HR], 0.203; 95%CI, 0.063-0.656; P=0.01), 3-year EFS (HR, 0.091; 95%CI, 0.023-0.355; P<0.01) and OS (HR, 0.102; 95%CI, 0.026-0.3971; P<0.01) in this cohort, as determined by Cox multivariate analysis. We identified, for the first time, a higher risk population of paediatric Ph- B-ALL patients with CD38+ CD58- who had a higher relapse risk and a shorter survival. Our results may allow better risk stratification and individualized treatment.

  5. Radiation-induced chromosomal instability in BALB/c and C57BL/6 mice: the difference is as clear as black and white

    NASA Technical Reports Server (NTRS)

    Ponnaiya, B.; Cornforth, M. N.; Ullrich, R. L.

    1997-01-01

    Genomic instability has been proposed to be the earliest step in radiation-induced tumorigenesis. It follows from this hypothesis that individuals highly susceptible to induction of tumors by radiation should exhibit enhanced radiation-induced instability. BALB/c white mice are considerably more sensitive to radiation-induced mammary cancer than C57BL/6 black mice. In this study, primary mammary epithelial cell cultures from these two strains were examined for the "delayed" appearance of chromosomal aberrations after exposure to 137Cs gamma radiation, as a measure of radiation-induced genomic instability. As expected, actively dividing cultures from both strains showed a rapid decline of initial asymmetrical aberrations with time postirradiation. However, after 16 population doublings, cells from BALB/c mice exhibited a marked increase in the frequency of chromatid-type breaks and gaps which remained elevated throughout the time course of the experiment (28 doublings). No such effect was observed for the cells of C57BL/6 mice; after the rapid clearance of initial aberrations, the frequency of chromatid-type aberrations in the irradiated population remained at or near those of nonirradiated controls. These results demonstrate a correlation between the latent expression of chromosomal damage in vitro and susceptibility for mammary tumors, and provide further support for the central role of radiation-induced instability in the process of tumorigenesis.

  6. Mustard gas surrogate, 2-chloroethyl ethylsulfide (2-CEES), induces centrosome amplification and aneuploidy in human and mouse cells : 2-CEES induces centrosome amplification and chromosome instability.

    PubMed

    Bennett, Richard A; Behrens, Elizabeth; Zinn, Ashtyn; Duncheon, Christian; Lamkin, Thomas J

    2014-08-01

    Mustard gas is a simple molecule with a deadly past. First used as a chemical weapon in World War I, its simple formulation has raised concerns over its use by terrorist organizations and unstable governments. Mustard gas is a powerful vesicant and alkylating agent that causes painful blisters on epithelial surfaces and increases the incidence of cancer in those exposed. The mechanism of mustard gas toxicity and tumorigenesis is not well understood but is thought to be mediated by its ability to induce oxidative stress and DNA damage. Interestingly, several proteins that have been shown to either be targets of mustard gas or mediate mustard gas toxicity have also been shown to regulate centrosome duplication. Centrosomes are small nonmembrane-bound organelles that direct the segregation of chromosomes during mitosis through the formation of the bipolar mitotic spindle. Cells with more or less than two centrosomes during mitosis can segregate their chromosomes unequally, resulting in chromosome instability, a common phenotype of cancer cells. In our studies, we show that subtoxic levels of 2-chloroethyl ethylsulfide (2-CEES), a mustard gas analog, induce centrosome amplification and chromosome instability in cells, which may hasten the mutation rate necessary for tumorigenesis. These data may explain why those exposed to mustard gas exhibit higher incidences of cancer than unexposed individuals of the same cohort.

  7. Chlorinated Water Modulates the Development of Colorectal Tumors with Chromosomal Instability and Gut Microbiota in Apc-Deficient Mice.

    PubMed

    Sasada, Tatsunari; Hinoi, Takao; Saito, Yasufumi; Adachi, Tomohiro; Takakura, Yuji; Kawaguchi, Yasuo; Sotomaru, Yusuke; Sentani, Kazuhiro; Oue, Naohide; Yasui, Wataru; Ohdan, Hideki

    2015-01-01

    The gastrointestinal tract is continuously exposed to a variety of chemicals and commensal bacteria. Recent studies have shown that changes in gut microbial populations caused by chlorine or other chemicals in the drinking water influence the development of human colorectal cancer, although the mechanism of tumorigenesis in the gut epithelium is obfuscated by the diversity of microflora and complexity of the tumor microenvironment. In this regard, mouse models that recapitulate human colorectal cancer are an invaluable tool. In this study, we used two conditional adenomatous polyposis coli (Apc) knockout mouse models to investigate the effect of chlorinated water on tumorigenesis in the digestive tract. Mice with colon-specific carcinoma--caused by either chromosomal (CDX2P 9.5-NLS Cre;Apc(+/flox), abbreviated to CPC;Apc) or microsatellite (CDX2P9.5-G19Cre;Apc(flox/flox) and CDX2P9.5-G22Cre;Apc(flox/flox)) instability, respectively--were administered chlorinated (10.0 mg/L chlorine) or tap (0.7 mg/L chlorine) water and evaluated for colon polyp formation. In CPC;Apc mice given chlorinated drinking water, tumors tended to develop in the colon, whereas in those that drank tap water, tumors were mostly observed in the small intestine. There was no difference in the rate of tumor formation of CDX2P9.5-G19Cre;Apc(flox/flox) and CDX2P9.5-G22Cre;Apc(flox/flox) mice consuming chlorinated as compared to tap water, suggesting that microsatellite instability in the Apc gene does not significantly affect tumorigenesis. Chlorinated water altered the enteric environment by reducing the fecal populations of the obligatory anaerobes Clostridium perfringens and C. difficile, as well as species belonging to the Atopobium cluster, including Enterobacteriaceae and Staphylococcus sp., which was associated with colon tumorigenesis in CPC;Apc mice. These results suggest that differences in tumorigenesis among CPC;Apc mice consuming chlorinated versus tap water may be due to differences

  8. Tumor-promoting/progressing role of additional chromosome instability in hepatic carcinogenesis in Sgo1 (Shugoshin 1) haploinsufficient mice

    PubMed Central

    Yamada, Hiroshi Y.; Zhang, Yuting; Reddy, Arun; Mohammed, Altaf; Lightfoot, Stan; Dai, Wei

    2015-01-01

    A major etiological risk factor for hepatocellular carcinoma (HCC) is infection by Hepatitis viruses, especially hepatitis B virus and hepatitis C virus. Hepatitis B virus and hepatitis C virus do not cause aggressive activation of an oncogenic pathway, but they transactivate a broad array of genes, cause chronic inflammation, and, through interference with mitotic processes, lead to mitotic error-induced chromosome instability (ME-CIN). However, how ME-CIN is involved in the development of HCC remains unclear. Delineating the effect of ME-CIN on HCC development should help in identifying measures to combat HCC. In this study, we used ME-CIN model mice haploinsufficient in Shugoshin 1 (Sgo1−/+) to assess the role of ME-CIN in HCC development. Treatment with the carcinogen azoxymethane caused Sgo1−/+ ME-CIN model mice to develop HCCs within 6 months, whereas control mice developed no HCC (P < 0.003). The HCC development was associated with expression of early HCC markers (glutamine synthetase, glypican 3, heat shock protein 70, and the serum marker alpha fetoprotein), although without fibrosis. ME-CIN preceded the expression of HCC markers, suggesting that ME-CIN is an important early event in HCC development. In 12-month-old untreated Sgo1 mice, persistent DNA damage, altered gene expression, and spontaneous HCCs were observed. Sgo1 protein accumulated in response to DNA damage in vitro. Overall, Sgo1−/+-mediated ME-CIN strongly promoted/progressed development of HCC in the presence of an initiator carcinogen, and it had a mild initiator effect by itself. Use of the ME-CIN model mice should help in identifying drugs to counteract the effects of ME-CIN and should accelerate anti-HCC drug development. PMID:25740822

  9. Variable content of double minute chromosomes is not correlated with degree of phenotype instability in methotrexate-resistant human cell lines

    SciTech Connect

    Masters, J.; Keeley, B.; Gay, H.; Attardi, G.

    1982-05-01

    Several variants resistant to 1.8 x 10/sup -4/ M DL-methotrexate (MTX) have been isolated from the human cell lines HeLa BU25 and VA/sub 2/-B by exposing them to progressively increasing concentrations of the drug. A striking variability of phenotype and chromosome constitution was observed among the different variants. All resistant cell lines exhibited a greatly increased dihydrofolic acid reductase (DHFR) activity and DHFR content; however, the DHFR activity levels varied considerably among the variants, ranging between about 35 and 275 times the parental level. An analysis of the correlaion of loss of double minute chromosomes and loss of DHFR activity in the absence of MTX has given results consistent with the idea that the double-minute chromosomes contain amplified DHFR genes. However, the most significant finding is that, in contrast to what has been reported in the mouse system, the recognizable double-minute chromosomes varied greatly in number in different variants without any relationship to either the level of DHFR activity or the degree of instability of MTX resistance in the absence of selective pressure. These and other observations point to the occurrence in the human MTX-resistant variants of another set of DHFR genes, representing a varied proportion of the total, which is associated with the regular chromosomes, and which may be unstable in the absence of selective pressure.

  10. Telomere Shortening and Associated Chromosomal Instability in Peripheral Blood Lymphocytes of Patients With Hodgkin's Lymphoma Prior to Any Treatment Are Predictive of Second Cancers

    SciTech Connect

    M'kacher, Radhia . E-mail: mkacher@igr.fr; Bennaceur-Griscelli, Annelise; Girinsky, Theodore; Koscielny, Serge; Delhommeau, Francois; Dossou, Julien; Violot, Dominique; Leclercq, Evelyne; Courtier, Marie Helene; Beron-Gaillard, Nadine; Assaf, Elias; Ribrag, Vincent; Carde, Patrice; Bourhis, Jean |; Feneux, Daniele; Bernheim, Alain; Parmentier, Claude

    2007-06-01

    Purpose: To investigate a potential link between telomere length, chromosomal instability, and the advent of a second cancer (SC) in patients with Hodgkin's lymphoma (HL), who are known to be at risk for SCs. This study was premised on the finding that telomere dysfunction and DNA repair pathways were related to many pathologic conditions. Methods and Materials: Three cohorts of patients with HL were studied: 73 who were prospectively followed >5 years after diagnosis (prospective HL cohort), 28 who developed a SC (SC HL cohort), and 18 long-term survivors with no evidence of disease or complication since their initial treatment (NED HL cohort). Telomere length was analyzed by a telomeric restriction fragment assay in peripheral blood lymphocytes. Thirty healthy donors and 70 patients with a newly diagnosed solid tumor were the control population. Results: Compared with controls, patients from the prospective HL cohort, before any treatment, showed age-independent shorter telomeres (mean, 8.3 vs. 11.7 kb in healthy donors; <6 kb in 18% in HL patients), increased spontaneous chromosomal abnormalities, and increased in vitro radiation sensitivity (p < 10{sup -4} each). After treatment, telomere shortening was associated with cytogenetic profiles characterized by the persistence of complex chromosomal rearrangement and clonal aberrations. Moreover, the two cases of SC in the prospective HL patients had short telomeres and CCR initially. In addition, the SC HL cohort was characterized by markedly short telomeres (6.6 vs. 9.7 kb in the NED HL cohort), the presence of complex chromosome rearrangements, and increased in vitro radiation sensitivity. Conclusions: An intimate relationship between pre-treatment telomere shortening, chromosomal instability, radiation sensitivity and occurrence of SC was found in HL patients.

  11. Knockdown of {alpha}II spectrin in normal human cells by siRNA leads to chromosomal instability and decreased DNA interstrand cross-link repair

    SciTech Connect

    McMahon, Laura W.; Zhang Pan; Sridharan, Deepa M.; Lefferts, Joel A.; Lambert, Muriel W.

    2009-04-03

    Nonerythroid {alpha}-spectrin ({alpha}IISp) is a structural protein involved in repair of DNA interstrand cross-links and is deficient in cells from patients with Fanconi anemia (FA), which are defective in ability to repair cross-links. In order to further demonstrate the importance of the role that {alpha}IISp plays in normal human cells and in the repair defect in FA, {alpha}IISp was knocked down in normal cells using siRNA. Depletion of {alpha}IISp in normal cells by siRNA resulted in chromosomal instability and cellular hypersensitivity to DNA interstrand cross-linking agents. An increased number of chromosomal aberrations were observed and, following treatment with a DNA interstrand cross-linking agent, mitomycin C, cells showed decreased cell growth and survival and decreased formation of damage-induced {alpha}IISp and XPF nuclear foci. Thus depletion of {alpha}IISp in normal cells leads to a number of defects observed in FA cells, such as chromosome instability and a deficiency in cross-link repair.

  12. Knockdown of αII spectrin in normal human cells by siRNA leads to chromosomal instability and decreased DNA interstrand cross-link repair

    PubMed Central

    McMahon, Laura W.; Zhang, Pan; Sridharan, Deepa M.; Lefferts, Joel A.; Lambert, Muriel W.

    2009-01-01

    Nonerythroid α-spectrin (αIISp) is a structural protein involved in repair of DNA interstrand cross-links and is deficient in cells from patients with Fanconi anemia (FA), which are defective in ability to repair cross-links. In order to further demonstrate the importance of the role that αIISp plays in normal human cells and in the repair defect in FA, αIISp was knocked down in normal cells using siRNA. Depletion of αIISp in normal cells by siRNA resulted in chromosomal instability and cellular hypersensitivity to DNA interstrand cross-linking agents. An increased number of chromosomal aberrations were observed and, following treatment with a DNA interstrand cross-linking agent, mitomycin C, cells showed decreased cell growth and survival and decreased formation of damage induced αIISp and XPF nuclear foci. Thus depletion of αIISp in normal cells leads to a number of defects observed in FA cells, such as chromosome instability and a deficiency in cross-link repair. PMID:19217883

  13. Nucleolytic processing of aberrant replication intermediates by an Exo1-Dna2-Sae2 axis counteracts fork collapse-driven chromosome instability

    PubMed Central

    Colosio, Arianna; Frattini, Camilla; Pellicanò, Grazia; Villa-Hernández, Sara; Bermejo, Rodrigo

    2016-01-01

    Problems during DNA replication underlie genomic instability and drive malignant transformation. The DNA damage checkpoint stabilizes stalled replication forks thus counteracting aberrant fork transitions, DNA breaks and chromosomal rearrangements. We analyzed fork processing in checkpoint deficient cells by coupling psoralen crosslinking with replication intermediate two-dimensional gel analysis. This revealed a novel role for Exo1 nuclease in resecting reversed replication fork structures and counteracting the accumulation of aberrant intermediates resembling fork cleavage products. Genetic analyses demonstrated a functional interplay of Exo1 with Mus81, Dna2 and Sae2 nucleases in promoting cell survival following replication stress, suggestive of concerted nucleolytic processing of stalled forks. While Mus81 and other Structure Specific Endonucleases do not contribute to obvious collapsed fork transitions, Dna2 promotes reversed fork resection likely by facilitating Exo1 access to nascent strands. Instead, Sae2 cooperates with Exo1 in counteracting putative fork cleavage events linked to double strand breaks formation and increased gross chromosomal rearrangement rates. Our data indicate that in checkpoint deficient cells diverse nuclease activities interface to eliminate aberrant replication intermediates and prevent chromosome instability. PMID:27672038

  14. Nucleolytic processing of aberrant replication intermediates by an Exo1-Dna2-Sae2 axis counteracts fork collapse-driven chromosome instability.

    PubMed

    Colosio, Arianna; Frattini, Camilla; Pellicanò, Grazia; Villa-Hernández, Sara; Bermejo, Rodrigo

    2016-12-15

    Problems during DNA replication underlie genomic instability and drive malignant transformation. The DNA damage checkpoint stabilizes stalled replication forks thus counteracting aberrant fork transitions, DNA breaks and chromosomal rearrangements. We analyzed fork processing in checkpoint deficient cells by coupling psoralen crosslinking with replication intermediate two-dimensional gel analysis. This revealed a novel role for Exo1 nuclease in resecting reversed replication fork structures and counteracting the accumulation of aberrant intermediates resembling fork cleavage products. Genetic analyses demonstrated a functional interplay of Exo1 with Mus81, Dna2 and Sae2 nucleases in promoting cell survival following replication stress, suggestive of concerted nucleolytic processing of stalled forks. While Mus81 and other Structure Specific Endonucleases do not contribute to obvious collapsed fork transitions, Dna2 promotes reversed fork resection likely by facilitating Exo1 access to nascent strands. Instead, Sae2 cooperates with Exo1 in counteracting putative fork cleavage events linked to double strand breaks formation and increased gross chromosomal rearrangement rates. Our data indicate that in checkpoint deficient cells diverse nuclease activities interface to eliminate aberrant replication intermediates and prevent chromosome instability.

  15. Correction of chromosomal instability and sensitivity to diverse mutagens by a cloned cDNA of the XRCC3 DNA repair gene

    SciTech Connect

    Tebbs, R.S.; Tucker, J.D.; Hwang, M.

    1995-07-03

    The mutagen-sensitive CHO line irs1SF was previously isolated on the basis of hypersensitivity to ionizing radiation and was found to be chromosomally unstable as well as cross-sensitive to diverse kinds of DNA-damaging agents. The analysis of somatic cell hybrids formed between irs1SF and human lymphocytes implicated a human gene (defined as XRCC3; x-ray repair cross-complementing), which partially restored mitomycin C resistance to the mutant. A functional cDNA that confers mitomycin C resistance was transferred to irs1SF cells by transforming them with an expression cDNA library and obtaining primary and secondary transformants. Functional cDNA clones were recovered from a cosmid library prepared from a secondary transformant. Transformants also showed partial correction of sensitivity to displatin and {gamma}-rays, efficient correction of chromosomal instability, and substantially improved plating efficiency and growth rate. The XRCC3 cDNA insert is {approx} 2.5 kb and detects an {approx} 3.0-kb mRNA on Northern blots. The cDNA was mapped by fluorescence in situ hybridization to human chromosome 14q32.3, which was consistent with the chromosome concordance data of two independent hybrid clone panels. 30 refs., 5 figs., 2 tabs.

  16. Development of a novel HAC-based “gain of signal” quantitative assay for measuring chromosome instability (CIN) in cancer cells

    PubMed Central

    Kim, Jung-Hyun; Lee, Hee-Sheung; Lee, Nicholas C. O.; Goncharov, Nikolay V.; Kumeiko, Vadim; Masumoto, Hiroshi; Earnshaw, William C.; Kouprina, Natalay; Larionov, Vladimir

    2016-01-01

    Accumulating data indicates that chromosome instability (CIN) common to cancer cells can be used as a target for cancer therapy. At present the rate of chromosome mis-segregation is quantified by laborious techniques such as coupling clonal cell analysis with karyotyping or fluorescence in situ hybridization (FISH). Recently, a novel assay was developed based on the loss of a non-essential human artificial chromosome (HAC) carrying a constitutively expressed EGFP transgene (“loss of signal” assay). Using this system, anticancer drugs can be easily ranked on by their effect on HAC loss. However, it is problematic to covert this “loss of signal” assay into a high-throughput screen to identify drugs and mutations that increase CIN levels. To address this point, we re-designed the HAC-based assay. In this new system, the HAC carries a constitutively expressed shRNA against the EGFP transgene integrated into human genome. Thus, cells that inherit the HAC display no green fluorescence, while cells lacking the HAC do. We verified the accuracy of this “gain of signal” assay by measuring the level of CIN induced by known antimitotic drugs and added to the list of previously ranked CIN inducing compounds, two newly characterized inhibitors of the centromere-associated protein CENP-E, PF-2771 and GSK923295 that exhibit the highest effect on chromosome instability measured to date. The “gain of signal” assay was also sensitive enough to detect increase of CIN after siRNA depletion of known genes controlling mitotic progression through distinct mechanisms. Hence this assay can be utilized in future experiments to uncover novel human CIN genes, which will provide novel insight into the pathogenesis of cancer. Also described is the possible conversion of this new assay into a high-throughput screen using a fluorescence microplate reader to characterize chemical libraries and identify new conditions that modulate CIN level. PMID:26943579

  17. Cancer of the ampulla of Vater: chromosome 17p allelic loss is associated with poor prognosis

    PubMed Central

    Scarpa, A; Di, P; Talamini, G; Falconi, M; Lemoine, N; Iacono, C; Achille, A; Baron, A; Zamboni, G

    2000-01-01

    BACKGROUND—Cancer of the ampulla of Vater kills 60% of affected patients. Local spread of the tumour (T stage) is the only reliable prognostic factor. Nevertheless, any cancer stage includes long term survivors and patients dying from the disease. The molecular anomalies involved in this process have the potential to serve as additional prognostic markers.
AIM—To evaluate if allelic losses (LOH) of chromosomes 17p and 18q may be of prognostic value in multivariate survival analysis.
METHODS—We examined 53 ampullary cancers for chromosome 17p and 18q LOH using microsatellite markers and DNA from paraffin embedded tumours. All patients were treated by surgery alone (pancreaticoduodenectomy). Multivariate survival analysis included age, sex, tumour size, macroscopic appearance, grade of differentiation, T stage, lymph node metastasis, and chromosome 17p and 18q status.
RESULTS—Chromosome 17p and 18q LOH were detected in 28 (53%) and 18 (34%) cancers, respectively. Multivariate survival analysis indicated chromosome 17p status as an independent prognostic factor together with T stage. The five year survival for chromosome 17p retention and 17p loss was 80% and 7%, respectively. The risk of death from cancer within the five year follow up period for patients with cancers harbouring chromosome 17p LOH was 11 times higher than that of patients with cancers retaining chromosome 17p (p<0.0001), regardless of the tumour stage at diagnosis.
CONCLUSIONS—Chromosome 17p status is an independent prognostic factor among ampullary cancers at the same stage. The combined use of T stage and chromosome 17p status may help in deciding whether ampullary cancer patients require additional therapy other than surgery alone.


Keywords: ampulla of Vater; cancer; loss of heterozygosity; microsatellites; allelotyping; microsatellite instability PMID:10807898

  18. Alpha-Particle-Induced Complex Chromosome Exchanges Transmitted through Extra-Thymic Lymphopoiesis In Vitro Show Evidence of Emerging Genomic Instability

    PubMed Central

    Sumption, Natalia; Goodhead, Dudley T.; Anderson, Rhona M.

    2015-01-01

    Human exposure to high-linear energy transfer α-particles includes environmental (e.g. radon gas and its decay progeny), medical (e.g. radiopharmaceuticals) and occupational (nuclear industry) sources. The associated health risks of α-particle exposure for lung cancer are well documented however the risk estimates for leukaemia remain uncertain. To further our understanding of α-particle effects in target cells for leukaemogenesis and also to seek general markers of individual exposure to α-particles, this study assessed the transmission of chromosomal damage initially-induced in human haemopoietic stem and progenitor cells after exposure to high-LET α-particles. Cells surviving exposure were differentiated into mature T-cells by extra-thymic T-cell differentiation in vitro. Multiplex fluorescence in situ hybridisation (M-FISH) analysis of naïve T-cell populations showed the occurrence of stable (clonal) complex chromosome aberrations consistent with those that are characteristically induced in spherical cells by the traversal of a single α-particle track. Additionally, complex chromosome exchanges were observed in the progeny of irradiated mature T-cell populations. In addition to this, newly arising de novo chromosome aberrations were detected in cells which possessed clonal markers of α-particle exposure and also in cells which did not show any evidence of previous exposure, suggesting ongoing genomic instability in these populations. Our findings support the usefulness and reliability of employing complex chromosome exchanges as indicators of past or ongoing exposure to high-LET radiation and demonstrate the potential applicability to evaluate health risks associated with α-particle exposure. PMID:26252014

  19. Correction of both spontaneous and DEB-induced chromosome instability in Fanconi anemia FA-C cells by FACC cDNA

    SciTech Connect

    Stavropoulos, D.J.; Tomkins, D.J.; Allingham-Hawkins, D.J.; Buchwald, M.

    1994-09-01

    Cells from all four Fanconi anemia complementation groups show hypersensitivity to cell-killing by mitomycin C (MMC), diepoxybutane (DEB) and other DNA cross-linking agents, and increased spontaneous and DEB-induced chromosome aberrations (CA). The extent of these phenotypes varies between lymphoblastoid cell lines from different complementation groups. Our data showed that the difference in MMC hypersensitivity and DEB-CA was not always coupled. While 230N (FA-B) had higher DEB-induced CA/cell than 536N (FA-C) (7.42 vs. 4.46 respectively), that latter was much more sensitive to cell-killing by MMC (dose at 10% survival, D{sub 10}: 5.2 vs. 1.2 ng/ml respectively). Strathdes et al. (1992) cloned a cDNA Fanconi anemia complementation group C (FACC) which complemented the hypersensitivity to MMC and DEB cell-killing of FA-C cells (536N) but not cells from the other three complementation groups. The present study was initiated to determine whether chromosome instability in 536N is also complemented by the FACC (FAC3) cDNA. The pREP4-FAC3 vector was transfected into 536N and transfectants selected with hygromycin B. The DEB D{sub 10} of 536N (1.0 {mu}M) was corrected to the control level (16.2 {mu}M for 3TO) by FACC (15.1 {mu}M for 536N-FACC), as previously demonstrated. Chromosome instability (cab, cse, ctb, cte) was determined without and with 0.1 {mu}g/ml DEB treatment. Spontaneous CA of 536N (0.30 aberrations/cell) was corrected to the control level (0.04 for 3TO) by FACC (0.06 for 536N-FACC). Similarly, the DEB-induced CA was corrected (2.74 for 536N vs. 0.06 and 0.02 for 3TO and 536N-FACC respectively). Thus, at least for FA complementation group C, hypersensitivity to cell-killing and chromosome instability are not dissociated and are most likely caused by the same gene defect.

  20. Dynamic Bcl-xL (S49) and (S62) Phosphorylation/Dephosphorylation during Mitosis Prevents Chromosome Instability and Aneuploidy in Normal Human Diploid Fibroblasts

    PubMed Central

    Baruah, Prasamit Saurav; Beauchemin, Myriam; Hébert, Josée; Bertrand, Richard

    2016-01-01

    Bcl-xL proteins undergo dynamic phosphorylation/dephosphorylation on Ser49 and Ser62 residues during mitosis. The expression of Bcl-xL(S49A), (S62A) and dual (S49/62A) phosphorylation mutants in tumor cells lead to severe mitotic defects associated with multipolar spindle, chromosome lagging and bridging, and micro-, bi- and multi-nucleated cells. Because the above observations were made in tumor cells which already display genomic instability, we now address the question: will similar effects occur in normal human diploid cells? We studied normal human diploid BJ foreskin fibroblast cells expressing Bcl-xL (wild type), (S49A), (S49D), (S62A), (S62D) and the dual-site (S49/62A) and (S49/62D) mutants. Cells expressing S49 and/or S62 phosphorylation mutants showed reduced kinetics of cell population doubling. These effects on cell population doubling kinetics correlated with early outbreak of senescence with no impact on the cell death rate. Senescent cells displayed typical senescence-associated phenotypes including high-level of senescence-associated β-galactosidase activity, interleukin-6 (IL-6) secretion, tumor suppressor p53 and cyclin-dependent kinase inhibitor p21Waf1/Cip1 activation as well as γH2A.X-associated nuclear chromatin foci. Fluorescence in situ hybridization analysis and Giemsa-banded karyotypes revealed that the expression of Bcl-xL phosphorylation mutants in normal diploid BJ cells provoked chromosome instability and aneuploidy. These findings suggest that dynamic Bcl-xL(S49) and (S62) phosphorylation/dephosphorylation cycles are important in the maintenance of chromosome integrity during mitosis in normal cells. They could impact future strategies aiming to develop and identify compounds that could target not only the anti-apoptotic domain of Bcl-xL protein, but also its mitotic domain for cancer therapy. PMID:27398719

  1. Dynamic Bcl-xL (S49) and (S62) Phosphorylation/Dephosphorylation during Mitosis Prevents Chromosome Instability and Aneuploidy in Normal Human Diploid Fibroblasts.

    PubMed

    Baruah, Prasamit Saurav; Beauchemin, Myriam; Hébert, Josée; Bertrand, Richard

    2016-01-01

    Bcl-xL proteins undergo dynamic phosphorylation/dephosphorylation on Ser49 and Ser62 residues during mitosis. The expression of Bcl-xL(S49A), (S62A) and dual (S49/62A) phosphorylation mutants in tumor cells lead to severe mitotic defects associated with multipolar spindle, chromosome lagging and bridging, and micro-, bi- and multi-nucleated cells. Because the above observations were made in tumor cells which already display genomic instability, we now address the question: will similar effects occur in normal human diploid cells? We studied normal human diploid BJ foreskin fibroblast cells expressing Bcl-xL (wild type), (S49A), (S49D), (S62A), (S62D) and the dual-site (S49/62A) and (S49/62D) mutants. Cells expressing S49 and/or S62 phosphorylation mutants showed reduced kinetics of cell population doubling. These effects on cell population doubling kinetics correlated with early outbreak of senescence with no impact on the cell death rate. Senescent cells displayed typical senescence-associated phenotypes including high-level of senescence-associated β-galactosidase activity, interleukin-6 (IL-6) secretion, tumor suppressor p53 and cyclin-dependent kinase inhibitor p21Waf1/Cip1 activation as well as γH2A.X-associated nuclear chromatin foci. Fluorescence in situ hybridization analysis and Giemsa-banded karyotypes revealed that the expression of Bcl-xL phosphorylation mutants in normal diploid BJ cells provoked chromosome instability and aneuploidy. These findings suggest that dynamic Bcl-xL(S49) and (S62) phosphorylation/dephosphorylation cycles are important in the maintenance of chromosome integrity during mitosis in normal cells. They could impact future strategies aiming to develop and identify compounds that could target not only the anti-apoptotic domain of Bcl-xL protein, but also its mitotic domain for cancer therapy.

  2. Deregulation of Rb-E2F1 Axis Causes Chromosomal Instability by Engaging the Transactivation Function of Cdc20–Anaphase-Promoting Complex/Cyclosome

    PubMed Central

    Nath, Somsubhra; Chowdhury, Abhishek; Dey, Sanjib; Roychoudhury, Anirban; Ganguly, Abira; Bhattacharyya, Dibyendu

    2014-01-01

    The E2F family of transcription factors regulates genes involved in various aspects of the cell cycle. Beyond the well-documented role in G1/S transition, mitotic regulation by E2F has also been reported. Proper mitotic progression is monitored by the spindle assembly checkpoint (SAC). The SAC ensures bipolar separation of chromosomes and thus prevents aneuploidy. There are limited reports on the regulation of the SAC by E2F. Our previous work identified the SAC protein Cdc20 as a novel transcriptional regulator of the mitotic ubiquitin carrier protein UbcH10. However, none of the Cdc20 transcription complex proteins have any known DNA binding domain. Here we show that an E2F1-DP1 heterodimer is involved in recruitment of the Cdc20 transcription complex to the UBCH10 promoter and in transactivation of the gene. We further show that inactivation of Rb can facilitate this transactivation process. Moreover, this E2F1-mediated regulation of UbcH10 influences mitotic progression. Deregulation of this pathway results in premature anaphase, chromosomal abnormalities, and aneuploidy. We conclude that excess E2F1 due to Rb inactivation recruits the complex of Cdc20 and the anaphase-promoting complex/cyclosome (Cdc20-APC/C) to deregulate the expression of UBCH10, leading to chromosomal instability in cancer cells. PMID:25368385

  3. Whole chromosome instability caused by Bub1 insufficiency drives tumorigenesis through tumor suppressor gene loss of heterozygosity

    PubMed Central

    Baker, Darren J.; Jin, Fang; Jeganathan, Karthik B.; van Deursen, Jan M.

    2010-01-01

    Summary Genetic alterations that promote chromosome missegregation have been proposed to drive tumorigenesis through loss of whole chromosomes containing key tumor suppressor genes. To test this unproven idea, we bred Bub1 mutant mice that inaccurately segregate their chromosomes onto p53+/−, ApcMin/+, Rb+/− or Pten+/− backgrounds. Bub1 insufficiency predisposed p53+/− mice to thymic lymphomas and ApcMin/+ mice to colonic tumors. These tumors consistently lacked the non-mutated tumor suppressor allele, but had gained a copy of the mutant allele. In contrast, Bub1 insufficiency had no impact on tumorigenesis in Rb+/− mice and inhibited prostatic intraepithelial neoplasia formation in Pten+/− mice. Thus, Bub1 insufficiency can drive tumor formation through tumor suppressor gene loss of heterozygosity, but only in restricted genetic and cellular contexts. PMID:19962666

  4. Chromosomal Instability Estimation Based on Next Generation Sequencing and Single Cell Genome Wide Copy Number Variation Analysis

    PubMed Central

    Dago, Angel E.; Leitz, Laura J.; Wang, Yipeng; Lee, Jerry; Werner, Shannon L.; Gendreau, Steven; Patel, Premal; Jia, Shidong; Zhang, Liangxuan; Tucker, Eric K.; Malchiodi, Michael; Graf, Ryon P.; Dittamore, Ryan; Marrinucci, Dena; Landers, Mark

    2016-01-01

    Genomic instability is a hallmark of cancer often associated with poor patient outcome and resistance to targeted therapy. Assessment of genomic instability in bulk tumor or biopsy can be complicated due to sample availability, surrounding tissue contamination, or tumor heterogeneity. The Epic Sciences circulating tumor cell (CTC) platform utilizes a non-enrichment based approach for the detection and characterization of rare tumor cells in clinical blood samples. Genomic profiling of individual CTCs could provide a portrait of cancer heterogeneity, identify clonal and sub-clonal drivers, and monitor disease progression. To that end, we developed a single cell Copy Number Variation (CNV) Assay to evaluate genomic instability and CNVs in patient CTCs. For proof of concept, prostate cancer cell lines, LNCaP, PC3 and VCaP, were spiked into healthy donor blood to create mock patient-like samples for downstream single cell genomic analysis. In addition, samples from seven metastatic castration resistant prostate cancer (mCRPC) patients were included to evaluate clinical feasibility. CTCs were enumerated and characterized using the Epic Sciences CTC Platform. Identified single CTCs were recovered, whole genome amplified, and sequenced using an Illumina NextSeq 500. CTCs were then analyzed for genome-wide copy number variations, followed by genomic instability analyses. Large-scale state transitions (LSTs) were measured as surrogates of genomic instability. Genomic instability scores were determined reproducibly for LNCaP, PC3, and VCaP, and were higher than white blood cell (WBC) controls from healthy donors. A wide range of LST scores were observed within and among the seven mCRPC patient samples. On the gene level, loss of the PTEN tumor suppressor was observed in PC3 and 5/7 (71%) patients. Amplification of the androgen receptor (AR) gene was observed in VCaP cells and 5/7 (71%) mCRPC patients. Using an in silico down-sampling approach, we determined that DNA copy

  5. Incidence, characterization and prognostic significance of chromosomal abnormalities in 640 patients with primary myelodysplastic syndromes. Grupo Cooperativo Español de Citogenética Hematológica.

    PubMed

    Solé, F; Espinet, B; Sanz, G F; Cervera, J; Calasanz, M J; Luño, E; Prieto, F; Granada, I; Hernández, J M; Cigudosa, J C; Diez, J L; Bureo, E; Marqués, M L; Arranz, E; Ríos, R; Martínez Climent, J A; Vallespí, T; Florensa, L; Woessner, S

    2000-02-01

    Recently, a consensus International Prognostic Scoring System (IPSS) for predicting outcome and planning therapy in the myelodysplastic syndromes (MDS) has been developed. However, the intermediate-risk cytogenetic subgroup defined by the IPSS includes a miscellaneous number of different single abnormalities for which real prognosis at present is uncertain. The main aims of this study were to evaluate in an independent series the prognostic value of the IPSS and to identify chromosomal abnormalities with a previously unrecognized good or poor prognosis in 640 patients. In univariate analyses, cases with single 1q abnormalities experienced poor survival, whereas those with trisomy 8 had a higher risk of acute leukaemic transformation than the remaining patients (P = 0.004 and P = 0.009 respectively). Patients with single del(12p) had a similar survival to patients with a normal karyotype and showed some trend for a better survival than other cases belonging to the IPSS intermediate-risk cytogenetic subgroup (P = 0.045). Multivariate analyses demonstrated that IPSS cytogenetic prognostic subgroup, proportion of bone marrow blasts and haemoglobin level were the main prognostic factors for survival, and the first two characteristics and platelet count were the best predictors of acute leukaemic transformation risk. A large international co-operative study should be carried out to clarify these findings.

  6. JC Virus T-Antigen in Colorectal Cancer Is Associated with p53 Expression and Chromosomal Instability, Independent of CpG Island Methylator Phenotype1

    PubMed Central

    Nosho, Katsuhiko; Shima, Kaori; Kure, Shoko; Irahara, Natsumi; Baba, Yoshifumi; Chen, Li; Kirkner, Gregory J; Fuchs, Charles S; Ogino, Shuji

    2009-01-01

    JC virus has a transforming gene encoding JC virus T-antigen (JCVT). JCVT may inactivate wild-type p53, cause chromosomal instability (CIN), and stabilize β-catenin. A link between JCVT and CpG island methylator phenotype (CIMP) has been suggested. However, no large-scale study has examined the relations of JCVT with molecular alterations, clinical outcome, or prognosis in colon cancer. We detected JCVT expression (by immunohistochemistry) in 271 (35%) of 766 colorectal cancers. We quantified DNA methylation in eight CIMP-specific promoters (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1) and eight other loci (CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14, WRN) by MethyLight. We examined loss of heterozygosity in 2p, 5q, 17q, and 18q. JCVT was significantly associated with p53 expression (P < .0001), p21 loss (P < .0001), CIN (≥2 chromosomal segments with LOH; P < .0001), nuclear β-catenin (P = .006), LINE-1 hypomethylation (P = .002), and inversely with CIMP-high (P = .0005) and microsatellite instability (MSI) (P < .0001), but not with PIK3CA mutation. In multivariate logistic regression analysis, the associations of JCVT with p53 [adjusted odds ratio (OR), 8.45; P < .0001], CIN (adjusted OR, 2.53; P = .003), cyclin D1 (adjusted OR, 1.57; P = .02), LINE-1 hypomethylation (adjusted OR, 1.97 for a 30% decline as a unit; P = .03), BRAF mutation (adjusted OR, 2.20; P = .04), and family history of colorectal cancer (adjusted OR, 0.64; P = .04) remained statistically significant. However, JCVT was no longer significantly associated with CIMP, MSI, β-catenin, or cyclooxygenase-2 expression in multivariate analysis. JCVT was unrelated with patient survival. In conclusion, JCVT expression in colorectal cancer is independently associated with p53 expression and CIN, which may lead to uncontrolled cell proliferation. PMID:19107235

  7. A genome-wide analysis of common fragile sites: What features determine chromosomal instability in the human genome?

    PubMed Central

    Fungtammasan, Arkarachai; Walsh, Erin; Chiaromonte, Francesca; Eckert, Kristin A.; Makova, Kateryna D.

    2012-01-01

    Chromosomal common fragile sites (CFSs) are unstable genomic regions that break under replication stress and are involved in structural variation. They frequently are sites of chromosomal rearrangements in cancer and of viral integration. However, CFSs are undercharacterized at the molecular level and thus difficult to predict computationally. Newly available genome-wide profiling studies provide us with an unprecedented opportunity to associate CFSs with features of their local genomic contexts. Here, we contrasted the genomic landscape of cytogenetically defined aphidicolin-induced CFSs (aCFSs) to that of nonfragile sites, using multiple logistic regression. We also analyzed aCFS breakage frequencies as a function of their genomic landscape, using standard multiple regression. We show that local genomic features are effective predictors both of regions harboring aCFSs (explaining ∼77% of the deviance in logistic regression models) and of aCFS breakage frequencies (explaining ∼45% of the variance in standard regression models). In our optimal models (having highest explanatory power), aCFSs are predominantly located in G-negative chromosomal bands and away from centromeres, are enriched in Alu repeats, and have high DNA flexibility. In alternative models, CpG island density, transcription start site density, H3K4me1 coverage, and mononucleotide microsatellite coverage are significant predictors. Also, aCFSs have high fragility when colocated with evolutionarily conserved chromosomal breakpoints. Our models are predictive of the fragility of aCFSs mapped at a higher resolution. Importantly, the genomic features we identified here as significant predictors of fragility allow us to draw valuable inferences on the molecular mechanisms underlying aCFSs. PMID:22456607

  8. Fusion of nearby inverted repeats by a replication-based mechanism leads to formation of dicentric and acentric chromosomes that cause genome instability in budding yeast.

    PubMed

    Paek, Andrew L; Kaochar, Salma; Jones, Hope; Elezaby, Aly; Shanks, Lisa; Weinert, Ted

    2009-12-15

    Large-scale changes (gross chromosomal rearrangements [GCRs]) are common in genomes, and are often associated with pathological disorders. We report here that a specific pair of nearby inverted repeats in budding yeast fuse to form a dicentric chromosome intermediate, which then rearranges to form a translocation and other GCRs. We next show that fusion of nearby inverted repeats is general; we found that many nearby inverted repeats that are present in the yeast genome also fuse, as does a pair of synthetically constructed inverted repeats. Fusion occurs between inverted repeats that are separated by several kilobases of DNA and share >20 base pairs of homology. Finally, we show that fusion of inverted repeats, surprisingly, does not require genes involved in double-strand break (DSB) repair or genes involved in other repeat recombination events. We therefore propose that fusion may occur by a DSB-independent, DNA replication-based mechanism (which we term "faulty template switching"). Fusion of nearby inverted repeats to form dicentrics may be a major cause of instability in yeast and in other organisms.

  9. Perceived Stress Levels, Chemotherapy, Radiation Treatment and Tumor Characteristics Are Associated with a Persistent Increased Frequency of Somatic Chromosomal Instability in Women Diagnosed with Breast Cancer: A One Year Longitudinal Study

    PubMed Central

    Aboalela, Noran; Lyon, Debra; Elswick, R. K.; Kelly, Debra Lynch; Brumelle, Jenni; Bear, Harry D.; Jackson-Cook, Colleen

    2015-01-01

    While advances in therapeutic approaches have resulted in improved survival rates for women diagnosed with breast cancer, subsets of these survivors develop persistent psychoneurological symptoms (fatigue, depression/anxiety, cognitive dysfunction) that compromise their quality of life. The biological basis for these persistent symptoms is unclear, but could reflect the acquisition of soma-wide chromosomal instability following the multiple biological/psychological exposures associated with the diagnosis/treatment of breast cancer. An essential first step toward testing this hypothesis is to determine if these cancer-related exposures are indeed associated with somatic chromosomal instability frequencies. Towards this end, we longitudinally studied 71 women (ages 23-71) with early-stage breast cancer and quantified their somatic chromosomal instability levels using a cytokinesis-blocked micronuclear/cytome assay at 4 timepoints: before chemotherapy (baseline); four weeks after chemotherapy initiation; six months after chemotherapy (at which time some women received radiotherapy); and one year following chemotherapy initiation. Overall, a significant change in instability frequencies was observed over time, with this change differing based on whether the women received radiotherapy (p=0.0052). Also, significantly higher instability values were observed one year after treatment initiation compared to baseline for the women who received: sequential taxotere/doxorubicin/cyclophosphamide (p<0.001) or taxotere/cyclophosphamide (p=0.014). Significant predictive associations for acquired micronuclear/cytome abnormality frequencies were also observed for race (p=0.0052), tumor type [luminal B tumors] (p=0.0053), and perceived stress levels (p=0.0129). The impact of perceived stress on micronuclear/cytome frequencies was detected across all visits, with the highest levels of stress being reported at baseline (p =0.0024). These findings suggest that the cancer

  10. [CD34(+)CD19(+) cells with CD123 overexpression are a novel prognostic marker in Ph chromosome-positive acute lymphoblastic leukemia].

    PubMed

    Kong, Yuan; Huang, Xiao-Jun; Hao, Le; Qin, Ya-Zhen; Jiang, Qian; Jiang, Hao; Liu, Yan-Rong

    2014-02-01

    This study was aimed to investigate the characteristics of CD123 expression on CD34(+)CD19(+) cells and its prognostic significance as a novel MRD biomarker in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) patients. Consecutive newly diagnosed Ph(+)ALL patients (n = 49) in Peking University Institute of Hematology from January 2010 to April 2012 were prospectively enrolled in this study. At diagnosis and different time points during treatment, CD123 expression on CD34(+)CD19(+) cells was examined by multiparameter flow cytometry(MFC). More than 10 CD34(+)CD19(+) cells with CD123 overexpression in bone marrow samples after complete remission were defined as FCM positive (FCM(+)). The BCR-ABL1[STBZ] transcript was detected by real-time quantitative polymerase chain reaction (RQ-PCR) concurrently. The results showed that mean fluorescence intensity of CD123 on CD34(+)CD19(+) cells in newly diagnosed Ph(+)ALL and relapsed Ph(+)ALL patients was significantly higher than that of normal B-cell progenitors [8.52(3.71-32.35) vs 8.93(4.79-29.74) vs 1.31(0.21-1.75), P < 0.05]. In addition, ratio of the CD34(+)CD19(+) cells with CD123 overexpression in newly diagnosed Ph(+)ALL and relapsed Ph(+)ALL patients were significantly higher than that of normal B-cell progenitors [84.63% (55.07%-99.96%) vs 84.50% (57.68%-99.80%) vs 0.99% (0.45%- 1.83%), P < 0.05]. CD34(+)CD19(+) cells with CD123 overexpression were detected in all newly diagnosed and relapsed Ph(+)ALL patients. A good correlation was found between the MRD results of CD34(+)CD19(+) cells with CD123 overexpression detected by MFC and that detected by RQ-PCR (n = 360 pairs, Spearman r = 0.90, P < 0.0001). Among 13 cases relapsed during follow up, 11 cases of them were detected by FCM(+) at a median time of 60 (30-73) days before the recurrence. It is concluded that as a complementary to RQ-PCR, detection of the CD34(+)CD19(+) cells with CD123 overexpression by MFC promises to be an efficient

  11. Systemic chromosome instability in Shugoshin-1 mice resulted in compromised glutathione pathway, activation of Wnt signaling and defects in immune system in the lung

    PubMed Central

    Yamada, H Y; Kumar, G; Zhang, Y; Rubin, E; Lightfoot, S; Dai, W; Rao, C V

    2016-01-01

    Mitotic error-mediated chromosome instability (CIN) can lead to aneuploidy, chromothripsis, DNA damage and/or whole chromosome gain/loss. CIN may prompt rapid accumulation of mutations and genomic alterations. Thus, CIN can promote carcinogenesis. This CIN process results from a mutation in certain genes or environmental challenge such as smoking, and is highly prevalent in various cancers, including lung cancer. A better understanding of the effects of CIN on carcinogenesis will lead to novel methods for cancer prevention and treatment. Previously Shugoshin-1 (Sgo1−/+) mice, a transgenic mouse model of CIN, showed mild proneness to spontaneous lung and liver cancers. In this study, adoptive (T/B-cell based) immunity-deficient RAG1−/− Sgo1−/+ double mutant mice developed lung adenocarcinomas more aggressively than did Sgo1−/+ or RAG1−/− mice, suggesting immune system involvement in CIN-mediated lung carcinogenesis. To identify molecular causes of the lung adenocarcinoma, we used systems biology approach, comparative RNAseq, to RAG1−/− and RAG1−/− Sgo1−/+. The comparative RNAseq data and follow-up analyses in the lungs of naive Sgo1−/+ mice demonstrate that, (i) glutathione is depleted, making the tissue vulnerable to oxidative stress, (ii) spontaneous DNA damage is increased, (iii) oncogenic Wnt signaling is activated, (iv) both major branches of the immune system are weakened through misregulations in signal mediators such as CD80 and calreticulin and (v) the actin cytoskeleton is misregulated. Overall, the results show multi-faceted roles of CIN in lung carcinoma development in Sgo1−/+ mice. Our model presents various effects of CIN and will help to identify potential targets to prevent CIN-driven carcinogenesis in the lung. PMID:27526110

  12. Bio-pathologic characteristics related to chromosome 11 aneusomy and cyclin D1 gene status in surgically resected stage I and II breast cancer: Identification of an adverse prognostic profile.

    PubMed

    Mottolese, Marcella; Orlandi, Giulia; Sperduti, Isabella; Merola, Roberta; Buglioni, Simonetta; Di Benedetto, Anna; Pinnarò, Paola; Perracchio, Letizia; Venturo, Irene; Cognetti, Francesco; Cianciulli, AnnaMaria

    2007-02-01

    We aimed at developing a more detailed understanding of cyclin D1 in early stage human breast cancer and defining the biologic profiles with different prognostic value correlating cyclin D1 gene amplification and chromosome 11 aneusomy with bio-pathologic variables of known clinical importance. Cyclin D1 gene amplification and chromosome 11 aneusomy were investigated using fluorescence in situ hybridization whereas cyclin D1, PgR, HER-2, Bcl2, p53, and Ki-67 expressions were analyzed by immunohistochemistry in 121 stage I or II breast cancer patients uniformly treated with cyclophosphamide/metotrexate/5-fluorouracil-based chemotherapy. Cyclin D1 was amplified in 6.6% and overexpressed in 32.2% of cases. Amplification was not associated with any selected bio-pathologic variables, whereas the chromosome 11 aneusomy level significantly increased in tumors with higher histologic grade (P < 0.01), higher tumor size (P < 0.003), p53 nuclear accumulation (P < 0.04), and ERalpha negativity (P < 0.049). Multiple correspondence analysis showed 4 different biologic tumor profiles. The first, characterized by high Ki-67 score, p53+, cyclin D1+, HER-2+, aneusomy level > 30%, ratio (cyclin D1 gene/CEP11) > 2, was associated with tumor relapse defining the most unfavorable biologic profile. Kaplan-Meier's method showed significantly shorter disease-free survival in patients with at least 3 variables positive out of the 6 detected by multiple correspondence analysis. In multivariate analysis, the identified biologic profile emerged as the only significant prognostic indicator. Our findings are of particular clinical interest for early stage breast cancer patients, because the assessment of biologic factors predictive of tumor aggressiveness may influence postoperative therapeutic strategies.

  13. DNA damage response curtails detrimental replication stress and chromosomal instability induced by the dietary carcinogen PhIP

    PubMed Central

    Mimmler, Maximilian; Peter, Simon; Kraus, Alexander; Stroh, Svenja; Nikolova, Teodora; Seiwert, Nina; Hasselwander, Solveig; Neitzel, Carina; Haub, Jessica; Monien, Bernhard H.; Nicken, Petra; Steinberg, Pablo; Shay, Jerry W.; Kaina, Bernd; Fahrer, Jörg

    2016-01-01

    PhIP is an abundant heterocyclic aromatic amine (HCA) and important dietary carcinogen. Following metabolic activation, PhIP causes bulky DNA lesions at the C8-position of guanine. Although C8-PhIP-dG adducts are mutagenic, their interference with the DNA replication machinery and the elicited DNA damage response (DDR) have not yet been studied. Here, we analyzed PhIP-triggered replicative stress and elucidated the role of the apical DDR kinases ATR, ATM and DNA-PKcs in the cellular defense response. First, we demonstrate that PhIP induced C8-PhIP-dG adducts and DNA strand breaks. This stimulated ATR-CHK1 signaling, phosphorylation of histone 2AX and the formation of RPA foci. In proliferating cells, PhIP treatment increased the frequency of stalled replication forks and reduced fork speed. Inhibition of ATR in the presence of PhIP-induced DNA damage strongly promoted the formation of DNA double-strand breaks, activation of the ATM-CHK2 pathway and hyperphosphorylation of RPA. The abrogation of ATR signaling potentiated the cell death response and enhanced chromosomal aberrations after PhIP treatment, while ATM and DNA-PK inhibition had only marginal effects. These results strongly support the notion that ATR plays a key role in the defense against cancer formation induced by PhIP and related HCAs. PMID:27599846

  14. HIGH-RESOLUTION GENOMIC ARRAYS FACILITATE DETECTION OF NOVEL CRYPTIC CHROMOSOMAL LESIONS IN MYELODYSPLASTIC SYNDROMES

    PubMed Central

    O’Keefe, Christine L.; Tiu, Ramon; Gondek, Lukasz P.; Powers, Jennifer; Theil, Karl S.; Kalaycio, Matt; Lichtin, Alan; Sekeres, Mikkael A.; Maciejewski, Jaroslaw P.

    2008-01-01

    Objective Unbalanced chromosomal aberrations are common in myelodysplastic syndromes, and have prognostic implications. An increased frequency of cytogenetic changes may reflect an inherent chromosomal instability due to failure of DNA repair. Therefore, it is likely that chromosomal defects in myelodysplastic syndromes may be more frequent than predicted by metaphase cytogenetics and new cryptic lesions may be revealed by precise analysis methods. Methods We used a novel high-resolution karyotyping technique, array-based comparative genomic hybridization, to investigate the frequency of cryptic chromosomal lesions in a cohort of 38 well-characterized myelodysplastic syndromes patients; results were confirmed by microsatellite quantitative PCR or single nucleotide polymorphism analysis. Results As compared to metaphase karyotyping, chromosomal abnormalities detected by array-based analysis were encountered more frequently and in a higher proportion of patients. For example, chromosomal defects were found in patients with a normal karyotype by traditional cytogenetics. In addition to verifying common abnormalities, previously cryptic defects were found in new regions of the genome. Cryptic changes often overlapped chromosomes and regions frequently identified as abnormal by metaphase cytogenetics. Conclusion The results underscore the instability of the myelodysplastic syndromes genome and highlight the utility of array-based karyotyping to study cryptic chromosomal changes which may provide new diagnostic information. PMID:17258073

  15. Prostate Cancer Cell Telomere Length Variability and Stromal Cell Telomere Length as Prognostic Markers for Metastasis and Death

    PubMed Central

    Heaphy, Christopher M.; Yoon, Ghil Suk; Peskoe, Sarah B.; Joshu, Corinne E.; Lee, Thomas K.; Giovannucci, Edward; Mucci, Lorelei A.; Kenfield, Stacey A.; Stampfer, Meir J.; Hicks, Jessica L.; De Marzo, Angelo M.; Platz, Elizabeth A.; Meeker, Alan K.

    2013-01-01

    Current prognostic indicators are imperfect predictors of outcome in men with clinicallylocalized prostate cancer. Thus, tissue-based markers are urgently needed to improve treatment and surveillance decision-making. Given that shortened telomeres enhance chromosomal instability and such instability is a hallmark of metastatic lesions, we hypothesized that alterations in telomere length in the primary cancer would predict risk of progression to metastasis and prostate cancer death. To test this hypothesis, we conducted a prospective cohort study of 596 surgically treated men who participated in the ongoing Health Professionals Follow-up Study. Men who had the combination of more variable telomere length among prostate cancer cells (cell-to-cell) and shorter telomere length in prostate cancer-associated stromal cells were substantially more likely to progress to metastasis or die of their prostate cancer. These findings point to the translational potential of this telomere biomarker for prognostication and risk stratification for individualized therapeutic and surveillance strategies. PMID:23779129

  16. Role of additional chromosomal changes in the prognostic value of t(4;14) and del(17p) in multiple myeloma: the IFM experience

    PubMed Central

    Hebraud, Benjamin; Magrangeas, Florence; Cleynen, Alice; Lauwers-Cances, Valerie; Chretien, Marie-Lorraine; Hulin, Cyrille; Leleu, Xavier; Yon, Edwige; Marit, Gerald; Karlin, Lionel; Roussel, Murielle; Stoppa, Anne-Marie; Belhadj, Karim; Voillat, Laurent; Garderet, Laurent; Macro, Margaret; Caillot, Denis; Mohty, Mohamad; Facon, Thierry; Moreau, Philippe; Attal, Michel; Munshi, Nikhil; Corre, Jill; Minvielle, Stephane

    2015-01-01

    In multiple myeloma, cytogenetic changes are important predictors of patient outcome. In this setting, the most important changes are deletion 17p, del(17p), and translocation of chromosomes 4 and 14, t(4;14), conferring a poor outcome. However, a certain degree of heterogeneity is observed in the survival of these high-risk patients. We hypothesized that other chromosomal changes may impact the outcome. We retrospectively analyzed a large series of 242 patients displaying either t(4;14) (157 patients) or del(17p) (110 patients), 25 patients presenting both abnormalities, using single nucleotide polymorphism array. In patients with t(4;14), del(1p32), del22q, and >30 chromosomal structural changes negatively impacted progression-free survival (PFS). For overall survival (OS), del(13q14), del(1p32), and the number of chromosomal structural changes worsened the prognosis of patients. For patients with del(17p), del6q worsened the prognosis of patients, whereas trisomy 15 and monosomy 14 were found to have a protective effect on PFS. For OS, del(1p32) worsened the prognosis of patients, whereas having >8 numerical changes was found to have a protective effect on survival. This study, which is the largest series of high-risk patients analyzed with the most modern genomic technique, identified 1 main factor negatively impacting survival: del(1p32). PMID:25636340

  17. Mre11 deficiency in Arabidopsis is associated with chromosomal instability in somatic cells and Spo11-dependent genome fragmentation during meiosis.

    PubMed

    Puizina, Jasna; Siroky, Jiri; Mokros, Petr; Schweizer, Dieter; Riha, Karel

    2004-08-01

    The Mre11/Rad50/Nbs1 complex is involved in many aspects of chromosome metabolism. Aberrant function of the complex is associated with defects in the DNA checkpoint, double-strand break repair, meiosis, and telomere maintenance. In this article, we report the consequences of Mre11 dysfunction for the stability of mitotic and meiotic chromosomes in Arabidopsis thaliana. Although plants homozygous for a T-DNA insertion in a conserved region of the MRE11 gene are viable, they exhibit growth defects and are infertile. Analysis of mitotic chromosomes prepared from the mutant plants revealed abundant dicentric chromosomes and chromosomal fragments. Fluorescence in situ hybridization showed that anaphase bridges are often formed by homologous chromosome arms. The frequency of chromosome fusions was not reduced in mre11 ku70 double mutants, suggesting that plants possess DNA end-joining activities independent of the Ku70/80 and Mre11 complexes. Cytogenetic examination of pollen mother cells revealed massive chromosome fragmentation and the absence of synapsis in the initial stages of meiosis. The fragmentation was substantially suppressed in mre11 spo11-1 double mutants, indicating that Mre11 is required for repair but not for the induction of Spo11-dependent meiotic DNA breaks in Arabidopsis.

  18. Development of a Novel Prognostic Marker to Link a Potential Tumor Suppressor Gene at Chromosome 6q to Aberrant Signal Transduction Pathway in Breast Cancer

    DTIC Science & Technology

    2005-08-01

    frequency of LOH is found in 6q24 region in breast cancers Laforin gene EPM2A is located in 6q24 in human genome (9-11). The long arm of chromosome 6 is...in patients (Wang et al., 2002). Although defects in the EPM2a gene have not been implicated in cancers, EPM2a is located in 6q24 of the human genome ...lymphoma, we treated the genomic DNA with bisulfite and sequenced 4 PCR products covering 102 CpG di-nucleotides within the 5’-CpG island. Our preliminary

  19. Philadelphia chromosome duplication as a ring-shaped chromosome.

    PubMed

    Borjas-Gutierrez, Cesar; Gonzalez-Garcia, Juan Ramon

    2016-01-01

    The gain of a second copy of the Philadelphia chromosome is one of the main secondary chromosomal changes related to the clonal evolution of cells with t(9;22) in chronic myelogenous leukemia. This gain causes the acquisition of another copy of the BCR/ABL1 fusion gene. Isochromosomes of the der(22) chromosome or double minute chromosomes are well known to lead an increased copy number of BCR/ABL1 gene. There is no antecedent of Philadelphia chromosome duplication as a ring chromosome. A recent published report contains evidence that strongly suggests that the Philadelphia chromosome was duplicated as a ring chromosome, observation that was overlooked by the authors. The instability inherent to the ring chromosome increases the risk of emergence of clones containing more and more BCR/ABL1 gene copies, which would produce increased fitness for clonal selection, resulting in worsening of the patient's prognosis.

  20. Aneuploid progeny of the American oyster, Crassostrea virginica, produced by tetraploid × diploid crosses: another example of chromosome instability in polyploid oysters.

    PubMed

    de Sousa, Joana Teixeira; Allen, Standish K; Baker, Haley; Matt, Joseph L

    2016-05-01

    The commercial production of triploids, and the creation of tetraploid broodstock to support it, has become an important technique in aquaculture of the eastern oyster, Crassostrea virginica. Tetraploids are produced by cytogenetic manipulation of embryos and have been shown to undergo chromosome loss (to become a mosaic) with unknown consequences for breeding. Our objective was to determine the extent of aneuploidy in triploid progeny produced from both mosaic and non-mosaic tetraploids. Six families of triploids were produced using a single diploid female and crossed with three mosaic and non-mosaic tetraploid male oysters. A second set of crosses was performed with the reciprocals. Chromosome counts of the resultant embryos were tallied at 2-4 cell stage and as 6-hour(h)-old embryos. A significant level of aneuploidy was observed in 6-h-old embryos. For crosses using tetraploid males, aneuploidy ranged from 53% to 77% of observed metaphases, compared to 36% in the diploid control. For crosses using tetraploid females, 51%-71% of metaphases were aneuploidy versus 53% in the diploid control. We conclude that somatic chromosome loss may be a regular feature of early development in triploids, and perhaps polyploid oysters in general. Other aspects of chromosome loss in polyploid oysters are also discussed.

  1. Knockdown of μ-calpain in Fanconi Anemia, FA-A, cells by siRNA Restores αII Spectrin levels and Corrects Chromosomal Instability and Defective DNA Interstrand Cross-link Repair†

    PubMed Central

    Zhang, Pan; Sridharan, Deepa; Lambert, Muriel W.

    2010-01-01

    We have previously shown that there is a deficiency in the structural protein, nonerythroid α spectrin (αIISp), in cells from patients with Fanconi anemia (FA). These studies indicate that this deficiency is due to reduced stability of αIISp and correlates with decreased repair of DNA interstrand cross-links and chromosomal instability in FA cells. An important factor in the stability of αIISp is its susceptibility to cleavage by the protease, μ-calpain. We hypothesized that increased μ-calpain cleavage of αIISp in FA cells leads to increased breakdown of αIISp and that knocking-down expression of μ-calpain in FA cells should restore levels of αIISp and correct a number of the phenotypic defects observed. The results showed that there is increased μ-calpain activity in FA-A, FA-C, FA-D2, FA-F and FA-G cells which could account for the deficiency in αIISp in these FA cells. Protein interaction studies indicated that FANCA and FANCG bind directly to μ-calpain. We hypothesize that this binding may lead to inhibition of μ-calpain activity in normal cells. Knocking-down μ-calpain by siRNA in FA-A cells restored levels of αIISp to normal and reversed a number of the cellular deficiencies in these cells. It corrected the DNA repair defect and the chromosomal instability observed after exposure to a DNA interstrand cross-linking agent. These studies indicated that FA proteins may play an important role in maintaining stability of αIISp in the cell by regulating its cleavage by μ-calpain. Thus by reducing breakdown of αIISp in FA cells, it may be possible to reverse a number of the cellular deficiencies observed in this disorder. PMID:20518497

  2. Human T-lymphotropic virus type 1 oncoprotein tax promotes unscheduled degradation of Pds1p/securin and Clb2p/cyclin B1 and causes chromosomal instability.

    PubMed

    Liu, Baoying; Liang, Min-Hui; Kuo, Yu-liang; Liao, Wei; Boros, Imre; Kleinberger, Tami; Blancato, Jan; Giam, Chou-Zen

    2003-08-01

    Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia. The HTLV-1 transactivator, Tax, is implicated as the viral oncoprotein. Naïve cells expressing Tax for the first time develop severe cell cycle abnormalities that include increased DNA synthesis, mitotic arrest, appearance of convoluted nuclei with decondensed DNA, and formation of multinucleated cells. Here we report that Tax causes a drastic reduction in Pds1p/securin and Clb2p/cyclin B levels in yeast, rodent, and human cells and a loss of cell viability. With a temperature-sensitive mutant of the CDC23 subunit of the anaphase-promoting complex (APC), cdc23(ts); a temperature-sensitive mutant of cdc20; and a cdh1-null mutant, we show that the diminution of Pds1p and Clb2p brought on by Tax is mediated via the Cdc20p-associated anaphase-promoting complex, APC(Cdc20p). This loss of Pds1p/securin and Clb2p/cyclin B1 occurred before cellular entry into mitosis, caused a G(2)/M cell cycle block, and was accompanied by severe chromosome aneuploidy in both Saccharomyces cerevisiae cells and human diploid fibroblasts. Our results support the notion that Tax aberrantly targets and activates APC(Cdc20p), leading to unscheduled degradation of Pds1p/securin and Clb2p/cyclin B1, a delay or failure in mitotic entry and progression, and faulty chromosome transmission. The chromosomal instability resulting from a Tax-induced deficiency in securin and cyclin B1 provides an explanation for the highly aneuploid nature of adult T-cell leukemia cells.

  3. Telomere attrition and chromosome instability via downregulation of TRF2 contributes to arsenic trioxide-induced apoptosis of human T-Cell leukemia cell line molt-4 cells.

    PubMed

    Jiao, Yangwen; Zhang, Weifang; Liu, Junqing; Ni, Wanmao; Xu, Weilai; Jin, Jie; Qian, Wenbin

    2007-08-01

    Overexpression of human telomere repeat binding factor 2 (TRF2), which may play an important role in the fate of cancer cells, has been observed in adult T-cell leukemia. Previous reports have shown that the inhibition of TRF2 results in the apoptosis of cancer cells. In this study, we demonstrated that arsenic trioxide (As2O3) induced in vitro growth inhibition and/or apoptosis of human T-cell leukemia cell line Molt-4 in a caspase-independent manner. Telomerase activity was not inhibited, although the level of the reverse transcriptase subunit of the human telomerase gene (hTERT) mRNA expression was down regulated during the early times and then recovered to the level found in untreated controls about 48 hours after treatment with As2O3. Furthermore, a remarkable telomere shortening related to exposure of As2O3 was observed in 50 population doubling. Inc ontrast, the alteration of telomere length did not occur after exposure to higher concentration of As2O3 (10 microM) for 24 hours and 48 hours, respectively, suggesting that the shortening of telomeres induced by As2O3 is dependent of a series of cell division cycles. Chromosomal analysis showed that As2O3 exposure caused chromosomal end-to-end fusion in human T-cell leukemia cells while downregulation of TRF2 was observed. Finally, the inhibition of TRF2 protein expression and the sensitivity to As2O3 in a panel of leukemia cell lines were checked. The data revealed that inhibition of TRF2 rendered leukemia cells more susceptible to As2O3. In conclusion, the downregulation of TRF2 by As2O3 contribute to chromosomal end-to-end fusion, and apoptosis in leukemia cells, suggesting that TRF2 could be an attractive target for new therapies of leukemia.

  4. Radiation-induced genomic instability and its implications for radiation carcinogenesis

    NASA Technical Reports Server (NTRS)

    Huang, Lei; Snyder, Andrew R.; Morgan, William F.

    2003-01-01

    Radiation-induced genomic instability is characterized by an increased rate of genetic alterations including cytogenetic rearrangements, mutations, gene amplifications, transformation and cell death in the progeny of irradiated cells multiple generations after the initial insult. Chromosomal rearrangements are the best-characterized end point of radiation-induced genomic instability, and many of the rearrangements described are similar to those found in human cancers. Chromosome breakage syndromes are defined by chromosome instability, and individuals with these diseases are cancer prone. Consequently, chromosomal instability as a phenotype may underlie some fraction of those changes leading to cancer. Here we attempt to relate current knowledge regarding radiation-induced chromosome instability with the emerging molecular information on the chromosome breakage syndromes. The goal is to understand how genetic and epigenetic factors might influence the onset of chromosome instability and the role of chromosomal instability in carcinogenesis.

  5. CNS germinomas are characterized by global demethylation, chromosomal instability and mutational activation of the Kit-, Ras/Raf/Erk- and Akt-pathways

    PubMed Central

    Schulte, Simone Laura; Waha, Andreas; Steiger, Barbara; Denkhaus, Dorota; Dörner, Evelyn; Calaminus, Gabriele; Leuschner, Ivo; Pietsch, Torsten

    2016-01-01

    CNS germinomas represent a unique germ cell tumor entity characterized by undifferentiated tumor cells and a high response rate to current treatment protocols. Limited information is available on their underlying genomic, epigenetic and biological alterations. We performed a genome-wide analysis of genomic copy number alterations in 49 CNS germinomas by molecular inversion profiling. In addition, CpG dinucleotide methylation was studied by immunohistochemistry for methylated cytosine residues. Mutational analysis was performed by resequencing of candidate genes including KIT and RAS family members. Ras/Erk and Akt pathway activation was analyzed by immunostaining with antibodies against phospho-Erk, phosho-Akt, phospho-mTOR and phospho-S6. All germinomas coexpressed Oct4 and Kit but showed an extensive global DNA demethylation compared to other tumors and normal tissues. Molecular inversion profiling showed predominant genomic instability in all tumors with a high frequency of regional gains and losses including high level gene amplifications. Activating mutations of KIT exons 11, 13, and 17 as well as a case with genomic KIT amplification and activating mutations or amplifications of RAS gene family members including KRAS, NRAS and RRAS2 indicated mutational activation of crucial signaling pathways. Co-activation of Ras/Erk and Akt pathways was present in 83% of germinomas. These data suggest that CNS germinoma cells display a demethylated nuclear DNA similar to primordial germ cells in early development. This finding has a striking coincidence with extensive genomic instability. In addition, mutational activation of Kit-, Ras/Raf/Erk- and Akt- pathways indicate the biological importance of these pathways and their components as potential targets for therapy. PMID:27391150

  6. Chromosomal Conditions

    MedlinePlus

    ... 150 babies is born with a chromosomal condition. Down syndrome is an example of a chromosomal condition. Because ... all pregnant women be offered prenatal tests for Down syndrome and other chromosomal conditions. A screening test is ...

  7. Cat eye syndrome chromosome breakpoint clustering: identification of two intervals also associated with 22q11 deletion syndrome breakpoints.

    PubMed

    McTaggart, K E; Budarf, M L; Driscoll, D A; Emanuel, B S; Ferreira, P; McDermid, H E

    1998-01-01

    The supernumerary cat eye syndrome (CES) chromosome is dicentric, containing two copies of 22pter-->q11.2. We have found that the duplication breakpoints are clustered in two intervals. The more proximal, most common interval is the 450-650 kb region between D22S427 and D22S36, which corresponds to the proximal deletion breakpoint interval found in the 22q11 deletion syndrome (DiGeorge/velocardiofacial syndrome). The more distal duplication breakpoint interval falls between CRKL and D22S112, which overlaps with the common distal deletion interval of the 22q11 deletion syndrome. We have therefore classified CES chromosomes into two types based on the location of the two breakpoints required to generate them. The smaller type I CES chromosomes are symmetrical, with both breakpoints located within the proximal interval. The larger type II CES chromosomes are either asymmetrical, with one breakpoint located in each of the two intervals, or symmetrical, with both breakpoints located in the distal interval. The co-localization of the breakpoints of these different syndromes, plus the presence of low-copy repeats adjacent to each interval, suggests the existence of several specific regions of chromosomal instability in 22q11.2 which are involved in the production of both deletions and duplications. Since the phenotype associated with the larger duplication does not appear to be more severe than that of the smaller duplication, determination of the type of CES chromosome does not currently have prognostic value.

  8. Cytogenetic Prognostication Within Medulloblastoma Subgroups

    PubMed Central

    Shih, David J.H.; Northcott, Paul A.; Remke, Marc; Korshunov, Andrey; Ramaswamy, Vijay; Kool, Marcel; Luu, Betty; Yao, Yuan; Wang, Xin; Dubuc, Adrian M.; Garzia, Livia; Peacock, John; Mack, Stephen C.; Wu, Xiaochong; Rolider, Adi; Morrissy, A. Sorana; Cavalli, Florence M.G.; Jones, David T.W.; Zitterbart, Karel; Faria, Claudia C.; Schüller, Ulrich; Kren, Leos; Kumabe, Toshihiro; Tominaga, Teiji; Shin Ra, Young; Garami, Miklós; Hauser, Peter; Chan, Jennifer A.; Robinson, Shenandoah; Bognár, László; Klekner, Almos; Saad, Ali G.; Liau, Linda M.; Albrecht, Steffen; Fontebasso, Adam; Cinalli, Giuseppe; De Antonellis, Pasqualino; Zollo, Massimo; Cooper, Michael K.; Thompson, Reid C.; Bailey, Simon; Lindsey, Janet C.; Di Rocco, Concezio; Massimi, Luca; Michiels, Erna M.C.; Scherer, Stephen W.; Phillips, Joanna J.; Gupta, Nalin; Fan, Xing; Muraszko, Karin M.; Vibhakar, Rajeev; Eberhart, Charles G.; Fouladi, Maryam; Lach, Boleslaw; Jung, Shin; Wechsler-Reya, Robert J.; Fèvre-Montange, Michelle; Jouvet, Anne; Jabado, Nada; Pollack, Ian F.; Weiss, William A.; Lee, Ji-Yeoun; Cho, Byung-Kyu; Kim, Seung-Ki; Wang, Kyu-Chang; Leonard, Jeffrey R.; Rubin, Joshua B.; de Torres, Carmen; Lavarino, Cinzia; Mora, Jaume; Cho, Yoon-Jae; Tabori, Uri; Olson, James M.; Gajjar, Amar; Packer, Roger J.; Rutkowski, Stefan; Pomeroy, Scott L.; French, Pim J.; Kloosterhof, Nanne K.; Kros, Johan M.; Van Meir, Erwin G.; Clifford, Steven C.; Bourdeaut, Franck; Delattre, Olivier; Doz, François F.; Hawkins, Cynthia E.; Malkin, David; Grajkowska, Wieslawa A.; Perek-Polnik, Marta; Bouffet, Eric; Rutka, James T.; Pfister, Stefan M.; Taylor, Michael D.

    2014-01-01

    Purpose Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. Patients and Methods Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. Results Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. Conclusion Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials. PMID

  9. Genomic Instability in Cancer

    PubMed Central

    Abbas, Tarek; Keaton, Mignon A.; Dutta, Anindya

    2013-01-01

    One of the fundamental challenges facing the cell is to accurately copy its genetic material to daughter cells. When this process goes awry, genomic instability ensues in which genetic alterations ranging from nucleotide changes to chromosomal translocations and aneuploidy occur. Organisms have developed multiple mechanisms that can be classified into two major classes to ensure the fidelity of DNA replication. The first class includes mechanisms that prevent premature initiation of DNA replication and ensure that the genome is fully replicated once and only once during each division cycle. These include cyclin-dependent kinase (CDK)-dependent mechanisms and CDK-independent mechanisms. Although CDK-dependent mechanisms are largely conserved in eukaryotes, higher eukaryotes have evolved additional mechanisms that seem to play a larger role in preventing aberrant DNA replication and genome instability. The second class ensures that cells are able to respond to various cues that continuously threaten the integrity of the genome by initiating DNA-damage-dependent “checkpoints” and coordinating DNA damage repair mechanisms. Defects in the ability to safeguard against aberrant DNA replication and to respond to DNA damage contribute to genomic instability and the development of human malignancy. In this article, we summarize our current knowledge of how genomic instability arises, with a particular emphasis on how the DNA replication process can give rise to such instability. PMID:23335075

  10. Radiation Induced Genomic Instability

    SciTech Connect

    Morgan, William F.

    2011-03-01

    Radiation induced genomic instability can be observed in the progeny of irradiated cells multiple generations after irradiation of parental cells. The phenotype is well established both in vivo (Morgan 2003) and in vitro (Morgan 2003), and may be critical in radiation carcinogenesis (Little 2000, Huang et al. 2003). Instability can be induced by both the deposition of energy in irradiated cells as well as by signals transmitted by irradiated (targeted) cells to non-irradiated (non-targeted) cells (Kadhim et al. 1992, Lorimore et al. 1998). Thus both targeted and non-targeted cells can pass on the legacy of radiation to their progeny. However the radiation induced events and cellular processes that respond to both targeted and non-targeted radiation effects that lead to the unstable phenotype remain elusive. The cell system we have used to study radiation induced genomic instability utilizes human hamster GM10115 cells. These cells have a single copy of human chromosome 4 in a background of hamster chromosomes. Instability is evaluated in the clonal progeny of irradiated cells and a clone is considered unstable if it contains three or more metaphase sub-populations involving unique rearrangements of the human chromosome (Marder and Morgan 1993). Many of these unstable clones have been maintained in culture for many years and have been extensively characterized. As initially described by Clutton et al., (Clutton et al. 1996) many of our unstable clones exhibit persistently elevated levels of reactive oxygen species (Limoli et al. 2003), which appear to be due dysfunctional mitochondria (Kim et al. 2006, Kim et al. 2006). Interestingly, but perhaps not surprisingly, our unstable clones do not demonstrate a “mutator phenotype” (Limoli et al. 1997), but they do continue to rearrange their genomes for many years. The limiting factor with this system is the target – the human chromosome. While some clones demonstrate amplification of this chromosome and thus lend

  11. Marker chromosomes.

    PubMed

    Rao, Kiran Prabhaker; Belogolovkin, Victoria

    2013-04-01

    Marker chromosomes are a morphologically heterogeneous group of structurally abnormal chromosomes that pose a significant challenge in prenatal diagnosis. Phenotypes associated with marker chromosomes are highly variable and range from normal to severely abnormal. Clinical outcomes are very difficult to predict when marker chromosomes are detected prenatally. In this review, we outline the classification, etiology, cytogenetic characterization, and clinical consequences of marker chromosomes, as well as practical approaches to prenatal diagnosis and genetic counseling.

  12. Genetic abnormalities and microsatellite instability in colorectal cancer.

    PubMed

    Iniesta, P; de Juan, C; Caldés, T; Vega, F J; Massa, M J; Cerdán, F J; López, J A; Fernández, C; Sánchez, A; Torres, A J; Balibrea, J L; Benito, M

    1998-01-01

    Our purpose was to investigate different genetic abnormalities, such as K-ras mutations, p53 alterations, and c-myc RNA overexpression, as well as microsatellite instability in 63 colorectal tumors obtained from patients that had undergone surgery. K-ras point mutations were analyzed by PCR-RFLP technique, followed by sequencing; p53 protein accumulation by immunohistochemistry; p53 gene mutations in exons 5-9 were studied by the SSCP and sequencing techniques, and c-myc overexpression by Northern blot. Microsatellite instability was performed at chromosomes 2p, 3p, and 11p by a PCR-based technique. Our data indicate a trend toward a poorer prognosis in patients who had K-ras transversions; besides, we have obtained a prevalence of c-myc RNA overexpression and p53 exon 7 mutations in the latest stages of tumor progression. In conclusion, our findings suggest that the recognition of molecular abnormalities might be used in colorectal cancer as a prognostic indicator or to determine the metastatic potential of colorectal adenocarcinomas.

  13. Collective instabilities

    SciTech Connect

    K.Y. Ng

    2003-08-25

    The lecture covers mainly Sections 2.VIII and 3.VII of the book ''Accelerator Physics'' by S.Y. Lee, plus mode-coupling instabilities and chromaticity-driven head-tail instability. Besides giving more detailed derivation of many equations, simple interpretations of many collective instabilities are included with the intention that the phenomena can be understood more easily without going into too much mathematics. The notations of Lee's book as well as the e{sup jwt} convention are followed.

  14. BubR1 as a prognostic marker for recurrence-free survival rates in epithelial ovarian cancers

    PubMed Central

    Lee, Y-K; Choi, E; Kim, M A; Park, P-G; Park, N-H; Lee, H

    2009-01-01

    Background: Epithelial ovarian cancer is one of the most lethal malignancies, and has a high recurrence rate. Thus, prognostic markers for recurrence are crucial for the care of ovarian cancer. As ovarian cancers frequently exhibit chromosome instability, we aimed at assessing the prognostic significance of two key mitotic kinases, BubR1 and Aurora A. Methods: We analysed paraffin-embedded tissue sections from 160 ovarian cancer patients whose clinical outcomes had been tracked after first-line treatment. Results: The median recurrence-free survival in patients with a positive and negative expression of BubR1 was 27 and 83 months, respectively (P<0.001). A positive BubR1 expression was also associated with advanced stage, serous histology and high grade. In contrast, Aurora A immunostaining did not correlate with any of the clinical parameters analysed. Conclusion: BubR1, but not Aurora A, is a prognostic marker for recurrence-free survival rates in epithelial ovarian cancers. PMID:19603021

  15. Prognostic utility of coronary computed tomographic angiography

    PubMed Central

    Otaki, Yuka; Berman, Daniel S.; Min, James K.

    2013-01-01

    Coronary computed tomographic angiography (CCTA) employing CT scanners of 64-detector rows or greater represents a noninvasive method that enables accurate detection and exclusion of anatomically obstructive coronary artery disease (CAD), providing excellent diagnostic information when compared to invasive angiography. There are numerous potential advantages of CCTA beyond simply luminal stenosis assessment including quantification of atherosclerotic plaque volume as well as assessment of plaque composition, extent, location and distribution. In recent years, an array of studies has evaluated the prognostic utility of CCTA findings of CAD for the prediction of major adverse cardiac events, all-cause death and plaque instability. This prognostic information enhances risk stratification and, if properly acted upon, may improve medical therapy and/or behavioral changes that may enhance event-free survival. The goal of the present article is to summarize the current status of the prognostic utility of CCTA findings of CAD. PMID:23809386

  16. Identification of Prostate Cancer Prognostic Markers

    DTIC Science & Technology

    2013-10-01

    aims. Ethics approval has been obtained for the samples collection of AIM1. The chromosome 16p13.3 gain was found to be associated with high Gleason...Prostate cancer, Genomic alteration, Fluorescence in situ hybridization (FISH), Prognostic markers, ectopic expression, gene silencing, cDNA cloning ...In regard to AIM1 and AIM2, we have recently obtained the final approval from the Ethics committee of our hospital after a lengthy process. We have

  17. Computational model for chromosomal instabilty

    NASA Astrophysics Data System (ADS)

    Zapperi, Stefano; Bertalan, Zsolt; Budrikis, Zoe; La Porta, Caterina

    2015-03-01

    Faithful segregation of genetic material during cell division requires alignment of the chromosomes between the spindle poles and attachment of their kinetochores to each of the poles. Failure of these complex dynamical processes leads to chromosomal instability (CIN), a characteristic feature of several diseases including cancer. While a multitude of biological factors regulating chromosome congression and bi-orientation have been identified, it is still unclear how they are integrated into a coherent picture. Here we address this issue by a three dimensional computational model of motor-driven chromosome congression and bi-orientation. Our model reveals that successful cell division requires control of the total number of microtubules: if this number is too small bi-orientation fails, while if it is too large not all the chromosomes are able to congress. The optimal number of microtubules predicted by our model compares well with early observations in mammalian cell spindles. Our results shed new light on the origin of several pathological conditions related to chromosomal instability.

  18. The Diagnostic and Prognostic Role of microRNA in Colorectal Cancer - a Comprehensive review.

    PubMed

    Mazeh, Haggi; Mizrahi, Ido; Ilyayev, Nadia; Halle, David; Brücher, Bjoern; Bilchik, Anton; Protic, Mladjan; Daumer, Martin; Stojadinovic, Alexander; Itzhak, Avital; Nissan, Aviram

    2013-01-01

    The discovery of microRNA, a group of regulatory short RNA fragments, has added a new dimension to the diagnosis and management of neoplastic diseases. Differential expression of microRNA in a unique pattern in a wide range of tumor types enables researches to develop a microRNA-based assay for source identification of metastatic disease of unknown origin. This is just one example of many microRNA-based cancer diagnostic and prognostic assays in various phases of clinical research.Since colorectal cancer (CRC) is a phenotypic expression of multiple molecular pathways including chromosomal instability (CIN), micro-satellite instability (MIS) and CpG islands promoter hypermethylation (CIMP), there is no one-unique pattern of microRNA expression expected in this disease and indeed, there are multiple reports published, describing different patterns of microRNA expression in CRC.The scope of this manuscript is to provide a comprehensive review of the scientific literature describing the dysregulation of and the potential role for microRNA in the management of CRC. A Pubmed search was conducted using the following MeSH terms, "microRNA" and "colorectal cancer". Of the 493 publications screened, there were 57 papers describing dysregulation of microRNA in CRC.

  19. Prognostics for Microgrid Components

    NASA Technical Reports Server (NTRS)

    Saxena, Abhinav

    2012-01-01

    Prognostics is the science of predicting future performance and potential failures based on targeted condition monitoring. Moving away from the traditional reliability centric view, prognostics aims at detecting and quantifying the time to impending failures. This advance warning provides the opportunity to take actions that can preserve uptime, reduce cost of damage, or extend the life of the component. The talk will focus on the concepts and basics of prognostics from the viewpoint of condition-based systems health management. Differences with other techniques used in systems health management and philosophies of prognostics used in other domains will be shown. Examples relevant to micro grid systems and subsystems will be used to illustrate various types of prediction scenarios and the resources it take to set up a desired prognostic system. Specifically, the implementation results for power storage and power semiconductor components will demonstrate specific solution approaches of prognostics. The role of constituent elements of prognostics, such as model, prediction algorithms, failure threshold, run-to-failure data, requirements and specifications, and post-prognostic reasoning will be explained. A discussion on performance evaluation and performance metrics will conclude the technical discussion followed by general comments on open research problems and challenges in prognostics.

  20. Toward IVHM Prognostics

    NASA Technical Reports Server (NTRS)

    Walsh, Kevin; Venti, Mike

    2007-01-01

    This viewgraph presentation reviews the prognostics of Integrated Vehicle Health Management. The contents include: 1) Aircraft Operations-Today's way of doing business; 2) Prognostics; 3) NASA's instrumentation data-system rack; 4) Data mining for IVHM; 5) NASA GRC's C-MAPSS generic engine model; and 6) Concluding thoughts.

  1. Chromosomal Flexibility

    ERIC Educational Resources Information Center

    Journal of College Science Teaching, 2005

    2005-01-01

    Scientists have shown that a genetic element on one chromosome may direct gene activity on another. Howard Hughes Medical Institute (HHMI) researchers report that a multitasking master-control region appears to over-see both a set of its own genes and a related gene on a nearby chromosome. The findings reinforce the growing importance of location…

  2. Modeling Chromosomes

    ERIC Educational Resources Information Center

    Robertson, Carol

    2016-01-01

    Learning about chromosomes is standard fare in biology classrooms today. However, students may find it difficult to understand the relationships among the "genome", "chromosomes", "genes", a "gene locus", and "alleles". In the simple activity described in this article, which follows the 5E approach…

  3. Prognostic factors in cancer.

    PubMed

    Gospodarowicz, Mary; O'Sullivan, Brian

    2003-01-01

    Diagnosis, prognosis, and treatment are the three core elements of the art of medicine. Modern medicine pays more attention to diagnosis and treatment but prognosis has been a part of the practice of medicine much longer than diagnosis. Cancer is a heterogeneous group of disease characterized by growth, invasion and metastasis. To plan the management of an individual cancer patient, the fundamental knowledge base includes the site of origin of the cancer, its morphologic type, and the prognostic factors specific to that particular patient and cancer. Most prognostic factors literature describes those factors that directly relate to the tumor itself. However, many other factors, not directly related to the tumor, also affect the outcome. To comprehensively represent these factors we propose three broad groupings of prognostic factors: 'tumor'-related prognostic factors, 'host'-related prognostic factors, and 'environment'-related prognostic factors. Some prognostic factors are essential to decisions about the goals and choice treatment, while others are less relevant for these purposes. To guide the use of various prognostic factors we have proposed a grouping of factors based on their relevance in everyday practice; these comprise 'essential,' 'additional,' and 'new and promising factors.' The availability of a comprehensive classification of prognostic factors assures an ordered and deliberate approach to the subject and provide safeguard against skewed approaches that may ignore large parts of the field. The current attention to tumor factors has diminished the importance of 'patient' (i.e., 'host'), and almost completely overshadows the importance of the 'environment'. This ignores the fact that the latter presents the greatest potential for immediate impact. The acceptance of a generic prognostic factor classification would facilitate communication and education about this most important subject in oncology.

  4. Mammalian chromosomes contain cis-acting elements that control replication timing, mitotic condensation, and stability of entire chromosomes.

    PubMed

    Thayer, Mathew J

    2012-09-01

    Recent studies indicate that mammalian chromosomes contain discrete cis-acting loci that control replication timing, mitotic condensation, and stability of entire chromosomes. Disruption of the large non-coding RNA gene ASAR6 results in late replication, an under-condensed appearance during mitosis, and structural instability of human chromosome 6. Similarly, disruption of the mouse Xist gene in adult somatic cells results in a late replication and instability phenotype on the X chromosome. ASAR6 shares many characteristics with Xist, including random mono-allelic expression and asynchronous replication timing. Additional "chromosome engineering" studies indicate that certain chromosome rearrangements affecting many different chromosomes display this abnormal replication and instability phenotype. These observations suggest that all mammalian chromosomes contain "inactivation/stability centers" that control proper replication, condensation, and stability of individual chromosomes. Therefore, mammalian chromosomes contain four types of cis-acting elements, origins, telomeres, centromeres, and "inactivation/stability centers", all functioning to ensure proper replication, condensation, segregation, and stability of individual chromosomes.

  5. TAO1 kinase maintains chromosomal stability by facilitating proper congression of chromosomes.

    PubMed

    Shrestha, Roshan L; Tamura, Naoka; Fries, Anna; Levin, Nicolas; Clark, Joanna; Draviam, Viji M

    2014-06-01

    Chromosomal instability can arise from defects in chromosome-microtubule attachment. Using a variety of drug treatments, we show that TAO1 kinase is required for ensuring the normal congression of chromosomes. Depletion of TAO1 reduces the density of growing interphase and mitotic microtubules in human cells, showing TAO1's role in controlling microtubule dynamics. We demonstrate the aneugenic nature of chromosome-microtubule attachment defects in TAO1-depleted cells using an error-correction assay. Our model further strengthens the emerging paradigm that microtubule regulatory pathways are important for resolving erroneous kinetochore-microtubule attachments and maintaining the integrity of the genome, regardless of the spindle checkpoint status.

  6. [Genomic instability in atherosclerosis].

    PubMed

    Dzhokhadze, T A; Buadze, T Zh; Gaiozishvili, M N; Kakauridze, N G; Lezhava, T A

    2014-11-01

    A comparative study of the level of genomic instability, parameters of quantitative and structural mutations of chromosomes (aberration, aneuploidy, polyploidy) in lymphocyte cultures from patients with atherosclerosis of age 80 years and older (control group - 30-35 years old) was conducted. The possibility of correction of disturbed genomic indicators by peptide bioregulators - Livagen (Lys-Glu-Asp-Ala) and cobalt ions with separate application or in combination was also studied. Control was lymphocyte culture of two healthy respective age groups. It was also shown that patients with atherosclerosis exhibit high level of genomic instability in all studied parameters, regardless of age, which may suggest that there is marked increase in chromatin condensation in atherosclerosis. It was also shown that Livagen (characterized by modifying influence on chromatin) separately and in combination with cobalt ions, promotes normalization of altered genomic indicators of atherosclerosis in both age groups. The results show that Livagen separately and in combination with cobalt ions has impact on chromatin of patients with atherosclerosis. The identified protective action of Livagen proves its efficacy in prevention of atherosclerosis.

  7. Magnetohydrodynamic instability

    NASA Technical Reports Server (NTRS)

    Priest, E. R.; Cargill, P.; Forbes, T. G.; Hood, A. W.; Steinolfson, R. S.

    1986-01-01

    There have been major advances in the theory of magnetic reconnection and of magnetic instability, with important implications for the observations, as follows: (1) Fast and slow magnetic shock waves are produced by the magnetohydrodynamics of reconnection and are potential particle accelerators. (2) The impulsive bursty regime of reconnection gives a rapid release of magnetic energy in a series of bursts. (3) The radiative tearing mode creates cool filamentary structures in the reconnection process. (4) The stability analyses imply that an arcade can become unstable when either its height or twist of plasma pressure become too great.

  8. Synthetic chromosomes.

    PubMed

    Schindler, Daniel; Waldminghaus, Torsten

    2015-11-01

    What a living organism looks like and how it works and what are its components-all this is encoded on DNA, the genetic blueprint. Consequently, the way to change an organism is to change its genetic information. Since the first pieces of recombinant DNA have been used to transform cells in the 1970s, this approach has been enormously extended. Bigger and bigger parts of the genetic information have been exchanged or added over the years. Now we are at a point where the construction of entire chromosomes becomes a reachable goal and first examples appear. This development leads to fundamental new questions, for example, about what is possible and desirable to build or what construction rules one needs to follow when building synthetic chromosomes. Here we review the recent progress in the field, discuss current challenges and speculate on the appearance of future synthetic chromosomes.

  9. Genomic Instability Induced by High and Low Let Ionizing Radiation

    NASA Astrophysics Data System (ADS)

    Limoli, C. L.; Ponnaiya, B.; Corcoran, J. J.; Giedzinski, E.; Kaplan, M. I.; Hartmann, A.; Morgan, W. F.

    Genomic instability is the increased rate of acquisition of alterations in the mammalian genome, and includes such diverse biological endpoints as chromosomal destabilization, aneuploidy, micronucleus formation, sister chromatid exchange, gene mutation and amplification, variations in colony size, reduced plating efficiency, and cellular transformation. Because these multiple endpoints persist long after initial radiation exposure, genomic instability has been proposed to operate as a driving force contributing to genetic plasticity and carcinogenic potential. Many of these radiation-induced endpoints depend qualitatively and quantitatively on genetic background, dose and LET. Differences in the frequency and temporal expression of chromosomal instability depend on all three of the foregoing factors. On the other hand, many of these endpoints appear independent of dose and show bystander effects, implicating non-nuclear targets and epigenetic regulatory mechanisms. The present work will survey results concerning the LET dependence of genomic instability and the role of epigenetic mechanisms, with a particular emphasis on the endpoint of chromosomal in tability

  10. Patterns of Chromosomal Aberrations in Solid Tumors

    PubMed Central

    Grade, Marian; Difilippantonio, Michael J.

    2016-01-01

    Chromosomal abnormalities are a defining feature of solid tumors. Such cytogenetic alterations are mainly classified into structural chromosomal aberrations and copy number alterations, giving rise to aneuploid karyotypes. The increasing detection of these genetic changes allowed the description of specific tumor entities and the associated patterns of gene expression. In fact, tumor-specific landscapes of gross genomic copy number changes, including aneuploidies of entire chromosome arms and chromosomes result in a global deregulation of the transcriptome of cancer cells. Furthermore, the molecular characterization of cytogenetic abnormalities has provided insights into the mechanisms of tumorigenesis and has, in a few instances, led to the clinical implementation of effective diagnostic and prognostic tools, as well as treatment strategies that target a specific genetic abnormality. PMID:26376875

  11. [Y chromosome structural abnormalities and Turner's syndrome].

    PubMed

    Ravel, C; Siffroi, J-P

    2009-06-01

    Although specifically male, the human Y chromosome may be observed in female karyotypes, mostly in women with Turner syndrome stigmata. In women with isolated gonadal dysgenesis but otherwise normal stature, the testis determining factor or SRY gene may have been removed from the Y chromosome or may be mutated. In other women with Turner syndrome, the karyotype is usually abnormal and shows a frequent 45,X/46,XY mosaicism. In these cases, the phenotype depends on the ratio between Y positive and 45,X cell lines in the body. When in mosaicism, Y chromosomes are likely to carry structural abnormalities which explain mitotic instability, such as the existence of two centromeres. Dicentric Y isochromosomes for the short arm (idic[Yp]) or ring Y chromosomes (r[Y]) are the most frequent abnormal Y chromosomes found in infertile patients and in Turner syndrome in mosaic with 45,X cells. Although monocentric, deleted Y chromosomes for the long arm and those carrying microdeletions in the AZF region are also instable and are frequently associated with a 45,X cell line. Management of infertile patients carrying such abnormal Y chromosomes must take into account the risk and the consequences of a mosaicism in the offspring.

  12. Unusual maternal uniparental isodisomic x chromosome mosaicism with asymmetric y chromosomal rearrangement.

    PubMed

    Lee, B Y; Kim, S Y; Park, J Y; Choi, E Y; Kim, D J; Kim, J W; Ryu, H M; Cho, Y H; Park, S Y; Seo, J T

    2014-01-01

    Infertile men with azoospermia commonly have associated microdeletions in the azoospermia factor (AZF) region of the Y chromosome, sex chromosome mosaicism, or sex chromosome rearrangements. In this study, we describe an unusual 46,XX and 45,X mosaicism with a rare Y chromosome rearrangement in a phenotypically normal male patient. The patient's karyotype was 46,XX[50]/45,X[25]/46,X,der(Y)(pter→q11.222::p11.2→pter)[25]. The derivative Y chromosome had a deletion at Yq11.222 and was duplicated at Yp11.2. Two copies of the SRY gene were confirmed by fluorescence in situ hybridization analysis, and complete deletion of the AZFb and AZFc regions was shown by multiplex-PCR for microdeletion analysis. Both X chromosomes of the predominant mosaic cell line (46,XX) were isodisomic and derived from the maternal gamete, as determined by examination of short tandem repeat markers. We postulate that the derivative Y chromosome might have been generated during paternal meiosis or early embryogenesis. Also, we suggest that the very rare mosaicism of isodisomic X chromosomes might be formed during maternal meiosis II or during postzygotic division derived from the 46,X,der(Y)/ 45,X lineage because of the instability of the derivative Y chromosome. To our knowledge, this is the first confirmatory study to verify the origin of a sex chromosome mosaicism with a Y chromosome rearrangement.

  13. Prognostics of Power MOSFET

    NASA Technical Reports Server (NTRS)

    Celaya, Jose Ramon; Saxena, Abhinav; Vashchenko, Vladislay; Saha, Sankalita; Goebel, Kai Frank

    2011-01-01

    This paper demonstrates how to apply prognostics to power MOSFETs (metal oxide field effect transistor). The methodology uses thermal cycling to age devices and Gaussian process regression to perform prognostics. The approach is validated with experiments on 100V power MOSFETs. The failure mechanism for the stress conditions is determined to be die-attachment degradation. Change in ON-state resistance is used as a precursor of failure due to its dependence on junction temperature. The experimental data is augmented with a finite element analysis simulation that is based on a two-transistor model. The simulation assists in the interpretation of the degradation phenomena and SOA (safe operation area) change.

  14. Constitutional ring chromosomes and tumour suppressor genes.

    PubMed Central

    Tommerup, N; Lothe, R

    1992-01-01

    The types of malignancy reported in carriers of constitutional ring chromosomes r(11), r(13), and r(22) are concordant with the chromosomal assignment of tumour suppressor loci associated with Wilms' tumour, retinoblastoma, and meningioma. It is suggested that the somatic instability of ring chromosomes may play a role in this association and that constitutional ring chromosomes may be a source for mapping of tumour suppressor loci with the potential for covering most or all of the human genome. The hypothesis predicts the presence of a locus on chromosome 10 associated with follicular carcinoma of the thyroid, in line with previous cytogenetic findings of rearrangements involving chromosome 10 in thyroid tumours, and a locus on chromosome 22 associated with testicular cancer. Development of neurofibromatoses (NF) that do not fulfil the clinical criteria of neurofibromatosis type 2 (NF2) in carriers with r(22) suggests either the presence of an additional NF locus on chromosome 22 or that ring chromosome mediated predisposition to somatic mutation of a specific tumour suppressor may be associated with atypical development of features usually associated with germline mutations. PMID:1336057

  15. [Immune response and digestive cancers: Prognostic and therapeutic implications].

    PubMed

    Bibeau, Frédéric; Bazille, Céline; Svrcek, Magali; Pierson, Rémi; Lagorce-Pagès, Christine; Cohen, Romain; André, Thierry

    2017-02-01

    The aim of this article is to emphasize the impact of the immune response in digestive cancers, especially from colorectal (CRC) origin. In this setting, an adaptive lymphocytic infiltrate underlines the prognostic impact of the immune response, because it is associated to a favorable outcome. The next challenge will be to validate, in a prospective therapeutic trial, the integration of the immune response as decisional parameter for adjuvant therapy. The immune response is also a predictive parameter in microsatellite instable metastatic CRC, characterized by an adaptive lymphocytic infiltrate, leading to a very high response rate to immune therapies. However, prognostic and predictive biomarkers still need to be optimized in order to better select patients. These data are also valuable for digestive non-colorectal cancers, which are briefly analyzed. The methodology for the assessment of these prognostic and predictive biomarkers, which represents an important issue in precision medicine, is also discussed.

  16. Induced dicentric chromosome formation promotes genomic rearrangements and tumorigenesis.

    PubMed

    Gascoigne, Karen E; Cheeseman, Iain M

    2013-07-01

    Chromosomal rearrangements can radically alter gene products and their function, driving tumor formation or progression. However, the molecular origins and evolution of such rearrangements are varied and poorly understood, with cancer cells often containing multiple, complex rearrangements. One mechanism that can lead to genomic rearrangements is the formation of a "dicentric" chromosome containing two functional centromeres. Indeed, such dicentric chromosomes have been observed in cancer cells. Here, we tested the ability of a single dicentric chromosome to contribute to genomic instability and neoplastic conversion in vertebrate cells. We developed a system to transiently and reversibly induce dicentric chromosome formation on a single chromosome with high temporal control. We find that induced dicentric chromosomes are frequently damaged and mis-segregated during mitosis, and that this leads to extensive chromosomal rearrangements including translocations with other chromosomes. Populations of pre-neoplastic cells in which a single dicentric chromosome is induced acquire extensive genomic instability and display hallmarks of cellular transformation including anchorage-independent growth in soft agar. Our results suggest that a single dicentric chromosome could contribute to tumor initiation.

  17. Chromosome Microarray.

    PubMed

    Anderson, Sharon

    2016-01-01

    Over the last half century, knowledge about genetics, genetic testing, and its complexity has flourished. Completion of the Human Genome Project provided a foundation upon which the accuracy of genetics, genomics, and integration of bioinformatics knowledge and testing has grown exponentially. What is lagging, however, are efforts to reach and engage nurses about this rapidly changing field. The purpose of this article is to familiarize nurses with several frequently ordered genetic tests including chromosomes and fluorescence in situ hybridization followed by a comprehensive review of chromosome microarray. It shares the complexity of microarray including how testing is performed and results analyzed. A case report demonstrates how this technology is applied in clinical practice and reveals benefits and limitations of this scientific and bioinformatics genetic technology. Clinical implications for maternal-child nurses across practice levels are discussed.

  18. Chromosome Analysis

    NASA Technical Reports Server (NTRS)

    1998-01-01

    Perceptive Scientific Instruments, Inc., provides the foundation for the Powergene line of chromosome analysis and molecular genetic instrumentation. This product employs image processing technology from NASA's Jet Propulsion Laboratory and image enhancement techniques from Johnson Space Center. Originally developed to send pictures back to earth from space probes, digital imaging techniques have been developed and refined for use in a variety of medical applications, including diagnosis of disease.

  19. Clonal analysis of delayed karyotypic abnormalities and gene mutations in radiation-induced genetic instability.

    PubMed Central

    Grosovsky, A J; Parks, K K; Giver, C R; Nelson, S L

    1996-01-01

    Many tumors exhibit extensive chromosomal instability, but karyotypic alterations will be significant in carcinogenesis only by influencing specific oncogenes or tumor suppressor loci within the affected chromosomal segments. In this investigation, the specificity of chromosomal rearrangements attributable to radiation-induced genomic instability is detailed, and a qualitative and quantitative correspondence with mutagenesis is demonstrated. Chromosomal abnormalities preferentially occurred near the site of prior rearrangements, resulting in complex abnormalities, or near the centromere, resulting in deletion or translocation of the entire chromosome arm, but no case of an interstitial chromosomal deletion was observed. Evidence for chromosomal instability in the progeny of irradiated cells also included clonal karyotypic heterogeneity. The persistence of instability was demonstrated for at least 80 generations by elevated mutation rates at the heterozygous, autosomal marker locus tk. Among those TK- mutants that showed a loss of heterozygosity, a statistically significant increase in mutation rate was observed only for those in which the loss of heterozygosity encompasses the telomeric region. This mutational specificity corresponds with the prevalence of terminal deletions, additions, and translocations, and the absence of interstitial deletions, in karyotypic analysis. Surprisingly, the elevated rate of TK- mutations is also partially attributable to intragenic base substitutions and small deletions, and DNA sequence analysis of some of these mutations is presented. Complex chromosomal abnormalities appear to be the most significant indicators of a high rate of persistent genetic instability which correlates with increased rates of both intragenic and chromosomal-scale mutations at tk. PMID:8887655

  20. Significance Analysis of Prognostic Signatures

    PubMed Central

    Beck, Andrew H.; Knoblauch, Nicholas W.; Hefti, Marco M.; Kaplan, Jennifer; Schnitt, Stuart J.; Culhane, Aedin C.; Schroeder, Markus S.; Risch, Thomas; Quackenbush, John; Haibe-Kains, Benjamin

    2013-01-01

    A major goal in translational cancer research is to identify biological signatures driving cancer progression and metastasis. A common technique applied in genomics research is to cluster patients using gene expression data from a candidate prognostic gene set, and if the resulting clusters show statistically significant outcome stratification, to associate the gene set with prognosis, suggesting its biological and clinical importance. Recent work has questioned the validity of this approach by showing in several breast cancer data sets that “random” gene sets tend to cluster patients into prognostically variable subgroups. This work suggests that new rigorous statistical methods are needed to identify biologically informative prognostic gene sets. To address this problem, we developed Significance Analysis of Prognostic Signatures (SAPS) which integrates standard prognostic tests with a new prognostic significance test based on stratifying patients into prognostic subtypes with random gene sets. SAPS ensures that a significant gene set is not only able to stratify patients into prognostically variable groups, but is also enriched for genes showing strong univariate associations with patient prognosis, and performs significantly better than random gene sets. We use SAPS to perform a large meta-analysis (the largest completed to date) of prognostic pathways in breast and ovarian cancer and their molecular subtypes. Our analyses show that only a small subset of the gene sets found statistically significant using standard measures achieve significance by SAPS. We identify new prognostic signatures in breast and ovarian cancer and their corresponding molecular subtypes, and we show that prognostic signatures in ER negative breast cancer are more similar to prognostic signatures in ovarian cancer than to prognostic signatures in ER positive breast cancer. SAPS is a powerful new method for deriving robust prognostic biological signatures from clinically annotated

  1. Radiation-induced genomic instability: radiation quality and dose response

    NASA Technical Reports Server (NTRS)

    Smith, Leslie E.; Nagar, Shruti; Kim, Grace J.; Morgan, William F.

    2003-01-01

    Genomic instability is a term used to describe a phenomenon that results in the accumulation of multiple changes required to convert a stable genome of a normal cell to an unstable genome characteristic of a tumor. There has been considerable recent debate concerning the importance of genomic instability in human cancer and its temporal occurrence in the carcinogenic process. Radiation is capable of inducing genomic instability in mammalian cells and instability is thought to be the driving force responsible for radiation carcinogenesis. Genomic instability is characterized by a large collection of diverse endpoints that include large-scale chromosomal rearrangements and aberrations, amplification of genetic material, aneuploidy, micronucleus formation, microsatellite instability, and gene mutation. The capacity of radiation to induce genomic instability depends to a large extent on radiation quality or linear energy transfer (LET) and dose. There appears to be a low dose threshold effect with low LET, beyond which no additional genomic instability is induced. Low doses of both high and low LET radiation are capable of inducing this phenomenon. This report reviews data concerning dose rate effects of high and low LET radiation and their capacity to induce genomic instability assayed by chromosomal aberrations, delayed lethal mutations, micronuclei and apoptosis.

  2. Radiation-induced genomic instability

    NASA Technical Reports Server (NTRS)

    Kronenberg, A.

    1994-01-01

    Quantitative assessment of the heritable somatic effects of ionizing radiation exposures has relied upon the assumption that radiation-induced lesions were 'fixed' in the DNA prior to the first postirradiation mitosis. Lesion conversion was thought to occur during the initial round of DNA replication or as a consequence of error-prone enzymatic processing of lesions. The standard experimental protocols for the assessment of a variety of radiation-induced endpoints (cell death, specific locus mutations, neoplastic transformation and chromosome aberrations) evaluate these various endpoints at a single snapshot in time. In contrast with the aforementioned approaches, some studies have specifically assessed radiation effects as a function of time following exposure. Evidence has accumulated in support of the hypothesis that radiation exposure induces a persistent destabilization of the genome. This instability has been observed as a delayed expression of lethal mutations, as an enhanced rate of accumulation of non-lethal heritable alterations, and as a progressive intraclonal chromosomal heterogeneity. The genetic controls and biochemical mechanisms underlying radiation-induced genomic instability have not yet been delineated. The aim is to integrate the accumulated evidence that suggests that radiation exposure has a persistent effect on the stability of the mammalian genome.

  3. Genome-wide mapping of histone H3K9me2 in acute myeloid leukemia reveals large chromosomal domains associated with massive gene silencing and sites of genome instability

    PubMed Central

    Popova, Evgenya Y.; Keasey, Nikki; Loughran, Thomas P.; Claxton, David F.

    2017-01-01

    A facultative heterochromatin mark, histone H3 lysine 9 dimethylation (H3K9me2), which is mediated by histone methyltransferases G9a/GLP (EHMT2/1), undergoes dramatic rearrangements during myeloid cell differentiation as observed by chromatin imaging. To determine whether these structural transitions also involve genomic repositioning of H3K9me2, we used ChIP-sequencing to map genome-wide topography of H3K9me2 in normal human granulocytes, normal CD34+ hematopoietic progenitors, primary myeloblasts from acute myeloid leukemia (AML) patients, and a model leukemia cell line K562. We observe that H3K9me2 naturally repositions from the previously designated “repressed” chromatin state in hematopoietic progenitors to predominant association with heterochromatin regions in granulocytes. In contrast, AML cells accumulate H3K9me2 on previously undefined large (> 100 Kb) genomic blocks that are enriched with AML-specific single nucleotide variants, sites of chromosomal translocations, and genes downregulated in AML. Specifically, the AML-specific H3K9me2 blocks are enriched with genes regulated by the proto-oncogene ERG that promotes stem cell characteristics. The AML-enriched H3K9me2 blocks (in contrast to the heterochromatin-associated H3K9me2 blocks enriched in granulocytes) are reduced by pharmacological inhibition of the histone methyltransferase G9a/GLP in K562 cells concomitantly with transcriptional activation of ERG and ETS1 oncogenes. Our data suggest that G9a/GLP mediate formation of transient H3K9me2 blocks that are preserved in AML myeloblasts and may lead to an increased rate of AML-specific mutagenesis and chromosomal translocations. PMID:28301528

  4. Littoral Refractivity Prognostic Advancement

    DTIC Science & Technology

    2009-09-30

    situational awareness of the 3D radio-frequency (RF) propagation environment and a quantitative diagnostic and prognostic capability for assessing sub- and...Rev. 8-98) Prescribed by ANSI Std Z39-18 2 with the benchmark showing the quantitative improvement with each stage of model development...grid point. Modified the NSWCDD littoral clutter model ( LCM ) to accept COAMPS® derived refractivity fields. Analyzed the impact on ducting of

  5. Chromosomal destabilization during gene amplification.

    PubMed Central

    Ruiz, J C; Wahl, G M

    1990-01-01

    Acentric extrachromosomal elements, such as submicroscopic autonomously replicating circular molecules (episomes) and double minute chromosomes, are common early, and in some cases initial, intermediates of gene amplification in many drug-resistant and tumor cell lines. In order to gain a more complete understanding of the amplification process, we investigated the molecular mechanisms by which such extrachromosomal elements are generated and we traced the fate of these amplification intermediates over time. The model system consists of a Chinese hamster cell line (L46) created by gene transfer in which the initial amplification product was shown previously to be an unstable extrachromosomal element containing an inverted duplication spanning more than 160 kilobases (J. C. Ruiz and G. M. Wahl, Mol. Cell. Biol. 8:4302-4313, 1988). In this study, we show that these molecules were formed by a process involving chromosomal deletion. Fluorescence in situ hybridization was performed at multiple time points on cells with amplified sequences. These studies reveal that the extrachromosomal molecules rapidly integrate into chromosomes, often near or at telomeres, and once integrated, the amplified sequences are themselves unstable. These data provide a molecular and cytogenetic chronology for gene amplification in this model system; an early event involves deletion to generate extrachromosomal elements, and subsequent integration of these elements precipitates a cascade of chromosome instability. Images PMID:2188107

  6. Microsatellite instability in early sporadic breast cancer.

    PubMed Central

    Shaw, J. A.; Walsh, T.; Chappell, S. A.; Carey, N.; Johnson, K.; Walker, R. A.

    1996-01-01

    We have studied the incidence of microsatellite instability at three trinucleotide repeats and seven dinucleotide repeats from five chromosomal regions, in a group of 30 mammographically detected 'early' invasive breast cancers and correlated its occurrence with clinicopathological parameters. The myotonic dystrophy (DM-1) trinucleotide repeat was analysed in 48 additional cases. In 4 out of 78 (5%) paired tumour-normal DNA samples we found evidence of somatic microsatellite instability at DM-1: a novel allele of a different size was seen in the tumour DNA which was not present in the normal DNA sample. All four tumours that showed evidence of instability were from the core group of 30 cases (13%) and were well or moderately differentiated, oestrogen receptor-positive, infiltrating ductal carcinomas. Two of these tumours were unstable at nine of ten loci studied, both trinucleotide and dinucleotide repeats. DNA prepared from different normal tissues showed no evidence of instability, for all four instability cases. These data indicate that microsatellite instability is specific to the tumour DNA and is an early event in the genesis of some sporadic breast cancers. Images Figure 1 PMID:8645585

  7. Unrepaired DNA damage facilitates elimination of uniparental chromosomes in interspecific hybrid cells.

    PubMed

    Wang, Zheng; Yin, Hao; Lv, Lei; Feng, Yingying; Chen, Shaopeng; Liang, Junting; Huang, Yun; Jiang, Xiaohua; Jiang, Hanwei; Bukhari, Ihtisham; Wu, Lijun; Cooke, Howard J; Shi, Qinghua

    2014-01-01

    Elimination of uniparental chromosomes occurs frequently in interspecific hybrid cells. For example, human chromosomes are always eliminated during clone formation when human cells are fused with mouse cells. However, the underlying mechanisms are still elusive. Here, we show that the elimination of human chromosomes in human-mouse hybrid cells is accompanied by continued cell division at the presence of DNA damage on human chromosomes. Deficiency in DNA damage repair on human chromosomes occurs after cell fusion. Furthermore, increasing the level of DNA damage on human chromosomes by irradiation accelerates human chromosome loss in hybrid cells. Our results indicate that the elimination of human chromosomes in human-mouse hybrid cells results from unrepaired DNA damage on human chromosomes. We therefore provide a novel mechanism underlying chromosome instability which may facilitate the understanding of carcinogenesis.

  8. Centromere destiny in dicentric chromosomes: New insights from the evolution of human chromosome 2 ancestral centromeric region.

    PubMed

    Chiatante, Giorgia; Giannuzzi, Giuliana; Calabrese, Francesco Maria; Eichler, Evan E; Ventura, Mario

    2017-03-15

    Dicentric chromosomes are products of genomic rearrangements that place two centromeres on the same chromosome. Due to the presence of two primary constrictions, they are inherently unstable and overcome their instability by epigenetically inactivating and/or deleting one of the two centromeres, thus resulting in functionally monocentric chromosomes that segregate normally during cell division. Our understanding to date of dicentric chromosome formation, behavior and fate has been largely inferred from observational studies in plants and humans as well as artificially produced de novo dicentrics in yeast and in human cells. We investigate the most recent product of a chromosome fusion event fixed in the human lineage, human chromosome 2, whose stability was acquired by the suppression of one centromere, resulting in a unique difference in chromosome number between humans (46 chromosomes) and our most closely related ape relatives (48 chromosomes). Using molecular cytogenetics, sequencing and comparative sequence data, we deeply characterize the relicts of the chromosome 2q ancestral centromere and its flanking regions, gaining insight into the ancestral organization that can be easily broadened to all acrocentric chromosome centromeres. Moreover, our analyses offered the opportunity to trace the evolutionary history of rDNA and satellite III sequences among great apes, thus suggesting a new hypothesis for the preferential inactivation of some human centromeres, including IIq. Our results suggest two possible centromere inactivation models to explain the evolutionarily stabilization of human chromosome 2 over the last 5-6 million years. Our results strongly favor centromere excision through a one-step process.

  9. Molecular Mechanisms of Radiation-Induced Genomic Instability in Human Cells

    SciTech Connect

    Howard L. Liber; Jeffrey L. Schwartz

    2005-10-31

    There are many different model systems that have been used to study chromosome instability. What is clear from all these studies is that conclusions concerning chromosome instability depend greatly on the model system and instability endpoint that is studied. The model system for our studies was the human B-lymphoblastoid cell line TK6. TK6 was isolated from a spontaneously immortalized lymphoblast culture. Thus there was no outside genetic manipulation used to immortalize them. TK6 is a relatively stable p53-normal immortal cell line (37). It shows low gene and chromosome mutation frequencies (19;28;31). Our general approach to studying instability in TK6 cells has been to isolate individual clones and analyze gene and chromosome mutation frequencies in each. This approach maximizes the possibility of detecting low frequency events that might be selected against in mass cultures.

  10. Electron heat flux instability

    NASA Astrophysics Data System (ADS)

    Saeed, Sundas; Sarfraz, M.; Yoon, P. H.; Lazar, M.; Qureshi, M. N. S.

    2017-02-01

    The heat flux instability is an electromagnetic mode excited by a relative drift between the protons and two-component core-halo electrons. The most prominent application may be in association with the solar wind where drifting electron velocity distributions are observed. The heat flux instability is somewhat analogous to the electrostatic Buneman or ion-acoustic instability driven by the net drift between the protons and bulk electrons, except that the heat flux instability operates in magnetized plasmas and possesses transverse electromagnetic polarization. The heat flux instability is also distinct from the electrostatic counterpart in that it requires two electron species with relative drifts with each other. In the literature, the heat flux instability is often called the 'whistler' heat flux instability, but it is actually polarized in the opposite sense to the whistler wave. This paper elucidates all of these fundamental plasma physical properties associated with the heat flux instability starting from a simple model, and gradually building up more complexity towards a solar wind-like distribution functions. It is found that the essential properties of the instability are already present in the cold counter-streaming electron model, and that the instability is absent if the protons are ignored. These instability characteristics are highly reminiscent of the electron firehose instability driven by excessive parallel temperature anisotropy, propagating in parallel direction with respect to the ambient magnetic field, except that the free energy source for the heat flux instability resides in the effective parallel pressure provided by the counter-streaming electrons.

  11. Relationships between chromosome structure and chromosomal aberrations

    NASA Astrophysics Data System (ADS)

    Eidelman, Yuri; Andreev, Sergey

    An interphase nucleus of human lymphocyte was simulated by the novel Monte Carlo tech-nique. The main features of interphase chromosome structure and packaging were taken into account: different levels of chromatin organisation; nonrandom localisation of chromosomes within a nucleus; chromosome loci dynamics. All chromosomes in a nucleus were modelled as polymer globules. A dynamic pattern of intra/interchromosomal contacts was simulated. The detailed information about chromosomal contacts, such as distribution of intrachromoso-mal contacts over the length of each chromosome and dependence of contact probability on genomic separation between chromosome loci, were calculated and compared to the new exper-imental data obtained by the Hi-C technique. Types and frequencies of simple and complex radiation-induced chromosomal exchange aberrations (CA) induced by X-rays were predicted with taking formation and decay of chromosomal contacts into account. Distance dependence of exchange formation probability was calculated directly. mFISH data for human lymphocytes were analysed. The calculated frequencies of simple CA agreed with the experimental data. Complex CA were underestimated despite the dense packaging of chromosome territories within a nucleus. Possible influence of chromosome-nucleus structural organisation on the frequency and spectrum of radiation-induced chromosome aberrations is discussed.

  12. Turbine instabilities: Case histories

    NASA Technical Reports Server (NTRS)

    Laws, C. W.

    1985-01-01

    Several possible causes of turbine rotor instability are discussed and the related design features of a wide range of turbomachinery types and sizes are considered. The instrumentation options available for detecting rotor instability and assessing its severity are also discussed.

  13. Kinesics of Affective Instability.

    ERIC Educational Resources Information Center

    Dil, Nasim

    1979-01-01

    Discusses the rationale of studying kinesics of affective instability, describes the phenonmenon of affective instability, examines the role of kinesics in the overall process of communication, and presents three case studies. (Author/AM)

  14. Genetic instability in Streptomyces ambofaciens: inducibility and associated genome plasticity.

    PubMed

    Simonet, J M; Schneider, D; Volff, J N; Dary, A; Decaris, B

    1992-06-15

    DNA amplification and deletions occur at high frequency in unstable regions localized on the Streptomyces ambofaciens chromosome. The structure of these regions was investigated, leading to the identification of internal reiterations which could play a role in the deletion and/or amplification mechanism(s). UV irradiation and treatments with mitomycin C, oxolinic acid and novobiocin were shown to efficiently induce genetic instability. Finally, mutator strains were isolated, in which genetic instability was dramatically increased. The involvement of an SOS-like response in genetic instability in S. ambofaciens is proposed.

  15. Human chromosome 8.

    PubMed Central

    Wood, S

    1988-01-01

    The role of human chromosome 8 in genetic disease together with the current status of the genetic linkage map for this chromosome is reviewed. Both hereditary genetic disease attributed to mutant alleles at gene loci on chromosome 8 and neoplastic disease owing to somatic mutation, particularly chromosomal translocations, are discussed. PMID:3070042

  16. Mitotic chromosome structure

    SciTech Connect

    Heermann, Dieter W.

    2012-07-15

    Mounting evidence is compiling linking the physical organizational structure of chromosomes and the nuclear structure to biological function. At the base of the physical organizational structure of both is the concept of loop formation. This implies that physical proximity within chromosomes is provided for otherwise distal genomic regions and thus hierarchically organizing the chromosomes. Together with entropy many experimental observations can be explained with these two concepts. Among the observations that can be explained are the measured physical extent of the chromosomes, their shape, mechanical behavior, the segregation into territories (chromosomal and territories within chromosomes), the results from chromosome conformation capture experiments, as well as linking gene expression to structural organization.

  17. Bystander effects in radiation-induced genomic instability

    NASA Technical Reports Server (NTRS)

    Morgan, William F.; Hartmann, Andreas; Limoli, Charles L.; Nagar, Shruti; Ponnaiya, Brian

    2002-01-01

    Exposure of GM10115 hamster-human hybrid cells to X-rays can result in the induction of chromosomal instability in the progeny of surviving cells. This instability manifests as the dynamic production of novel sub-populations of cells with unique cytogenetic rearrangements involving the "marker" human chromosome. We have used the comet assay to investigate whether there was an elevated level of endogenous DNA breaks in chromosomally unstable clones that could provide a source for the chromosomal rearrangements and thus account for the persistent instability observed. Our results indicate no significant difference in comet tail measurement between non-irradiated and radiation-induced chromosomally unstable clones. Using two-color fluorescence in situ hybridization we also investigated whether recombinational events involving the interstitial telomere repeat-like sequences in GM10115 cells were involved at frequencies higher than random processes would otherwise predict. Nine of 11 clones demonstrated a significantly higher than expected involvement of these interstitial telomere repeat-like sequences at the recombination junction between the human and hamster chromosomes. Since elevated levels of endogenous breaks were not detected in unstable clones we propose that epigenetic or bystander effects (BSEs) lead to the activation of recombinational pathways that perpetuate the unstable phenotype. Specifically, we expand upon the hypothesis that radiation induces conditions and/or factors that stimulate the production of reactive oxygen species (ROS). These reactive intermediates then contribute to a chronic pro-oxidant environment that cycles over multiple generations, promoting chromosomal recombination and other phenotypes associated with genomic instability.

  18. Evolutionary interaction between W/Y chromosome and transposable elements.

    PubMed

    Śliwińska, Ewa B; Martyka, Rafał; Tryjanowski, Piotr

    2016-06-01

    The W/Y chromosome is unique among chromosomes as it does not recombine in its mature form. The main side effect of cessation of recombination is evolutionary instability and degeneration of the W/Y chromosome, or frequent W/Y chromosome turnovers. Another important feature of W/Y chromosome degeneration is transposable element (TEs) accumulation. Transposon accumulation has been confirmed for all W/Y chromosomes that have been sequenced so far. Models of W/Y chromosome instability include the assemblage of deleterious mutations in protein coding genes, but do not include the influence of transposable elements that are accumulated gradually in the non-recombining genome. The multiple roles of genomic TEs, and the interactions between retrotransposons and genome defense proteins are currently being studied intensively. Small RNAs originating from retrotransposon transcripts appear to be, in some cases, the only mediators of W/Y chromosome function. Based on the review of the most recent publications, we present knowledge on W/Y evolution in relation to retrotransposable element accumulation.

  19. Instability of rectangular jets

    NASA Technical Reports Server (NTRS)

    Tam, Christopher K. W.; Thies, Andrew T.

    1992-01-01

    The instability of rectangular jets is investigated using a vortex sheet model. It is shown that such jets support four linearly independent families of instability waves. Within each family there are infinitely many modes. A way to classify these modes according to the characteristics of their mode shapes or eigenfunctions is proposed. A parametric study of the instability wave characteristics has been carried out. A sample of the numerical results is reported here. It is found that the first and third modes of each instability wave family are corner modes. The pressure fluctuations associated with these instability waves are localized near the corners of the jet. The second mode, however, is a center mode with maximum fluctuations concentrated in the central portion of the jet flow. The center mode has the largest spatial growth rate. It is anticipated that as the instability waves propagate downstream the center mode would emerge as the dominant instability of the jet.

  20. B Chromosomes - A Matter of Chromosome Drive.

    PubMed

    Houben, Andreas

    2017-01-01

    B chromosomes are supernumerary chromosomes which are often preferentially inherited, deviating from usual Mendelian segregation. The balance between the so-called chromosome drive and the negative effects that the presence of Bs applies on the fitness of their host determines the frequency of Bs in a particular population. Drive is the key for understanding most B chromosomes. Drive occurs in many ways at pre-meiotic, meiotic or post-meiotic divisions, but the molecular mechanism remains unclear. The cellular mechanism of drive is reviewed based on the findings obtained for the B chromosomes of rye, maize and other species. How novel analytical tools will expand our ability to uncover the biology of B chromosome drive is discussed.

  1. Microsatellite instability in prostate cancer

    SciTech Connect

    Shan, A.L.; Wick, M.J.; Persons, D.L.

    1994-09-01

    Microsatellite instability (MIN) has been documented in hereditary nonpolyposis colorectal cancer (HNPCC) as well as in sporadic forms of human cancers. Two of the genes which appear to be responsible for this particular tumor phenotype, hMSH2 and hMLH1, have now been identified. To determine the potential role of these mutator genes in prostate cancer, we have examined 95 prostate adenocarcinomas (40 paraffin embedded and 55 fresh frozen) for the presence of genetic instability at four microsatellite markers. The markers are localized to chromosome arms 5q(APC-CA1), 8p(Mfd 210Z), 15q(635/636), and 17q(p53-CA). Patients from whom paraffin embedded material was obtained were divided into short term (<3 years, n=18), and long term (>3 years, n=22) survivors. Of the 95 tumors examined, only four tumors (4%) demonstrated MIN: two tumors demonstrated MIN at 3 loci (p53-CA, APC-CA1, 635/636), one tumor demonstrated MIN at 2 loci (APC-CA1 and 635/636), and one tumor demonstrated instability at 635/636 only. All tumors exhibiting MIN had Gleason scores of {ge} 4+4. A correlation between MIN and survival was not observed. Information on family history was limited. However, of the two patients demonstrating MIN at three loci, one patient was diagnosed with a second malignancy (TCC of the ureter), but otherwise had a negative family history, while the second patient had one first degree relative with esophageal cancer. The patient demonstrating MIN at two loci had a negative family history, while the remaining patient had two first degree relatives with cancer (prostate and stomach). These results suggest that hMSH2 and hMLH1 (as reflected by the small percentage of tumors displaying MIN) do not play a prominent role in the process of prostate tumorigenesis.

  2. The Precarious Prokaryotic Chromosome

    PubMed Central

    2014-01-01

    Evolutionary selection for optimal genome preservation, replication, and expression should yield similar chromosome organizations in any type of cells. And yet, the chromosome organization is surprisingly different between eukaryotes and prokaryotes. The nuclear versus cytoplasmic accommodation of genetic material accounts for the distinct eukaryotic and prokaryotic modes of genome evolution, but it falls short of explaining the differences in the chromosome organization. I propose that the two distinct ways to organize chromosomes are driven by the differences between the global-consecutive chromosome cycle of eukaryotes and the local-concurrent chromosome cycle of prokaryotes. Specifically, progressive chromosome segregation in prokaryotes demands a single duplicon per chromosome, while other “precarious” features of the prokaryotic chromosomes can be viewed as compensations for this severe restriction. PMID:24633873

  3. B-chromosome evolution.

    PubMed Central

    Camacho, J P; Sharbel, T F; Beukeboom, L W

    2000-01-01

    B chromosomes are extra chromosomes to the standard complement that occur in many organisms. They can originate in a number of ways including derivation from autosomes and sex chromosomes in intra- and interspecies crosses. Their subsequent molecular evolution resembles that of univalent sex chromosomes, which involves gene silencing, heterochromatinization and the accumulation of repetitive DNA and transposons. B-chromosome frequencies in populations result from a balance between their transmission rates and their effects on host fitness. Their long-term evolution is considered to be the outcome of selection on the host genome to eliminate B chromosomes or suppress their effects and on the B chromosome's ability to escape through the generation of new variants. Because B chromosomes interact with the standard chromosomes, they can play an important role in genome evolution and may be useful for studying molecular evolutionary processes. PMID:10724453

  4. Widespread telomere instability in prostatic lesions.

    PubMed

    Tu, LiRen; Huda, Nazmul; Grimes, Brenda R; Slee, Roger B; Bates, Alison M; Cheng, Liang; Gilley, David

    2016-05-01

    A critical function of the telomere is to disguise chromosome ends from cellular recognition as double strand breaks, thereby preventing aberrant chromosome fusion events. Such chromosome end-to-end fusions are known to initiate genomic instability via breakage-fusion-bridge cycles. Telomere dysfunction and other forms of genomic assault likely result in misregulation of genes involved in growth control, cell death, and senescence pathways, lowering the threshold to malignancy and likely drive disease progression. Shortened telomeres and anaphase bridges have been reported in a wide variety of early precursor and malignant cancer lesions including those of the prostate. These findings are being extended using methods for the analysis of telomere fusions (decisive genetic markers for telomere dysfunction) specifically within human tissue DNA. Here we report that benign prostatic hyperplasia (BPH), high-grade prostatic intraepithelial neoplasia (PIN), and prostate cancer (PCa) prostate lesions all contain similarly high frequencies of telomere fusions and anaphase bridges. Tumor-adjacent, histologically normal prostate tissue generally did not contain telomere fusions or anaphase bridges as compared to matched PCa tissues. However, we found relatively high levels of telomerase activity in this histologically normal tumor-adjacent tissue that was reduced but closely correlated with telomerase levels in corresponding PCa samples. Thus, we present evidence of high levels of telomere dysfunction in BPH, an established early precursor (PIN) and prostate cancer lesions but not generally in tumor adjacent normal tissue. Our results suggest that telomere dysfunction may be a common gateway event leading to genomic instability in prostate tumorigenesis. .

  5. Supernumerary small ring chromosome.

    PubMed Central

    Kaffe, S; Kim, H J; Hsu, L Y; Brill, C B; Hirschhorn, K

    1977-01-01

    A supernumerary small ring chromosome was found in 30% of cultured peripheral leucocytes and 50% of skin fibroblasts in a 6-year-old boy with mild mental retardation and midline cleft palate. The extra chromosome appeared to carry a densely staining region on Giemsa banding. The banding patterns of the remaining 46 chromosomes were normal. C banding indicated that the ring chromosome contained mainly centromeric constitutive heterochromatin. Chromosome analysis of both parents showed normal karyotypes by both conventional and banding techniques; thus the origin of the ring chromosome could not be determined. Images PMID:604496

  6. Prognostic Biomarkers in Ovarian Cancer

    PubMed Central

    Huang, Jie; Hu, Wei; Sood, Anil K

    2014-01-01

    Epithelial ovarian cancer (EOC) remains the most lethal gynecological malignancy despite several decades of progress in diagnosis and treatment. Taking advantage of the robust development of discovery and utility of prognostic biomarkers, clinicians and researchers are developing personalized and targeted treatment strategies. This review encompasses recently discovered biomarkers of ovarian cancer, the utility of published prognostic biomarkers for EOC (especially biomarkers related to angiogenesis and key signaling pathways), and their integration into clinical practice. PMID:22045356

  7. Generalities on combustion instabilities

    NASA Astrophysics Data System (ADS)

    Kuentzmann, Paul

    The main manifestations of combustion instabilities are reviewed, and the specific characteristics of instabilities in solid-propellant rocket engines are analyzed, with the Minuteman III third-stage engine and the SRB engine of Titan 34 D considered as examples. The main approaches for predicting combustion instabilities are discussed, including the linear approach based on the acoustic balance, the nonlinear mode-coupling approach, and the nonlinear approach using numerical calculation. Projected directions for future research are also examined.

  8. Ordinary electromagnetic mode instability

    NASA Technical Reports Server (NTRS)

    Cheng, C. Z.

    1974-01-01

    The instability of the ordinary electromagnetic mode propagating perpendicular to an external magnetic field is studied for a single-species plasma with ring velocity distribution. The marginal instability boundaries for both the purely growing mode and the propagating growing modes are calculated from the instability criteria. The dispersion characteristics for various sets of plasma parameters are also given. The typical growth rates are of the order of the cyclotron frequency.

  9. Instability in Rotating Machinery

    NASA Technical Reports Server (NTRS)

    1985-01-01

    The proceedings contain 45 papers on a wide range of subjects including flow generated instabilities in fluid flow machines, cracked shaft detection, case histories of instability phenomena in compressors, turbines, and pumps, vibration control in turbomachinery (including antiswirl techniques), and the simulation and estimation of destabilizing forces in rotating machines. The symposium was held to serve as an update on the understanding and control of rotating machinery instability problems.

  10. A framework to quantify karyotype variation associated with CHO cell line instability at a single-cell level.

    PubMed

    Baik, Jong Youn; Lee, Kelvin H

    2017-05-01

    Chinese hamster ovary (CHO) cells, the major mammalian host cells for biomanufacturing of therapeutic proteins, have been extensively investigated to enhance productivity and product quality. However, cell line instability resulting in unexpected changes in productivity or product quality continues to be a challenge. Based on previous reports about causes and characteristics of production instability, we hypothesized that chromosomal rearrangements due to genomic instability are associated with production instability and that these events can be characterized. We developed a production instability model using secreted alkaline phosphatase (SEAP)-expressing CHO cells (CHO-SEAP) as well as a framework to quantify chromosomal rearrangements by karyotyping. In the absence of methotrexate (MTX), CHO-SEAP cells exhibited a slightly increased growth rate, a significantly decreased specific productivity, and changes in the chromosomal rearrangement ratio of seven chromosomes. In contrast, when MTX was re-introduced, the growth rate and SEAP productivity reversed to the initial values, demonstrating the reversibility of production instability in CHO-SEAP cells. Fluorescence in situ hybridization analysis identified that the SEAP genes were incorporated in the chromosomal rearrangement (insertion) part of the der(Z9) chromosome. Karyotype analysis indicated that the insertion ratio of the der(Z9) chromosome decreased in the CHO-SEAP cells grown without MTX, demonstrating a correlation between chromosomal rearrangement and production instability. Our results support a mechanism for production instability, wherein a randomly generated chromosomal rearrangement (or genotype) results in cells with a growth advantage that is also associated with non (or low)-producing traits. As a result, the non-producing cells grow faster and thereby outgrow the producing population. Biotechnol. Bioeng. 2017;114: 1045-1053. © 2016 Wiley Periodicals, Inc.

  11. Ring chromosome 4.

    PubMed Central

    McDermott, A; Voyce, M A; Romain, D

    1977-01-01

    A mentally and physically retarded boy with a 46,XY,ring (4) (p16q35) chromosome complement is described. Chromosome banding showed that the amount of chromosome material deleted from the ring chromosome 4 was minimal, apparently no more than the telomeres. Chromosomal aberrations appear to be restricted to the production of double-sized dicentric rings, and aneuploidy. The mosiacism resulting from the behavioural peculiarities of ring chromosomes is described as dynamic mosaicism. It is suggested that the clinical features associated with this ring chromosome are more likely to be the result of the effects of a diploid/monosomy 4/polysomy 4 mosaicism than to the deficiency of the telomeric regions of the chromosome. Images PMID:881718

  12. Chromosome Disorder Outreach

    MedlinePlus

    ... BLOG Join Us Donate You are not alone. Chromosome Disorder Outreach, Inc. is a non-profit organization, ... Support For all those diagnosed with any rare chromosome disorder. Since 1992, CDO has supported the parents ...

  13. Human X chromosome

    SciTech Connect

    1993-12-31

    Chapter 21, describes in detail the human X chromosome. X chromatin (or Barr body) formation, inactivation and reactivation of the X chromosome, X;Y translocations, and sex reversal are discussed. 30 refs., 3 figs.

  14. Abnormal human sex chromosome constitutions

    SciTech Connect

    1993-12-31

    Chapter 22, discusses abnormal human sex chromosome constitution. Aneuploidy of X chromosomes with a female phenotype, sex chromosome aneuploidy with a male phenotype, and various abnormalities in X chromosome behavior are described. 31 refs., 2 figs.

  15. Chromosomal Disorders and Autism.

    ERIC Educational Resources Information Center

    Gillberg, Christopher

    1998-01-01

    This paper reviews the literature on chromosomal aberrations in autism, especially possible gene markers. It notes that Chromosome 15 and numerical and structural abnormalities of the sex chromosomes have been most frequently reported as related to the genesis of autism. (Author/DB)

  16. The human Y chromosome.

    PubMed Central

    Goodfellow, P; Darling, S; Wolfe, J

    1985-01-01

    Despite its central role in sex determination, genetic analysis of the Y chromosome has been slow. This poor progress has been due to the paucity of available genetic markers. Whereas the X chromosome is known to include at least 100 functional genetic loci, only three or four loci have been ascribed to the Y chromosome and even the existence of several of these loci is controversial. Other factors limiting genetic analysis are the small size of the Y chromosome, which makes cytogenetic definition difficult, and the absence of extensive recombination. Based on cytogenetic observation and speculation, a working model of the Y chromosome has been proposed. In this classical model the Y chromosome is defined into subregions; an X-Y homologous meiotic pairing region encompassing most of the Y chromosome short arm and, perhaps, including a pseudoautosomal region of sex chromosome exchange; a pericentric region containing the sex determining gene or genes; and a long arm heterochromatic genetically inert region. The classical model has been supported by studies on the MIC2 loci, which encode a cell surface antigen defined by the monoclonal antibody 12E7. The X linked locus MIC2X, which escapes X inactivation, maps to the tip of the X chromosome short arm and the homologous locus MIC2Y maps to the Y chromosome short arm; in both cases, these loci are within the proposed meiotic pairing region. MIC2Y is the first biochemically defined, expressed locus to be found on the human Y chromosome. The proposed simplicity of the classical model has been challenged by recent molecular analysis of the Y chromosome. Using cloned probes, several groups have shown that a major part of the Y chromosome short arm is unlikely to be homologous to the X chromosome short arm. A substantial block of sequences of the short arm are homologous to sequences of the X chromosome long arm but well outside the pairing region. In addition, the short arm contains sequences shared with the Y chromosome

  17. Radiation induced genomic instability in bystander cells

    NASA Astrophysics Data System (ADS)

    Zhou, H.; Gu, S.; Randers-Pehrson, G.; Hei, T.

    There is considerable evidence that exposure to ionizing radiation may induce a heritable genomic instability that leads to a persisting increased frequency of genetic and functional changes in the non-irradiated progeny of a wide variety of irradiated cells Genomic instability is measured as delayed expressions in chromosomal alterations micronucleus formation gene mutations and decreased plating efficiency During the last decade numerous studies have shown that radiation could induce bystander effect in non-irradiated neighboring cells similar endpoints have also been used in genomic instability studies Both genomic instability and the bystander effect are phenomena that result in a paradigm shift in our understanding of radiation biology In the past it seemed reasonable to assume that the production of single- and double-strand DNA breaks are due to direct energy deposition of energy by a charged particle to the nucleus It turns out that biology is not quite that simple Using the Columbia University charged particle microbeam and the highly sensitive human hamster hybrid AL cell mutagenic assay we irradiated 10 of the cells with a lethal dose of 30 alpha particles through the nucleus After overnight incubation the remaining viable bystander cells were replated in dishes for colony formation Clonal isolates were expanded and cultured for 6 consecutive weeks to assess plating efficiency and mutation frequency Preliminary results indicated that there was no significant decrease in plating efficiency among the bystander colonies when compared with

  18. Introduction to biology and chromosomal instabilities in cancer

    NASA Astrophysics Data System (ADS)

    Kroll, K. M.; Ferrantini, A.; Domany, E.

    2010-10-01

    The recent decade has witnessed a surge of physicists to biology. Some of the activities of the participating groups focus on bona fide physics questions, posed on biological systems (such as the physics of molecular motors, for example). Another kind of research in which physicists take part alongside computer scientists and applied mathematicians, deals with questions that are of direct interest to biologists; they come under the umbrella of computational and systems biology. The topic of these lectures lies at the most biological end of this spectrum, addressing problems of clinical relevance which were posed and initiated by biologists. The objective of these lectures is to help the curious physicist to learn and to understand more about this emerging, highly interdisciplinary field of research, by providing brief introductions to molecular biology and cancer research. This is followed by a cursory review of some recent research done by the “Domany group” and its collaborations with biological and clinical labs. Furthermore, we mention (mainly in footnotes) a small subset of studies in which physicists have contributed to this field during the past years. A more detailed review of recent contributions by physicists is beyond the scope of this introductory text. The introductory nature of these lecture notes naturally induces a strong bias regarding publications cited; consequently, these lecture notes do not provide a fair, historically correct and updated review of relevant literature.

  19. Acentric chromosome ends are prone to fusion with functional chromosome ends through a homology-directed rearrangement.

    PubMed

    Ohno, Yuko; Ogiyama, Yuki; Kubota, Yoshino; Kubo, Takuya; Ishii, Kojiro

    2016-01-08

    The centromeres of many eukaryotic chromosomes are established epigenetically on potentially variable tandem repeats; hence, these chromosomes are at risk of being acentric. We reported previously that artificially created acentric chromosomes in the fission yeast Schizosaccharomyces pombe can be rescued by end-to-end fusion with functional chromosomes. Here, we show that most acentric/functional chromosome fusion events in S. pombe cells harbouring an acentric chromosome I differed from the non-homologous end-joining-mediated rearrangements that result in deleterious dicentric fusions in normal cells, and were elicited by a previously unidentified homologous recombination (HR) event between chromosome end-associated sequences. The subtelomere repeats associated with the non-fusogenic ends were also destabilized in the surviving cells, suggesting a causal link between general subtelomere destabilization and acentric/functional chromosome fusion. A mutational analysis indicated that a non-canonical HR pathway was involved in the rearrangement. These findings are indicative of a latent mechanism that conditionally induces general subtelomere instability, presumably in the face of accidental centromere loss events, resulting in rescue of the fatal acentric chromosomes by interchromosomal HR.

  20. Sex chromosome mosaicism in males carrying Y chromosome long arm deletions.

    PubMed

    Siffroi, J P; Le Bourhis, C; Krausz, C; Barbaux, S; Quintana-Murci, L; Kanafani, S; Rouba, H; Bujan, L; Bourrouillou, G; Seifer, I; Boucher, D; Fellous, M; McElreavey, K; Dadoune, J P

    2000-12-01

    Microdeletions of the long arm of the Y chromosome (Yq) are a common cause of male infertility. Since large structural rearrangements of the Y chromosome are commonly associated with a 45,XO/46,XY chromosomal mosaicism, we studied whether submicroscopic Yq deletions could also be associated with the development of 45,XO cell lines. We studied blood samples from 14 infertile men carrying a Yq microdeletion as revealed by polymerase chain reaction (PCR). Patients were divided into two groups: group 1 (n = 6), in which karyotype analysis demonstrated a 45,X/46,XY mosaicism, and group 2 (n = 8) with apparently a normal 46,XY karyotype. 45,XO cells were identified by fluorescence in-situ hybridization (FISH) using X and Y centromeric probes. Lymphocytes from 11 fertile men were studied as controls. In addition, sperm cells were studied in three oligozoospermic patients in group 2. Our results showed that large and submicroscopic Yq deletions were associated with significantly increased percentages of 45,XO cells in lymphocytes and of sperm cells nullisomic for gonosomes, especially for the Y chromosome. Moreover, two isodicentric Y chromosomes, classified as normal by cytogenetic methods, were detected. Therefore, Yq microdeletions may be associated with Y chromosomal instability leading to the formation of 45,XO cell lines.

  1. Tying up loose ends: telomeres, genomic instability and lamins

    PubMed Central

    Eissenberg, Joel C.

    2016-01-01

    On casual inspection, the eukaryotic nucleus is a deceptively simple organelle. Far from being a bag of chromatin, the nucleus is, in some ways, a structural and functional extension of the chromosomes it contains. Recently, interest has intensified in how chromosome compartmentalization and dynamics affect nuclear function. Different studies uncovered functional interactions between chromosomes and the filamentous nuclear meshwork comprised of lamin proteins. Here, we summarize recent research suggesting that telomeres, the capping structures that protect chromosome ends, are stabilized by lamin-binding and that alterations in nuclear lamins lead to defects in telomere compartmentalization, homeostasis and function. Telomere dysfunction contributes to the genomic instability that characterizes aging-related diseases, and might be an important factor in the pathophysiology of lamin-related diseases. PMID:27010504

  2. DNA damage in cells exhibiting radiation-induced genomic instability

    DOE PAGES

    Keszenman, Deborah J.; Kolodiuk, Lucia; Baulch, Janet E.

    2015-02-22

    Cells exhibiting radiation induced genomic instability exhibit varied spectra of genetic and chromosomal aberrations. Even so, oxidative stress remains a common theme in the initiation and/or perpetuation of this phenomenon. Isolated oxidatively modified bases, abasic sites, DNA single strand breaks and clustered DNA damage are induced in normal mammalian cultured cells and tissues due to endogenous reactive oxygen species generated during normal cellular metabolism in an aerobic environment. While sparse DNA damage may be easily repaired, clustered DNA damage may lead to persistent cytotoxic or mutagenic events that can lead to genomic instability. In this study, we tested the hypothesismore » that DNA damage signatures characterised by altered levels of endogenous, potentially mutagenic, types of DNA damage and chromosomal breakage are related to radiation-induced genomic instability and persistent oxidative stress phenotypes observed in the chromosomally unstable progeny of irradiated cells. The measurement of oxypurine, oxypyrimidine and abasic site endogenous DNA damage showed differences in non-double-strand breaks (DSB) clusters among the three of the four unstable clones evaluated as compared to genomically stable clones and the parental cell line. These three unstable clones also had increased levels of DSB clusters. The results of this study demonstrate that each unstable cell line has a unique spectrum of persistent damage and lead us to speculate that alterations in DNA damage signaling and repair may be related to the perpetuation of genomic instability.« less

  3. DNA damage in cells exhibiting radiation-induced genomic instability

    SciTech Connect

    Keszenman, Deborah J.; Kolodiuk, Lucia; Baulch, Janet E.

    2015-02-22

    Cells exhibiting radiation induced genomic instability exhibit varied spectra of genetic and chromosomal aberrations. Even so, oxidative stress remains a common theme in the initiation and/or perpetuation of this phenomenon. Isolated oxidatively modified bases, abasic sites, DNA single strand breaks and clustered DNA damage are induced in normal mammalian cultured cells and tissues due to endogenous reactive oxygen species generated during normal cellular metabolism in an aerobic environment. While sparse DNA damage may be easily repaired, clustered DNA damage may lead to persistent cytotoxic or mutagenic events that can lead to genomic instability. In this study, we tested the hypothesis that DNA damage signatures characterised by altered levels of endogenous, potentially mutagenic, types of DNA damage and chromosomal breakage are related to radiation-induced genomic instability and persistent oxidative stress phenotypes observed in the chromosomally unstable progeny of irradiated cells. The measurement of oxypurine, oxypyrimidine and abasic site endogenous DNA damage showed differences in non-double-strand breaks (DSB) clusters among the three of the four unstable clones evaluated as compared to genomically stable clones and the parental cell line. These three unstable clones also had increased levels of DSB clusters. The results of this study demonstrate that each unstable cell line has a unique spectrum of persistent damage and lead us to speculate that alterations in DNA damage signaling and repair may be related to the perpetuation of genomic instability.

  4. Towards Prognostics of Electrolytic Capacitors

    NASA Technical Reports Server (NTRS)

    Celaya, Jose R.; Kulkarni, Chetan; Biswas, Gautam; Goegel, Kai

    2011-01-01

    A remaining useful life prediction algorithm and degradation model for electrolytic capacitors is presented. Electrolytic capacitors are used in several applications ranging from power supplies on critical avionics equipment to power drivers for electro-mechanical actuators. These devices are known for their low reliability and given their criticality in electronics subsystems they are a good candidate for component level prognostics and health management research. Prognostics provides a way to assess remaining useful life of a capacitor based on its current state of health and its anticipated future usage and operational conditions. In particular, experimental results of an accelerated aging test under electrical stresses are presented. The capacitors used in this test form the basis for a remaining life prediction algorithm where a model of the degradation process is suggested. This preliminary remaining life prediction algorithm serves as a demonstration of how prognostics methodologies could be used for electrolytic capacitors.

  5. Prognostic stratification in the treatment of AML.

    PubMed

    Asou, Norio

    Current treatment of acute myeloid leukemia (AML) still relies on intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). AML is a heterogeneous neoplasm characterized by distinct chromosomal and genetic abnormalities. Recent comprehensive gene analyses have highlighted distinct genetic subgroups that are associated with different responses to chemotherapy. Therefore, the molecular landscape of AML is fundamental to the development of novel therapeutic approaches and provides opportunities for individualization of therapy. In addition, the age-related incidence of clonal hematopoiesis is high, affecting nearly 10% of healthy people more than 65 years of age. Clonal hematopoiesis is confirmed by the presence of mutations related to AML including genes involved in DNA methylation, chromatin modification and RNA splicing. In the analysis of gene mutation profiles in secondary AML (s-AML) from myelodysplastic syndromes and myeloproliferative neoplasms, secondary-type gene mutations were identified with >95% specificity in s-AML as compared with de novo AML, including RNA splicing, chromatin modification and cohesion complex genes, and were highly associated with poor responses to chemotherapy as well as TP53 mutation. It is important to identify genetic subgroups at relatively high-risk of relapses who should receive allogeneic HSCT during the first remission. In this review, prognostic stratification for individualized treatment of AML is discussed.

  6. Buckling instability in arteries.

    PubMed

    Vandiver, Rebecca M

    2015-04-21

    Arteries can become tortuous in response to abnormal growth stimuli, genetic defects and aging. It is suggested that a buckling instability is a mechanism that might lead to artery tortuosity. Here, the buckling instability in arteries is studied by examining asymmetric modes of bifurcation of two-layer cylindrical structures that are residually stressed. These structures are loaded by an axial force, internal pressure and have nonlinear, anisotropic, hyperelastic responses to stresses. Strain-softening and reduced opening angle are shown to lower the critical internal pressure leading to buckling. In addition, the ratio of the media thickness to the adventitia thickness is shown to have a dramatic impact on arterial instability.

  7. Causes of genome instability: the effect of low dose chemical exposures in modern society

    PubMed Central

    Langie, Sabine A.S.; Koppen, Gudrun; Desaulniers, Daniel; Al-Mulla, Fahd; Al-Temaimi, Rabeah; Amedei, Amedeo; Azqueta, Amaya; Bisson, William H.; Brown, Dustin; Brunborg, Gunnar; Charles, Amelia K.; Chen, Tao; Colacci, Annamaria; Darroudi, Firouz; Forte, Stefano; Gonzalez, Laetitia; Hamid, Roslida A.; Knudsen, Lisbeth E.; Leyns, Luc; Lopez de Cerain Salsamendi, Adela; Memeo, Lorenzo; Mondello, Chiara; Mothersill, Carmel; Olsen, Ann-Karin; Pavanello, Sofia; Raju, Jayadev; Rojas, Emilio; Roy, Rabindra; Ryan, Elizabeth; Ostrosky-Wegman, Patricia; Salem, Hosni K.; Scovassi, Ivana; Singh, Neetu; Vaccari, Monica; Van Schooten, Frederik J.; Valverde, Mahara; Woodrick, Jordan; Zhang, Luoping; van Larebeke, Nik; Kirsch-Volders, Micheline; Collins, Andrew R.

    2015-01-01

    Genome instability is a prerequisite for the development of cancer. It occurs when genome maintenance systems fail to safeguard the genome’s integrity, whether as a consequence of inherited defects or induced via exposure to environmental agents (chemicals, biological agents and radiation). Thus, genome instability can be defined as an enhanced tendency for the genome to acquire mutations; ranging from changes to the nucleotide sequence to chromosomal gain, rearrangements or loss. This review raises the hypothesis that in addition to known human carcinogens, exposure to low dose of other chemicals present in our modern society could contribute to carcinogenesis by indirectly affecting genome stability. The selected chemicals with their mechanisms of action proposed to indirectly contribute to genome instability are: heavy metals (DNA repair, epigenetic modification, DNA damage signaling, telomere length), acrylamide (DNA repair, chromosome segregation), bisphenol A (epigenetic modification, DNA damage signaling, mitochondrial function, chromosome segregation), benomyl (chromosome segregation), quinones (epigenetic modification) and nano-sized particles (epigenetic pathways, mitochondrial function, chromosome segregation, telomere length). The purpose of this review is to describe the crucial aspects of genome instability, to outline the ways in which environmental chemicals can affect this cancer hallmark and to identify candidate chemicals for further study. The overall aim is to make scientists aware of the increasing need to unravel the underlying mechanisms via which chemicals at low doses can induce genome instability and thus promote carcinogenesis. PMID:26106144

  8. Causes of genome instability: the effect of low dose chemical exposures in modern society.

    PubMed

    Langie, Sabine A S; Koppen, Gudrun; Desaulniers, Daniel; Al-Mulla, Fahd; Al-Temaimi, Rabeah; Amedei, Amedeo; Azqueta, Amaya; Bisson, William H; Brown, Dustin G; Brunborg, Gunnar; Charles, Amelia K; Chen, Tao; Colacci, Annamaria; Darroudi, Firouz; Forte, Stefano; Gonzalez, Laetitia; Hamid, Roslida A; Knudsen, Lisbeth E; Leyns, Luc; Lopez de Cerain Salsamendi, Adela; Memeo, Lorenzo; Mondello, Chiara; Mothersill, Carmel; Olsen, Ann-Karin; Pavanello, Sofia; Raju, Jayadev; Rojas, Emilio; Roy, Rabindra; Ryan, Elizabeth P; Ostrosky-Wegman, Patricia; Salem, Hosni K; Scovassi, A Ivana; Singh, Neetu; Vaccari, Monica; Van Schooten, Frederik J; Valverde, Mahara; Woodrick, Jordan; Zhang, Luoping; van Larebeke, Nik; Kirsch-Volders, Micheline; Collins, Andrew R

    2015-06-01

    Genome instability is a prerequisite for the development of cancer. It occurs when genome maintenance systems fail to safeguard the genome's integrity, whether as a consequence of inherited defects or induced via exposure to environmental agents (chemicals, biological agents and radiation). Thus, genome instability can be defined as an enhanced tendency for the genome to acquire mutations; ranging from changes to the nucleotide sequence to chromosomal gain, rearrangements or loss. This review raises the hypothesis that in addition to known human carcinogens, exposure to low dose of other chemicals present in our modern society could contribute to carcinogenesis by indirectly affecting genome stability. The selected chemicals with their mechanisms of action proposed to indirectly contribute to genome instability are: heavy metals (DNA repair, epigenetic modification, DNA damage signaling, telomere length), acrylamide (DNA repair, chromosome segregation), bisphenol A (epigenetic modification, DNA damage signaling, mitochondrial function, chromosome segregation), benomyl (chromosome segregation), quinones (epigenetic modification) and nano-sized particles (epigenetic pathways, mitochondrial function, chromosome segregation, telomere length). The purpose of this review is to describe the crucial aspects of genome instability, to outline the ways in which environmental chemicals can affect this cancer hallmark and to identify candidate chemicals for further study. The overall aim is to make scientists aware of the increasing need to unravel the underlying mechanisms via which chemicals at low doses can induce genome instability and thus promote carcinogenesis.

  9. Bacterial Genome Instability

    PubMed Central

    Darmon, Elise

    2014-01-01

    SUMMARY Bacterial genomes are remarkably stable from one generation to the next but are plastic on an evolutionary time scale, substantially shaped by horizontal gene transfer, genome rearrangement, and the activities of mobile DNA elements. This implies the existence of a delicate balance between the maintenance of genome stability and the tolerance of genome instability. In this review, we describe the specialized genetic elements and the endogenous processes that contribute to genome instability. We then discuss the consequences of genome instability at the physiological level, where cells have harnessed instability to mediate phase and antigenic variation, and at the evolutionary level, where horizontal gene transfer has played an important role. Indeed, this ability to share DNA sequences has played a major part in the evolution of life on Earth. The evolutionary plasticity of bacterial genomes, coupled with the vast numbers of bacteria on the planet, substantially limits our ability to control disease. PMID:24600039

  10. Analysis of plant meiotic chromosomes by chromosome painting.

    PubMed

    Lysak, Martin A; Mandáková, Terezie

    2013-01-01

    Chromosome painting (CP) refers to visualization of large chromosome regions, entire chromosome arms, or entire chromosomes via fluorescence in situ hybridization (FISH). For CP in plants, contigs of chromosome-specific bacterial artificial chromosomes (BAC) from the target species or from a closely related species (comparative chromosome painting, CCP) are typically applied as painting probes. Extended pachytene chromosomes provide the highest resolution of CP in plants. CP enables identification and tracing of particular chromosome regions and/or entire chromosomes throughout all meiotic stages as well as corresponding chromosome territories in premeiotic interphase nuclei. Meiotic pairing and structural chromosome rearrangements (typically inversions and translocations) can be identified by CP. Here, we describe step-by-step protocols of CP and CCP in plant species including chromosome preparation, BAC DNA labeling, and multicolor FISH.

  11. Distal Radioulnar Joint Instability

    PubMed Central

    Mirghasemi, Ali R.; Lee, Daniel J.; Rahimi, Narges; Rashidinia, Shervin

    2015-01-01

    Distal radioulnar joint (DRUJ) instability is a common clinical condition but a frequently missed diagnosis. Both surgical and nonsurgical treatments are possible for chronic cases of DRUJ instability. Nonsurgical treatment can be considered as the primary therapy in less active patients, while surgery should be considered to recover bone and ligament injuries if nonsurgical treatment fails to restore forearm stability and function. The appropriate choice of treatment depends on the individual patient and specific derangement of the DRUJ PMID:26328241

  12. Prediction of Algebraic Instabilities

    NASA Astrophysics Data System (ADS)

    Zaretzky, Paula; King, Kristina; Hill, Nicole; Keithley, Kimberlee; Barlow, Nathaniel; Weinstein, Steven; Cromer, Michael

    2016-11-01

    A widely unexplored type of hydrodynamic instability is examined - large-time algebraic growth. Such growth occurs on the threshold of (exponentially) neutral stability. A new methodology is provided for predicting the algebraic growth rate of an initial disturbance, when applied to the governing differential equation (or dispersion relation) describing wave propagation in dispersive media. Several types of algebraic instabilities are explored in the context of both linear and nonlinear waves.

  13. Equilibrium Electroconvective Instability

    NASA Astrophysics Data System (ADS)

    Rubinstein, I.; Zaltzman, B.

    2015-03-01

    Since its prediction 15 years ago, hydrodynamic instability in concentration polarization at a charge-selective interface has been attributed to nonequilibrium electro-osmosis related to the extended space charge which develops at the limiting current. This attribution had a double basis. On the one hand, it has been recognized that neither equilibrium electro-osmosis nor bulk electroconvection can yield instability for a perfectly charge-selective solid. On the other hand, it has been shown that nonequilibrium electro-osmosis can. The first theoretical studies in which electro-osmotic instability was predicted and analyzed employed the assumption of perfect charge selectivity for the sake of simplicity and so did the subsequent studies of various time-dependent and nonlinear features of electro-osmotic instability. In this Letter, we show that relaxing the assumption of perfect charge selectivity (tantamount to fixing the electrochemical potential of counterions in the solid) allows for the equilibrium electroconvective instability. In addition, we suggest a simple experimental test for determining the true, either equilibrium or nonequilibrium, origin of instability in concentration polarization.

  14. Prognostic factors in prostate cancer.

    PubMed

    Braeckman, Johan; Michielsen, Dirk

    2007-01-01

    In the nineteenth century the main goal of medicine was predictive: diagnose the disease and achieve a satisfying prognosis of the patient's chances. Today the effort has shifted to cure the disease. Since the twentieth century, the word prognosis has also been used in nonmedical contexts, for example in corporate finance or elections. The most accurate form of prognosis is achieved statistically. Based on different prognostic factors it should be possible to tell patients how they are expected to do after prostate cancer has been diagnosed and how different treatments may change this outcome. A prognosis is a prediction. The word prognosis comes from the Greek word (see text) and means foreknowing. In the nineteenth century this was the main goal of medicine: diagnose the disease and achieve a satisfying prognosis of the patient's chances. Today the effort has shifted towards seeking a cure. Prognostic factors in (prostate) cancer are defined as "variables that can account for some of the heterogeneity associated with the expected course and outcome of a disease". Bailey defined prognosis as "a reasoned forecast concerning the course, pattern, progression, duration, and end of the disease. Prognostic factors are not only essential to understand the natural history and the course of the disease, but also to predict possible different outcomes of different treatments or perhaps no treatment at all. This is extremely important in a disease like prostate cancer where there is clear evidence that a substantial number of cases discovered by prostate-specific antigen (PSA) testing are unlikely ever to become clinically significant, not to mention mortal. Furthermore, prognostic factors are of paramount importance for correct interpretation of clinical trials and for the construction of future trials. Finally, according to WHO national screening committee criteria for implementing a national screening programme, widely accepted prognostic factors must be defined before

  15. Propagating Instabilities in Solids

    NASA Astrophysics Data System (ADS)

    Kyriakides, Stelios

    1998-03-01

    Instability is one of the factors which limit the extent to which solids can be loaded or deformed and plays a pivotal role in the design of many structures. Such instabilities often result in localized deformation which precipitates catastrophic failure. Some materials have the capacity to recover their stiffness following a certain amount of localized deformation. This local recovery in stiffness arrests further local deformation and spreading of the instability to neighboring material becomes preferred. Under displacement controlled loading the propagation of the transition fronts can be achieved in a steady-state manner at a constant stress level known as the propagation stress. The stresses in the transition fronts joining the highly deformed zone to the intact material overcome the instability nucleation stresses and, as a result, the propagation stress is usually much lower than the stress required to nucleate the instability. The classical example of this class of material instabilities is L/"uders bands which tend to affect mild steels and other metals. Recent work has demonstrated that propagating instabilities occur in several other materials. Experimental and analytical results from four examples will be used to illustrate this point: First the evolution of L=FCders bands in mild steel strips will be revisited. The second example involves the evolution of stress induced phase transformations (austenite to martensite phases and the reverse) in a shape memory alloy under displacement controlled stretching. The third example is the crushing behavior of cellular materials such as honeycombs and foams made from metals and polymers. The fourth example involves the axial broadening/propagation of kink bands in aligned fiber/matrix composites under compression. The microstructure and, as a result, the micromechanisms governing the onset, localization, local arrest and propagation of instabilities in each of the four materials are vastly different. Despite this

  16. Is delayed genomic instability specifically induced by high-LET particles?

    NASA Astrophysics Data System (ADS)

    Testard, Isabelle; Sabatier, Laure

    1998-12-01

    Ionizing radiation can induce a large variety of damages in the DNA. The processing or repair of this damage occurs in the first minutes up to several hours after irradiation. Afterwhile the remaining lesions are fixed in an irreparable state. However, in recent years, data have accumulated to suggest that genomic instability can manifest in the progeny of irradiated cells leading to accumulation of damage through cell generations. Different biological endpoints were described: delayed cell death, delayed mutations, de novo chromosomal instability. The question regarding the ability of sparsely ionizing X-or γ-rays to induce such phenomenon is still unclear for normal cells. In most of the reports, high linear energy transfer (LET) particles are able to induce genomic instability but not low-LET particles. The mechanisms underlying this phenomenon are still unknown. In human fibroblasts irradiated by heavy ions in a large range of LETs, we showed that the chromosomal instability is characterized by telomeric associations (TAS) involving specific chromosomes. The same instability is observed during the senescence process and during the first passages after viral transfection. The specific chromosomal instability that we observed after irradiation would not be a direct consequence of irradiation but would be a natural phenomenon occurring after many cell divisions. The effect of the irradiation would lie on the bypass of the senescence process that would permit cells with end to end fusions to survive and be transmitted through cell generations, accumulating chromosome rearrangements and chromosome imbalances. Research on molecular mechanisms of chromosomal instability is focused on the role of telomeres in end to end fusions. Such observations could contribute to understand why chromosomal instability is not a dose dependant phenomenon. Why high-LET particles would be so potent in inducing delayed instability? The answer might lie in the study of primary effects of

  17. Temporal Dependence of Chromosomal Aberration on Radiation Quality and Cellular Genetic Background

    NASA Technical Reports Server (NTRS)

    Lu, Tao; Zhang, Ye; Krieger, Stephanie; Yeshitla, Samrawit; Goss, Rosalin; Bowler, Deborah; Kadhim, Munira; Wilson, Bobby; Wu, Honglu

    2017-01-01

    Radiation induced cancer risks are driven by genetic instability. It is not well understood how different radiation sources induce genetic instability in cells with different genetic background. Here we report our studies on genetic instability, particularly chromosome instability using fluorescence in situ hybridization (FISH), in human primary lymphocytes, normal human fibroblasts, and transformed human mammary epithelial cells in a temporal manner after exposure to high energy protons and Fe ions. The chromosome spread was prepared 48 hours, 1 week, 2 week, and 1 month after radiation exposure. Chromosome aberrations were analyzed with whole chromosome specific probes (chr. 3 and chr. 6). After exposure to protons and Fe ions of similar cumulative energy (??), Fe ions induced more chromosomal aberrations at early time point (48 hours) in all three types of cells. Over time (after 1 month), more chromosome aberrations were observed in cells exposed to Fe ions than in the same type of cells exposed to protons. While the mammary epithelial cells have higher intrinsic genetic instability and higher rate of initial chromosome aberrations than the fibroblasts, the fibroblasts retained more chromosomal aberration after long term cell culture (1 month) in comparison to their initial frequency of chromosome aberration. In lymphocytes, the chromosome aberration frequency at 1 month after exposure to Fe ions was close to unexposed background, and the chromosome aberration frequency at 1 month after exposure to proton was much higher. In addition to human cells, mouse bone marrow cells isolated from strains CBA/CaH and C57BL/6 were irradiated with proton or Fe ions and were analyzed for chromosome aberration at different time points. Cells from CBA mice showed similar frequency of chromosome aberration at early and late time points, while cells from C57 mice showed very different chromosome aberration rate at early and late time points. Our results suggest that relative

  18. Chromosomal differentiation of cells

    SciTech Connect

    1993-12-31

    Chapter 16, discusses the chromosomal differentiation of cells. The chromosomes of differentiated cells have been much less studies than those of meristematic or germline cells, probably because such cells do not usually divide spontaneously. However, in many cases they can be induced to undergo mitosis. 26 refs., 2 figs.

  19. Loss of heterozygosity and microsatellite instability as predictive markers among Iranian esophageal cancer patients

    PubMed Central

    Forghanifard, Mohammad Mahdi; Vahid, Elham Emami; Dadkhah, Ezzat; Gholamin, Mehran; Noghabi, Samaneh Broumand; Ghahraman, Martha; Farzadnia, Mehdi; Abbaszadegan, Mohammad Reza

    2016-01-01

    Objective(s): Variation in microsatellite sequences that are dispersed in the genome has been linked to a deficiency in cellular mismatch repair system and defects in several genes of this system are involved in carcinogenesis. Our aim in this study was to illustrate microsatellite DNA alteration in esophageal cancer. Materials and Methods: DNA was extracted from formalin fixed paraffin embedded (FFPE) tissues from surgical and matched margin-normal samples. Microsatellite instability (MSI) and loss of heterozygosity (LOH) were studied in 50 cases of esophageal squamous cell carcinoma (ESCC) by amplifying six microsatellite markers: D13S260 (13q12.3), D13S267 (13q12.3), D9S171 (9p21), D2S123 (2p), D5S2501 (5q21) and TP53 (17p13.1) analyzed on 6% denaturing polyacrylamide gel electrophoresis. Results: Statistical analysis indicated a near significant reverse correlation between grade and LOH (P= 0.068, correlation coefficient= -0.272). Specifically, increased LOH in tumor DNA has a significant correlation with increased differentiation from poorly differentiated to well differentiated tumors (P= 0.002 and P= 0.016 respectively). In addition, higher number of chromosomal loci with LOH showed a reverse correlation with lymph node metastasis (P= 0.026, correlation coefficient= -0.485). Furthermore, there was a positive correlation between addiction and MSI (P= 0.026, correlation coefficient= 0.465). Conclusion: Microsatellite DNA alterations may be a prognostic tool for detection and the evolution of prognosis in patients with SCC of esophagus. It can be concluded that regional lymph node metastasis would be less likely with increased heterozygote loci and addiction with any of opium, cigarette, water pipe or alcohol can be a susceptibility factor(s) for MSI. PMID:27635196

  20. XYY chromosome anomaly and schizophrenia.

    PubMed

    Rajagopalan, M; MacBeth, R; Varma, S L

    1998-02-07

    Sex chromosome anomalies have been associated with psychoses, and most of the evidence is linked to the presence of an additional X chromosome. We report a patient with XYY chromosome anomaly who developed schizophrenia.

  1. Sexually antagonistic chromosomal cuckoos

    PubMed Central

    Rice, William R.; Gavrilets, Sergey; Friberg, Urban

    2009-01-01

    The two kinds of sex chromosomes in the heterogametic parent are transmitted to offspring with different sexes, causing opposite-sex siblings to be completely unrelated for genes located on these chromosomes. Just as the nest-parasitic cuckoo chick is selected to harm its unrelated nest-mates in order to garner more shared resources, sibling competition causes the sex chromosomes to be selected to harm siblings that do not carry them. Here we quantify and contrast this selection on the X and Y, or Z and W, sex chromosomes. We also develop a hypothesis for how this selection can contribute to the decay of the non-recombining sex chromosome. PMID:19364719

  2. Capturing Chromosome Conformation

    NASA Astrophysics Data System (ADS)

    Dekker, Job; Rippe, Karsten; Dekker, Martijn; Kleckner, Nancy

    2002-02-01

    We describe an approach to detect the frequency of interaction between any two genomic loci. Generation of a matrix of interaction frequencies between sites on the same or different chromosomes reveals their relative spatial disposition and provides information about the physical properties of the chromatin fiber. This methodology can be applied to the spatial organization of entire genomes in organisms from bacteria to human. Using the yeast Saccharomyces cerevisiae, we could confirm known qualitative features of chromosome organization within the nucleus and dynamic changes in that organization during meiosis. We also analyzed yeast chromosome III at the G1 stage of the cell cycle. We found that chromatin is highly flexible throughout. Furthermore, functionally distinct AT- and GC-rich domains were found to exhibit different conformations, and a population-average 3D model of chromosome III could be determined. Chromosome III emerges as a contorted ring.

  3. RAD21 cohesin overexpression is a prognostic and predictive marker exacerbating poor prognosis in KRAS mutant colorectal carcinomas

    PubMed Central

    Deb, S; Xu, H; Tuynman, J; George, J; Yan, Y; Li, J; Ward, R L; Mortensen, N; Hawkins, N J; McKay, M J; Ramsay, R G; Fox, S B

    2014-01-01

    Background: RAD21 is a component of the cohesion complex and is integral to chromosome segregation and error-free DNA repair. RAD21 is functionally important in tumour progression but its role in colorectal carcinoma (CRC) is unclear. We therefore assessed its clinicopathological and prognostic significance in CRC, as well as its effect on chemosensitivity. Methods: A retrospective observation study examined RAD21 expression in 652 CRCs using a tissue microarray approach. Correlation with clinicopathological factors including gender, tumour grade, mucinous subtype, TNM stage, disease-specific survival (DSS), BRAF and KRAS mutation status, tumour p53 immunostaining, tumour microsatellite instability and tumour CpG island methylator phenotype was performed. Colorectal cancer cell clones with stable RAD21 knockdown were generated and tested for cellular sensitivity to conventional chemotherapeutic drugs. Results: RAD21 expression was significantly correlated with male gender (56.7% vs 43.3%, P=0.02), well-differentiated histology (14.4% vs 4.0%, P=0.0001), higher T-stage (36.1% vs 27.0%, P=0.01), presence of metastasis (18.8% vs 12.6%, P=0.03), and shorter DSS (hazard ratio (HR) 1.4, 95% CI 1.1 to 1.9, P=0.01) in both univariate and multivariate analysis. RAD21 expression was associated with shorter DSS in patients with KRAS mutant tumours (HR:2.6, 95% CI:1.4–4.3, P=0.001) and in patients receiving adjuvant chemoradiotherapy (HR:1.9, 95% CI:1.2–3.0, P=0.008). Colorectal cancer cells with RAD21 knockdown exhibited enhanced sensitivity to 5-fluorouracil, either alone or in combination with oxaliplatin. Conclusions: RAD21 expression in CRC is associated with aggressive disease especially in KRAS mutant tumours and resistance to chemoradiotherapy. RAD21 may be an important novel therapeutic target. PMID:24548858

  4. Towards Prognostics for Electronics Components

    NASA Technical Reports Server (NTRS)

    Saha, Bhaskar; Celaya, Jose R.; Wysocki, Philip F.; Goebel, Kai F.

    2013-01-01

    Electronics components have an increasingly critical role in avionics systems and in the development of future aircraft systems. Prognostics of such components is becoming a very important research field as a result of the need to provide aircraft systems with system level health management information. This paper focuses on a prognostics application for electronics components within avionics systems, and in particular its application to an Isolated Gate Bipolar Transistor (IGBT). This application utilizes the remaining useful life prediction, accomplished by employing the particle filter framework, leveraging data from accelerated aging tests on IGBTs. These tests induced thermal-electrical overstresses by applying thermal cycling to the IGBT devices. In-situ state monitoring, including measurements of steady-state voltages and currents, electrical transients, and thermal transients are recorded and used as potential precursors of failure.

  5. Chromosome-specific staining to detect genetic rearrangements associated with chromosome 3 and/or chromosome 17

    DOEpatents

    Gray, Joe W.; Pinkel, Daniel; Kallioniemi, Olli-Pekka; Kallioniemi, Anne; Sakamoto, Masaru

    2009-10-06

    Methods and compositions for staining based upon nucleic acid sequence that employ .[.nudeic.]. .Iadd.nucleic .Iaddend.acid probes are provided. Said methods produce staining patterns that can be tailored for specific cytogenetic analyses. Said probes are appropriate for in situ hybridization and stain both interphase and metaphase chromosomal material with reliable signals. The nucleic acid probes are typically of a complexity greater than 50 kb, the complexity depending upon the cytogenetic application. Methods and reagents are provided for the detection of genetic rearrangements. Probes and test kits are provided for use in detecting genetic rearrangements, particularly for use in tumor cytogenetics, in the detection of disease related loci, specifically cancer, such as chronic myelogenous leukemia (CML), retinoblastoma, ovarian and uterine cancers, and for biological dosimetry. Methods and reagents are described for cytogenetic research, for the differentiation of cytogenetically similar but genetically different diseases, and for many prognostic and diagnostic applications.

  6. Chromosome-specific staining to detect genetic rearrangements associated with chromosome 3 and/or chromosome 17

    DOEpatents

    Gray, Joe W.; Pinkel, Daniel; Kallioniemi, Olli-Pekka; Kallioniemi, Anne; Sakamoto, Masaru

    2002-01-01

    Methods and compositions for staining based upon nucleic acid sequence that employ nudeic acid probes are provided. Said methods produce staining patterns that can be tailored for specific cytogenetic analyses. Said probes are appropriate for in situ hybridization and stain both interphase and metaphase chromosomal material with reliable signals. The nucleic acid probes are typically of a complexity greater than 50 kb, the complexity depending upon the cytogenetic application. Methods and reagents are provided for the detection of genetic rearrangements. Probes and test kits are provided for use in detecting genetic rearrangements, particularly for use in tumor cytogenetics, in the detection of disease related loci, specifically cancer, such as chronic myelogenous leukemia (CML), retinoblastoma, ovarian and uterine cancers, and for biological dosimetry. Methods and reagents are described for cytogenetic research, for the differentiation of cytogenetically similar but genetically different diseases, and for many prognostic and diagnostic applications.

  7. Chromosome-specific staining to detect genetic rearrangements associated with chromosome 3 and/or chromosome 17

    DOEpatents

    Gray, Joe W.; Pinkel, Daniel; Kallioniemi, Olli-Pekka; Kallioniemi, Anne; Sakamoto, Masaru

    2008-09-09

    Methods and compositions for staining based upon nucleic acid sequence that employ nucleic acid probes are provided. Said methods produce staining patterns that can be tailored for specific cytogenetic analyses. Said probes are appropriate for in situ hybridization and stain both interphase and metaphase chromosomal material with reliable signals. The nucleic acid probes are typically of a complexity greater than 50 kb, the complexity depending upon the cytogenetic application. Methods and reagents are provided for the detection of genetic rearrangements. Probes and test kits are provided for use in detecting genetic rearrangements, particularly for use in tumor cytogenetics, in the detection of disease related loci, specifically cancer, such as chronic myelogenous leukemia (CML), retinoblastoma, ovarian and uterine cancers, and for biological dosimetry. Methods and reagents are described for cytogenetic research, for the differentiation of cytogenetically similar but genetically different diseases, and for many prognostic and diagnostic applications.

  8. Dislocation motion and instability

    NASA Astrophysics Data System (ADS)

    Zhu, Yichao; Chapman, Stephen Jonathan; Acharya, Amit

    2013-08-01

    The Peach-Koehler expression for the stress generated by a single (non-planar) curvilinear dislocation is evaluated to calculate the dislocation self stress. This is combined with a law of motion to give the self-induced motion of a general dislocation curve. A stability analysis of a rectilinear, uniformly translating dislocation is then performed. The dislocation is found to be susceptible to a helical instability, with the maximum growth rate occurring when the dislocation is almost, but not exactly, pure screw. The non-linear evolution of the instability is determined numerically, and implications for slip band formation and non-Schmid behavior in yielding are discussed.

  9. Abnormalities in Chromosomes 1q and 13 Independently Correlate With Factors of Poor Prognosis in Multiple Myeloma

    PubMed Central

    Kim, Miyoung; Ju, Young-Su; Lee, Eun Jin; Kang, Hee Jung; Kim, Han-Sung; Cho, Hyoun Chan; Kim, Hyo Jung; Kim, Jung-Ah; Lee, Dong Soon

    2016-01-01

    Background We comprehensively profiled cytogenetic abnormalities in multiple myeloma (MM) and analyzed the relationship between cytogenetic abnormalities of undetermined prognostic significance and established prognostic factors. Methods The karyotype of 333 newly diagnosed MM cases was analyzed in association with established prognostic factors. Survival analysis was also performed. Results MM with abnormal karyotypes (41.1%) exhibited high international scoring system (ISS) stage, frequent IgA type, elevated IgG or IgA levels, elevated calcium levels, elevated creatine (Cr) levels, elevated β2-microglobulin levels, and decreased Hb levels. Structural abnormalities in chromosomes 1q, 4, and 13 were independently associated with elevated levels of IgG or IgA, calcium, and Cr, respectively. Chromosome 13 abnormalities were associated with poor prognosis and decreased overall survival. Conclusions This is the first study to demonstrate that abnormalities in chromosomes 1q, 4, and 13 are associated with established factors for poor prognosis, irrespective of the presence of other concurrent chromosomal abnormalities. Chromosome 13 abnormalities have a prognostic impact on overall survival in association with elevated Cr levels. Frequent centromeric breakpoints appear to be related to MM pathogenesis. PMID:27578511

  10. Replication fork instability and the consequences of fork collisions from rereplication

    PubMed Central

    Alexander, Jessica L.; Orr-Weaver, Terry L.

    2016-01-01

    Replication forks encounter obstacles that must be repaired or bypassed to complete chromosome duplication before cell division. Proteomic analysis of replication forks suggests that the checkpoint and repair machinery travels with unperturbed forks, implying that they are poised to respond to stalling and collapse. However, impaired fork progression still generates aberrations, including repeat copy number instability and chromosome rearrangements. Deregulated origin firing also causes fork instability if a newer fork collides with an older one, generating double-strand breaks (DSBs) and partially rereplicated DNA. Current evidence suggests that multiple mechanisms are used to repair rereplication damage, yet these can have deleterious consequences for genome integrity. PMID:27898391

  11. Ontogeny of Unstable Chromosomes Generated by Telomere Error in Budding Yeast.

    PubMed

    Beyer, Tracey; Weinert, Ted

    2016-10-01

    DNA replication errors at certain sites in the genome initiate chromosome instability that ultimately leads to stable genomic rearrangements. Where instability begins is often unclear. And, early instability may form unstable chromosome intermediates whose transient nature also hinders mechanistic understanding. We report here a budding yeast model that reveals the genetic ontogeny of genome rearrangements, from initial replication error to unstable chromosome formation to their resolution. Remarkably, the initial error often arises in or near the telomere, and frequently forms unstable chromosomes. Early unstable chromosomes may then resolve to an internal "collection site" where a dicentric forms and resolves to an isochromosome (other outcomes are possible at each step). The initial telomere-proximal unstable chromosome is increased in mutants in telomerase subunits, Tel1, and even Rad9, with no known telomere-specific function. Defects in Tel1 and in Rrm3, a checkpoint protein kinase with a role in telomere maintenance and a DNA helicase, respectively, synergize dramatically to generate unstable chromosomes, further illustrating the consequence of replication error in the telomere. Collectively, our results suggest telomeric replication errors may be a common cause of seemingly unrelated genomic rearrangements located hundreds of kilobases away.

  12. Ontogeny of Unstable Chromosomes Generated by Telomere Error in Budding Yeast

    PubMed Central

    Weinert, Ted

    2016-01-01

    DNA replication errors at certain sites in the genome initiate chromosome instability that ultimately leads to stable genomic rearrangements. Where instability begins is often unclear. And, early instability may form unstable chromosome intermediates whose transient nature also hinders mechanistic understanding. We report here a budding yeast model that reveals the genetic ontogeny of genome rearrangements, from initial replication error to unstable chromosome formation to their resolution. Remarkably, the initial error often arises in or near the telomere, and frequently forms unstable chromosomes. Early unstable chromosomes may then resolve to an internal "collection site" where a dicentric forms and resolves to an isochromosome (other outcomes are possible at each step). The initial telomere-proximal unstable chromosome is increased in mutants in telomerase subunits, Tel1, and even Rad9, with no known telomere-specific function. Defects in Tel1 and in Rrm3, a checkpoint protein kinase with a role in telomere maintenance and a DNA helicase, respectively, synergize dramatically to generate unstable chromosomes, further illustrating the consequence of replication error in the telomere. Collectively, our results suggest telomeric replication errors may be a common cause of seemingly unrelated genomic rearrangements located hundreds of kilobases away. PMID:27716774

  13. SPOP mutation leads to genomic instability in prostate cancer.

    PubMed

    Boysen, Gunther; Barbieri, Christopher E; Prandi, Davide; Blattner, Mirjam; Chae, Sung-Suk; Dahija, Arun; Nataraj, Srilakshmi; Huang, Dennis; Marotz, Clarisse; Xu, Limei; Huang, Julie; Lecca, Paola; Chhangawala, Sagar; Liu, Deli; Zhou, Pengbo; Sboner, Andrea; de Bono, Johann S; Demichelis, Francesca; Houvras, Yariv; Rubin, Mark A

    2015-09-16

    Genomic instability is a fundamental feature of human cancer often resulting from impaired genome maintenance. In prostate cancer, structural genomic rearrangements are a common mechanism driving tumorigenesis. However, somatic alterations predisposing to chromosomal rearrangements in prostate cancer remain largely undefined. Here, we show that SPOP, the most commonly mutated gene in primary prostate cancer modulates DNA double strand break (DSB) repair, and that SPOP mutation is associated with genomic instability. In vivo, SPOP mutation results in a transcriptional response consistent with BRCA1 inactivation resulting in impaired homology-directed repair (HDR) of DSB. Furthermore, we found that SPOP mutation sensitizes to DNA damaging therapeutic agents such as PARP inhibitors. These results implicate SPOP as a novel participant in DSB repair, suggest that SPOP mutation drives prostate tumorigenesis in part through genomic instability, and indicate that mutant SPOP may increase response to DNA-damaging therapeutics.

  14. SPOP mutation leads to genomic instability in prostate cancer

    PubMed Central

    Boysen, Gunther; Barbieri, Christopher E; Prandi, Davide; Blattner, Mirjam; Chae, Sung-Suk; Dahija, Arun; Nataraj, Srilakshmi; Huang, Dennis; Marotz, Clarisse; Xu, Limei; Huang, Julie; Lecca, Paola; Chhangawala, Sagar; Liu, Deli; Zhou, Pengbo; Sboner, Andrea; de Bono, Johann S

    2015-01-01

    Genomic instability is a fundamental feature of human cancer often resulting from impaired genome maintenance. In prostate cancer, structural genomic rearrangements are a common mechanism driving tumorigenesis. However, somatic alterations predisposing to chromosomal rearrangements in prostate cancer remain largely undefined. Here, we show that SPOP, the most commonly mutated gene in primary prostate cancer modulates DNA double strand break (DSB) repair, and that SPOP mutation is associated with genomic instability. In vivo, SPOP mutation results in a transcriptional response consistent with BRCA1 inactivation resulting in impaired homology-directed repair (HDR) of DSB. Furthermore, we found that SPOP mutation sensitizes to DNA damaging therapeutic agents such as PARP inhibitors. These results implicate SPOP as a novel participant in DSB repair, suggest that SPOP mutation drives prostate tumorigenesis in part through genomic instability, and indicate that mutant SPOP may increase response to DNA-damaging therapeutics. DOI: http://dx.doi.org/10.7554/eLife.09207.001 PMID:26374986

  15. Targeted Segment Transfer from Rye Chromosome 2R to Wheat Chromosomes 2A, 2B, and 7B.

    PubMed

    Ren, Tianheng; Li, Zhi; Yan, Benju; Tan, Feiquan; Tang, Zongxiang; Fu, Shulan; Yang, Manyu; Ren, Zhenglong

    2017-03-10

    Increased chromosome instability was induced by a rye (Secale cereale L.) monosomic 2R chromosome into wheat (Triticum aestivum L.). Centromere breakage and telomere dysfunction result in high rates of chromosome aberrations, including breakages, fissions, fusions, deletions, and translocations. Plants with target traits were sequentially selected to produce a breeding population, from which 3 translocation lines with target traits have been selected. In these lines, wheat chromosomes 2A, 2B, and 7B recombined with segments of the rye chromosome arm 2RL. This was detected by FISH analysis using repeat sequences pSc119.2, pAs1 and genomic DNA of rye together as probes. The translocation chromosomes in these lines were named as 2ASMR, 2BSMR, and 7BSMR. The small segments that were transferred into wheat consisted of pSc119.2 repeats and other chromatin regions that conferred resistance to stripe rust and expressed target traits. These translocation lines were highly resistant to stripe rust, and expressed several typical traits that were associated with chromosome arm 2RL, which are better than those of its wheat parent, disomic addition, and substitution lines that show agronomic characteristics. The integration of molecular methods and conventional techniques to improve wheat breeding schemes are discussed.

  16. De novo balanced complex chromosome rearrangements involving chromosomes 1B and 3B of wheat and 1R of rye.

    PubMed

    Ren, Tianheng; Li, Zhi; Yan, Benju; Tan, Feiquan; Tang, Zongxiang; Fu, Shulan; Yang, Manyu; Ren, Zhenglong

    2016-12-01

    Complex chromosome rearrangements (CCRs) are defined as structural abnormalities involving more than two chromosome breaks, coupled with exchanges of chromosomal segments. Information on CCRs in plants is limited. In the present study, a plant (26-4) harboring translocation chromosomes 1RS.1BL and 4RS.4DL was selected from a double monosomic (1R and 4R) addition line, which was derived from the hybrid between wheat cultivar MY11 and a Chinese local rye variety. The genome of the plant with double alien translocation chromosomes in the monosomic form showed more instability than that harboring a single translocation. The CCRs involving chromosomes 1RS.1BL and 3B, which were generated de novo in this plant, showed double monosomic translocation chromosomes. A new CCR line with balanced reciprocal translocations 1RS.3BL and 3BS.1BL was developed, which presented normal morphological traits of wheat and underwent rapid growth in the field. A new 1RS.1BL translocation line was also selected from the progeny of plant 26-4. The CCRs and simple 1RS.1BL translocation lines showed significant improvement in grain yield, number of spikes per square meter, kernel number per spike, and resistance to stripe rust and powdery mildew. The CCR line exhibited better agronomic traits and adult plant resistance in the field than its sister line, which harbored a simple 1RS.1BL translocation. The CCRs are remarkable genetic resources for crop improvement.

  17. Sequential cloning of chromosomes

    DOEpatents

    Lacks, Sanford A.

    1995-07-18

    A method for sequential cloning of chromosomal DNA of a target organism is disclosed. A first DNA segment homologous to the chromosomal DNA to be sequentially cloned is isolated. The first segment has a first restriction enzyme site on either side. A first vector product is formed by ligating the homologous segment into a suitably designed vector. The first vector product is circularly integrated into the target organism's chromosomal DNA. The resulting integrated chromosomal DNA segment includes the homologous DNA segment at either end of the integrated vector segment. The integrated chromosomal DNA is cleaved with a second restriction enzyme and ligated to form a vector-containing plasmid, which is replicated in a host organism. The replicated plasmid is then cleaved with the first restriction enzyme. Next, a DNA segment containing the vector and a segment of DNA homologous to a distal portion of the previously isolated DNA segment is isolated. This segment is then ligated to form a plasmid which is replicated within a suitable host. This plasmid is then circularly integrated into the target chromosomal DNA. The chromosomal DNA containing the circularly integrated vector is treated with a third, retrorestriction (class IIS) enzyme. The cleaved DNA is ligated to give a plasmid that is used to transform a host permissive for replication of its vector. The sequential cloning process continues by repeated cycles of circular integration and excision. The excision is carried out alternately with the second and third enzymes.

  18. Sequential cloning of chromosomes

    DOEpatents

    Lacks, S.A.

    1995-07-18

    A method for sequential cloning of chromosomal DNA of a target organism is disclosed. A first DNA segment homologous to the chromosomal DNA to be sequentially cloned is isolated. The first segment has a first restriction enzyme site on either side. A first vector product is formed by ligating the homologous segment into a suitably designed vector. The first vector product is circularly integrated into the target organism`s chromosomal DNA. The resulting integrated chromosomal DNA segment includes the homologous DNA segment at either end of the integrated vector segment. The integrated chromosomal DNA is cleaved with a second restriction enzyme and ligated to form a vector-containing plasmid, which is replicated in a host organism. The replicated plasmid is then cleaved with the first restriction enzyme. Next, a DNA segment containing the vector and a segment of DNA homologous to a distal portion of the previously isolated DNA segment is isolated. This segment is then ligated to form a plasmid which is replicated within a suitable host. This plasmid is then circularly integrated into the target chromosomal DNA. The chromosomal DNA containing the circularly integrated vector is treated with a third, retrorestriction (class IIS) enzyme. The cleaved DNA is ligated to give a plasmid that is used to transform a host permissive for replication of its vector. The sequential cloning process continues by repeated cycles of circular integration and excision. The excision is carried out alternately with the second and third enzymes. 9 figs.

  19. Human chromosome 22.

    PubMed Central

    Kaplan, J C; Aurias, A; Julier, C; Prieur, M; Szajnert, M F

    1987-01-01

    The acrocentric chromosome 22, one of the shortest human chromosomes, carries about 52 000 kb of DNA. The short arm is made up essentially of heterochromatin and, as in other acrocentric chromosomes, it contains ribosomal RNA genes. Ten identified genes have been assigned to the long arm, of which four have already been cloned and documented (the cluster of lambda immunoglobulin genes, myoglobin, the proto-oncogene c-sis, bcr). In addition, about 10 anonymous DNA segments have been cloned from chromosome 22 specific DNA libraries. About a dozen diseases, including at least four different malignancies, are related to an inherited or acquired pathology of chromosome 22. They have been characterised at the phenotypic or chromosome level or both. In chronic myelogenous leukaemia, with the Ph1 chromosome, and Burkitt's lymphoma, with the t(8;22) variant translocation, the molecular pathology is being studied at the DNA level, bridging for the first time the gap between cytogenetics and molecular genetics. PMID:3550088

  20. Sequential cloning of chromosomes

    SciTech Connect

    Lacks, S.A.

    1991-12-31

    A method for sequential cloning of chromosomal DNA and chromosomal DNA cloned by this method are disclosed. The method includes the selection of a target organism having a segment of chromosomal DNA to be sequentially cloned. A first DNA segment, having a first restriction enzyme site on either side. homologous to the chromosomal DNA to be sequentially cloned is isolated. A first vector product is formed by ligating the homologous segment into a suitably designed vector. The first vector product is circularly integrated into the target organism`s chromosomal DNA. The resulting integrated chromosomal DNA segment includes the homologous DNA segment at either end of the integrated vector segment. The integrated chromosomal DNA is cleaved with a second restriction enzyme and ligated to form a vector-containing plasmid, which is replicated in a host organism. The replicated plasmid is then cleaved with the first restriction enzyme. Next, a DNA segment containing the vector and a segment of DNA homologous to a distal portion of the previously isolated DNA segment is isolated. This segment is then ligated to form a plasmid which is replicated within a suitable host. This plasmid is then circularly integrated into the target chromosomal DNA. The chromosomal DNA containing the circularly integrated vector is treated with a third, retrorestriction enzyme. The cleaved DNA is ligated to give a plasmid that is used to transform a host permissive for replication of its vector. The sequential cloning process continues by repeated cycles of circular integration and excision. The excision is carried out alternately with the second and third enzymes.

  1. Evaluation of allelic instability in MEN 2A and FMTC tumors

    SciTech Connect

    Schuster, M.K.; Bratti, L.M.; Rothschild, C.B.

    1994-09-01

    Allelic instability of genomic DNA in tumors derived from individuals with multiple endocrine neoplasia type 2A (MEN 2A) or medullary thyroid carcinoma (MTC) was evaluated. Fourteen highly polymorphic dinucleotide repeat polymorphism markers from 5 different chromosomes were tested. Allelic difference between tumor and peripheral blood leukocyte DNA was observed in 4 of 9 tumors, 2 of which showed allelic instability at more than 1 locus. Pet 1, a sporadic, moderately aggressive MTC, revealed allelic instability at 5 different loci from 4 chromosomes. Rut1, an aggressive MTC from a patient with MEN 2A, revealed genetic instability at 3 different loci, all located on chromosome 10. Microsatellite instability has been associated with hereditary nonpolyposis colon cancer (HNPCC) and has been attributed to germline mutations in hMSH2. In MEN 2A and familial MTC, the initiating event in tumorigenesis is a germline mutation in the receptor tyrosine kinase RET. Progression to full tumor development likely required additional somatic mutations. The presence of microsatellite instability in some MTCs suggests that these additional mutations may affect DNA repair genes such as hMSH2 that has been associated with HNPCC.

  2. THE HUMAN CHROMOSOME

    PubMed Central

    Abuelo, J. G.; Moore, Dorothy E.

    1969-01-01

    Human lymphocytes were grown in short-term tissue culture and were arrested in metaphase with Colcemid. Their chromosomes were prepared by the Langmuir trough-critical point drying technique and were examined under the electron microscope. In addition, some chromosomes were digested with trypsin, Pronase, or DNase. The chromosomes consist entirely of tightly packed, 240 ± 50-A chromatin fibers. Trypsin and Pronase treatments induce relaxation of fiber packing and reveal certain underlying fiber arrangements. Furthermore, trypsin treatment demonstrates that the chromatin fiber has a 25–50 A trypsin-resistant core surrounded by a trypsin-sensitive sheath. DNase digestion suggests that this core contains DNA. PMID:5775795

  3. Chromosome Segregation Mechanisms

    PubMed Central

    Nicklas, R. Bruce

    1974-01-01

    Most aspects of chromosome distribution to the daughter cells in meiosis and mitosis are now understood, at the cellular level. The most striking evidence that the proposed explanation is valid is that it correctly predicts the outcome of experiments on living cells in which the experimenter (1) can determine the distribution of any chosen chromosome to a chosen daughter cell, (2) can induce a mal-orientation, and (3) can stabilize a mal-orientation, causing non-disjunction of a chosen bivalent. Recent reviews of chromosome distribution mechanisms are also considered, in an attempt to clarify the remaining unsolved problems. PMID:4442702

  4. Electromagnetic ion beam instabilities

    NASA Technical Reports Server (NTRS)

    Gary, S. P.; Foosland, D. W.; Smith, C. W.; Lee, M. A.; Goldstein, M. L.

    1984-01-01

    The linear theory of electromagnetic instabilities driven by an energetic ion beam streaming parallel to a magnetic field in a homogeneous Vlasov plasma is considered. Numerical solutions of the full dispersion equation are presented. At propagation parallel to the magnetic field, there are four distinct instabilities. A sufficiently energetic beam gives rise to two unstable modes with right-hand polarization, one resonant with the beam, the other nonresonant. A beam with sufficiently large T (perpendicular to B)/T (parallel to B) gives rise to the left-hand ion cyclotron anisotropy instability at relatively small beam velocities, and a sufficiently hot beam drives unstable a left-hand beam resonant mode. The parametric dependences of the growth rates for the three high beam velocity instabilities are presented here. In addition, some properties at oblique propagation are examined. It is demonstrated that, as the beam drift velocity is increased, relative maxima in growth rates can arise at harmonics of the ion cyclotron resonance for both right and left elliptically polarized modes.

  5. Partial Torus Instability

    NASA Astrophysics Data System (ADS)

    Olmedo, Oscar; Zhang, J.

    2010-05-01

    Flux ropes are now generally accepted to be the magnetic configuration of Coronal Mass Ejections (CMEs), which may be formed prior or during solar eruptions. In this study, we model the flux rope as a current-carrying partial torus loop with its two footpoints anchored in the photosphere, and investigate its instability in the context of the torus instability (TI). Previous studies on TI have focused on the configuration of a circular torus and revealed the existence of a critical decay index. Our study reveals that the critical index is a function of the fractional number of the partial torus, defined by the ratio between the arc length of the partial torus above the photosphere and the circumference of a circular torus of equal radius. We refer to this finding the partial torus instability (PTI). It is found that a partial torus with a smaller fractional number has a smaller critical index, thus requiring a more gradually decreasing magnetic field to stabilize the flux rope. On the other hand, the partial torus with a larger fractional number has a larger critical index. In the limit of a circular torus when the fractional number approaches one, the critical index goes to a maximum value that depends on the distribution of the external magnetic field. We demonstrate that the partial torus instability helps us to understand the confinement, growth, and eventual eruption of a flux rope CME.

  6. [Psychodynamics of childhood instability].

    PubMed

    Flavigny, C

    1988-01-01

    This work focuses on the Anglo-Saxon idea concerning "hyperactivity" and "hyperkinesis" and the French-language idea of "child psycho-motor instability". The author's own personal study (having two separate parts, on the one hand studying the psychic functioning of parent and their interaction with their child, and on the other, studying material gathered on the individual psychotherapy of unstable children), goes along with the French school of thought, highlighting the extent of incestuous sexual advances toward children (especially boys) in the family unit and the sexual nature (in the sense of child sexuality) of this excitement as the source of their instability, justifying a comparison between the unstable child and a Don Juan-type of instability. What comes out is epistemological thinking on Anglo-Saxon and French-language ideas, in particular criticism of the pre-suppositions in the Anglo-Saxon way of seeing things, which seems only to envisage the characterization of a syndromic range, rather than an organic etiology, this being more often implicit; distanced by the idea of psychodynamics, which predominate in the French-language studies, integrating the symptom of "psycho-motor instability" in the general "wholeness" of the child and evaluating ways of parent-child interaction.

  7. Generic Software Architecture for Prognostics (GSAP) User Guide

    NASA Technical Reports Server (NTRS)

    Teubert, Christopher Allen; Daigle, Matthew John; Watkins, Jason; Sankararaman, Shankar; Goebel, Kai

    2016-01-01

    The Generic Software Architecture for Prognostics (GSAP) is a framework for applying prognostics. It makes applying prognostics easier by implementing many of the common elements across prognostic applications. The standard interface enables reuse of prognostic algorithms and models across systems using the GSAP framework.

  8. Specimen banks for cancer prognostic factor research.

    PubMed

    Burke, H B; Henson, D E

    1998-10-01

    Prognostic factors are necessary for determining whether a patient will require therapy, for selecting the optimal therapy, and for evaluating the effectiveness of the therapy chosen. Research in prognostic factors has been hampered by long waiting times and a paucity of outcomes. Specimen banks can solve these problems, but their implementation and use give rise to many important and complex issues. This paper presents an overview of some of the issues related to the use of specimen banks in prognostic factor research.

  9. Cell-autonomous correction of ring chromosomes in human induced pluripotent stem cells

    NASA Astrophysics Data System (ADS)

    Bershteyn, Marina; Hayashi, Yohei; Desachy, Guillaume; Hsiao, Edward C.; Sami, Salma; Tsang, Kathryn M.; Weiss, Lauren A.; Kriegstein, Arnold R.; Yamanaka, Shinya; Wynshaw-Boris, Anthony

    2014-03-01

    Ring chromosomes are structural aberrations commonly associated with birth defects, mental disabilities and growth retardation. Rings form after fusion of the long and short arms of a chromosome, and are sometimes associated with large terminal deletions. Owing to the severity of these large aberrations that can affect multiple contiguous genes, no possible therapeutic strategies for ring chromosome disorders have been proposed. During cell division, ring chromosomes can exhibit unstable behaviour leading to continuous production of aneuploid progeny with low viability and high cellular death rate. The overall consequences of this chromosomal instability have been largely unexplored in experimental model systems. Here we generated human induced pluripotent stem cells (iPSCs) from patient fibroblasts containing ring chromosomes with large deletions and found that reprogrammed cells lost the abnormal chromosome and duplicated the wild-type homologue through the compensatory uniparental disomy (UPD) mechanism. The karyotypically normal iPSCs with isodisomy for the corrected chromosome outgrew co-existing aneuploid populations, enabling rapid and efficient isolation of patient-derived iPSCs devoid of the original chromosomal aberration. Our results suggest a fundamentally different function for cellular reprogramming as a means of `chromosome therapy' to reverse combined loss-of-function across many genes in cells with large-scale aberrations involving ring structures. In addition, our work provides an experimentally tractable human cellular system for studying mechanisms of chromosomal number control, which is of critical relevance to human development and disease.

  10. DNA Secondary Structure at Chromosomal Fragile Sites in Human Disease

    PubMed Central

    Thys, Ryan G; Lehman, Christine E; Pierce, Levi C. T; Wang, Yuh-Hwa

    2015-01-01

    DNA has the ability to form a variety of secondary structures that can interfere with normal cellular processes, and many of these structures have been associated with neurological diseases and cancer. Secondary structure-forming sequences are often found at chromosomal fragile sites, which are hotspots for sister chromatid exchange, chromosomal translocations, and deletions. Structures formed at fragile sites can lead to instability by disrupting normal cellular processes such as DNA replication and transcription. The instability caused by disruption of replication and transcription can lead to DNA breakage, resulting in gene rearrangements and deletions that cause disease. In this review, we discuss the role of DNA secondary structure at fragile sites in human disease. PMID:25937814

  11. Distilling the Verification Process for Prognostics Algorithms

    NASA Technical Reports Server (NTRS)

    Roychoudhury, Indranil; Saxena, Abhinav; Celaya, Jose R.; Goebel, Kai

    2013-01-01

    The goal of prognostics and health management (PHM) systems is to ensure system safety, and reduce downtime and maintenance costs. It is important that a PHM system is verified and validated before it can be successfully deployed. Prognostics algorithms are integral parts of PHM systems. This paper investigates a systematic process of verification of such prognostics algorithms. To this end, first, this paper distinguishes between technology maturation and product development. Then, the paper describes the verification process for a prognostics algorithm as it moves up to higher maturity levels. This process is shown to be an iterative process where verification activities are interleaved with validation activities at each maturation level. In this work, we adopt the concept of technology readiness levels (TRLs) to represent the different maturity levels of a prognostics algorithm. It is shown that at each TRL, the verification of a prognostics algorithm depends on verifying the different components of the algorithm according to the requirements laid out by the PHM system that adopts this prognostics algorithm. Finally, using simplified examples, the systematic process for verifying a prognostics algorithm is demonstrated as the prognostics algorithm moves up TRLs.

  12. Chromosome doubling method

    DOEpatents

    Kato, Akio

    2006-11-14

    The invention provides methods for chromosome doubling in plants. The technique overcomes the low yields of doubled progeny associated with the use of prior techniques for doubling chromosomes in plants such as grasses. The technique can be used in large scale applications and has been demonstrated to be highly effective in maize. Following treatment in accordance with the invention, plants remain amenable to self fertilization, thereby allowing the efficient isolation of doubled progeny plants.

  13. Chromosome evolution in Eulipotyphla.

    PubMed

    Biltueva, L; Vorobieva, N

    2012-01-01

    We integrated chromosome painting information on 5 core-insectivora species available in the literature with new Zoo-FISH data for Iberian shrew (Sorex granarius) and Altai mole (Talpa altaica). Our analysis of these 7 species allowed us to determine the chromosomal features of Eulipotyphla genomes and to update the previously proposed ancestral karyotype for 2 main groups of the Sorex genus. The chromosome painting evidence with human painting probes (HSA) reveals the presence of the 2 unique associations HSA4/5 and 1/10p/12/22b, which support Eulipotyphla. There are a series of synapomorphies both for Erinaceidae (HSA3/1/5, 3/17, 11/15 and 10/20) and for Soricinae (HSA5/9, 6/7/16, 8/3/21 and 11/12/22). We found associations that link Talpidae/Erinaceidae (HSA7/8, 1/5 and 1/19p), Talpidae/Soricidae (HSA1/8/4) and Erinaceidae/Soricidae (HSA4/20 and 2/13). Genome conservation in Eulipotyphla was estimated on the basis of the number of evolutionary breaks in the ancestral mammalian chromosomes. In total, 7 chromosomes of the boreo-eutherian ancestor (BEA8 or 10, 9, 17, 18, 20-22) were retained in all eulipotyphlans studied; among them moles show the highest level of chromosome conservation. The integration of sequence data into the chromosome painting information allowed us to further examine the chromosomal syntenies within a phylogenetic perspective. Based on our analysis we offer the most parsimonious reconstruction of phylogenetic relationships in Eulipotyphla. The cytogenetic reconstructions based on these data do not conflict with molecular phylogenies supporting basal position of Talpidae in the order.

  14. [Sex chromosomes and meiosis].

    PubMed

    Guichaoua, M-R; Geoffroy-Siraudin, C; Tassistro, V; Ghalamoun-Slaimi, R; Perrin, J; Metzler-Guillemain, C

    2009-01-01

    Sex chromosome behaviour fundamentally differs between male and female meiosis. In oocyte, X chromosomes synapse giving a XX bivalent which is not recognizable in their morphology and behaviour from autosomal bivalents. In human male, X and Y chromosomes differ from one another in their morphology and their genetic content, leading to a limited pairing and preventing genetic recombination, excepted in homologous region PAR1. During pachytene stage of the first meiotic prophase, X and Y chromosomes undergo a progressive condensation and form a transcriptionally silenced peripheral XY body. The condensation of the XY bivalent during pachytene stage led us to describe four pachytene substages and to localize the pachytene checkpoint between substages 2 and 3. We also defined the pachytene index (PI=P1+P2/P1+P2+P3+P4) which is always less than 0.50 in normal meiosis. XY body undergoes decondensation at diplotene stage, but transcriptional inactivation of the two sex chromosomes or Meiotic Sex Chromosome Inactivation (MSCI) persists through to the end of spermatogenesis. Sex chromosome inactivation involves several proteins, some of them were now identified. Two isoforms of the HP1 protein, HP1beta and HP1gamma, are involved in the facultative heterochromatinization of the XY body, but the initiation of this process involves the phosphorylation of the protein H2AX by the kinase ATR whose recruitment depends on BRCA1. Extensive researches on the inactivation of the sex chromosomes during male meiosis will allow to a better understanding of some male infertilities.

  15. Genetic markers on chromosome 7.

    PubMed Central

    Tsui, L C

    1988-01-01

    Chromosome 7 is frequently associated with chromosome aberrations, rearrangements, and deletions. It also contains many important genes, gene families, and disease loci. This brief review attempts to summarise these and other interesting aspects of chromosome 7. With the rapid accumulation of cloned genes and polymorphic DNA fragments, this chromosome has become an excellent substrate for molecular genetic studies. PMID:3290488

  16. Epilepsy and chromosomal abnormalities

    PubMed Central

    2010-01-01

    Background Many chromosomal abnormalities are associated with Central Nervous System (CNS) malformations and other neurological alterations, among which seizures and epilepsy. Some of these show a peculiar epileptic and EEG pattern. We describe some epileptic syndromes frequently reported in chromosomal disorders. Methods Detailed clinical assessment, electrophysiological studies, survey of the literature. Results In some of these congenital syndromes the clinical presentation and EEG anomalies seems to be quite typical, in others the manifestations appear aspecific and no strictly linked with the chromosomal imbalance. The onset of seizures is often during the neonatal period of the infancy. Conclusions A better characterization of the electro clinical patterns associated with specific chromosomal aberrations could give us a valuable key in the identification of epilepsy susceptibility of some chromosomal loci, using the new advances in molecular cytogenetics techniques - such as fluorescent in situ hybridization (FISH), subtelomeric analysis and CGH (comparative genomic hybridization) microarray. However further studies are needed to understand the mechanism of epilepsy associated with chromosomal abnormalities. PMID:20438626

  17. Incidental Prenatal Diagnosis of Sex Chromosome Aneuploidies: Health, Behavior, and Fertility

    PubMed Central

    Pieters, J. J. P. M.; Kooper, A. J. A.; van Kessel, A. Geurts; Braat, D. D. M.; Smits, A. P. T.

    2011-01-01

    Objective. To assess the diagnostic relevance of incidental prenatal findings of sex chromosome aneuploidies. Methods. We searched with medical subject headings (MeSHs) and keywords in Medline and the Cochrane Library and systematically screened publications on postnatally diagnosed sex chromosomal aneuploidies from 2006 to 2011 as well as publications on incidentally prenatally diagnosed sex chromosomal aneuploidies from 1980 to 2011. Results. Postnatally diagnosed sex chromosomal aneuploidies demonstrated three clinical relevant domains of abnormality: physical (22–100%), behavior (0–56%), and reproductive health (47–100%), while incidentally prenatally diagnosed sex chromosomal aneuploidies demonstrated, respectively, 0–33%, 0–40%, and 0–36%. Conclusion. In the literature incidental prenatal diagnosis of sex chromosomal aneuploidies is associated with normal to mildly affected phenotypes. This contrasts sharply with those of postnatally diagnosed sex chromosomal aneuploidies and highlights the importance of this ascertainment bias towards the prognostic value of diagnosis of fetal sex chromosomal aneuploidies. This observation should be taken into account, especially when considering excluding the sex chromosomes in invasive prenatal testing using Rapid Aneuploidy Detection. PMID:22191050

  18. Micromechanics of human mitotic chromosomes

    NASA Astrophysics Data System (ADS)

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

    2011-02-01

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

  19. Motile kinetochores and polar ejection forces dictate chromosome position on the vertebrate mitotic spindle

    PubMed Central

    1994-01-01

    We argue that hypotheses for how chromosomes achieve a metaphase alignment, that are based solely on a tug-of-war between poleward pulling forces produced along the length of opposing kinetochore fibers, are no longer tenable for vertebrates. Instead, kinetochores move themselves and their attached chromosomes, poleward and away from the pole, on the ends of relatively stationary but shortening/elongating kinetochore fiber microtubules. Kinetochores are also "smart" in that they switch between persistent constant-velocity phases of poleward and away from the pole motion, both autonomously and in response to information within the spindle. Several molecular mechanisms may contribute to this directional instability including kinetochore-associated microtubule motors and kinetochore microtubule dynamic instability. The control of kinetochore directional instability, to allow for congression and anaphase, is likely mediated by a vectorial mechanism whose magnitude and orientation depend on the density and orientation or growth of polar microtubules. Polar microtubule arrays have been shown to resist chromosome poleward motion and to push chromosomes away from the pole. These "polar ejection forces" appear to play a key role in regulating kinetochore directional instability, and hence, positions achieved by chromosomes on the spindle. PMID:8294508

  20. Hybrid Bearing Prognostic Test Rig

    NASA Technical Reports Server (NTRS)

    Dempsey, Paula J.; Certo, Joseph M.; Handschuh, Robert F.; Dimofte, Florin

    2005-01-01

    The NASA Glenn Research Center has developed a new Hybrid Bearing Prognostic Test Rig to evaluate the performance of sensors and algorithms in predicting failures of rolling element bearings for aeronautics and space applications. The failure progression of both conventional and hybrid (ceramic rolling elements, metal races) bearings can be tested from fault initiation to total failure. The effects of different lubricants on bearing life can also be evaluated. Test conditions monitored and recorded during the test include load, oil temperature, vibration, and oil debris. New diagnostic research instrumentation will also be evaluated for hybrid bearing damage detection. This paper summarizes the capabilities of this new test rig.

  1. Microsatellite Instability Assay — EDRN Public Portal

    Cancer.gov

    Microsatellite analysis (MSA) is a promising new technique for the surveillance of bladder cancer. The technology, which permits the separation by electrophoresis of polymerase chain reaction (PCR)-amplified sequences from non-malignant and malignant sources, has been applied to the diagnosis of solid tumors arising in colon, lung, oropharynx, kidney and bladder. MSA can detect genetic changes indicative of carcinoma from urothelial cells obtained in voided urine specimens. The genetic profile of DNA purified from urine is compared to that of DNA purified from peripheral lymphocytes that are considered normal. Once the DNA from uroepithelial cells has been obtained, PCR is performed with specific oligonucleotide primers for each chromosomal locus. The PCR products are then examined for evidence of microsatellite instability (MSI) and loss of heterozygosity (LOH), which are genetic characteristics of epithelial tumors. Preliminary work shows that MSA detects 95% of cancers.

  2. Instability in poroelastic media

    NASA Astrophysics Data System (ADS)

    Pramanik, Satyajit; Wettlaufer, John

    2016-11-01

    Fluid flow in deformable porous materials, which play significant role in different biological and geological systems of wide range of scales, is a highly nonlinear problem. Feedback from the elastic deformation of the solid skeleton on the fluid flow and vice-versa gives rise to pattern formation in the porosity structure of the skeleton. We view some of these patterns as instabilities of the coupled fluid-solid system. Due to highly nonlinear nature of the problem, very little has been understood about this instability. Here, we use a minimal poroelastic theory to understand the pattern formation in a fluid-saturated poroelastic material and discuss the similarities/differences with viscous fingering in non-deformable porous media.

  3. [Orthostatic tremor inducing instability].

    PubMed

    Manrique-Huarte, Raquel; Arcocha, Juan; Pérez-Fernández, Nicolás

    2012-01-01

    Orthostatic tremor (OT) is a neurological disease of unknown aetiology. It is defined by the presence of a 10-20 Hz tremor in the legs while standing still. Symptoms described are dizziness and instability that diminish if the patient sits down or leans on something; drinking small amounts of alcohol significantly reduces OT. Due to the dizziness and/or unsteadiness, these patients are usually referred to the neuro-otology department. We report 4 cases diagnosed with OT. The diagnosis of OT should be considered for patients with instability. The clinical history is a key factor to suspect this entity, and the diagnosis is given by the register of 10-20 Hz contractions on limb electromyography. Treatment for this disease consists of medical treatment; the first option is clonazepam.

  4. Wrist Instability After Injury

    PubMed Central

    Muminagic, Sahib; Kapidzic, Tarik

    2012-01-01

    Fractures of the bones that make the wrist joint together with injury to the ligaments and joint capsules are frequent traumas. It can cause besides limited movement also the pathological mobility. These mild injuries often do not provide the degree of recognizable symptoms and signs. They are diagnosed by X-ray imaging, stress images. Before arthrography was an important method, but nowadays arthroscopy has the advantage. Fresh bone and ligament injuries can be and should be repaired in the early posttraumatic period. Unrecognized and undiagnosed injuries are leading to instability of the wrist, to motion abnormalities or impingement overload syndrome. In the treatment of instability important place have reconstruction of the ligaments and arthrodesis of the wrist. PMID:23678318

  5. Modulation instability: The beginning

    NASA Astrophysics Data System (ADS)

    Noskov, Roman; Belov, Pavel; Kivshar, Yuri

    2012-11-01

    The study of metal nanoparticles plays a central role in the emerging novel technologies employing optics beyond the diffraction limit. Combining strong surface plasmon resonances, high intrinsic nonlinearities and deeply subwavelength scales, arrays of metal nanoparticles offer a unique playground to develop novel concepts for light manipulation at the nanoscale. Here we suggest a novel principle to control localized optical energy in chains of nonlinear subwavelength metal nanoparticles based on the fundamental nonlinear phenomenon of modulation instability. In particular, we demonstrate that modulation instability can lead to the formation of long-lived standing and moving nonlinear localized modes of several distinct types such as bright and dark solitons, oscillons, and domain walls. We analyze the properties of these nonlinear localized modes and reveal different scenarios of their dynamics including transformation of one type of mode to another. We believe this work paves a way towards the development of nonlinear nanophotonics circuitry.

  6. Instabilities in sensory processes

    NASA Astrophysics Data System (ADS)

    Balakrishnan, J.

    2014-07-01

    In any organism there are different kinds of sensory receptors for detecting the various, distinct stimuli through which its external environment may impinge upon it. These receptors convey these stimuli in different ways to an organism's information processing region enabling it to distinctly perceive the varied sensations and to respond to them. The behavior of cells and their response to stimuli may be captured through simple mathematical models employing regulatory feedback mechanisms. We argue that the sensory processes such as olfaction function optimally by operating in the close proximity of dynamical instabilities. In the case of coupled neurons, we point out that random disturbances and fluctuations can move their operating point close to certain dynamical instabilities triggering synchronous activity.

  7. Open field lines instabilities

    SciTech Connect

    Pozzoli, R. |

    1995-09-01

    The results of some recent theoretical papers dealing with flute-like instabilities in the scrape-off layer of a tokamak with limiter configuration, where the magnetic field intersects conducting walls, are briefly recalled. Attention is then paid to the instability driven by the electron temperature gradient across the field in conjunction with the formation of the Debye sheath at the boundary, and to the effects due to the inclination of the end walls with respect to the magnetic field. When a divertor configuration is considered, important modifications are found owing to the strong deformations of the flux tubes passing near the {ital x}-point, which contrast the onset of flute-like perturbations, and to the stochasticity of field lines that can be excited by magnetic field perturbations. {copyright} {ital 1995 American Institute of Physics.}

  8. Induction of Genomic Instability In Vivo by Low Doses of 137Cs gamma rays

    SciTech Connect

    Rithidech, Kanokporn; Simon, Sanford, R.; Whorton, Elbert, B.

    2006-01-06

    The overall goal of this project is to determine if low doses (below or equal to the level traditionally requiring human radiation protection, i.e. less than or equal to 10 cGy) of low LET radiation can induce genomic instability. The magnitude of genomic instability was measured as delayed chromosome instability in bone marrow cells of exposed mice with different levels of endogenous DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activity, i.e. high (C57BL/6J mice), intermediate (BALB/cJ mice), and extremely low (Scid mice). In addition, at early time points (1 and 4 hrs) following irradiation, levels of activation of nuclear factor-kappa B (NF-{kappa}B), a transcription factor known to be involved in regulating the expression of genes responsible for cell protection following stimuli, were measured in these cells. Bone marrow cells were collected at different times following irradiation, i.e. 1 hr, 4 hrs, 1 month, and 6 months. A total of five mice per dose per strain were sacrificed at each time point for sample collection. As a result, a total of 80 mice from each strain were used. The frequency and the type of metaphase chromosome aberrations in bone marrow cells collected from exposed mice at different times following irradiation were used as markers for radiation-induced genomic instability. A three-color fluorescence in situ hybridization (FISH) protocol for mouse chromosomes 1, 2, and 3 was used for the analysis of delayed stable chromosomal aberrations in metaphase cells. All other visible chromatid-type aberrations and gross structural abnormalities involving non-painted chromosomes were also evaluated on the same metaphase cells used for scoring the stable chromosomal aberrations of painted chromosomes. Levels of nuclear factor-kappa B (NF-{kappa}B) activation were also determined in cells at 1 and 4 hrs following irradiation (indicative of early responses).

  9. Modulation instability: The beginning

    NASA Astrophysics Data System (ADS)

    Zakharov, V. E.; Ostrovsky, L. A.

    2009-03-01

    We discuss the early history of an important field of “sturm and drang” in modern theory of nonlinear waves. It is demonstrated how scientific demand resulted in independent and almost simultaneous publications by many different authors on modulation instability, a phenomenon resulting in a variety of nonlinear processes such as envelope solitons, envelope shocks, freak waves, etc. Examples from water wave hydrodynamics, electrodynamics, nonlinear optics, and convection theory are given.

  10. Chronic ankle instability: Current perspectives

    PubMed Central

    Al-Mohrej, Omar A.; Al-Kenani, Nader S.

    2016-01-01

    Ankle sprain is reported to be among the most common recurrent injuries. About 20% of acute ankle sprain patients develop chronic ankle instability. The failure of functional rehabilitation after acute ankle sprain leads to the development of chronic ankle instability. Differentiation between functional and anatomical ankle instability is very essential to guide the proper treatment. Stability testing by varus stress test and anterior drawer test should be carried out. Subtalar instability is an important pathology that is commonly by passed during the assessment of chronic ankle instability. Unlike acute ankle sprain, chronic ankle instability might require surgical intervention. The surgical and conservative management options can be very much developed by in-depth knowledge of the ankle anatomy, biomechanics, and pathology. Anatomical repair, augmentation by tendon, or both are the basic methods of surgical intervention. Arthroscopy is becoming more popular in the management of chronic ankle instability. PMID:27843798

  11. Combustion instability analysis

    NASA Technical Reports Server (NTRS)

    Chung, T. J.

    1990-01-01

    A theory and computer program for combustion instability analysis are presented. The basic theoretical foundation resides in the concept of entropy-controlled energy growth or decay. Third order perturbation expansion is performed on the entropy-controlled acoustic energy equation to obtain the first order integrodifferential equation for the energy growth factor in terms of the linear, second, and third order energy growth parameters. These parameters are calculated from Navier-Stokes solutions with time averages performed on as many Navier-Stokes time steps as required to cover at least one peak wave period. Applications are made for a 1-D Navier-Stokes solution for the Space Shuttle Main Engine (SSME) thrust chamber with cross section area variations taken into account. It is shown that instability occurs when the mean pressure is set at 2000 psi with 30 percent disturbances. Instability also arises when the mean pressure is set at 2935 psi with 20 percent disturbances. The system with mean pressures and disturbances more adverse that these cases were shown to be unstable.

  12. Prognostic markers in acute pancreatitis.

    PubMed

    Gomatos, Ilias P; Xiaodong, Xu; Ghaneh, Paula; Halloran, Christopher; Raraty, Michael; Lane, Brian; Sutton, Robert; Neoptolemos, John P

    2014-04-01

    Acute pancreatitis has a mortality rate of 5-10%. Early deaths are mainly due to multiorgan failure and late deaths are due to septic complications from pancreatic necrosis. The recently described 2012 Revised Atlanta Classification and the Determinant Classification both provide a more accurate description of edematous and necrotizing pancreatitis and local complications. The 2012 Revised Atlanta Classification uses the modified Marshall scoring system for assessing organ dysfunction. The Determinant Classification uses the sepsis-related organ failure assessment scoring system for organ dysfunction and, unlike the 2012 Revised Atlanta Classification, includes infected necrosis as a criterion of severity. These scoring systems are used to assess systemic complications requiring intensive therapy unit support and intra-abdominal complications requiring minimally invasive interventions. Numerous prognostic systems and markers have been evaluated but only the Glasgow system and serum CRP levels provide pragmatic prognostic accuracy early on. Novel concepts using genetic, transcriptomic and proteomic profiling and also functional imaging for the identification of specific disease patterns are now required.

  13. [Prognostic study of liver abscess].

    PubMed

    Nouira, Ramzi; Bedoui, Riadh; Miaadi, Naoufel; Guesmi, Fethi; Ben Achour, Jamel; Hani, Mohamed; Daghfous, Mounir; Ben Osman, Samia; Zoghlami, Ayoub; Najah, Nabil

    2003-04-01

    The objective of this work is to study factors of prognostic of mortality of abscesses of the liver. We have treated between 1990 and 2000 in our service, 38 patient for abscess of the liver. The symptoms are dominated by the pain of the right hypochondria (37 cases) and the fever (34 cases). An unique abscess has been recovered in 25 cases. Some multiple localizations have been observed in 12 cases. 21 patients have been operated. The bacteriological study at all patients revealed the presence of germ in 27 cases. In 6 cases, there were two germs. It was a bacillus negative gram in 26 cases and a cocci positive gram in 7 cases. Six complications have been observed at the operated patients. In 5 cases, it was a septic shock having leads to the death. After survey univariate and multivariate the only factor of bad prognostic recovered is the septic shock. The aetiology was identified in only 9 cases; it was abscess cholangiotis.

  14. Prognostic Analysis System and Methods of Operation

    NASA Technical Reports Server (NTRS)

    MacKey, Ryan M. E. (Inventor); Sneddon, Robert (Inventor)

    2014-01-01

    A prognostic analysis system and methods of operating the system are provided. In particular, a prognostic analysis system for the analysis of physical system health applicable to mechanical, electrical, chemical and optical systems and methods of operating the system are described herein.

  15. Distributed Prognostics based on Structural Model Decomposition

    NASA Technical Reports Server (NTRS)

    Daigle, Matthew J.; Bregon, Anibal; Roychoudhury, I.

    2014-01-01

    Within systems health management, prognostics focuses on predicting the remaining useful life of a system. In the model-based prognostics paradigm, physics-based models are constructed that describe the operation of a system and how it fails. Such approaches consist of an estimation phase, in which the health state of the system is first identified, and a prediction phase, in which the health state is projected forward in time to determine the end of life. Centralized solutions to these problems are often computationally expensive, do not scale well as the size of the system grows, and introduce a single point of failure. In this paper, we propose a novel distributed model-based prognostics scheme that formally describes how to decompose both the estimation and prediction problems into independent local subproblems whose solutions may be easily composed into a global solution. The decomposition of the prognostics problem is achieved through structural decomposition of the underlying models. The decomposition algorithm creates from the global system model a set of local submodels suitable for prognostics. Independent local estimation and prediction problems are formed based on these local submodels, resulting in a scalable distributed prognostics approach that allows the local subproblems to be solved in parallel, thus offering increases in computational efficiency. Using a centrifugal pump as a case study, we perform a number of simulation-based experiments to demonstrate the distributed approach, compare the performance with a centralized approach, and establish its scalability. Index Terms-model-based prognostics, distributed prognostics, structural model decomposition ABBREVIATIONS

  16. Whole chromosome aneuploidy: big mutations drive adaptation by phenotypic leap

    PubMed Central

    Chen, Guangbo; Rubinstein, Boris; Li, Rong

    2012-01-01

    Despite its wide existence, the adaptive role of aneuploidy (the abnormal state of having unequal number of different chromosomes) has been a subject of debate. Cellular aneuploidy has been associated with enhanced resistance to stress, whereas on the organismal level it is detrimental to multi-cellular species. Certain aneuploid karyotypes are deleterious for specific environments, but karyotype diversity in a population potentiates adaptive evolution. To reconcile these paradoxical observations, this review distinguishes the role of aneuploidy in cellular versus organismal evolution. Further, it proposes a population genetics perspective to examine the behavior of aneuploidy on a populational versus individual level. By altering the copy number of a significant portion of the genome, aneuploidy introduces large phenotypic leap that enables small cell populations to explore a wide phenotypic landscape, from which adaptive traits can be selected. The production of chromosome number variation can be further increased by stress- or mutation-induced chromosomal instability, fueling rapid cellular adaptation. PMID:22926916

  17. Model-Based Prognostics of Hybrid Systems

    NASA Technical Reports Server (NTRS)

    Daigle, Matthew; Roychoudhury, Indranil; Bregon, Anibal

    2015-01-01

    Model-based prognostics has become a popular approach to solving the prognostics problem. However, almost all work has focused on prognostics of systems with continuous dynamics. In this paper, we extend the model-based prognostics framework to hybrid systems models that combine both continuous and discrete dynamics. In general, most systems are hybrid in nature, including those that combine physical processes with software. We generalize the model-based prognostics formulation to hybrid systems, and describe the challenges involved. We present a general approach for modeling hybrid systems, and overview methods for solving estimation and prediction in hybrid systems. As a case study, we consider the problem of conflict (i.e., loss of separation) prediction in the National Airspace System, in which the aircraft models are hybrid dynamical systems.

  18. "Chromosome": a knowledge-based system for the chromosome classification.

    PubMed

    Ramstein, G; Bernadet, M

    1993-01-01

    Chromosome, a knowledge-based analysis system has been designed for the classification of human chromosomes. Its aim is to perform an optimal classification by driving a tool box containing the procedures of image processing, pattern recognition and classification. This paper presents the general architecture of Chromosome, based on a multiagent system generator. The image processing tool box is described from the met aphasic enhancement to the fine classification. Emphasis is then put on the knowledge base intended for the chromosome recognition. The global classification process is also presented, showing how Chromosome proceeds to classify a given chromosome. Finally, we discuss further extensions of the system for the karyotype building.

  19. Complex Chromosomal Rearrangements in B-Cell Lymphoma: Evidence of Chromoanagenesis? A Case Report

    PubMed Central

    Ortega, Veronica; Chaubey, Alka; Mendiola, Christina; Ehman, William; Vadlamudi, Kumari; Dupont, Barbara; Velagaleti, Gopalrao

    2016-01-01

    Genomic instability is a well-known hallmark of cancer. Recent genome sequencing studies have led to the identification of novel phenomena called chromothripsis and chromoanasynthesis in which complex genomic rearrangements are thought to be derived from a single catastrophic event rather than by several incremental steps. A new term chromoanagenesis or chromosomal rebirth was coined recently to group these two one-step catastrophic events together. These phenomena suggest an evolutionary modality for cancer cells to circumvent individual mutational events with one simultaneous shattering of chromosomes resulting in the random reassembling of segmented genetic material to form complex derivative chromosomes. We report a case of possible chromoanagenesis in a patient with diffuse large B-cell lymphoma. Chromosome analysis from the biopsy showed a complex karyotype with multiple numerical and structural rearrangements including a translocation of chromosomes 3 and 7 involving the BCL6 gene region, with the derivative chromosome further rearranging with chromosomes 14, 7, and 22 with involvement of the IGH gene region. Fluorescence in situ hybridization studies confirmed these findings. Chromosomal microarray studies showed multiple complex copy number variations including a chromosome 12 abnormality, the complexity of which appears to suggest the phenomenon of chromoanagenesis. Our case further illustrates that lymphomagenesis can be complex and may arise from a catastrophic event resulting in multiple complex chromosome rearrangements. PMID:27108385

  20. Homoeologous shuffling and chromosome compensation maintain genome balance in resynthesized allopolyploid Brassica napus.

    PubMed

    Xiong, Zhiyong; Gaeta, Robert T; Pires, J Chris

    2011-05-10

    Polyploidy has contributed to the evolution of eukaryotes, particularly flowering plants. The genomic consequences of polyploidy have been extensively studied, but the mechanisms for chromosome stability and diploidization in polyploids remain largely unknown. By using new cytogenetic tools to identify all of the homoeologous chromosomes, we conducted a cytological investigation of 50 resynthesized Brassica napus allopolyploids across generations S(0:1) to S(5:6) and in the S(10:11) generation. Changes in copy number of individual chromosomes were detected in the S(0:1) generation and increased in subsequent generations, despite the fact that the mean chromosome number among lines was approximately 38. The chromosome complement of individual plants (segregants) ranged from 36 to 42, with a bias toward the accumulation of extra chromosomes. Karyotype analysis of the S(10:11) generation detected aneuploidy and inter- and intragenomic rearrangements, chromosome breakage and fusion, rDNA changes, and loss of repeat sequences. Chromosome sets with extensive homoeology showed the greatest instability. Dosage balance requirements maintained chromosome numbers at or near the tetraploid level, and the loss and gain of chromosomes frequently involved homoeologous chromosome replacement and compensation. These data indicate that early generations of resynthesized B. napus involved aneuploidy and gross chromosomal rearrangements, and that dosage balance mechanisms enforced chromosome number stability. Seed yield and pollen viability were inversely correlated with increasing aneuploidy, and the greatest fertility was observed in two lines that were additive for parental chromosomes. These data on resynthesized B. napus and the correlation of fertility with additive karyotypes cast light on the origins and establishment of natural B. napus.

  1. Telomere fusion threshold identifies a poor prognostic subset of breast cancer patients.

    PubMed

    Simpson, K; Jones, R E; Grimstead, J W; Hills, R; Pepper, C; Baird, D M

    2015-06-01

    Telomere dysfunction and fusion can drive genomic instability and clonal evolution in human tumours, including breast cancer. Telomere length is a critical determinant of telomere function and has been evaluated as a prognostic marker in several tumour types, but it has yet to be used in the clinical setting. Here we show that high-resolution telomere length analysis, together with a specific telomere fusion threshold, is highly prognostic for overall survival in a cohort of patients diagnosed with invasive ductal carcinoma of the breast (n = 120). The telomere fusion threshold defined a small subset of patients with an extremely poor clinical outcome, with a median survival of less than 12 months (HR = 21.4 (7.9-57.6), P < 0.0001). Furthermore, this telomere length threshold was independent of ER, PGR, HER2 status, NPI, or grade and was the dominant variable in multivariate analysis. We conclude that the fusogenic telomere length threshold provides a powerful, independent prognostic marker with clinical utility in breast cancer. Larger prospective studies are now required to determine the optimal way to incorporate high-resolution telomere length analysis into multivariate prognostic algorithms for patients diagnosed with breast cancer.

  2. Sex Chromosome Drive

    PubMed Central

    Helleu, Quentin; Gérard, Pierre R.; Montchamp-Moreau, Catherine

    2015-01-01

    Sex chromosome drivers are selfish elements that subvert Mendel's first law of segregation and therefore are overrepresented among the products of meiosis. The sex-biased progeny produced then fuels an extended genetic conflict between the driver and the rest of the genome. Many examples of sex chromosome drive are known, but the occurrence of this phenomenon is probably largely underestimated because of the difficulty to detect it. Remarkably, nearly all sex chromosome drivers are found in two clades, Rodentia and Diptera. Although very little is known about the molecular and cellular mechanisms of drive, epigenetic processes such as chromatin regulation could be involved in many instances. Yet, its evolutionary consequences are far-reaching, from the evolution of mating systems and sex determination to the emergence of new species. PMID:25524548

  3. Meiotic sex chromosome inactivation.

    PubMed

    Turner, James M A

    2007-05-01

    X chromosome inactivation is most commonly studied in the context of female mammalian development, where it performs an essential role in dosage compensation. However, another form of X-inactivation takes place in the male, during spermatogenesis, as germ cells enter meiosis. This second form of X-inactivation, called meiotic sex chromosome inactivation (MSCI) has emerged as a novel paradigm for studying the epigenetic regulation of gene expression. New studies have revealed that MSCI is a special example of a more general mechanism called meiotic silencing of unsynapsed chromatin (MSUC), which silences chromosomes that fail to pair with their homologous partners and, in doing so, may protect against aneuploidy in subsequent generations. Furthermore, failure in MSCI is emerging as an important etiological factor in meiotic sterility.

  4. Suppressing shape instabilities to discover the Bjerknes force instability (L).

    PubMed

    Alibakhshi, Mohammad A; Holt, R Glynn

    2011-11-01

    For sufficiently strong acoustic forcing in a standing wave field, subresonant size bubbles are predicted to be repelled from the pressure antinode. Single bubble sonoluminescence (SBSL) conditions in water do not allow the observation of this instability. This study investigates the possibility that increasing the viscosity of the host liquid can preferentially suppress shape instabilities of a bubble and allow SBSL experiments to be limited by the Bjerknes force instability.

  5. Prenatal diagnosis of the derivative chromosome 22 associated with cat eye syndrome by fluorescence in situ hybridization.

    PubMed

    Reeser, S L; Donnenfeld, A E; Miller, R C; Sellinger, B S; Emanuel, B S; Driscoll, D A

    1994-11-01

    Cytogenetic studies of cultured amniocytes demonstrated a karyotype of 46,XX/47,XX, +mar. A bisatellited, dicentric, distamycin-DAPI negative, NOR-positive marker was present in 76 per cent of the metaphases examined. Similar markers have been associated with cat eye syndrome (CES). We report on the utilization of fluorescence in situ hybridization (FISH) with a 14/22 alpha-satellite probe and a chromosome 22-specific cosmid for locus D22S9 to determine the origin of the prenatally detected supernumerary marker chromosome. FISH studies demonstrated that the marker is a derivative of chromosome 22 and enabled us to provide the family with additional prognostic information.

  6. Vibrios Commonly Possess Two Chromosomes

    PubMed Central

    Okada, Kazuhisa; Iida, Tetsuya; Kita-Tsukamoto, Kumiko; Honda, Takeshi

    2005-01-01

    The prevalence of the two-chromosome configuration was investigated in 34 species of vibrios and closely related species. Pulsed-field gel electrophoresis of undigested genomic DNA suggested that vibrios commonly have two chromosomes. The size of the large chromosome is predominantly within a narrow range (3.0 to 3.3 Mb), whereas the size of the small chromosome varies considerably among the vibrios (0.8 to 2.4 Mb). This fact suggests that the structure of the small chromosome is more flexible than that of the large chromosome during the evolution of vibrios. PMID:15629946

  7. Chromosomes and clinical anatomy.

    PubMed

    Gardner, Robert James McKinlay

    2016-07-01

    Chromosome abnormalities may cast light on the nature of mechanisms whereby normal anatomy evolves, and abnormal anatomy arises. Correlating genotype to phenotype is an exercise in which the geneticist and the anatomist can collaborate. The increasing power of the new genetic methodologies is enabling an increasing precision in the delineation of chromosome imbalances, even to the nucleotide level; but the classical skills of careful observation and recording remain as crucial as they always have been. Clin. Anat. 29:540-546, 2016. © 2016 Wiley Periodicals, Inc.

  8. Radiative-convective instability

    NASA Astrophysics Data System (ADS)

    Emanuel, Kerry; Wing, Allison A.; Vincent, Emmanuel M.

    2014-03-01

    equilibrium (RCE) is a simple paradigm for the statistical equilibrium the earth's climate would exhibit in the absence of lateral energy transport. It has generally been assumed that for a given solar forcing and long-lived greenhouse gas concentration, such a state would be unique, but recent work suggests that more than one stable equilibrium may be possible. Here we show that above a critical specified sea surface temperature, the ordinary RCE state becomes linearly unstable to large-scale overturning circulations. The instability migrates the RCE state toward one of the two stable equilibria first found by Raymond and Zeng (2000). It occurs when the clear-sky infrared opacity of the lower troposphere becomes so large, owing to high water vapor concentration, that variations of the radiative cooling of the lower troposphere are governed principally by variations in upper tropospheric water vapor. We show that the instability represents a subcritical bifurcation of the ordinary RCE state, leading to either a dry state with large-scale descent, or to a moist state with mean ascent; these states may be accessed by finite amplitude perturbations to ordinary RCE in the subcritical state, or spontaneously in the supercritical state. As first suggested by Raymond (2000) and Sobel et al. (2007), the latter corresponds to the phenomenon of self-aggregation of moist convection, taking the form of cloud clusters or tropical cyclones. We argue that the nonrobustness of self-aggregation in cloud system resolving models may be an artifact of running such models close to the critical temperature for instability.

  9. Characterization of genomic instability in Saccharomyces cerevisiae and engaging teaching strategies described in two curricula

    NASA Astrophysics Data System (ADS)

    Keller, Alexandra P.

    Cancer arises through an accumulation of mutations in the genome. In cancer cells, mutations are frequently caused by DNA rearrangements, which include chromosomal breakages, deletions, insertions, and translocations. Such events contribute to genomic instability, a known hallmark of cancer. To study cycles of chromosomal instability, we are using baker's yeast as a model organism. In yeast, a ChrVII system was previously developed (Admire et al., 2006), in which a disomic yeast strain was used to identify regions of instability on ChrVII. Using this system, a fragile site on the left arm of ChrVII (Admire et al., 2006) was identified and characterized. This study led to insight into mechanisms involved in chromosomal rearrangements and mutations that arise from them as well as to an understanding of mechanisms involved in genomic instability. To further our understanding of genomic instability, I devised a strategy to study instability on a different chromosome (ChrV) (Figure 3), so that we could determine whether lessons learned from the ChrVII system are applicable to other chromosomes, and/or whether other mechanisms of instability could be identified. A suitable strain was generated and analyzed, and our findings suggest that frequencies of instability on the right arm of ChrV are similar to those found in ChrVII. The results from the work in ChrV described in this paper support the idea that the instability found on ChrVII is not an isolated occurrence. My research was supported by an NSF GK-12 grant. The aim of this grant is to improve science education in middle schools, and as part of my participation in this program, I studied and practiced effective science communication methodologies. In attempts to explain my research to middle school students, I collaborated with others to develop methods for explaining genetics and the most important techniques I used in my research. While developing these methods, I learned more about what motivates people to learn

  10. Non-conventional Fishbone Instabilities

    SciTech Connect

    Ya.I. Kolesnichenko; V.V. Lutsenko; V.S. Marchenko; R.B. White

    2004-11-10

    New instabilities of fishbone type are predicted. First, a trapped-particle-induced m = n = 1 instability with the mode structure having nothing to do with the conventional rigid kink displacement. This instability takes place when the magnetic field is weak, so that the precession frequency of the energetic ions is not small as compared to the frequency of the corresponding Alfven continuum at r = 0 and the magnetic shear is small inside the q = 1 radius [the case relevant to spherical tori]. Second, an Energetic Particle Mode fishbone instability driven by circulating particles. Third, a double-kink-mode instability driven by the circulating energetic ions. In particular, the latter can have two frequencies simultaneously: we refer to it as ''doublet'' fishbones. This instability can occur when the radial profile of the energetic ions has an off-axis maximum inside the region of the mode localization.

  11. Validation of cytogenetic risk groups according to International Prognostic Scoring Systems by peripheral blood CD34+FISH: results from a German diagnostic study in comparison with an international control group

    PubMed Central

    Braulke, Friederike; Platzbecker, Uwe; Müller-Thomas, Catharina; Götze, Katharina; Germing, Ulrich; Brümmendorf, Tim H.; Nolte, Florian; Hofmann, Wolf-Karsten; Giagounidis, Aristoteles A. N.; Lübbert, Michael; Greenberg, Peter L.; Bennett, John M.; Solé, Francesc; Mallo, Mar; Slovak, Marilyn L.; Ohyashiki, Kazuma; Le Beau, Michelle M.; Tüchler, Heinz; Pfeilstöcker, Michael; Nösslinger, Thomas; Hildebrandt, Barbara; Shirneshan, Katayoon; Aul, Carlo; Stauder, Reinhard; Sperr, Wolfgang R.; Valent, Peter; Fonatsch, Christa; Trümper, Lorenz; Haase, Detlef; Schanz, Julie

    2015-01-01

    International Prognostic Scoring Systems are used to determine the individual risk profile of myelodysplastic syndrome patients. For the assessment of International Prognostic Scoring Systems, an adequate chromosome banding analysis of the bone marrow is essential. Cytogenetic information is not available for a substantial number of patients (5%–20%) with dry marrow or an insufficient number of metaphase cells. For these patients, a valid risk classification is impossible. In the study presented here, the International Prognostic Scoring Systems were validated based on fluorescence in situ hybridization analyses using extended probe panels applied to cluster of differentiation 34 positive (CD34+) peripheral blood cells of 328 MDS patients of our prospective multicenter German diagnostic study and compared to chromosome banding results of 2902 previously published patients with myelodysplastic syndromes. For cytogenetic risk classification by fluorescence in situ hybridization analyses of CD34+ peripheral blood cells, the groups differed significantly for overall and leukemia-free survival by uni- and multivariate analyses without discrepancies between treated and untreated patients. Including cytogenetic data of fluorescence in situ hybridization analyses of peripheral CD34+ blood cells (instead of bone marrow banding analysis) into the complete International Prognostic Scoring System assessment, the prognostic risk groups separated significantly for overall and leukemia-free survival. Our data show that a reliable stratification to the risk groups of the International Prognostic Scoring Systems is possible from peripheral blood in patients with missing chromosome banding analysis by using a comprehensive probe panel (clinicaltrials.gov identifier:01355913). PMID:25344522

  12. Characterization of chromosomal architecture in Arabidopsis by chromosome conformation capture

    PubMed Central

    2013-01-01

    Background The packaging of long chromatin fibers in the nucleus poses a major challenge, as it must fulfill both physical and functional requirements. Until recently, insights into the chromosomal architecture of plants were mainly provided by cytogenetic studies. Complementary to these analyses, chromosome conformation capture technologies promise to refine and improve our view on chromosomal architecture and to provide a more generalized description of nuclear organization. Results Employing circular chromosome conformation capture, this study describes chromosomal architecture in Arabidopsis nuclei from a genome-wide perspective. Surprisingly, the linear organization of chromosomes is reflected in the genome-wide interactome. In addition, we study the interplay of the interactome and epigenetic marks and report that the heterochromatic knob on the short arm of chromosome 4 maintains a pericentromere-like interaction profile and interactome despite its euchromatic surrounding. Conclusion Despite the extreme condensation that is necessary to pack the chromosomes into the nucleus, the Arabidopsis genome appears to be packed in a predictive manner, according to the following criteria: heterochromatin and euchromatin represent two distinct interactomes; interactions between chromosomes correlate with the linear position on the chromosome arm; and distal chromosome regions have a higher potential to interact with other chromosomes. PMID:24267747

  13. The role of dicentric chromosome formation and secondary centromere deletion in the evolution of myeloid malignancy.

    PubMed

    Mackinnon, Ruth N; Campbell, Lynda J

    2011-01-01

    Dicentric chromosomes have been identified as instigators of the genome instability associated with cancer, but this instability is often resolved by one of a number of different secondary events. These include centromere inactivation, inversion, and intercentromeric deletion. Deletion or excision of one of the centromeres may be a significant occurrence in myeloid malignancy and other malignancies but has not previously been widely recognized, and our reports are the first describing centromere deletion in cancer cells. We review what is known about dicentric chromosomes and the mechanisms by which they can undergo stabilization in both constitutional and cancer genomes. The failure to identify centromere deletion in cancer cells until recently can be partly explained by the standard approaches to routine diagnostic cancer genome analysis, which do not identify centromeres in the context of chromosome organization. This hitherto hidden group of primary dicentric, secondary monocentric chromosomes, together with other unrecognized dicentric chromosomes, points to a greater role for dicentric chromosomes in cancer initiation and progression than is generally acknowledged. We present a model that predicts and explains a significant role for dicentric chromosomes in the formation of unbalanced translocations in malignancy.

  14. Novel Cauchy-horizon instability

    SciTech Connect

    Maeda, Hideki; Torii, Takashi; Harada, Tomohiro

    2005-03-15

    The evolution of weak discontinuity is investigated on horizons in the n-dimensional static solutions in the Einstein-Maxwell-scalar-{lambda} system, including the Reissner-Nordstroem-(anti) de Sitter black hole. The analysis is essentially local and nonlinear. We find that the Cauchy horizon is unstable, whereas both the black hole event horizon and the cosmological event horizon are stable. This new instability, the so-called kink instability, of the Cauchy horizon is completely different from the well-known 'infinite-blueshift' instability. The kink instability makes the analytic continuation beyond the Cauchy horizon unstable.

  15. Study of cavitating inducer instabilities

    NASA Technical Reports Server (NTRS)

    Young, W. E.; Murphy, R.; Reddecliff, J. M.

    1972-01-01

    An analytic and experimental investigation into the causes and mechanisms of cavitating inducer instabilities was conducted. Hydrofoil cascade tests were performed, during which cavity sizes were measured. The measured data were used, along with inducer data and potential flow predictions, to refine an analysis for the prediction of inducer blade suction surface cavitation cavity volume. Cavity volume predictions were incorporated into a linearized system model, and instability predictions for an inducer water test loop were generated. Inducer tests were conducted and instability predictions correlated favorably with measured instability data.

  16. Short- and long-term effects of chromosome mis-segregation and aneuploidy.

    PubMed

    Santaguida, Stefano; Amon, Angelika

    2015-08-01

    Dividing cells that experience chromosome mis-segregation generate aneuploid daughter cells, which contain an incorrect number of chromosomes. Although aneuploidy interferes with the proliferation of untransformed cells, it is also, paradoxically, a hallmark of cancer, a disease defined by increased proliferative potential. These contradictory effects are also observed in mouse models of chromosome instability (CIN). CIN can inhibit and promote tumorigenesis. Recent work has provided insights into the cellular consequences of CIN and aneuploidy. Chromosome mis-segregation per se can alter the genome in many more ways than just causing the gain or loss of chromosomes. The short- and long-term effects of aneuploidy are caused by gene-specific effects and a stereotypic aneuploidy stress response. Importantly, these recent findings provide insights into the role of aneuploidy in tumorigenesis.

  17. Chromosome Variations And Human Behavior

    ERIC Educational Resources Information Center

    Soudek, D.

    1974-01-01

    Article focused on the science of cytogenetics, which studied the transmission of the units of heredity called chromosomes, and considered the advantage of proper diagnosis of genetic diseases, treated on the chromosomal level. (Author/RK)

  18. An Integrated Approach for Gear Health Prognostics

    NASA Technical Reports Server (NTRS)

    He, David; Bechhoefer, Eric; Dempsey, Paula; Ma, Jinghua

    2012-01-01

    In this paper, an integrated approach for gear health prognostics using particle filters is presented. The presented method effectively addresses the issues in applying particle filters to gear health prognostics by integrating several new components into a particle filter: (1) data mining based techniques to effectively define the degradation state transition and measurement functions using a one-dimensional health index obtained by whitening transform; (2) an unbiased l-step ahead RUL estimator updated with measurement errors. The feasibility of the presented prognostics method is validated using data from a spiral bevel gear case study.

  19. Chromosomes, cancer and radiosensitivity

    SciTech Connect

    Samouhos, E.

    1983-08-01

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

  20. Why Chromosome Palindromes?

    PubMed Central

    Betrán, Esther; Demuth, Jeffery P.; Williford, Anna

    2012-01-01

    We look at sex-limited chromosome (Y or W) evolution with particular emphasis on the importance of palindromes. Y chromosome palindromes consist of inverted duplicates that allow for local recombination in an otherwise nonrecombining chromosome. Since palindromes enable intrachromosomal gene conversion that can help eliminate deleterious mutations, they are often highlighted as mechanisms to protect against Y degeneration. However, the adaptive significance of recombination resides in its ability to decouple the evolutionary fates of linked mutations, leading to both a decrease in degeneration rate and an increase in adaptation rate. Our paper emphasizes the latter, that palindromes may exist to accelerate adaptation by increasing the potential targets and fixation rates of incoming beneficial mutations. This hypothesis helps reconcile two enigmatic features of the “palindromes as protectors” view: (1) genes that are not located in palindromes have been retained under purifying selection for tens of millions of years, and (2) under models that only consider deleterious mutations, gene conversion benefits duplicate gene maintenance but not initial fixation. We conclude by looking at ways to test the hypothesis that palindromes enhance the rate of adaptive evolution of Y-linked genes and whether this effect can be extended to palindromes on other chromosomes. PMID:22844637

  1. The Y Chromosome

    ERIC Educational Resources Information Center

    Offner, Susan

    2010-01-01

    The Y chromosome is of great interest to students and can be used to teach about many important biological concepts in addition to sex determination. This paper discusses mutation, recombination, mammalian sex determination, sex determination in general, and the evolution of sex determination in mammals. It includes a student activity that…

  2. PARTIAL TORUS INSTABILITY

    SciTech Connect

    Olmedo, Oscar; Zhang Jie

    2010-07-20

    Flux ropes are now generally accepted to be the magnetic configuration of coronal mass ejections (CMEs), which may be formed prior to or during solar eruptions. In this study, we model the flux rope as a current-carrying partial torus loop with its two footpoints anchored in the photosphere, and investigate its stability in the context of the torus instability (TI). Previous studies on TI have focused on the configuration of a circular torus and revealed the existence of a critical decay index of the overlying constraining magnetic field. Our study reveals that the critical index is a function of the fractional number of the partial torus, defined by the ratio between the arc length of the partial torus above the photosphere and the circumference of a circular torus of equal radius. We refer to this finding as the partial torus instability (PTI). It is found that a partial torus with a smaller fractional number has a smaller critical index, thus requiring a more gradually decreasing magnetic field to stabilize the flux rope. On the other hand, a partial torus with a larger fractional number has a larger critical index. In the limit of a circular torus when the fractional number approaches 1, the critical index goes to a maximum value. We demonstrate that the PTI helps us to understand the confinement, growth, and eventual eruption of a flux-rope CME.

  3. Partial Torus Instability

    NASA Astrophysics Data System (ADS)

    Olmedo, Oscar; Zhang, Jie

    2010-07-01

    Flux ropes are now generally accepted to be the magnetic configuration of coronal mass ejections (CMEs), which may be formed prior to or during solar eruptions. In this study, we model the flux rope as a current-carrying partial torus loop with its two footpoints anchored in the photosphere, and investigate its stability in the context of the torus instability (TI). Previous studies on TI have focused on the configuration of a circular torus and revealed the existence of a critical decay index of the overlying constraining magnetic field. Our study reveals that the critical index is a function of the fractional number of the partial torus, defined by the ratio between the arc length of the partial torus above the photosphere and the circumference of a circular torus of equal radius. We refer to this finding as the partial torus instability (PTI). It is found that a partial torus with a smaller fractional number has a smaller critical index, thus requiring a more gradually decreasing magnetic field to stabilize the flux rope. On the other hand, a partial torus with a larger fractional number has a larger critical index. In the limit of a circular torus when the fractional number approaches 1, the critical index goes to a maximum value. We demonstrate that the PTI helps us to understand the confinement, growth, and eventual eruption of a flux-rope CME.

  4. Microtearing instability in ITER*

    NASA Astrophysics Data System (ADS)

    Wong, King-Lap; Mikkelsen, David; Budny, Robert; Breslau, Joshua

    2010-11-01

    Microtearing modes are found to be unstable in some regions of a simulated ITER H-mode plasma [1] with the GS2 code [2]. Modes with kρs>1 are in the interior (r/a˜0.65-0.85) while longer wavelength modes are in the pedestal region. This instability may keep the pedestal within the peeling-ballooning stability boundary [3]. Microtearing modes can produce stochastic magnetic field similar to RMP coils; they may have similar effects on ELMs by increasing the pedestal width. The possibility of using this technique for ELM mitigation in ITER is explored. We propose to use a deuterium gas jet to control the microtearing instability and the Chirikov parameter at the edge. Preliminary evaluation of its effectiveness will be presented and the limitations of the GS2 code will be discussed based on our understanding from NSTX [4]. *This work is supported by USDoE contract DE-AC02-09CH11466. [4pt] [1] R. V. Budny, Nucl. Fusion (2009)[0pt] [2] W. Dorland et al., Phys. Rev. Lett. (2000).[0pt] [3] P. B. Snyder et al.,Nucl. Fusion (2009).[0pt] [4] K. L. Wong et al., Phys. Rev. Lett. (2007).

  5. Frequency of Early and Late Chromosome Aberrations in Different Types of Cells After Proton and Fe Ion Irradiation

    NASA Astrophysics Data System (ADS)

    Lu, Tao; Wu, Honglu; Zhang, Ye; Yeshitla, Samrawit; Kadhim, Munira; Wilson, Bobby; Bowler, Deborah

    2016-07-01

    DNA damages induced by space radiation, consisting of protons and high-LET charged particles, can be complex in nature, which are often left unrepaired and cause chromosomal aberrations. Increased level of genomic instability is attributed to tumorigenesis and increased cancer risks. To investigate genomic instability induced by charged particles, human lymphocytes ex vivo, human fibroblasts, and human mammary epithelial cells, as well as mouse bone marrow stem cells isolated from CBA/CaH and C57BL/6 strains were exposed to high energy protons and Fe ions. Metaphase chromosome spreads at different cell divisions after radiation exposure were collected and, chromosome aberrations were analyzed with fluorescence in situ hybridization with whole chromosome-specific probes for human cells. With proton irradiation, levels of chromosome aberrations decreased by about 50% in both lymphocytes and epithelial cells after multiple cell divisions, compared to initial chromosome aberrations at 48 hours post irradiation in both cell types. With Fe ion irradiation, however, the frequency of chromosome aberrations in lymphocytes after multiple cell divisions was significantly lower than that in epithelial cells at comparable cell divisions, while their initial chromosome aberrations were at similar levels. Similar to the human cells, after Fe ion irradiation, the frequency of late chromosome aberrations was similar to that of the early damages for radio-sensitive CBA cells, but different for radio-resistant C57 cells. Our results suggest that relative biological effectiveness (RBE) values are dependent not only on radiation sources, but also on cell types and cell divisions.

  6. [Dicentric Y chromosome].

    PubMed

    Abdelmoula, N Bouayed; Amouri, A

    2005-01-01

    Dicentric Y chromosomes are the most common Y structural abnormalities and their influence on gonadal and somatic development is extremely variable. Here, we report the third comprehensive review of the literature concerning dicentric Y chromosomes reported since 1994. We find 78 new cases for which molecular studies (PCR or FISH) have been widely applied to investigate SRY (68% of cases), GBY, ZFY, RFS4Y, GCY and different genes at AZF region. For dic(Yq), all cases (n = 20) were mosaic for 45,X and 4 of them were also mosaic for a 46,XY cell line. When breakpoints were available (15/20 cases), they were in Yp11. 50% of cases were phenotypic female and 20% phenotypic male while 20% of cases were reported with gonadal dysgenesis. Gonadal histology was defined in 8 cases but only in one case, gonadal tissu was genetically investigated because of gonadoblastoma. For dic(Yp) (n = 55), mosaicism concerned only 45,X cell line and was found in 50 cases while the remainder five cases were homogeneous. When breakpoints were available, it was at Yq11 in 50 cases and at Yq12 in two cases. 54% of cases were phenotypic female, 26% were phenotypic male and 18% were associated with genitalia ambiguous. SRY was analyzed in 33 cases, sequenced in 9 cases and was muted in only one case. Gonads were histologically explored in 34 cases and genetically investigated in 8 cases. Gonadoblastoma was found in only two cases. Through this review, it seems that phenotype-genotype correlations are still not possible and that homogeneous studies of dic(Y) in more patients using molecular tools for structural characterization of the rearranged Y chromosome and assessment of mosaicism in many organs are necessary to clarify the basis of the phenotypic heterogeneity of dicentric Y chromosomes and then to help phenotypic prediction of such chromosome rearrangement.

  7. Instability vaccination: A structural design to reduce Rayleigh Taylor instability

    NASA Astrophysics Data System (ADS)

    Esmaeili, Amin

    2013-10-01

    Instability vaccination can be defined as designing a structure to stimulate the system in order to develop immunity against its instability. In this work we have tried to do this stabilization by a new technique. Previously some suppression of R-M instability was done by insertion of magnetic field, but in this work we have tried to do this suppression by proposing a configuration similar to the shape of instability, we call it instability vaccination. This design will reduce the rotations (mostly rotations of Rayleigh Taylor instability) in the fluids that cause more mixing and instabilities. In this paper, we consider the evolution of the interface between two ideal semi-infinite fluid surfaces, using two-dimensional Riemann solver, to solve the Euler equations. First, we performed evolution of a rectangular disorder between the 2 surfaces using two-dimensional Riemann problem for the equations of Euler. Next, the interface was replaced with a perturbation that was part rectangular and part semi-circular (like a mushroom). The simulation was continued till some time steps using the HLL method. We have seen that the rotations of Rayleigh Taylor (R-T) instability were decreased in the second case. Email: amin@cavelab.cs.tsukuba.ac.jp

  8. Chromosomal abnormalities in neutron-induced acute myeloid leukemias in CBA/H mice

    SciTech Connect

    Bouffler, S.D.; Meijne, E.I.M.; Huiskamp, R.

    1996-09-01

    Acute myeloid leukemias (AMLs) induced in CBA/H mice by 1 MeV fission neutrons have been examined for chromosomal abnormalities by G-band analysis. In common with X-ray- and {alpha}-particle-induced AMLs in CBA/H mice, more than 90% (16/17) of the myeloid leukemias had chromosome 2 abnormalities, in this case, all interstitial deletions. Chromosome 2 breakpoints were not wholly consistent, but clustering in three specific G-band regions was observed. Very distal (H-region) breakpoints were more common in the neutron AMLs than in X-ray- or {alpha}-particle-induced leukemias. These data indicate that neutron-induced AMLs in CBA/H mice are not characterized by a specific chromosome deletion but that a variety of chromosome 2 deletion types are associated with the disease. Trisomy of chromosome 1 (12.5% AMLs) and aneusomy of chromosomes 6 (31% AMLs) and Y (37.5% AMLs) were noted. While chromatid breakage was observed occasionally in neutron-induced AML, no clear indications of persistent chromosomal instability or high levels of stable chromosomal change were apparent. 19 refs., 1 fig., 1 tab.

  9. Prognostic markers of acute decompensated heart failure: the emerging roles of cardiac biomarkers and prognostic scores.

    PubMed

    Cohen-Solal, Alain; Laribi, Said; Ishihara, Shiro; Vergaro, Giuseppe; Baudet, Mathilde; Logeart, Damien; Mebazaa, Alexandre; Gayat, Etienne; Vodovar, Nicolas; Pascual-Figal, Domingo A; Seronde, Marie-France

    2015-01-01

    Rapidly assessing outcome in patients with acute decompensated heart failure is important but prognostic factors may differ from those used routinely for stable chronic heart failure. Multiple plasma biomarkers, besides the classic natriuretic peptides, have recently emerged as potential prognosticators. Furthermore, prognostic scores that combine clinical and biochemical data may also be useful. However, compared with the scores used in chronic heart failure, scores for acute decompensated heart failure have not been validated. This article reviews potential biomarkers, with a special focus on biochemical biomarkers, and possible prognostic scores that could be used by the clinician when assessing outcome in patients with acute heart failure.

  10. Diagnostic and Prognostic Biomarkers in Melanoma

    PubMed Central

    Leininger, Jennifer; Hamby, Carl; Safai, Bijan

    2014-01-01

    Melanoma is a lethal melanocytic neoplasm. Unfortunately, the histological diagnosis can be difficult at times. Distinguishing ambiguous melanocytic neoplasms that are benign nevi from those that represent true melanoma is important both for treatment and prognosis. Diagnostic biomarkers currently used to assist in the diagnosis of melanoma are usually specific only for melanocytic neoplasms and not necessarily for their ability to metastasize. Traditional prognostic biomarkers include depth of invasion and mitotic count. Newer diagnostic and prognostic biomarkers utilize immunohistochemical staining as well as ribonucleic acid, micro-ribonucleic acid, and deoxyribonucleic acid assays and fluorescence in situ hybridization. Improved diagnostic and prognostic biomarkers are of increasing importance in the treatment of melanoma with the development of newer and more targeted therapies. Herein, the authors review many of the common as well as newer diagnostic and prognostic biomarkers used in melanoma. PMID:25013535

  11. Tumor-Specific Chromosome Mis-Segregation Controls Cancer Plasticity by Maintaining Tumor Heterogeneity

    PubMed Central

    Hu, Yuanjie; Ru, Ning; Xiao, Huasheng; Chaturbedi, Abhishek; Hoa, Neil T.; Tian, Xiao-Jun; Zhang, Hang; Ke, Chao; Yan, Fengrong; Nelson, Jodi; Li, Zhenzhi; Gramer, Robert; Yu, Liping; Siegel, Eric; Zhang, Xiaona; Jia, Zhenyu; Jadus, Martin R.; Limoli, Charles L.; Linskey, Mark E.; Xing, Jianhua; Zhou, Yi-Hong

    2013-01-01

    Aneuploidy with chromosome instability is a cancer hallmark. We studied chromosome 7 (Chr7) copy number variation (CNV) in gliomas and in primary cultures derived from them. We found tumor heterogeneity with cells having Chr7-CNV commonly occurs in gliomas, with a higher percentage of cells in high-grade gliomas carrying more than 2 copies of Chr7, as compared to low-grade gliomas. Interestingly, all Chr7-aneuploid cell types in the parental culture of established glioma cell lines reappeared in single-cell-derived subcultures. We then characterized the biology of three syngeneic glioma cultures dominated by different Chr7-aneuploid cell types. We found phenotypic divergence for cells following Chr7 mis-segregation, which benefited overall tumor growth in vitro and in vivo. Mathematical modeling suggested the involvement of chromosome instability and interactions among cell subpopulations in restoring the optimal equilibrium of tumor cell types. Both our experimental data and mathematical modeling demonstrated that the complexity of tumor heterogeneity could be enhanced by the existence of chromosomes with structural abnormality, in addition to their mis-segregations. Overall, our findings show, for the first time, the involvement of chromosome instability in maintaining tumor heterogeneity, which underlies the enhanced growth, persistence and treatment resistance of cancers. PMID:24282558

  12. [Diagnosis of MDS: morphology, chromosome abnormalities and genetic mutations].

    PubMed

    Hata, Tomoko

    2015-10-01

    Myelodysplastic syndromes (MDS) are a group of hematological neoplasms associated with ineffective hematopoiesis and that can transform into acute leukemia. The clinical classification of MDS which is defined by cytopenia, the rate of blasts in peripheral blood and bone marrow, dysplasia, and chromosomal abnormalities, has undergone continuous revision. To increase the accuracy of dysplastic evaluation, IWGM-MDS and the Research Committee for Idiopathic Hematopoietic Disorders, Ministry of Health, Labour and Welfare, Japan have proposed a quantitative and qualitative definition of dysplasia. Recently, refining the definition of dysgranulopoiesis was proposed by IWGM-MDS. Neutrophils with abnormal clumping of chromatin, and harboring more than 4 nuclear projections, were recognized as dysplastic features. At present, karyotypic abnormalities are detected in approximately 50% of de novo MDS and these remain the most critical prognostic factor. In the new cytogenetic scoring system, cytogenetic abnormalities were classified into five prognostic subgroups. This new classification was adopted by the revised IPSS. Approximately 80% to 90% of MDS patients have detectable mutations by whole-exon sequencing or whole genome sequencing. Many genetic mutations had biological and prognostic significance. It is important to further understand the utility of this factor in determining prognosis and in selecting among therapeutic options.

  13. Nuclear anomalies, chromosomal aberrations and proliferation rates in cultured lymphocytes of head and neck cancer patients.

    PubMed

    George, Alex; Dey, Rupraj; Bhuria, Vikas; Banerjee, Shouvik; Ethirajan, Sivakumar; Siluvaimuthu, Ashok; Saraswathy, Radha

    2014-01-01

    Head and neck cancers (HNC) are extremely complex disease types and it is likely that chromosomal instability is involved in the genetic mechanisms of its genesis. However, there is little information regarding the background levels of chromosome instability in these patients. In this pilot study, we examined spontaneous chromosome instability in short-term lymphocyte cultures (72 hours) from 72 study subjects - 36 newly diagnosed HNC squamous cell carcinoma patients and 36 healthy ethnic controls. We estimated chromosome instability (CIN) using chromosomal aberration (CA) analysis and nuclear level anomalies using the Cytokinesis Block Micronucleus Cytome Assay (CBMN Cyt Assay). The proliferation rates in cultures of peripheral blood lymphocytes (PBL) were assessed by calculating the Cytokinesis Block Proliferation Index (CBPI). Our results showed a significantly higher mean level of spontaneous chromosome type aberrations (CSAs), chromatid type aberration (CTAs) dicentric chromosomes (DIC) and chromosome aneuploidy (CANEUP) in patients (CSAs, 0.0294±0.0038; CTAs, 0.0925±0.0060; DICs, 0.0213±0.0028; and CANEUPs, 0.0308±0.0035) compared to controls (CSAs, 0.0005±0.0003; CTAs, 0.0058±0.0015; DICs, 0.0005±0.0003; and CANEUPs, 0.0052±0.0013) where p<0.001. Similarly, spontaneous nuclear anomalies showed significantly higher mean level of micronuclei (MNi), nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) among cases (MNi, 0.01867±0.00108; NPBs, 0.01561±0.00234; NBUDs, 0.00658±0.00068) compared with controls (MNi, 0.00027±0.00009; NPBs, 0.00002±0.00002; NBUDs, 0.00011±0.00007).The evaluation of CBPI supported genomic instability in the peripheral blood lymphocytes showing a significantly lower proliferation rate in HNC patients (1.525±0.005552) compared to healthy subjects (1.686±0.009520 ) (p<0.0001). In conclusion, our preliminary results showed that visible spontaneous genomic instability and low rate proliferation in the cultured peripheral

  14. [Chromosomal organization of the genomes of small-chromosome plants].

    PubMed

    Muravenko, O V; Zelenin, A V

    2009-11-01

    An effective approach to study the chromosome organization in genomes of plants with small chromosomes and/or with low-informative C-banding patterns was developed in the course of investigation of the karyotypes of cotton plant, camomile, flax, and pea. To increase the resolving power of chromosome analysis, methods were worked out for revealing early replication patterns on chromosomes and for artificial impairment of mitotic chromosome condensation with the use of a DNA intercalator, 9-aminoacridine (9-AMA). To estimate polymorphism of the patterns of C-banding of small chromosomes on preparations obtained with the use of 9-AMA, it is necessary to choose a length interval that must not exceed three average sizes of metaphase chromosomes without the intercalator. The use of 9-AMA increases the resolution of differential C- and OR-banding and the precision of physical chromosome mapping by the FISH method. Of particular importance in studying small chromosomes is optimization of the computer-aided methods used to obtain and process chromosome images. The complex approach developed for analysis of the chromosome organization in plant genomes was used to study the karyotypes of 24 species of the genus Linum L. It permitted their chromosomes to be identified for the first time, and, in addition, B chromosomes were discovered and studied in the karyotypes of the species of the section Syllinum. By similarity of the karyotypes, the studied flax species were distributed in eight groups in agreement with the clusterization of these species according to the results of RAPD analysis performed in parallel. Systematic positions and phylogenetic relationships of the studied flax species were verified. Out results can serve as an important argument in favour of the proposal to develop a special program for sequencing the genome of cultivated flax (L. usitatissimum L.), which is a major representative of small-chromosome species.

  15. New type of genome instability in Drosophila melanogaster

    SciTech Connect

    Georgiev, P.G.; Simonova, O.B.; Gerasimova, T.I.

    1988-11-01

    During crossing of two stable laboratory lines, y/sup 2/sc/sup 1w/sup aG// and Df(1)Pgd-kz/FM4, y/sup 31d/sc/sup 8/dm B, consistent instability originated reproducibly in progeny containing a y/sup 2/sc/sup 1/w/sup aG/ chromosome and autosomes of both lines. It is expressed in active mutagenesis observed over the course of several tens of generations. Destabilization occurs independently of direction of crossing. Mutagenesis occurs both in somatic and in sex cells of males and females. It displays high locus specificity. A transpositional nature was shown for at least some of the mutations. Results of the experiments concerning hybridization in situ with different mobile elements indicates an absence or low frequency of tranpositional bursts in the system. Possible mechanisms of induction of genetic instability in the system described are discussed.

  16. Liquid propellant rocket combustion instability

    NASA Technical Reports Server (NTRS)

    Harrje, D. T.

    1972-01-01

    The solution of problems of combustion instability for more effective communication between the various workers in this field is considered. The extent of combustion instability problems in liquid propellant rocket engines and recommendations for their solution are discussed. The most significant developments, both theoretical and experimental, are presented, with emphasis on fundamental principles and relationships between alternative approaches.

  17. Research on aviation fuel instability

    NASA Technical Reports Server (NTRS)

    Baker, C. E.; Bittker, D. A.; Cohen, S. M.; Seng, G. T.

    1983-01-01

    The underlying causes of fuel thermal degradation are discussed. Topics covered include: nature of fuel instability and its temperature dependence, methods of measuring the instability, chemical mechanisms involved in deposit formation, and instrumental methods for characterizing fuel deposits. Finally, some preliminary thoughts on design approaches for minimizing the effects of lowered thermal stability are briefly discussed.

  18. Bony instability of the shoulder.

    PubMed

    Bushnell, Brandon D; Creighton, R Alexander; Herring, Marion M

    2008-09-01

    Instability of the shoulder is a common problem treated by many orthopaedists. Instability can result from baseline intrinsic ligamentous laxity or a traumatic event-often a dislocation that injures the stabilizing structures of the glenohumeral joint. Many cases involve soft-tissue injury only and can be treated successfully with repair of the labrum and ligamentous tissues. Both open and arthroscopic approaches have been well described, with recent studies of arthroscopic soft-tissue techniques reporting results equal to those of the more traditional open techniques. Over the last decade, attention has focused on the concept of instability of the shoulder mediated by bony pathology such as a large bony Bankart lesion or an engaging Hill-Sachs lesion. Recent literature has identified unrecognized large bony lesions as a primary cause of failure of arthroscopic reconstruction for instability, a major cause of recurrent instability, and a difficult diagnosis to make. Thus, although such bony lesions may be relatively rare compared with soft-tissue pathology, they constitute a critically important entity in the management of shoulder instability. Smaller bony lesions may be amenable to arthroscopic treatment, but larger lesions often require open surgery to prevent recurrent instability. This article reviews recent developments in the diagnosis and treatment of bony instability.

  19. Instabilities in uranium plasma.

    NASA Technical Reports Server (NTRS)

    Tidman, D. A.

    1971-01-01

    The nonlinear evolution of unstable sound waves in a uranium plasma has been calculated using a multiple time-scale asymptotic expansion scheme. The fluid equations used include the fission power density, radiation diffusion, and the effects of the changing degree of ionization of the uranium atoms. The nonlinear growth of unstable waves is shown to be limited by mode coupling to shorter wavelength waves which are damped by radiation diffusion. This mechanism limits the wave pressure fluctuations to values of order delta P/P equal to about .00001 in the plasma of a typical gas-core nuclear rocket engine. The instability is thus not expected to present a control problem for this engine.

  20. Marital instability after midlife.

    PubMed

    Wu, Z; Penning, M J

    1997-09-01

    "Divorce in later life has been shown to produce dramatic declines in the economic, psychological, and physical well-being of marital partners. This study examines the prevalence and determinants of marital disruption after midlife using Becker's theory of marital instability. Using recent Canadian national data, the marital outcomes of women and men who were married as of age 40 are tracked across the remaining years of the marriage. Cox proportional hazard regression models indicate stabilizing effects of the duration of the marriage, the age at first marriage, the presence of young children, as well as of remarriage for middle-aged and older persons. Other significant risk factors include education, heterogamous marital status, premarital cohabitation, number of siblings, and region."

  1. Neurocardiovascular Instability and Cognition

    PubMed Central

    O’Callaghan, Susan; Kenny, Rose Anne

    2016-01-01

    Neurocardiovascular instability (NCVI) refers to abnormal neural control of the cardiovascular system affecting blood pressure and heart rate behavior. Autonomic dysfunction and impaired cerebral autoregulation in aging contribute to this phenomenon characterized by hypotension and bradyarrhythmia. Ultimately, this increases the risk of falls and syncope in older people. NCVI is common in patients with neurodegenerative disorders including dementia. This review discusses the various syndromes that characterize NCVI icluding hypotension, carotid sinus hypersensitivity, postprandial hypotension and vasovagal syncope and how they may contribute to the aetiology of cognitive decline. Conversely, they may also be a consequence of a common neurodegenerative process. Regardless, recognition of their association is paramount in optimizing management of these patients. PMID:27505017

  2. Spartan deficiency causes genomic instability and progeroid phenotypes

    PubMed Central

    Maskey, Reeja S.; Kim, Myoung Shin; Baker, Darren J.; Childs, Bennett; Malureanu, Liviu A.; Jeganathan, Karthik B.; Machida, Yuka; van Deursen, Jan M.; Machida, Yuichi J.

    2014-01-01

    Spartan (also known as DVC1 and C1orf124) is a PCNA-interacting protein implicated in translesion synthesis, a DNA damage tolerance process that allows the DNA replication machinery to replicate past nucleotide lesions. However, the physiological relevance of Spartan has not been established. Here we report that Spartan insufficiency in mice causes chromosomal instability, cellular senescence and early onset of age-related phenotypes. Whereas complete loss of Spartan causes early embryonic lethality, hypomorphic mice with low amounts of Spartan are viable. These mice are growth retarded and develop cataracts, lordokyphosis and cachexia at a young age. Cre-mediated depletion of Spartan from conditional knockout mouse embryonic fibroblasts results in impaired lesion bypass, incomplete DNA replication, formation of micronuclei and chromatin bridges and eventually cell death. These data demonstrate that Spartan plays a key role in maintaining structural and numerical chromosome integrity and suggest a link between Spartan insufficiency and progeria. PMID:25501849

  3. Degeneration of a Nonrecombining Chromosome

    NASA Astrophysics Data System (ADS)

    Rice, William R.

    1994-01-01

    Comparative studies suggest that sex chromosomes begin as ordinary autosomes that happen to carry a major sex determining locus. Over evolutionary time the Y chromosome is selected to stop recombining with the X chromosome, perhaps in response to accumulation of alleles beneficial to the heterogametic but harmful to the homogametic sex. Population genetic theory predicts that a nonrecombining Y chromosome should degenerate. Here this prediction is tested by application of specific selection pressures to Drosophila melanogaster populations. Results demonstrate the decay of a nonrecombining, nascent Y chromosome and the capacity for recombination to ameliorate such decay.

  4. Combustion Instabilities Modeled

    NASA Technical Reports Server (NTRS)

    Paxson, Daniel E.

    1999-01-01

    NASA Lewis Research Center's Advanced Controls and Dynamics Technology Branch is investigating active control strategies to mitigate or eliminate the combustion instabilities prevalent in lean-burning, low-emission combustors. These instabilities result from coupling between the heat-release mechanisms of the burning process and the acoustic flow field of the combustor. Control design and implementation require a simulation capability that is both fast and accurate. It must capture the essential physics of the system, yet be as simple as possible. A quasi-one-dimensional, computational fluid dynamics (CFD) based simulation has been developed which may meet these requirements. The Euler equations of mass, momentum, and energy have been used, along with a single reactive species transport equation to simulate coupled thermoacoustic oscillations. A very simple numerical integration scheme was chosen to reduce computing time. Robust boundary condition procedures were incorporated to simulate various flow conditions (e.g., valves, open ends, and choked inflow) as well as to accommodate flow reversals that may arise during large flow-field oscillations. The accompanying figure shows a sample simulation result. A combustor with an open inlet, a choked outlet, and a large constriction approximately two thirds of the way down the length is shown. The middle plot shows normalized, time-averaged distributions of the relevant flow quantities, and the bottom plot illustrates the acoustic mode shape of the resulting thermoacoustic oscillation. For this simulation, the limit cycle peak-to-peak pressure fluctuations were 13 percent of the mean. The simulation used 100 numerical cells. The total normalized simulation time was 50 units (approximately 15 oscillations), which took 26 sec on a Sun Ultra2.

  5. Internal rotor friction instability

    NASA Technical Reports Server (NTRS)

    Walton, J.; Artiles, A.; Lund, J.; Dill, J.; Zorzi, E.

    1990-01-01

    The analytical developments and experimental investigations performed in assessing the effect of internal friction on rotor systems dynamic performance are documented. Analytical component models for axial splines, Curvic splines, and interference fit joints commonly found in modern high speed turbomachinery were developed. Rotor systems operating above a bending critical speed were shown to exhibit unstable subsynchronous vibrations at the first natural frequency. The effect of speed, bearing stiffness, joint stiffness, external damping, torque, and coefficient of friction, was evaluated. Testing included material coefficient of friction evaluations, component joint quantity and form of damping determinations, and rotordynamic stability assessments. Under conditions similar to those in the SSME turbopumps, material interfaces experienced a coefficient of friction of approx. 0.2 for lubricated and 0.8 for unlubricated conditions. The damping observed in the component joints displayed nearly linear behavior with increasing amplitude. Thus, the measured damping, as a function of amplitude, is not represented by either linear or Coulomb friction damper models. Rotordynamic testing of an axial spline joint under 5000 in.-lb of static torque, demonstrated the presence of an extremely severe instability when the rotor was operated above its first flexible natural frequency. The presence of this instability was predicted by nonlinear rotordynamic time-transient analysis using the nonlinear component model developed under this program. Corresponding rotordynamic testing of a shaft with an interference fit joint demonstrated the presence of subsynchronous vibrations at the first natural frequency. While subsynchronous vibrations were observed, they were bounded and significantly lower in amplitude than the synchronous vibrations.

  6. Metrics for Offline Evaluation of Prognostic Performance

    NASA Technical Reports Server (NTRS)

    Saxena, Abhinav; Celaya, Jose; Saha, Bhaskar; Saha, Sankalita; Goebel, Kai

    2010-01-01

    Prognostic performance evaluation has gained significant attention in the past few years. Currently, prognostics concepts lack standard definitions and suffer from ambiguous and inconsistent interpretations. This lack of standards is in part due to the varied end-user requirements for different applications, time scales, available information, domain dynamics, etc. to name a few. The research community has used a variety of metrics largely based on convenience and their respective requirements. Very little attention has been focused on establishing a standardized approach to compare different efforts. This paper presents several new evaluation metrics tailored for prognostics that were recently introduced and were shown to effectively evaluate various algorithms as compared to other conventional metrics. Specifically, this paper presents a detailed discussion on how these metrics should be interpreted and used. These metrics have the capability of incorporating probabilistic uncertainty estimates from prognostic algorithms. In addition to quantitative assessment they also offer a comprehensive visual perspective that can be used in designing the prognostic system. Several methods are suggested to customize these metrics for different applications. Guidelines are provided to help choose one method over another based on distribution characteristics. Various issues faced by prognostics and its performance evaluation are discussed followed by a formal notational framework to help standardize subsequent developments.

  7. Vehicle Integrated Prognostic Reasoner (VIPR) Metric Report

    NASA Technical Reports Server (NTRS)

    Cornhill, Dennis; Bharadwaj, Raj; Mylaraswamy, Dinkar

    2013-01-01

    This document outlines a set of metrics for evaluating the diagnostic and prognostic schemes developed for the Vehicle Integrated Prognostic Reasoner (VIPR), a system-level reasoner that encompasses the multiple levels of large, complex systems such as those for aircraft and spacecraft. VIPR health managers are organized hierarchically and operate together to derive diagnostic and prognostic inferences from symptoms and conditions reported by a set of diagnostic and prognostic monitors. For layered reasoners such as VIPR, the overall performance cannot be evaluated by metrics solely directed toward timely detection and accuracy of estimation of the faults in individual components. Among other factors, overall vehicle reasoner performance is governed by the effectiveness of the communication schemes between monitors and reasoners in the architecture, and the ability to propagate and fuse relevant information to make accurate, consistent, and timely predictions at different levels of the reasoner hierarchy. We outline an extended set of diagnostic and prognostics metrics that can be broadly categorized as evaluation measures for diagnostic coverage, prognostic coverage, accuracy of inferences, latency in making inferences, computational cost, and sensitivity to different fault and degradation conditions. We report metrics from Monte Carlo experiments using two variations of an aircraft reference model that supported both flat and hierarchical reasoning.

  8. On Applying the Prognostic Performance Metrics

    NASA Technical Reports Server (NTRS)

    Saxena, Abhinav; Celaya, Jose; Saha, Bhaskar; Saha, Sankalita; Goebel, Kai

    2009-01-01

    Prognostics performance evaluation has gained significant attention in the past few years. As prognostics technology matures and more sophisticated methods for prognostic uncertainty management are developed, a standardized methodology for performance evaluation becomes extremely important to guide improvement efforts in a constructive manner. This paper is in continuation of previous efforts where several new evaluation metrics tailored for prognostics were introduced and were shown to effectively evaluate various algorithms as compared to other conventional metrics. Specifically, this paper presents a detailed discussion on how these metrics should be interpreted and used. Several shortcomings identified, while applying these metrics to a variety of real applications, are also summarized along with discussions that attempt to alleviate these problems. Further, these metrics have been enhanced to include the capability of incorporating probability distribution information from prognostic algorithms as opposed to evaluation based on point estimates only. Several methods have been suggested and guidelines have been provided to help choose one method over another based on probability distribution characteristics. These approaches also offer a convenient and intuitive visualization of algorithm performance with respect to some of these new metrics like prognostic horizon and alpha-lambda performance, and also quantify the corresponding performance while incorporating the uncertainty information.

  9. Prognostic Significance of Nuclear Phospho-ATM Expression in Melanoma

    PubMed Central

    Bhandaru, Madhuri; Martinka, Magdalena; McElwee, Kevin J.; Rotte, Anand

    2015-01-01

    UV radiation induced genomic instability is one of the leading causes for melanoma. Phosphorylation of Ataxia Telangiectasia Mutated (ATM) is one of the initial events that follow DNA damage. Phospho-ATM (p-ATM) plays a key role in the activation of DNA repair and several oncogenic pathways as well as in the maintenance of genomic integrity. The present study was therefore performed to understand the significance of p-ATM in melanoma progression and to correlate it with patient prognosis. Tissue microarray and immunohistochemical analysis were employed to study the expression of p-ATM in melanoma patients. A total of 366 melanoma patients (230 primary melanoma and 136 metastatic melanoma) were used for the study. Chi-square test, Kaplan-Meier, univariate and multivariate Cox regression analysis were used to elucidate the prognostic significance of p-ATM expression. Results revealed that both loss of, and gain in, p-ATM expression were associated with progression of melanoma from normal nevi to metastatic melanoma. Patients whose samples showed negative or strong p-ATM staining had significantly worse 5-year survival compared to patients who had weak to moderate expression. Loss of p-ATM expression was associated with relatively better 5-year survival, but the corresponding 10-year survival curve almost overlapped with that of strong p-ATM expression. p-ATM expression was found to be an independent prognostic factor for 5-year but not for 10-year patient survival. In conclusion our findings show that loss of p-ATM expression and gain-in p-ATM expression are indicators of worse melanoma patient survival. PMID:26275218

  10. Prognostic Significance of Nuclear Phospho-ATM Expression in Melanoma.

    PubMed

    Bhandaru, Madhuri; Martinka, Magdalena; McElwee, Kevin J; Rotte, Anand

    2015-01-01

    UV radiation induced genomic instability is one of the leading causes for melanoma. Phosphorylation of Ataxia Telangiectasia Mutated (ATM) is one of the initial events that follow DNA damage. Phospho-ATM (p-ATM) plays a key role in the activation of DNA repair and several oncogenic pathways as well as in the maintenance of genomic integrity. The present study was therefore performed to understand the significance of p-ATM in melanoma progression and to correlate it with patient prognosis. Tissue microarray and immunohistochemical analysis were employed to study the expression of p-ATM in melanoma patients. A total of 366 melanoma patients (230 primary melanoma and 136 metastatic melanoma) were used for the study. Chi-square test, Kaplan-Meier, univariate and multivariate Cox regression analysis were used to elucidate the prognostic significance of p-ATM expression. Results revealed that both loss of, and gain in, p-ATM expression were associated with progression of melanoma from normal nevi to metastatic melanoma. Patients whose samples showed negative or strong p-ATM staining had significantly worse 5-year survival compared to patients who had weak to moderate expression. Loss of p-ATM expression was associated with relatively better 5-year survival, but the corresponding 10-year survival curve almost overlapped with that of strong p-ATM expression. p-ATM expression was found to be an independent prognostic factor for 5-year but not for 10-year patient survival. In conclusion our findings show that loss of p-ATM expression and gain-in p-ATM expression are indicators of worse melanoma patient survival.

  11. Expression of CRM1 and CDK5 shows high prognostic accuracy for gastric cancer

    PubMed Central

    Sun, Yu-Qin; Xie, Jian-Wei; Xie, Hong-Teng; Chen, Peng-Chen; Zhang, Xiu-Li; Zheng, Chao-Hui; Li, Ping; Wang, Jia-Bin; Lin, Jian-Xian; Cao, Long-Long; Huang, Chang-Ming; Lin, Yao

    2017-01-01

    AIM To evaluate the predictive value of the expression of chromosomal maintenance (CRM)1 and cyclin-dependent kinase (CDK)5 in gastric cancer (GC) patients after gastrectomy. METHODS A total of 240 GC patients who received standard gastrectomy were enrolled in the study. The expression level of CRM1 and CDK5 was detected by immunohistochemistry. The correlations between CRM1 and CDK5 expression and clinicopathological factors were explored. Univariate and multivariate survival analyses were used to identify prognostic factors for GC. Receiver operating characteristic analysis was used to compare the accuracy of the prediction of clinical outcome by the parameters. RESULTS The expression of CRM1 was significantly related to size of primary tumor (P = 0.005), Borrmann type (P = 0.006), degree of differentiation (P = 0.004), depth of invasion (P = 0.008), lymph node metastasis (P = 0.013), TNM stage (P = 0.002) and distant metastasis (P = 0.015). The expression of CDK5 was significantly related to sex (P = 0.048) and Lauren’s classification (P = 0.011). Multivariate Cox regression analysis identified that CRM1 and CDK5 co-expression status was an independent prognostic factor for overall survival (OS) of patients with GC. Integration of CRM1 and CDK5 expression could provide additional prognostic value for OS compared with CRM1 or CDK5 expression alone (P = 0.001). CONCLUSION CRM1 and CDK5 co-expression was an independent prognostic factors for GC. Combined CRM1 and CDK5 expression could provide a prognostic model for OS of GC. PMID:28373767

  12. Terahertz radiation increases genomic instability in human lymphocytes.

    PubMed

    Korenstein-Ilan, Avital; Barbul, Alexander; Hasin, Pini; Eliran, Alon; Gover, Avraham; Korenstein, Rafi

    2008-08-01

    Terahertz radiation is increasingly being applied in new and evolving technologies applied in areas such as homeland security and medical imaging. Thus a timely assessment of the potential hazards and health effects of occupational and general population exposure to THz radiation is required. We applied continuous-wave (CW) 0.1 THz radiation (0.031 mW/ cm(2)) to dividing lymphocytes for 1, 2 and 24 h and examined the changes in chromosome number of chromosomes 1, 10, 11 and 17 and changes in the replication timing of their centromeres using interphase fluorescence in situ hybridization (FISH). Chromosomes 11 and 17 were most vulnerable (about 30% increase in aneuploidy after 2 and 24 h of exposure), while chromosomes 1 and 10 were not affected. We observed changes in the asynchronous mode of replication of centromeres 11, 17 and 1 (by 40%) after 2 h of exposure and of all four centromeres after 24 h of exposure (by 50%). It is speculated that these effects are caused by radiation-induced low-frequency collective vibrational modes of proteins and DNA. Our results demonstrate that exposure of lymphocytes in vitro to a low power density of 0.1 THz radiation induces genomic instability. These findings, if verified, may suggest that such exposure may result in an increased risk of cancer.

  13. SOME CHROMOSOME NUMBERS OF DRAPARNALDIA.

    PubMed

    Carroll, J W; Deason, T R

    1969-03-01

    The variability exhibited by Draparnaldia both in nature and in the laboratory makes it difficult to identify the species. The natural variability of Draparnaldia was amplified by the environmental conditions and the media used in this study. With the hope that chromosome studies would aid in taxonomic characterization by providing additional differentiating criteria, special attention was devoted to adapting techniques which could be used to determine chromosome numbers of Draparnaldia isolates. The chromosome numbers reported herein are as follows: (1) Draparnaldia glomerata, Isolate #1, isolated from Davis Falls, Montevallo, Alabama, was found to have a chromosome number of 13. (2) Draparnaldia Isolate #2, an unidentified species obtained from Anniston, Alabama, was found to have a chromosome number of 13. (3) Draparnaldia acuta, Isolate #3 from Northwood Lake, Northport, Alabama, exhibited 26 chromosomes. (4) Draparnaldia plumosa strain 423 (Indiana Culture Collection), 418/a (Cambridge) was observed to have a chromosome number of 13.

  14. Gravitational Instabilities in Circumstellar Disks

    NASA Astrophysics Data System (ADS)

    Kratter, Kaitlin; Lodato, Giuseppe

    2016-09-01

    Star and planet formation are the complex outcomes of gravitational collapse and angular momentum transport mediated by protostellar and protoplanetary disks. In this review, we focus on the role of gravitational instability in this process. We begin with a brief overview of the observational evidence for massive disks that might be subject to gravitational instability and then highlight the diverse ways in which the instability manifests itself in protostellar and protoplanetary disks: the generation of spiral arms, small-scale turbulence-like density fluctuations, and fragmentation of the disk itself. We present the analytic theory that describes the linear growth phase of the instability supplemented with a survey of numerical simulations that aim to capture the nonlinear evolution. We emphasize the role of thermodynamics and large-scale infall in controlling the outcome of the instability. Despite apparent controversies in the literature, we show a remarkable level of agreement between analytic predictions and numerical results. In the next part of our review, we focus on the astrophysical consequences of the instability. We show that the disks most likely to be gravitationally unstable are young and relatively massive compared with their host star, Md/M*≥0.1. They will develop quasi-stable spiral arms that process infall from the background cloud. Although instability is less likely at later times, once infall becomes less important, the manifestations of the instability are more varied. In this regime, the disk thermodynamics, often regulated by stellar irradiation, dictates the development and evolution of the instability. In some cases the instability may lead to fragmentation into bound companions. These companions are more likely to be brown dwarfs or stars than planetary mass objects. Finally, we highlight open questions related to the development of a turbulent cascade in thin disks and the role of mode-mode coupling in setting the maximum angular

  15. Aurora Kinase A Is a Prognostic Marker in Colorectal Adenocarcinoma

    PubMed Central

    Koh, Hyun Min; Jang, Bo Geun; Hyun, Chang Lim; Kim, Young Sill; Hyun, Jin Won; Chang, Weon Young; Maeng, Young Hee

    2017-01-01

    Background Aurora kinase A (AURKA), or STK15/BTAK, is a member of the serine/threonine kinase family and plays important roles in mitosis and chromosome stability. This study investigated the clinical significance of AURKA expression in colorectal cancer patients in Korea. Methods AURKA protein expression was evaluated by immunohistochemistry in 151 patients with colorectal adenocarcinoma using tissue microarray blocks. We analyzed the relationship between clinicopathological characteristics and AURKA expression. In addition, the prognostic significance of various clinicopathological data for progression-free survival (PFS) was assessed. Also we evaluated copy number variations by array comparative genomic hybridization and AURKA gene amplification using fluorescence in situ hybridization in colorectal carcinoma tissues. Results AURKA gene amplification was found more frequently in the 20q13.2–13.33 gain-positive group than the group with no significant gain on the AURKA-containing locus. AURKA protein expression was detected in 45% of the cases (68/151). Positive staining for AURKA was observed more often in male patients (p = .035) and distally located tumors (p = .021). PFS was shorter in patients with AURKA expression compared to those with low-level AURKA expression (p < .001). Univariate analysis revealed that AURKA expression (p = .001), age (p = .034), lymphatic invasion (p = .001), perineural invasion (p = .002), and TNM stage (p = .013) significantly affected PFS. In a multivariate analysis of PFS, a Cox proportional hazard model confirmed that AURKA expression was an independent and significant prognostic factor in colorectal adenocarcinoma (hazard ratio, 3.944; p < .001). Conclusions AURKA could serve as an independent factor to predict a poor prognosis in Korean colorectal adenocarcinoma patients. PMID:28013532

  16. Cryocooler Prognostic Health Management System

    NASA Astrophysics Data System (ADS)

    Shah, A.; Penswick, L.; Dodson, C.; Roberts, T.

    2008-03-01

    High performance sensors are playing an increasingly important role in all aspects of all critical DoD missions. There is a family of sensors that operate with improved sensitivities if cooled to very low (cryogenic) temperatures. For these sensors, a healthy and reliable mechanical refrigeration system (cryocooler) is required. The ability to accurately predict the "health" or remaining useful life of the cryocooler has significant benefits from the viewpoint of ensuring that mission critical functions can be carried out with a high probability of success. The paper provides an overview and approaches used for the development of a Cryocooler Prognostic Health Management System (CPHMS) capable of assessing the cryocooler "health" from the viewpoint of the level of performance degradation and/or the potential for near term failure. Additionally, it quantifies the reliable remaining useful life of the cryocooler. While the proposed system is focused on the specific application to linear drive cryocoolers, especially for DoD, many of the attributes of the system can be applied to other specialized system hardware in both commercial and U.S. Government agency for situations where it is critical that all aspects of the hardware "health" and "remaining useful life" be fully understood. Several benefits of the health monitoring system are also described in the paper.

  17. Automated Chromosome Breakage Assessment

    NASA Technical Reports Server (NTRS)

    Castleman, Kenneth

    1985-01-01

    An automated karyotyping machine was built at JPL in 1972. It does computerized karyotyping, but it has some hardware limitations. The image processing hardware that was available at a reasonable price in 1972 was marginal, at best, for this job. In the meantime, NASA has developed an interest in longer term spaceflights and an interest in using chromosome breakage studies as a dosimeter for radiation or perhaps other damage that might occur to the tissues. This uses circulating lymphocytes as a physiological dosimeter looking for chromosome breakage on long-term spaceflights. For that reason, we have reactivated the automated karyotyping work at JPL. An update on that work, and a description of where it appears to be headed is presented.

  18. Chromosome 19 International Workshop

    SciTech Connect

    Pericak-Vance, M.A. . Medical Center); Ropers, H.H. . Dept. of Human Genetics); Carrano, A.J. )

    1993-01-04

    The Second International Workshop on Human Chromosome 19 was hosted on January 25 and 26, 1992, by the Department of Human Genetics, University Hospital Nijmegen, The Netherlands, at the 'Meerdal Conference Center'. The workshop was supported by a grant from the European Community obtained through HUGO, the Dutch Research Organization (NWO) and the Muscular Dystrophy Association (MDA). Travel support for American participants was provided by the Department of Energy. The goals of this workshop were to produce genetic, physical and integrated maps of chromosome 19, to identify inconsistencies and gaps, and to discuss and exchange resources and techniques available for the completion of these maps. The second day of the meeting was largely devoted to region or disease specific efforts. In particular, the meeting served as a platform for assessing and discussing the recent progress made into the molecular elucidation of myotonic dystrophy.

  19. Chromosomal evolution in Rodentia.

    PubMed

    Romanenko, S A; Perelman, P L; Trifonov, V A; Graphodatsky, A S

    2012-01-01

    Rodentia is the most species-rich mammalian order and includes several important laboratory model species. The amount of new information on karyotypic and phylogenetic relations within and among rodent taxa is rapidly increasing, but a synthesis of these data is currently lacking. Here, we have integrated information drawn from conventional banding studies, recent comparative painting investigations and molecular phylogenetic reconstructions of different rodent taxa. This permitted a revision of several ancestral karyotypic reconstructions, and a more accurate depiction of rodent chromosomal evolution.

  20. Diverse system stresses: common mechanisms of chromosome fragmentation.

    PubMed

    Stevens, J B; Abdallah, B Y; Liu, G; Ye, C J; Horne, S D; Wang, G; Savasan, S; Shekhar, M; Krawetz, S A; Hüttemann, M; Tainsky, M A; Wu, G S; Xie, Y; Zhang, K; Heng, H H Q

    2011-06-30

    Chromosome fragmentation (C-Frag) is a newly identified MCD (mitotic cell death), distinct from apoptosis and MC (mitotic catastrophe). As different molecular mechanisms can induce C-Frag, we hypothesize that the general mechanism of its induction is a system response to cellular stress. A clear link between C-Frag and diverse system stresses generated from an array of molecular mechanisms is shown. Centrosome amplification, which is also linked to diverse mechanisms of stress, is shown to occur in association with C-Frag. This led to a new model showing that diverse stresses induce common, MCD. Specifically, different cellular stresses target the integral chromosomal machinery, leading to system instability and triggering of MCD by C-Frag. This model of stress-induced cell death is also applicable to other types of cell death. The current study solves the previously confusing relationship between the diverse molecular mechanisms of chromosome pulverization, suggesting that incomplete C-Frag could serve as the initial event responsible for forms of genome chaos including chromothripsis. In addition, multiple cell death types are shown to coexist with C-Frag and it is more dominant than apoptosis at lower drug concentrations. Together, this study suggests that cell death is a diverse group of highly heterogeneous events that are linked to stress-induced system instability and evolutionary potential.

  1. Construction of human chromosome 21-specific yeast artificial chromosomes

    SciTech Connect

    McCormick, M.K.; Shero, J.H.; Hieter, P.A.; Antonarakis, S.E. ); Cheung, Meichi; Kan, Yuetwai )

    1989-12-01

    Chromosome 21-specific yeast artificial chromosomes (YACs) have been constructed by a method that performs all steps in agarose, allowing size selection by pulsed-field gel electrophoresis and the use of nanogram to microgram quantities of DNA. The DNA sources used were hybrid cell line WAV-17, containing chromosome 21 as the only human chromosome and flow-sorted chromosome 21. The transformation efficiency of ligation products was similar to that obtained in aqueous transformations and yielded YACs with sizes ranging from 100 kilobases (kb) to > 1 megabase when polyamines were included in the transformation procedure. Twenty-five YACs containing human DNA have been obtained from a mouse-human hybrid, ranging in size from 200 to > 1000 kb, with an average size of 410 kb. Ten of these YACs were localized to subregions of chromosome 21 by hybridization of RNA probes to a panel of somatic cell hybrid DNA. Twenty-one human YACs, ranging in size from 100 to 500 kb, with an average size of 150 kb, were obtained from {approx} 50 ng of flow-sorted chromosome 21 DNA. Three were localized to subregions of chromosome 21. YACs will aid the construction of a physical map of human chromosome 21 and the study of disorders associated with chromosome 21 such as Alzheimer disease and Down syndrome.

  2. Genomic instability caused by hepatitis B virus: into the hepatoma inferno.

    PubMed

    Hsieh, Yi-Hsuan; Hsu, Jye-Lin; Su, Ih-Jen; Huang, Wenya

    2011-06-01

    Chronic hepatitis B virus (HBV) infection is an important cause of hepatocellular carcinoma (HCC) worldwide, especially in Asia. HBV induces HCC through multiple oncogenic pathways. Hepatitis-induced hepatocyte inflammation and regeneration stimulates cell proliferation. The interplay between the viral and host factors activates oncogenic signaling pathways and triggers cell transformation. In this review, we summarize previous studies, which reported that HBV induces host genomic instability and that HBV-induced genomic instability is a significant factor that accelerates carcinogenesis. The various types of genomic changes in HBV-induced HCC--chromosomal instability, telomere attrition, and gene-level mutations--are reviewed. In addition, the two viral factors, HBx and the pre-S2 mutant large surface antigen, are discussed for their roles in promoting genomic instability as their main features as viral oncoproteins.

  3. A Genome-Wide Survey of Genetic Instability by Transposition in Drosophila Hybrids

    PubMed Central

    Vela, Doris; Fontdevila, Antonio; Vieira, Cristina; García Guerreiro, María Pilar

    2014-01-01

    Hybridization between species is a genomic instability factor involved in increasing mutation rate and new chromosomal rearrangements. Evidence of a relationship between interspecific hybridization and transposable element mobilization has been reported in different organisms, but most studies are usually performed with particular TEs and do not discuss the real effect of hybridization on the whole genome. We have therefore studied whole genome instability of Drosophila interspecific hybrids, looking for the presence of new AFLP markers in hybrids. A high percentage (27–90%) of the instability markers detected corresponds to TEs belonging to classes I and II. Moreover, three transposable elements (Osvaldo, Helena and Galileo) representative of different families, showed an overall increase of transposition rate in hybrids compared to parental species. This research confirms the hypothesis that hybridization induces genomic instability by transposition bursts and suggests that genomic stress by transposition could contribute to a relaxation of mechanisms controlling TEs in the Drosophila genome. PMID:24586475

  4. Interpreting Chromosome Aberration Spectra

    NASA Technical Reports Server (NTRS)

    Levy, Dan; Reeder, Christopher; Loucas, Bradford; Hlatky, Lynn; Chen, Allen; Cornforth, Michael; Sachs, Rainer

    2007-01-01

    Ionizing radiation can damage cells by breaking both strands of DNA in multiple locations, essentially cutting chromosomes into pieces. The cell has enzymatic mechanisms to repair such breaks; however, these mechanisms are imperfect and, in an exchange process, may produce a large-scale rearrangement of the genome, called a chromosome aberration. Chromosome aberrations are important in killing cells, during carcinogenesis, in characterizing repair/misrepair pathways, in retrospective radiation biodosimetry, and in a number of other ways. DNA staining techniques such as mFISH ( multicolor fluorescent in situ hybridization) provide a means for analyzing aberration spectra by examining observed final patterns. Unfortunately, an mFISH observed final pattern often does not uniquely determine the underlying exchange process. Further, resolution limitations in the painting protocol sometimes lead to apparently incomplete final patterns. We here describe an algorithm for systematically finding exchange processes consistent with any observed final pattern. This algorithm uses aberration multigraphs, a mathematical formalism that links the various aspects of aberration formation. By applying a measure to the space of consistent multigraphs, we will show how to generate model-specific distributions of aberration processes from mFISH experimental data. The approach is implemented by software freely available over the internet. As a sample application, we apply these algorithms to an aberration data set, obtaining a distribution of exchange cycle sizes, which serves to measure aberration complexity. Estimating complexity, in turn, helps indicate how damaging the aberrations are and may facilitate identification of radiation type in retrospective biodosimetry.

  5. Spectral karyotyping identifies recurrent complex rearrangements of chromosomes 8, 17, and 20 in osteosarcomas.

    PubMed

    Bayani, Jane; Zielenska, Maria; Pandita, Ajay; Al-Romaih, Khaldoun; Karaskova, Jana; Harrison, Karen; Bridge, Julia A; Sorensen, Poul; Thorner, Paul; Squire, Jeremy A

    2003-01-01

    Conventional cytogenetic studies have shown that osteosarcomas (OSs) are often highly aneuploid, with a large number of both structural and numerical chromosomal alterations. To investigate the complexity of OS karyotypes in detail, we applied spectral karyotyping (SKY) to a series of 14 primary OS tumors and four established OS cell lines. A total of 531 rearrangements were identified by SKY, of which 300 breakpoints could be assigned to a specific chromosome band. There was an average of 38.5 breakpoints identified by SKY per primary tumor. Chromosome 20 was involved in a disproportionately high number of structural rearrangements, with 38 different aberrations being detected. Chromosomal rearrangements between chromosomes 20 and 8 were evident in four tumors. FISH analysis using a 20q13 subtelomeric probe identified frequent involvement of 20q in complex structural rearrangements of OS cell lines. Characterization of the structural aberrations of chromosomes 8 and 17 by use of SKY demonstrated frequent duplication or partial gains of chromosome bands 8q23-24 and 17p11-13. Other chromosomes frequently involved in structural alteration were chromosomes 1 (47 rearrangements) and 6 (38 rearrangements). Centromeric rearrangements often involving chromosomes 1, 6, 13, 14, 17, and 20 were present. Four of the 14 primary OS tumors were characterized by nonclonal changes that included both structural and numerical alterations. In summary, OS tumors have a very high frequency of structural and numerical alterations, compounded by gross changes in ploidy. This intrinsic karyotype instability leads to a diversity of rearrangements and the acquisition of composite chromosomal rearrangements, with the highest frequency of alteration leading to gain of 8q23-24 and 17p11-13 and rearrangement of 20q. These findings suggest that specific sequences mapping to these chromosomal regions will likely have a role in the development and progression of OS.

  6. Human MLH1 suppresses the insertion of telomeric sequences at intra-chromosomal sites in telomerase-expressing cells.

    PubMed

    Jia, Pingping; Chastain, Megan; Zou, Ying; Her, Chengtao; Chai, Weihang

    2016-11-29

    Aberrant formation of interstitial telomeric sequences (ITSs) promotes genome instabilities. However, it is unclear how aberrant ITS formation is suppressed in human cells. Here, we report that MLH1, a key protein involved in mismatch repair (MMR), suppresses telomeric sequence insertion (TSI) at intra-chromosomal regions. The frequency of TSI can be elevated by double-strand break (DSB) inducer and abolished by ATM/ATR inhibition. Suppression of TSI requires MLH1 recruitment to DSBs, indicating that MLH1's role in DSB response/repair is important for suppressing TSI. Moreover, TSI requires telomerase activity but is independent of the functional status of p53 and Rb. Lastly, we show that TSI is associated with chromosome instabilities including chromosome loss, micronuclei formation and chromosome breakage that are further elevated by replication stress. Our studies uncover a novel link between MLH1, telomerase, telomere and genome stability.

  7. Cytogenetic features of 5q deletion and 5q- syndrome in myelodysplastic syndrome in Korea; marker chromosomes proved to be chromosome 5 with interstitial deletion by fluorescence in situ hybridization.

    PubMed

    Lee, Hye Ryun; Oh, Bora; Hong, Dae Sik; Zang, Dae Young; Yoon, Hwi-Joong; Kim, Hyeoung Joon; Kim, Inho; Ahn, Jae-Sook; Cheong, June-Won; Lee, Kyung-A; Cho, Kyung Sam; Lee, Mark Hong; Bang, Soo-Mee; Kim, Tae Young; Yun, Yeo-Min; Min, Yoo Hong; Lee, You Kyoung; Lee, Dong Soon

    2010-12-01

    We characterized the cytogenetic changes and prognostic characteristics of 133 Korean patients with myelodysplastic syndrome (MDS), focusing on 5q- syndrome and MDS with chromosome abnormalities involving 5q deletion according to World Health Organization 2008 classification. In all patients, G banding and fluorescence in situ hybridization for 5q were performed, and in MDS patients with 5q deletion, the deleted region on chromosome 5 was mapped with fluorescence in situ hybridization for EGR1, CSF1R, and PDGFRB. The frequency of isolated del(5q) syndrome and 5q deletion was 2.2% (3 of 137 patients) and 15.3% (21 of 137 patients), respectively. International Prognostic Scoring System (IPSS) groups were low risk (5.8%), intermediate 1 (51.1%), intermediate 2 (27.8%), and high risk (15.3%). The patients with del(5q) were significantly older (62 years) and showed an unfavorable survival compared to patients without del(5q). Half (53%) of the patients with del(5q) also had complex chromosome abnormalities, including chromosome 7 abnormalities. Of the patients with del(5q), 93.3% were deleted for all three regions on 5q, compared to 66.7% of patients with isolated del(5q). Marker chromosomes proved to be chromosome 5 with interstitial deletion of q arm by fluorescence in situ hybridization in three patients. The biological characteristics of MDS in Korea seem to be markedly different from those of Caucasians, with Koreans having a younger age, lower frequencies of 5q- syndrome, higher frequencies of complex cytogenetic abnormalities including del(5q), and poorer prognosis. We infer that additional chromosome abnormalities contribute to the adverse prognostic impact in patients with del(5q).

  8. Prognostic Disclosures to Children: A Historical Perspective

    PubMed Central

    Sisk, Bryan A.; Bluebond-Langner, Myra; Wiener, Lori; Mack, Jennifer; Wolfe, Joanne

    2016-01-01

    Prognostic disclosure to children has perpetually challenged clinicians and parents. In this article, we review the historical literature on prognostic disclosure to children in the United States using cancer as an illness model. Prior to 1948, there was virtually no literature focused on prognostic disclosure to children. As articles began to be published in the 1950s and 1960s, many clinicians and researchers initially recommended a “protective” approach to disclosure, where children were shielded from the harms of bad news. We identified four main arguments in the literature at this time supporting this “protective” approach. By the late 1960s, however, a growing number of clinicians and researchers were recommending a more “open” approach, where children were included in discussions of diagnosis, which at the time was often synonymous with a terminal prognosis. Four different arguments in the literature were used at this time supporting this “open” approach. Then by the late 1980s, the recommended approach to prognostic disclosure in pediatrics shifted largely from “never tell” to “always tell”. In recent years, however, there has been a growing appreciation for the complexity of prognostic disclosure in pediatrics. Current understanding of pediatric disclosure does not lead to simple “black and white” recommendations for disclosure practices. As with most difficult questions, we are left to balance competing factors on a case-by-case basis. We highlight four categories of current considerations related to prognostic disclosure in pediatrics, and we offer several approaches to prognostic disclosure for clinicians who care for these young patients and their families. PMID:27561728

  9. B Chromosomes – A Matter of Chromosome Drive

    PubMed Central

    Houben, Andreas

    2017-01-01

    B chromosomes are supernumerary chromosomes which are often preferentially inherited, deviating from usual Mendelian segregation. The balance between the so-called chromosome drive and the negative effects that the presence of Bs applies on the fitness of their host determines the frequency of Bs in a particular population. Drive is the key for understanding most B chromosomes. Drive occurs in many ways at pre-meiotic, meiotic or post-meiotic divisions, but the molecular mechanism remains unclear. The cellular mechanism of drive is reviewed based on the findings obtained for the B chromosomes of rye, maize and other species. How novel analytical tools will expand our ability to uncover the biology of B chromosome drive is discussed. PMID:28261259

  10. Phase Instability in Semiconductor Lasers

    NASA Astrophysics Data System (ADS)

    Gil, L.; Lippi, G. L.

    2014-11-01

    For many years, the apparent absence of a phase instability has characterized lasers as peculiar nonlinear oscillators. We show that this unusual feature is solely due to the approximations used in writing the standard models. A new, careful derivation of the fundamental equations, based on codimension 2 bifurcation theory, shows the possible existence of dynamical regimes displaying either a pure phase instability, or mixed phase-amplitude turbulence. A comparison to existing experimental results convincingly shows that the Benjamin-Feir instability, common to all nonlinear wave problems, is a fundamental, satisfactory interpretation for their deterministic multimode dynamics.

  11. Analysis of structures causing instabilities.

    PubMed

    Wilhelm, Thomas

    2007-07-01

    We present a simple new method to systematically identify all topological structures (e.g., positive feedback loops) potentially leading to locally unstable steady states: ICSA-The instability causing structure analysis. Systems without any instability causing structure (i.e., not fulfilling the necessary topological condition for instabilities) cannot have unstable steady states. It follows that common bistability or multistability and Hopf bifurcations are excluded and sustained oscillations and deterministic chaos are most unlikely. The ICSA leads to new insights into the topological organization of chemical and biochemical systems, such as metabolic, gene regulatory, and signal transduction networks.

  12. Chromosome-specific staining to detect genetic rearrangements associated with chromosome 3 and/or chromosome 17

    DOEpatents

    Gray, Joe W.; Pinkel, Daniel; Kallioniemi, Olli-Pekka; Kallioniemi, Anne; Sakamoto, Masaru

    2009-10-06

    Methods and compositions for staining based upon nucleic acid sequence that employ nudeic nucleic acid probes are provided. Said methods produce staining patterns that can be tailored for specific cytogenetic analyses. Said probes are appropriate for in situ hybridization and stain both interphase and metaphase chromosomal material with reliable signals. The nucleic acid probes are typically of a complexity greater than 50 kb, the complexity depending upon the cytogenetic application. Methods and reagents are provided for the detection of genetic rearrangements. Probes and test kits are provided for use in detecting genetic rearrangements, particularly for use in tumor cytogenetics, in the detection of disease related loci, specifically cancer, such as chronic myelogenous leukemia (CML), retinoblastoma, ovarian and uterine cancers, and for biological dosimetry. Methods and reagents are described for cytogenetic research, for the differentiation of cytogenetically similar but genetically different diseases, and for many prognostic and diagnostic applications.

  13. Resistive instabilities in tokamaks

    SciTech Connect

    Rutherford, P.H.

    1985-10-01

    Low-m tearing modes constitute the dominant instability problem in present-day tokamaks. In this lecture, the stability criteria for representative current profiles with q(0)-values slightly less than unit are reviewed; ''sawtooth'' reconnection to q(0)-values just at, or slightly exceeding, unity is generally destabilizing to the m = 2, n = 1 and m = 3, n = 2 modes, and severely limits the range of stable profile shapes. Feedback stabilization of m greater than or equal to 2 modes by rf heating or current drive, applied locally at the magnetic islands, appears feasible; feedback by island current drive is much more efficient, in terms of the radio-frequency power required, then feedback by island heating. Feedback stabilization of the m = 1 mode - although yielding particularly beneficial effects for resistive-tearing and high-beta stability by allowing q(0)-values substantially below unity - is more problematical, unless the m = 1 ideal-MHD mode can be made positively stable by strong triangular shaping of the central flux surfaces. Feedback techniques require a detectable, rotating MHD-like signal; the slowing of mode rotation - or the excitation of non-rotating modes - by an imperfectly conducting wall is also discussed.

  14. Chronic ankle instability.

    PubMed

    Gerstner Garces, Juan Bernardo

    2012-09-01

    Chronic instability of the ankle and anterolateral impingement syndrome are abnormalities that present as a result of inversion and forced plantar-flexion traumas of the foot, despite strict conservative management in the ER and in rehabilitation. A conservative approach is always the first choice of treatment, including anti-inflammatory medications, rehabilitation and proprioception, infiltration with steroids in impingement cases, and use of orthotics, whose true effectiveness is the subject of multiple studies and much debate. Good to excellent results can be obtained surgically with a minimally invasive approach, such as the arthroscopic technique presented herein. Such an approach is useful in managing a combination of conditions such as anterolateral impingement, synovitis, and osteochondral lesions of the talus. The method is easily reproducible, its learning curve is rapid, and it has the advantage of not preventing the use other arthroscopic methods, or open anatomic or nonanatomic methods (tendon transfers), in the case of failure. No nerve lesion was recorded, probably owing to the use of the security zone, and neither was there any arthrofibrosis, possibly related to the use of nonsteroidal anti-inflammatory medications in the immediate postsurgical period coupled with aggressive rehabilitation from the fourth week. The success of the technique is due to multidisciplinary team work leading to the ultimate achievement of patient satisfaction. This technique is not indicated for patients with a high sports demand or for sport professionals, until further biomechanical studies on its use and success are completed.

  15. Instabilities in the aether

    SciTech Connect

    Carroll, Sean M.; Dulaney, Timothy R.; Gresham, Moira I.; Tam, Heywood

    2009-03-15

    We investigate the stability of theories in which Lorentz invariance is spontaneously broken by fixed-norm vector 'aether' fields. Models with generic kinetic terms are plagued either by ghosts or by tachyons, and are therefore physically unacceptable. There are precisely three kinetic terms that are not manifestly unstable: a sigma model ({partial_derivative}{sub {mu}}A{sub {nu}}){sup 2}, the Maxwell Lagrangian F{sub {mu}}{sub {nu}}F{sup {mu}}{sup {nu}}, and a scalar Lagrangian ({partial_derivative}{sub {mu}}A{sup {mu}}){sup 2}. The timelike sigma-model case is well defined and stable when the vector norm is fixed by a constraint; however, when it is determined by minimizing a potential there is necessarily a tachyonic ghost, and therefore an instability. In the Maxwell and scalar cases, the Hamiltonian is unbounded below, but at the level of perturbation theory there are fewer degrees of freedom and the models are stable. However, in these two theories there are obstacles to smooth evolution for certain choices of initial data.

  16. Patterns of chromosomal variation in natural populations of the neoallotetraploid Tragopogon mirus (Asteraceae)

    PubMed Central

    Chester, M; Riley, R K; Soltis, P S; Soltis, D E

    2015-01-01

    Cytological studies have shown many newly formed allopolyploids (neoallopolyploids) exhibit chromosomal variation as a result of meiotic irregularities, but few naturally occurring neoallopolyploids have been examined. Little is known about how long chromosomal variation may persist and how it might influence the establishment and evolution of allopolyploids in nature. In this study we assess chromosomal composition in a natural neoallotetraploid, Tragopogon mirus, and compare it with T. miscellus, which is an allotetraploid of similar age (~40 generations old). We also assess whether parental gene losses in T. mirus correlate with entire or partial chromosome losses. Of 37 T. mirus individuals that were karyotyped, 23 (62%) were chromosomally additive of the parents, whereas the remaining 14 individuals (38%) had aneuploid compositions. The proportion of additive versus aneuploid individuals differed from that found previously in T. miscellus, in which aneuploidy was more common (69% Fisher's exact test, P=0.0033). Deviations from parental chromosome additivity within T. mirus individuals also did not reach the levels observed in T. miscellus, but similar compensated changes were observed. The loss of T. dubius-derived genes in two T. mirus individuals did not correlate with any chromosomal changes, indicating a role for smaller-scale genetic alterations. Overall, these data for T. mirus provide a second example of prolonged chromosomal instability in natural neoallopolyploid populations. PMID:25370212

  17. A Distributed Prognostic Health Management Architecture

    NASA Technical Reports Server (NTRS)

    Bhaskar, Saha; Saha, Sankalita; Goebel, Kai

    2009-01-01

    This paper introduces a generic distributed prognostic health management (PHM) architecture with specific application to the electrical power systems domain. Current state-of-the-art PHM systems are mostly centralized in nature, where all the processing is reliant on a single processor. This can lead to loss of functionality in case of a crash of the central processor or monitor. Furthermore, with increases in the volume of sensor data as well as the complexity of algorithms, traditional centralized systems become unsuitable for successful deployment, and efficient distributed architectures are required. A distributed architecture though, is not effective unless there is an algorithmic framework to take advantage of its unique abilities. The health management paradigm envisaged here incorporates a heterogeneous set of system components monitored by a varied suite of sensors and a particle filtering (PF) framework that has the power and the flexibility to adapt to the different diagnostic and prognostic needs. Both the diagnostic and prognostic tasks are formulated as a particle filtering problem in order to explicitly represent and manage uncertainties; however, typically the complexity of the prognostic routine is higher than the computational power of one computational element ( CE). Individual CEs run diagnostic routines until the system variable being monitored crosses beyond a nominal threshold, upon which it coordinates with other networked CEs to run the prognostic routine in a distributed fashion. Implementation results from a network of distributed embedded devices monitoring a prototypical aircraft electrical power system are presented, where the CEs are Sun Microsystems Small Programmable Object Technology (SPOT) devices.

  18. Evaluating Algorithm Performance Metrics Tailored for Prognostics

    NASA Technical Reports Server (NTRS)

    Saxena, Abhinav; Celaya, Jose; Saha, Bhaskar; Saha, Sankalita; Goebel, Kai

    2009-01-01

    Prognostics has taken a center stage in Condition Based Maintenance (CBM) where it is desired to estimate Remaining Useful Life (RUL) of the system so that remedial measures may be taken in advance to avoid catastrophic events or unwanted downtimes. Validation of such predictions is an important but difficult proposition and a lack of appropriate evaluation methods renders prognostics meaningless. Evaluation methods currently used in the research community are not standardized and in many cases do not sufficiently assess key performance aspects expected out of a prognostics algorithm. In this paper we introduce several new evaluation metrics tailored for prognostics and show that they can effectively evaluate various algorithms as compared to other conventional metrics. Specifically four algorithms namely; Relevance Vector Machine (RVM), Gaussian Process Regression (GPR), Artificial Neural Network (ANN), and Polynomial Regression (PR) are compared. These algorithms vary in complexity and their ability to manage uncertainty around predicted estimates. Results show that the new metrics rank these algorithms in different manner and depending on the requirements and constraints suitable metrics may be chosen. Beyond these results, these metrics offer ideas about how metrics suitable to prognostics may be designed so that the evaluation procedure can be standardized. 1

  19. Ectopic Expression of Testis Germ Cell Proteins in Cancer and Its Potential Role in Genomic Instability

    PubMed Central

    Nielsen, Aaraby Yoheswaran; Gjerstorff, Morten Frier

    2016-01-01

    Genomic instability is a hallmark of human cancer and an enabling factor for the genetic alterations that drive cancer development. The processes involved in genomic instability resemble those of meiosis, where genetic material is interchanged between homologous chromosomes. In most types of human cancer, epigenetic changes, including hypomethylation of gene promoters, lead to the ectopic expression of a large number of proteins normally restricted to the germ cells of the testis. Due to the similarities between meiosis and genomic instability, it has been proposed that activation of meiotic programs may drive genomic instability in cancer cells. Some germ cell proteins with ectopic expression in cancer cells indeed seem to promote genomic instability, while others reduce polyploidy and maintain mitotic fidelity. Furthermore, oncogenic germ cell proteins may indirectly contribute to genomic instability through induction of replication stress, similar to classic oncogenes. Thus, current evidence suggests that testis germ cell proteins are implicated in cancer development by regulating genomic instability during tumorigenesis, and these proteins therefore represent promising targets for novel therapeutic strategies. PMID:27275820

  20. Polymer Models of Interphase Chromosomes

    NASA Astrophysics Data System (ADS)

    Martin, Joshua; Kondev, Jané; Bressen, Debra; Haber, James

    2006-03-01

    Experiments during interphase, the growth phase of the cell cycle in eukaryotic cells, have shown that parts of chromosomes are tethered to the nuclear periphery[1]. Using a simple polymer model of interphase chromosomes that includes tethering, we compute the probability distribution for the distance between two marked points on the chromosome. These calculations are inspired by recent experiments with two or more fluorescent markers placed along the chromosome[2]. We demonstrate how experiments of this kind, in conjunction with simpe polymer models, can be used to systematically dissect the spatial organization of interphase chromosomes in the nucleus of living cells. This comparison of theory with experiments has lead to the conclusion that the structure of chromosome III in yeast is consistent with a 10nm-fiber model of chromatin. [1]Wallace F. Marshall. Current Biology, 12, 2002. [2] Kerstin Bystricky, Patrick Heun, Lutz Gehlen, Jörg Langowski and Susan M. Gasser. PNAS, 101(47) 2004

  1. Microsatellite instability in human mammary epithelial cells transformed by heavy ions

    NASA Astrophysics Data System (ADS)

    Yanada, S.; Yang, T. C.; George, K.; Okayasu, R.; Ando, K.; Tsujii, H.

    1998-11-01

    We analyzed DNA and proteins obtained from normal and transformed human mammary epithelial cells for studying the neoplastic transformation by high-LET irradiation in vitro. We also examined microsatellite instability in human mammary cells transformed to various stages of carcinogenesis, such as normal, growth variant and tumorigenic, using microsatellite marker D5S177 on the chromosome 5 and CY17 on the Chromosome 10. Microsatellite instabilities were detected in the tumorigenic stage. These results suggest that microsatellite instability may play a role in the progression of tumorigenecity. The cause of the genomic instability has been suggested as abnormalities of DNA-repair systems which may be due to one of the three reasons: 1) alterations of cell cycle regulating genes. 2) mutations in any of the DNA mismatch repair genes, 3) mutation in any of the DNA strand breaks repair genes. No abnormality of these genes and encoded proteins, however was found in the present studies. These studies thus suggest that the microsatellite instability is induced by an alternative mechanism.

  2. Clustering instability of focused swimmers

    NASA Astrophysics Data System (ADS)

    Lauga, Eric; Nadal, Francois

    2016-12-01

    One of the hallmarks of active matter is its rich nonlinear dynamics and instabilities. Recent numerical simulations of phototactic algae showed that a thin jet of swimmers, obtained from hydrodynamic focusing inside a Poiseuille flow, was unstable to longitudinal perturbations with swimmers dynamically clustering (Jibuti L. et al., Phys. Rev. E, 90, (2014) 063019). As a simple starting point to understand these instabilities, we consider in this paper an initially homogeneous one-dimensional line of aligned swimmers moving along the same direction, and characterise its instability using both a continuum framework and a discrete approach. In both cases, we show that hydrodynamic interactions between the swimmers lead to instabilities in density for which we compute the growth rate analytically. Lines of pusher-type swimmers are predicted to remain stable while lines of pullers (such as flagellated algae) are predicted to always be unstable.

  3. Fluid Instabilities inside Astrophysical Explosions

    NASA Astrophysics Data System (ADS)

    Chen, Ke-Jung; Woosley, Stan; Heger, Alexander; Almgren, Ann; Zheng, Weiqun

    2014-11-01

    We present our results from the simulations of fluid instabilities inside supernovae with a new radiation-hydrodynamic code, CASTRO. Massive stars are ten times more massive than Sun. Observational and theoretical studies suggest that these massive stars tend to end their lives with energetic explosions, so-called supernovae. Many fluid instabilities occur during the supernova explosions. The fluid instabilities can be driven by hydrodynamics, nuclear burning, or radiation. In this talk, we discuss about the possible physics of fluid instabilities found in our simulations and how the resulting mixing affects the observational signatures of supernovae. This work was supported by the DOE HEP Program under contract DE-SC0010676; the National Science Foundation (AST 0909129) and the NASA Theory Program (NNX14AH34G).

  4. Evaporative instabilities in climbing films

    NASA Astrophysics Data System (ADS)

    Hosoi, A. E.; Bush, John W. M.

    2001-09-01

    We consider flow in a thin film generated by partially submerging an inclined rigid plate in a reservoir of ethanol or methanol water solution and wetting its surface. Evaporation leads to concentration and surface tension gradients that drive flow up the plate. An experimental study indicates that the climbing film is subject to two distinct instabilities. The first is a convective instability characterized by flattened convection rolls aligned in the direction of flow and accompanied by free-surface deformations; in the meniscus region, this instability gives rise to pronounced ridge structures aligned with the mean flow. The second instability, evident when the plate is nearly vertical, takes the form of transverse surface waves propagating up the plate.

  5. Histone acetylation in insect chromosomes.

    PubMed

    Allfrey, V G; Pogo, B G; Littau, V C; Gershey, E L; Mirsky, A E

    1968-01-19

    Acetylation of histones takes place along the salivary gland chromosomes of Chironomus thummi when RNA synthesis is active. It can be observed but not measured quantitatively by autoradiography of chromosome squashes. The "fixatives" commonly used in preparing squashes of insect chromosomes preferentially extract the highly acetylated "arginine-rich" histone fractions; the use of such fixatives may explain the reported absence of histone acetylation in Drosophila melanogaster.

  6. Waves and instabilities in plasmas

    SciTech Connect

    Chen, L.

    1987-01-01

    The contents of this book are: Plasma as a Dielectric Medium; Nyquist Technique; Absolute and Convective Instabilities; Landau Damping and Phase Mixing; Particle Trapping and Breakdown of Linear Theory; Solution of Viasov Equation via Guilding-Center Transformation; Kinetic Theory of Magnetohydrodynamic Waves; Geometric Optics; Wave-Kinetic Equation; Cutoff and Resonance; Resonant Absorption; Mode Conversion; Gyrokinetic Equation; Drift Waves; Quasi-Linear Theory; Ponderomotive Force; Parametric Instabilities; Problem Sets for Homework, Midterm and Final Examinations.

  7. Instability following total knee arthroplasty.

    PubMed

    Rodriguez-Merchan, E Carlos

    2011-10-01

    Background Knee prosthesis instability (KPI) is a frequent cause of failure of total knee arthroplasty. Moreover, the degree of constraint required to achieve immediate and long-term stability in total knee arthroplasty (TKA) is frequently debated. Questions This review aims to define the problem, analyze risk factors, and review strategies for prevention and treatment of KPI. Methods A PubMed (MEDLINE) search of the years 2000 to 2010 was performed using two key words: TKA and instability. One hundred and sixty-five initial articles were identified. The most important (17) articles as judged by the author were selected for this review. The main criteria for selection were that the articles addressed and provided solutions to the diagnosis and treatment of KPI. Results Patient-related risk factors predisposing to post-operative instability include deformity requiring a large surgical correction and aggressive ligament release, general or regional neuromuscular pathology, and hip or foot deformities. KPI can be prevented in most cases with appropriate selection of implants and good surgical technique. When ligament instability is anticipated post-operatively, the need for implants with a greater degree of constraint should be anticipated. In patients without significant varus or valgus malalignment and without significant flexion contracture, the posterior cruciate ligament (PCL) can be retained. However, the PCL should be sacrificed when deformity exists particularly in patients with rheumatoid arthritis, previous patellectomy, previous high tibial osteotomy or distal femoral osteotomy, and posttraumatic osteoarthritis with disruption of the PCL. In most cases, KPI requires revision surgery. Successful outcomes can only be obtained if the cause of KPI is identified and addressed. Conclusions Instability following TKA is a common cause of the need for revision. Typically, knees with deformity, rheumatoid arthritis, previous patellectomy or high tibial osteotomy, and

  8. Magnetothermal instability in cooling flows

    NASA Technical Reports Server (NTRS)

    Loewenstein, Michael

    1990-01-01

    The effect of magnetic fields on thermal instability in cooling flows is investigated using linear, Eulerian perturbation analysis. As contrasted with the zero magnetic-field case, hydromagnetic stresses support perturbations against acceleration caused by buoyancy - comoving evolution results and global growth rates are straightforward to obtain for a given cooling flow entropy distribution. In addition, background and induced magnetic fields ensure that conductive damping of thermal instability is greatly reduced.

  9. Material Instabilities in Particulate Systems

    NASA Technical Reports Server (NTRS)

    Goddard, J. D.

    1999-01-01

    Following is a brief summary of a theoretical investigation of material (or constitutive) instability associated with shear induced particle migration in dense particulate suspensions or granular media. It is shown that one can obtain a fairly general linear-stability analysis, including the effects of shear-induced anisotropy in the base flow as well as Reynolds dilatancy. A criterion is presented here for simple shearing instability in the absence of inertia and dilatancy.

  10. The evolution and clinical relevance of prognostic classification systems in myelofibrosis.

    PubMed

    Bose, Prithviraj; Verstovsek, Srdan

    2016-03-01

    Primary myelofibrosis, the most aggressive of the classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), is a clonal disorder characterized by often debilitating constitutional symptoms and splenomegaly, bone marrow fibrosis and resultant cytopenias, extramedullary hematopoiesis, risk of leukemic transformation, and shortened survival. Post-polycythemia vera and post-essential thrombocythemia myelofibrosis represent similar entities, although some differences are being recognized. Attempts to classify patients with myelofibrosis into prognostic categories have been made since the late 1980s, and these scoring systems continue to evolve as new information becomes available. Over the last decade, the molecular pathogenesis of MPNs has been elucidated considerably, and the Janus kinase (JAK) 1/2 inhibitor ruxolitinib is the first drug specifically approved by the US Food and Drug Administration to treat patients with intermediate-risk and high-risk myelofibrosis. This article reviews the evolution of prognostic criteria in myelofibrosis, emphasizing the major systems widely in use today, as well as recently described, novel systems that incorporate emerging data regarding somatic mutations. Risk factors for thrombosis and conversion to MPN blast phase also are discussed. Finally, the practical usefulness of the current prognostic classification systems in terms of clinical decision making is discussed, particularly within the context of some of their inherent weaknesses. Cancer 2016;122:681-692. © 2015 American Cancer Society.

  11. Genomic Instability and Cancer: Lessons Learned from Human Papillomaviruses

    PubMed Central

    Korzeniewski, Nina; Spardy, Nicole; Duensing, Anette; Duensing, Stefan

    2010-01-01

    High-risk HPV E6 and E7 oncoproteins cooperate to subvert critical host cell cycle checkpoint control mechanisms in order to promote viral genome replication. This results not only in aberrant proliferation but also in host cellular changes that can promote genomic instability. The HPV-16 E7 oncoprotein was found to induce centrosome abnormalities thereby disrupting mitotic fidelity and increasing the risk for chromosome missegregation and aneuploidy. In addition, expression of the high-risk HPV E7 oncoprotein stimulates DNA replication stress as a potential source of DNA breakage and structural chromosomal instability. Proliferation of genomically unstable cells is sustained by several mechanisms including the accelerated degradation of claspin by HPV-16 E7 and the degradation of p53 by the high-risk HPV E6 oncoprotein. These results highlight the oncogenic potential of aberrant proliferation and opens new avenues for prevention of malignant progression, not only in HPV-associated cervical cancer but also in non-virally associated malignancies with disrupted cell cycle checkpoint control mechanisms. PMID:21075512

  12. Suppression of gross chromosomal rearrangements by a new alternative replication factor C complex

    SciTech Connect

    Banerjee, Soma; Sikdar, Nilabja; Myung, Kyungjae

    2007-10-26

    Defects in DNA replication fidelity lead to genomic instability. Gross chromosomal rearrangement (GCR), a type of genomic instability, is highly enhanced by various initial mutations affecting DNA replication. Frequent observations of GCRs in many cancers strongly argue the importance of maintaining high fidelity of DNA replication to suppress carcinogenesis. Recent genome wide screens in Saccharomyces cerevisiae identified a new GCR suppressor gene, ELG1, enhanced level of genome instability gene 1. Its physical interaction with proliferating cell nuclear antigen (PCNA) and complex formation with Rfc2-5p proteins suggest that Elg1 functions to load/unload PCNA onto DNA during a certain DNA metabolism. High level of DNA damage accumulation and enhanced phenotypes with mutations in genes involved in cell cycle checkpoints, homologous recombination (HR), or chromatin assembly in the elg1 strain suggest that Elg1p-Rfc2-5p functions in a fundamental DNA metabolism to suppress genomic instability.

  13. Instability of enclosed horizons

    NASA Astrophysics Data System (ADS)

    Kay, Bernard S.

    2015-03-01

    We point out that there are solutions to the scalar wave equation on dimensional Minkowski space with finite energy tails which, if they reflect off a uniformly accelerated mirror due to (say) Dirichlet boundary conditions on it, develop an infinite stress-energy tensor on the mirror's Rindler horizon. We also show that, in the presence of an image mirror in the opposite Rindler wedge, suitable compactly supported arbitrarily small initial data on a suitable initial surface will develop an arbitrarily large stress-energy scalar near where the two horizons cross. Also, while there is a regular Hartle-Hawking-Israel-like state for the quantum theory between these two mirrors, there are coherent states built on it for which there are similar singularities in the expectation value of the renormalized stress-energy tensor. We conjecture that in other situations with analogous enclosed horizons such as a (maximally extended) Schwarzschild black hole in equilibrium in a (stationary spherical) box or the (maximally extended) Schwarzschild-AdS spacetime, there will be similar stress-energy singularities and almost-singularities—leading to instability of the horizons when gravity is switched on and matter and gravity perturbations are allowed for. All this suggests it is incorrect to picture a black hole in equilibrium in a box or a Schwarzschild-AdS black hole as extending beyond the past and future horizons of a single Schwarzschild (/Schwarzschild-AdS) wedge. It would thus provide new evidence for 't Hooft's brick wall model while seeming to invalidate the picture in Maldacena's ` Eternal black holes in AdS'. It would thereby also support the validity of the author's matter-gravity entanglement hypothesis and of the paper ` Brick walls and AdS/CFT' by the author and Ortíz.

  14. Elastic instabilities in rubber

    NASA Astrophysics Data System (ADS)

    Gent, Alan

    2009-03-01

    Materials that undergo large elastic deformations can exhibit novel instabilities. Several examples are described: development of an aneurysm on inflating a rubber tube; non-uniform stretching on inflating a spherical balloon; formation of internal cracks in rubber blocks at a critical level of triaxial tension or when supersaturated with a dissolved gas; surface wrinkling of a block at a critical amount of compression; debonding or fracture of constrained films on swelling, and formation of ``knots'' on twisting stretched cylindrical rods. These various deformations are analyzed in terms of a simple strain energy function, using Rivlin's theory of large elastic deformations, and the results are compared with experimental measurements of the onset of unstable states. Such comparisons provide new tests of Rivlin's theory and, at least in principle, critical tests of proposed strain energy functions for rubber. Moreover the onset of highly non-uniform deformations has serious implications for the fatigue life and fracture resistance of rubber components. [4pt] References: [0pt] R. S. Rivlin, Philos. Trans. Roy. Soc. Lond. Ser. A241 (1948) 379--397. [0pt] A. Mallock, Proc. Roy. Soc. Lond. 49 (1890--1891) 458--463. [0pt] M. A. Biot, ``Mechanics of Incremental Deformations'', Wiley, New York, 1965. [0pt] A. N. Gent and P. B. Lindley, Proc. Roy. Soc. Lond. A 249 (1958) 195--205. [0pt] A. N. Gent, W. J. Hung and M. F. Tse, Rubb. Chem. Technol. 74 (2001) 89--99. [0pt] A. N. Gent, Internatl. J. Non-Linear Mech. 40 (2005) 165--175.

  15. Vector-Resonance-Multimode Instability

    NASA Astrophysics Data System (ADS)

    Sergeyev, S. V.; Kbashi, H.; Tarasov, N.; Loiko, Yu.; Kolpakov, S. A.

    2017-01-01

    The modulation and multimode instabilities are the main mechanisms which drive spontaneous spatial and temporal pattern formation in a vast number of nonlinear systems ranging from biology to laser physics. Using an Er-doped fiber laser as a test bed, here for the first time we demonstrate both experimentally and theoretically a new type of a low-threshold vector-resonance-multimode instability which inherits features of multimode and modulation instabilities. The same as for the multimode instability, a large number of longitudinal modes can be excited without mode synchronization. To enable modulation instability, we modulate the state of polarization of the lasing signal with the period of the beat length by an adjustment of the in-cavity birefringence and the state of polarization of the pump wave. As a result, we show the regime's tunability from complex oscillatory to periodic with longitudinal mode synchronization in the case of resonance matching between the beat and cavity lengths. Apart from the interest in laser physics for unlocking the tunability and stability of dynamic regimes, the proposed mechanism of the vector-resonance-multimode instability can be of fundamental interest for the nonlinear dynamics of various distributed systems.

  16. Vertical Instability at IPNS RCS.

    SciTech Connect

    Wang, S.; Brumwell, F. R.; Dooling, J. C.; Harkay, K. C.; Kustom, R.; McMichael, G. E.; Middendorf, M. E.; Nassiri, A.; Accelerator Systems Division

    2008-01-01

    The rapid cycling synchrotron (RCS) of the intense pulsed neutron source (IPNS) at ANL accelerates > 3.0 times 10{sup 12} protons from 50 MeV to 450 MeV with 30-Hz repetition frequency. During the acceleration cycle, the rf frequency varies from 2.21 MHz to 5.14 MHz. Presently, the beam current is limited by a vertical instability. By analyzing turn-by-turn beam position monitor (BPM) data, large- amplitude mode 0 and mode 1 vertical beam centroid oscillations were observed in the later part of the acceleration cycle. The oscillations start in the tail of the bunch, build up, and remain localized in the tail half of the bunch. This vertical instability was compared with a head-tail instability that was intentionally induced in the RCS by adjusting the trim sextupoles. It appears that our vertical instability is not a classical head-tail instability [1]. More data analysis and experiments were performed to characterize the instability.

  17. Diagnosis, progression patterns and prognostication in mastocytosis.

    PubMed

    Sperr, Wolfgang R; Valent, Peter

    2012-06-01

    Mastocytosis is a heterogeneous group of disorders defined by abnormal growth and accumulation of clonal mast cells. CM is the predominant variant in childhood, whereas the majority of adult patients present with systemic mastocytosis. In over 80% of the latter patients, the KIT mutation D816V is detectable. Whereas childhood mastocytosis often resolves spontaneously before adolescence and has a good prognosis, in most adult patients mastocytosis is a persistent systemic disorder. The course and prognosis in these patients are variable; in indolent variants, the clinical course remains stable over years or even decades. In advanced mastocytosis, the prognosis is less favorable despite novel drugs counteracting growth of neoplastic mast cells. Although WHO criteria are clearly separating prognostic subsets of mastocytosis, little is known about specific prognostic factors predicting the outcome in individual patients. In this article, we review current concepts in mastocytosis, including prognostic parameters for indolent and advanced systemic mastocytosis.

  18. Prognostic Awareness and Communication of Prognostic Information in Malignant Glioma: A Systematic Review

    PubMed Central

    Diamond, Eli L.; Corner, Geoffrey W.; DeRosa, Antonio; Breitbart, William; Applebaum, Allison J.

    2016-01-01

    Malignant glioma (MG) is a devastating neurological disease with a uniformly poor prognosis and a clinical course characterized by progressive functional and cognitive impairment. A small body of literature addresses patients’ and caregivers’ prognostic awareness (PA), or understanding of prognosis in patients with cancer. Studies that examine PA and desire for prognostic information among patients with MG are limited. We sought to review the existing literature on PA and communication of prognostic information to patients with MG. Fourteen studies examining PA or experience and preferences regarding communication of prognostic information were included. The definition and measurement of PA across studies varied, and the prevalence of accurate PA ranged from 25% to 100% of participants. There is likely a subset of patients who do not desire accurate prognostic information, although the patient and disease characteristics that predict this preference are currently unknown. This review suggests that patients with MG desire prognostic information communicated in a manner that preserves hope. Systematic investigation to define communication needs for prognostic information in the unique clinical setting of MG is needed. PMID:24874468

  19. Prognostic awareness and communication of prognostic information in malignant glioma: a systematic review.

    PubMed

    Diamond, Eli L; Corner, Geoffrey W; De Rosa, Antonio; Breitbart, William; Applebaum, Allison J

    2014-09-01

    Malignant glioma (MG) is a devastating neurological disease with a uniformly poor prognosis and a clinical course characterized by progressive functional and cognitive impairment. A small body of literature addresses patients' and caregivers' prognostic awareness (PA), or understanding of prognosis in patients with cancer. Studies that examine PA and desire for prognostic information among patients with MG are limited. We sought to review the existing literature on PA and communication of prognostic information to patients with MG. Fourteen studies examining PA or experience and preferences regarding communication of prognostic information were included. The definition and measurement of PA across studies varied, and the prevalence of accurate PA ranged from 25 to 100 % of participants. There is likely a subset of patients who do not desire accurate prognostic information, although the patient and disease characteristics that predict this preference are currently unknown. This review suggests that patients with MG desire prognostic information communicated in a manner that preserves hope. Systematic investigation to define communication needs for prognostic information in the unique clinical setting of MG is needed.

  20. Somatic Mosaicism in Cases with Small Supernumerary Marker Chromosomes

    PubMed Central

    Liehr, Thomas; Karamysheva, Tatyana; Merkas, Martina; Brecevic, Lukrecija; Hamid, Ahmed B.; Ewers, Elisabeth; Mrasek, Kristin; Kosyakova, Nadezda; Weise, Anja

    2010-01-01

    Somatic mosaicism is something that is observed in everyday lives of cytogeneticists. Chromosome instability is one of the leading causes of large-scale genome variation analyzable since the correct human chromosome number was established in 1956. Somatic mosaicism is also a well-known fact to be present in cases with small supernumerary marker chromosomes (sSMC), i.e. karyotypes of 47,+mar/46. In this study, the data available in the literature were collected concerning the frequency mosaicism in different subgroups of patients with sSMC. Of 3124 cases with sSMC 1626 (52%) present with somatic mosaicism. Some groups like patients with Emanuel-, cat-eye- or i(18p)- syndrome only tend rarely to develop mosaicism, while in Pallister-Killian syndrome every patient is mosaic. In general, acrocentric and non-acrocentric derived sSMCs are differently susceptible to mosaicism; non-acrocentric derived ones are hereby the less stable ones. Even though, in the overwhelming majority of the cases, somatic mosaicism does not have any detectable clinical effects, there are rare cases with altered clinical outcomes due to mosaicism. This is extremely important for prenatal genetic counseling. Overall, as mosaicism is something to be considered in at least every second sSMC case, array-CGH studies cannot be offered as a screening test to reliably detect this kind of chromosomal aberration, as low level mosaic cases and cryptic mosaics are missed by that. PMID:21358988

  1. Molecular cytogenetic analysis of dicentric chromosomes in acute myeloid leukemia.

    PubMed

    Sarova, Iveta; Brezinova, Jana; Zemanova, Zuzana; Ransdorfova, Sarka; Izakova, Silvia; Svobodova, Karla; Pavlistova, Lenka; Berkova, Adela; Cermak, Jaroslav; Jonasova, Anna; Siskova, Magda; Michalova, Kyra

    2016-04-01

    Dicentric chromosomes (DCs) have been described in many hematological diseases, including acute myeloid leukemia (AML). They are markers of cancer and induce chromosomal instability, leading to the formation of other chromosomal aberrations and the clonal evolution of pathological cells. Our knowledge of the roles and behavior of human DCs is often derived from studies of induced DCs and cell lines. It is difficult to identify all the DCs in the karyotypes of patients because of the limitations of metaphase cytogenetic methods. The aim of this study was to revise the karyotypes of 20 AML patients in whom DCs were found with conventional G-banding or multicolor fluorescence in situ hybridization (mFISH) with (multi)centromeric probes and to characterize the DCs at the molecular cytogenetic level. FISH analyses confirmed 23 of the 29 expected DCs in 18 of 20 patients and identified 13 others that had not been detected cytogenetically. Fourteen DCs were altered by other chromosomal changes. In conclusion, karyotypes with DCs are usually very complex, and we have shown that they often contain more than one DC, which can be missed with conventional or mFISH methods. Our study indicates an association between number of DCs in karyotype and very short survival of patients.

  2. The Transient Inactivation of the Master Cell Cycle Phosphatase Cdc14 Causes Genomic Instability in Diploid Cells of Saccharomyces cerevisiae

    PubMed Central

    Quevedo, Oliver; Ramos-Pérez, Cristina; Petes, Thomas D.; Machín, Félix

    2015-01-01

    Genomic instability is a common feature found in cancer cells . Accordingly, many tumor suppressor genes identified in familiar cancer syndromes are involved in the maintenance of the stability of the genome during every cell division and are commonly referred to as caretakers. Inactivating mutations and epigenetic silencing of caretakers are thought to be the most important mechanisms that explain cancer-related genome instability. However, little is known of whether transient inactivation of caretaker proteins could trigger genome instability and, if so, what types of instability would occur. In this work, we show that a brief and reversible inactivation, during just one cell cycle, of the key phosphatase Cdc14 in the model organism Saccharomyces cerevisiae is enough to result in diploid cells with multiple gross chromosomal rearrangements and changes in ploidy. Interestingly, we observed that such transient loss yields a characteristic fingerprint whereby trisomies are often found in small-sized chromosomes, and gross chromosome rearrangements, often associated with concomitant loss of heterozygosity, are detected mainly on the ribosomal DNA-bearing chromosome XII. Taking into account the key role of Cdc14 in preventing anaphase bridges, resetting replication origins, and controlling spindle dynamics in a well-defined window within anaphase, we speculate that the transient loss of Cdc14 activity causes cells to go through a single mitotic catastrophe with irreversible consequences for the genome stability of the progeny. PMID:25971663

  3. The Transient Inactivation of the Master Cell Cycle Phosphatase Cdc14 Causes Genomic Instability in Diploid Cells of Saccharomyces cerevisiae.

    PubMed

    Quevedo, Oliver; Ramos-Pérez, Cristina; Petes, Thomas D; Machín, Félix

    2015-07-01

    Genomic instability is a common feature found in cancer cells . Accordingly, many tumor suppressor genes identified in familiar cancer syndromes are involved in the maintenance of the stability of the genome during every cell division and are commonly referred to as caretakers. Inactivating mutations and epigenetic silencing of caretakers are thought to be the most important mechanisms that explain cancer-related genome instability. However, little is known of whether transient inactivation of caretaker proteins could trigger genome instability and, if so, what types of instability would occur. In this work, we show that a brief and reversible inactivation, during just one cell cycle, of the key phosphatase Cdc14 in the model organism Saccharomyces cerevisiae is enough to result in diploid cells with multiple gross chromosomal rearrangements and changes in ploidy. Interestingly, we observed that such transient loss yields a characteristic fingerprint whereby trisomies are often found in small-sized chromosomes, and gross chromosome rearrangements, often associated with concomitant loss of heterozygosity, are detected mainly on the ribosomal DNA-bearing chromosome XII. Taking into account the key role of Cdc14 in preventing anaphase bridges, resetting replication origins, and controlling spindle dynamics in a well-defined window within anaphase, we speculate that the transient loss of Cdc14 activity causes cells to go through a single mitotic catastrophe with irreversible consequences for the genome stability of the progeny.

  4. The XXXXY Chromosome Anomaly

    PubMed Central

    Zaleski, Witold A.; Houston, C. Stuart; Pozsonyi, J.; Ying, K. L.

    1966-01-01

    The majority of abnormal sex chromosome complexes in the male have been considered to be variants of Klinefelter's syndrome but an exception should probably be made in the case of the XXXXY individual who has distinctive phenotypic features. Clinical, radiological and cytological data on three new cases of XXXXY syndrome are presented and 30 cases from the literature are reviewed. In many cases the published clinical and radiological data were supplemented and re-evaluated. Mental retardation, usually severe, was present in all cases. Typical facies was observed in many; clinodactyly of the fifth finger was seen in nearly all. Radiological examination revealed abnormalities in the elbows and wrists in all the 19 personally evaluated cases, and other skeletal anomalies were very frequent. Cryptorchism is very common and absence of Leydig's cells may differentiate the XXXXY chromosome anomaly from polysomic variants of Klinefelter's syndrome. The relationship of this syndrome to Klinefelter's syndrome and to Down's syndrome is discussed. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6Fig. 7Fig. 8Fig. 9Fig. 10Fig. 11Fig. 12Fig. 13Fig. 14Fig. 15 PMID:4222822

  5. Msh2 deficiency leads to chromosomal abnormalities, centrosome amplification, and telomere capping defect

    SciTech Connect

    Wang, Yisong; Liu, Yie

    2006-01-01

    Msh2 is a key mammalian DNA mismatch repair (MMR) gene and mutations or deficiencies in mammalian Msh2 gene result in microsatellite instability (MSI+) and the development of cancer. Here, we report that primary mouse embryonic fibroblasts (MEFs) deficient in the murine MMR gene Msh2 (Msh2-/-) showed a significant increase in chromosome aneuploidy, centrosome amplification, and defective mitotic spindle organization and unequal chromosome segregation. Although Msh2-/- mouse tissues or primary MEFs had no apparent change in telomerase activity, telomere length, or recombination at telomeres, Msh2-/- MEFs showed an increase in chromosome end-to-end fusions or chromosome ends without detectable telomeric DNA. These data suggest that MSH2 helps to maintain genomic stability through the regulation of the centrosome and normal telomere capping in vivo and that defects in MMR can contribute to oncogenesis through multiple pathways.

  6. Ring chromosome 13: lack of distinct syndromes based on different breakpoints on 13q.

    PubMed Central

    Brandt, C A; Hertz, J M; Petersen, M B; Vogel, F; Noer, H; Mikkelsen, M

    1992-01-01

    A stillborn male child with anencephaly and multiple malformations was found to have the karyotype 46,XY,r(13) (p11q21.1). The breakpoint at 13q21.1, determined by high resolution banding, is the most proximal breakpoint ever reported in patients with ring chromosome 13. In situ hybridisation with the probe L1.26 confirmed the derivation from chromosome 13 and DNA polymorphism analysis showed maternal origin of the ring chromosome. Our results, together with a review of previous reports of cases with ring chromosome 13 with identified breakpoints, could neither support the theory of distinct clinical syndromes based on different breakpoints on 13q nor correlate the severity of symptoms with instability of the ring. Images PMID:1433229

  7. Analysis of chromosomal aberrations and recombination by allelic bias in RNA-Seq

    PubMed Central

    Weissbein, Uri; Schachter, Maya; Egli, Dieter; Benvenisty, Nissim

    2016-01-01

    Genomic instability has profound effects on cellular phenotypes. Studies have shown that pluripotent cells with abnormal karyotypes may grow faster, differentiate less and become more resistance to apoptosis. Previously, we showed that microarray gene expression profiles can be utilized for the analysis of chromosomal aberrations by comparing gene expression levels between normal and aneuploid samples. Here we adopted this method for RNA-Seq data and present eSNP-Karyotyping for the detection of chromosomal aberrations, based on measuring the ratio of expression between the two alleles. We demonstrate its ability to detect chromosomal gains and losses in pluripotent cells and their derivatives, as well as meiotic recombination patterns. This method is advantageous since it does not require matched diploid samples for comparison, is less sensitive to global expression changes caused by the aberration and utilizes already available gene expression profiles to determine chromosomal aberrations. PMID:27385103

  8. Chromosome Connections: Compelling Clues to Common Ancestry

    ERIC Educational Resources Information Center

    Flammer, Larry

    2013-01-01

    Students compare banding patterns on hominid chromosomes and see striking evidence of their common ancestry. To test this, human chromosome no. 2 is matched with two shorter chimpanzee chromosomes, leading to the hypothesis that human chromosome 2 resulted from the fusion of the two shorter chromosomes. Students test that hypothesis by looking for…

  9. Chromosomal rearrangement interferes with meiotic X chromosome inactivation.

    PubMed

    Homolka, David; Ivanek, Robert; Capkova, Jana; Jansa, Petr; Forejt, Jiri

    2007-10-01

    Heterozygosity for certain mouse and human chromosomal rearrangements is characterized by the incomplete meiotic synapsis of rearranged chromosomes, by their colocalization with the XY body in primary spermatocytes, and by male-limited sterility. Previously, we argued that such X-autosomal associations could interfere with meiotic sex chromosome inactivation. Recently, supporting evidence has reported modifications of histones in rearranged chromosomes by a process called the meiotic silencing of unsynapsed chromatin (MSUC). Here, we report on the transcriptional down-regulation of genes within the unsynapsed region of the rearranged mouse chromosome 17, and on the subsequent disturbance of X chromosome inactivation. The partial transcriptional suppression of genes in the unsynapsed chromatin was most prominent prior to the mid-pachytene stage of primary spermatocytes. Later, during the mid-late pachytene, the rearranged autosomes colocalized with the XY body, and the X chromosome failed to undergo proper transcriptional silencing. Our findings provide direct evidence on the MSUC acting at the mRNA level, and implicate that autosomal asynapsis in meiosis may cause male sterility by interfering with meiotic sex chromosome inactivation.

  10. Distance between homologous chromosomes results from chromosome positioning constraints.

    PubMed

    Heride, Claire; Ricoul, Michelle; Kiêu, Kien; von Hase, Johann; Guillemot, Vincent; Cremer, Christoph; Dubrana, Karine; Sabatier, Laure

    2010-12-01

    The organization of chromosomes is important for various biological processes and is involved in the formation of rearrangements often observed in cancer. In mammals, chromosomes are organized in territories that are radially positioned in the nucleus. However, it remains unclear whether chromosomes are organized relative to each other. Here, we examine the nuclear arrangement of 10 chromosomes in human epithelial cancer cells by three-dimensional FISH analysis. We show that their radial position correlates with the ratio of their gene density to chromosome size. We also observe that inter-homologue distances are generally larger than inter-heterologue distances. Using numerical simulations taking radial position constraints into account, we demonstrate that, for some chromosomes, radial position is enough to justify the inter-homologue distance, whereas for others additional constraints are involved. Among these constraints, we propose that nucleolar organizer regions participate in the internal positioning of the acrocentric chromosome HSA21, possibly through interactions with nucleoli. Maintaining distance between homologous chromosomes in human cells could participate in regulating genome stability and gene expression, both mechanisms that are key players in tumorigenesis.

  11. Genetic mapping of the pericentric region of human chromosome 10

    SciTech Connect

    Schuster, M.K.

    1994-12-31

    A genetic linkage map of the pericentric region of human chromosome 10 has been generated to better define the region containing the gene causing the multiple endocrine neoplasia type 2A (MEN-2A) disease, earlier limited to a 15.1 cM interval. 6 new markers have been added to this interval, where the markers are separated by an average of 2.65 cM. These new markers were used to evaluate three large MEN-3A families and did not reveal any recombinants that could better define the MEN-2A containing region. These families were used, however, to determine risks for individuals who were potential gene carriers. Six individuals were determined to be gene carriers and one individual, who had a thyroidectomy based on clinical testing results, was determined not to be a gene carrier. These results suggest that conventional clinical criteria need to be altered to include results from genetic testing. Since the map was generated, the RET proto-oncogene has been identified as the MEN-2A disease gene. The markers have been used to analyze familial and sporadic medullary thryoid carcinomas (MTCs). This analysis has determined one tumor (NL5) has retained heterozygosity for a limited region encompassing the RET region but has lost heterozygosity at all flanking loci on chromosome 10 tested, losing the allele which segregated with MEN-2A, suggesting a chromosomal rearrangement involving the RET locus. An analysis of sporadic and familial allelic instability with several dinucleotide repeat markers from chromosome 10 as well as other chromosomes. Similar results have been observed in colorectal cancer involving mutation in a mismatch repair enzyme (hMSH2). It is difficult to envision a direct role for the RET proto-oncogene in genetic instability, as seen in the colorectal tumors. Consequently, the genetic instability seen in the MEN-2A tumors, perhaps caused by mutations in the hMSH2 gene, may be the result of secondary effects developing independently from RET in MEN-2A tumors.

  12. The inactive X chromosome is epigenetically unstable and transcriptionally labile in breast cancer

    PubMed Central

    Chaligné, Ronan; Popova, Tatiana; Mendoza-Parra, Marco-Antonio; Saleem, Mohamed-Ashick M.; Gentien, David; Ban, Kristen; Piolot, Tristan; Leroy, Olivier; Mariani, Odette

    2015-01-01

    Disappearance of the Barr body is considered a hallmark of cancer, although whether this corresponds to genetic loss or to epigenetic instability and transcriptional reactivation is unclear. Here we show that breast tumors and cell lines frequently display major epigenetic instability of the inactive X chromosome, with highly abnormal 3D nuclear organization and global perturbations of heterochromatin, including gain of euchromatic marks and aberrant distributions of repressive marks such as H3K27me3 and promoter DNA methylation. Genome-wide profiling of chromatin and transcription reveal modified epigenomic landscapes in cancer cells and a significant degree of aberrant gene activity from the inactive X chromosome, including several genes involved in cancer promotion. We demonstrate that many of these genes are aberrantly reactivated in primary breast tumors, and we further demonstrate that epigenetic instability of the inactive X can lead to perturbed dosage of X-linked factors. Taken together, our study provides the first integrated analysis of the inactive X chromosome in the context of breast cancer and establishes that epigenetic erosion of the inactive X can lead to the disappearance of the Barr body in breast cancer cells. This work offers new insights and opens up the possibility of exploiting the inactive X chromosome as an epigenetic biomarker at the molecular and cytological levels in cancer. PMID:25653311

  13. A DNA unwinding element and an ARS consensus comprise a replication origin within a yeast chromosome.

    PubMed Central

    Huang, R Y; Kowalski, D

    1993-01-01

    We have defined a replication origin, ORI305, within chromosome III of Saccharomyces cerevisiae by means of mutational analysis. cis-acting elements required for origin activity in the chromosome, as assayed by two-dimensional gel electrophoresis of replication intermediates, are the same as those required for the function of an autonomously replicating sequence, ARS305, in a plasmid. Essential elements include (i) an 11 bp sequence that is a near match to the ARS consensus and (ii) a broad sequence directly 3' to the consensus near match. Origin function is inactivated by point mutations in the essential near match sequence, suggesting that the sequence contributes to specifying the origin in the chromosome. Other consensus near matches with different sequences are present but are not required. The essential 3'-flanking sequence exhibits DNA helical instability and is sensitive to deletion mutations that stabilize the DNA helix. The wild-type 3'-flanking sequence can be functionally substituted by dissimilar sequences that also exhibit helical instability. The requirement for DNA helical instability indicates that the essential 3'-flanking sequence serves as a DNA unwinding element in the chromosome. Images PMID:8223462

  14. Translational compensation of genomic instability in neuroblastoma

    PubMed Central

    Dassi, Erik; Greco, Valentina; Sidarovich, Viktoryia; Zuccotti, Paola; Arseni, Natalia; Scaruffi, Paola; Paolo Tonini, Gian; Quattrone, Alessandro

    2015-01-01

    Cancer-associated gene expression imbalances are conventionally studied at the genomic, epigenomic and transcriptomic levels. Given the relevance of translational control in determining cell phenotypes, we evaluated the translatome, i.e., the transcriptome engaged in translation, as a descriptor of the effects of genetic instability in cancer. We performed this evaluation in high-risk neuroblastomas, which are characterized by a low frequency of point mutations or known cancer-driving genes and by the presence of several segmental chromosomal aberrations that produce gene-copy imbalances that guide aggressiveness. We thus integrated genome, transcriptome, translatome and miRome profiles in a representative panel of high-risk neuroblastoma cell lines. We identified a number of genes whose genomic imbalance was corrected by compensatory adaptations in translational efficiency. The transcriptomic level of these genes was predictive of poor prognosis in more than half of cases, and the genomic imbalances found in their loci were shared by 27 other tumor types. This homeostatic process is also not limited to copy number-altered genes, as we showed the translational stoichiometric rebalance of histone genes. We suggest that the translational buffering of fluctuations in these dose-sensitive transcripts is a potential driving process of neuroblastoma evolution. PMID:26399178

  15. Prognostic Factors in Childhood Leukemia (ALL or AML)

    MedlinePlus

    ... Diagnosis, and Types Prognostic Factors in Childhood Leukemia (ALL or AML) Certain factors that can affect a ... myelogenous leukemia (AML). Prognostic factors for children with ALL Children with ALL are often divided into risk ...

  16. Libration-driven multipolar instabilities

    NASA Astrophysics Data System (ADS)

    Cébron, D.; Vantieghem, S.; Herreman, W.

    2014-01-01

    We consider rotating flows in non-axisymmetric enclosures that are driven by libration, i.e. by a small periodic modulation of the rotation rate. Thanks to its simplicity, this model is relevant to various contexts, from industrial containers (with small oscillations of the rotation rate) to fluid layers of terrestial planets (with length-of-day variations). Assuming a multipolar $n$-fold boundary deformation, we first obtain the two-dimensional basic flow. We then perform a short-wavelength local stability analysis of the basic flow, showing that an instability may occur in three dimensions. We christen it the Libration Driven Multipolar Instability (LDMI). The growth rates of the LDMI are computed by a Floquet analysis in a systematic way, and compared to analytical expressions obtained by perturbation methods. We then focus on the simplest geometry allowing the LDMI, a librating deformed cylinder. To take into account viscous and confinement effects, we perform a global stability analysis, which shows that the LDMI results from a parametric resonance of inertial modes. Performing numerical simulations of this librating cylinder, we confirm that the basic flow is indeed established and report the first numerical evidence of the LDMI. Numerical results, in excellent agreement with the stability results, are used to explore the non-linear regime of the instability (amplitude and viscous dissipation of the driven flow). We finally provide an example of LDMI in a deformed spherical container to show that the instability mechanism is generic. Our results show that the previously studied libration driven elliptical instability simply corresponds to the particular case $n=2$ of a wider class of instabilities. Summarizing, this work shows that any oscillating non-axisymmetric container in rotation may excite intermittent, space-filling LDMI flows, and this instability should thus be easy to observe experimentally.

  17. Advances in plant chromosome genomics.

    PubMed

    Doležel, Jaroslav; Vrána, Jan; Cápal, Petr; Kubaláková, Marie; Burešová, Veronika; Simková, Hana

    2014-01-01

    Next generation sequencing (NGS) is revolutionizing genomics and is providing novel insights into genome organization, evolution and function. The number of plant genomes targeted for sequencing is rising. For the moment, however, the acquisition of full genome sequences in large genome species remains difficult, largely because the short reads produced by NGS platforms are inadequate to cope with repeat-rich DNA, which forms a large part of these genomes. The problem of sequence redundancy is compounded in polyploids, which dominate the plant kingdom. An approach to overcoming some of these difficulties is to reduce the full nuclear genome to its individual chromosomes using flow-sorting. The DNA acquired in this way has proven to be suitable for many applications, including PCR-based physical mapping, in situ hybridization, forming DNA arrays, the development of DNA markers, the construction of BAC libraries and positional cloning. Coupling chromosome sorting with NGS offers opportunities for the study of genome organization at the single chromosomal level, for comparative analyses between related species and for the validation of whole genome assemblies. Apart from the primary aim of reducing the complexity of the template, taking a chromosome-based approach enables independent teams to work in parallel, each tasked with the analysis of a different chromosome(s). Given that the number of plant species tractable for chromosome sorting is increasing, the likelihood is that chromosome genomics - the marriage of cytology and genomics - will make a significant contribution to the field of plant genetics.

  18. Visualization of early chromosome condensation

    PubMed Central

    Kireeva, Natashe; Lakonishok, Margot; Kireev, Igor; Hirano, Tatsuya; Belmont, Andrew S.

    2004-01-01

    Current models of mitotic chromosome structure are based largely on the examination of maximally condensed metaphase chromosomes. Here, we test these models by correlating the distribution of two scaffold components with the appearance of prophase chromosome folding intermediates. We confirm an axial distribution of topoisomerase IIα and the condensin subunit, structural maintenance of chromosomes 2 (SMC2), in unextracted metaphase chromosomes, with SMC2 localizing to a 150–200-nm-diameter central core. In contrast to predictions of radial loop/scaffold models, this axial distribution does not appear until late prophase, after formation of uniformly condensed middle prophase chromosomes. Instead, SMC2 associates throughout early and middle prophase chromatids, frequently forming foci over the chromosome exterior. Early prophase condensation occurs through folding of large-scale chromatin fibers into condensed masses. These resolve into linear, 200–300-nm-diameter middle prophase chromatids that double in diameter by late prophase. We propose a unified model of chromosome structure in which hierarchical levels of chromatin folding are stabilized late in mitosis by an axial “glue.” PMID:15353545

  19. Cohesin in determining chromosome architecture

    SciTech Connect

    Haering, Christian H.; Jessberger, Rolf

    2012-07-15

    Cells use ring-like structured protein complexes for various tasks in DNA dynamics. The tripartite cohesin ring is particularly suited to determine chromosome architecture, for it is large and dynamic, may acquire different forms, and is involved in several distinct nuclear processes. This review focuses on cohesin's role in structuring chromosomes during mitotic and meiotic cell divisions and during interphase.

  20. Organization of the bacterial chromosome.

    PubMed Central

    Krawiec, S; Riley, M

    1990-01-01

    Recent progress in studies on the bacterial chromosome is summarized. Although the greatest amount of information comes from studies on Escherichia coli, reports on studies of many other bacteria are also included. A compilation of the sizes of chromosomal DNAs as determined by pulsed-field electrophoresis is given, as well as a discussion of factors that affect gene dosage, including redundancy of chromosomes on the one hand and inactivation of chromosomes on the other hand. The distinction between a large plasmid and a second chromosome is discussed. Recent information on repeated sequences and chromosomal rearrangements is presented. The growing understanding of limitations on the rearrangements that can be tolerated by bacteria and those that cannot is summarized, and the sensitive region flanking the terminator loci is described. Sources and types of genetic variation in bacteria are listed, from simple single nucleotide mutations to intragenic and intergenic recombinations. A model depicting the dynamics of the evolution and genetic activity of the bacterial chromosome is described which entails acquisition by recombination of clonal segments within the chromosome. The model is consistent with the existence of only a few genetic types of E. coli worldwide. Finally, there is a summary of recent reports on lateral genetic exchange across great taxonomic distances, yet another source of genetic variation and innovation. PMID:2087223

  1. Prognosis Research Strategy (PROGRESS) 2: prognostic factor research.

    PubMed

    Riley, Richard D; Hayden, Jill A; Steyerberg, Ewout W; Moons, Karel G M; Abrams, Keith; Kyzas, Panayiotis A; Malats, Núria; Briggs, Andrew; Schroter, Sara; Altman, Douglas G; Hemingway, Harry

    2013-01-01

    Prognostic factor research aims to identify factors associated with subsequent clinical outcome in people with a particular disease or health condition. In this article, the second in the PROGRESS series, the authors discuss the role of prognostic factors in current clinical practice, randomised trials, and developing new interventions, and explain why and how prognostic factor research should be improved.

  2. Microsatellite instability confounds engraftment analysis of hematopoietic stem-cell transplantation.

    PubMed

    Tseng, Li-Hui; Tang, Jih-Luh; Haley, Lisa; Beierl, Katie; Gocke, Christopher D; Eshleman, James R; Lin, Ming-Tseh

    2014-07-01

    Polymorphic short tandem-repeat, or microsatellite, loci have been widely used to analyze chimerism status after allogeneic hematopoietic stem-cell transplantation. In molecular diagnostic laboratories, it is recommended to calculate mixed chimerism for at least 2 informative loci and to avoid microsatellite loci on chromosomes with copy number changes. In this report, we show that microsatellite instability observed in 2 patients with acute leukemia may confound chimerism analysis. Interpretation errors may occur even if 2 to 3 loci are analyzed because of length variation in multiple microsatellite loci. Although microsatellite loci with length variation should not be selected for chimerism analysis, the presence of microsatellite instability, like copy number alteration because of aberrant chromosomes, provides evidence of recurrent or residual cancer cells after hematopoietic stem-cell transplantation.

  3. Methyl-CpG-binding domain sequencing reveals a prognostic methylation signature in neuroblastoma.

    PubMed

    Decock, Anneleen; Ongenaert, Maté; Cannoodt, Robrecht; Verniers, Kimberly; De Wilde, Bram; Laureys, Geneviève; Van Roy, Nadine; Berbegall, Ana P; Bienertova-Vasku, Julie; Bown, Nick; Clément, Nathalie; Combaret, Valérie; Haber, Michelle; Hoyoux, Claire; Murray, Jayne; Noguera, Rosa; Pierron, Gaelle; Schleiermacher, Gudrun; Schulte, Johannes H; Stallings, Ray L; Tweddle, Deborah A; De Preter, Katleen; Speleman, Frank; Vandesompele, Jo

    2016-01-12

    Accurate assessment of neuroblastoma outcome prediction remains challenging. Therefore, this study aims at establishing novel prognostic tumor DNA methylation biomarkers. In total, 396 low- and high-risk primary tumors were analyzed, of which 87 were profiled using methyl-CpG-binding domain (MBD) sequencing for differential methylation analysis between prognostic patient groups. Subsequently, methylation-specific PCR (MSP) assays were developed for 78 top-ranking differentially methylated regions and tested on two independent cohorts of 132 and 177 samples, respectively. Further, a new statistical framework was used to identify a robust set of MSP assays of which the methylation score (i.e. the percentage of methylated assays) allows accurate outcome prediction. Survival analyses were performed on the individual target level, as well as on the combined multimarker signature. As a result of the differential DNA methylation assessment by MBD sequencing, 58 of the 78 MSP assays were designed in regions previously unexplored in neuroblastoma, and 36 are located in non-promoter or non-coding regions. In total, 5 individual MSP assays (located in CCDC177, NXPH1, lnc-MRPL3-2, lnc-TREX1-1 and one on a region from chromosome 8 with no further annotation) predict event-free survival and 4 additional assays (located in SPRED3, TNFAIP2, NPM2 and CYYR1) also predict overall survival. Furthermore, a robust 58-marker methylation signature predicting overall and event-free survival was established. In conclusion, this study encompasses the largest DNA methylation biomarker study in neuroblastoma so far. We identified and independently validated several novel prognostic biomarkers, as well as a prognostic 58-marker methylation signature.

  4. Methyl-CpG-binding domain sequencing reveals a prognostic methylation signature in neuroblastoma

    PubMed Central

    Decock, Anneleen; Ongenaert, Maté; Cannoodt, Robrecht; Verniers, Kimberly; De Wilde, Bram; Laureys, Geneviève; Van Roy, Nadine; Berbegall, Ana P.; Bienertova-Vasku, Julie; Bown, Nick; Clément, Nathalie; Combaret, Valérie; Haber, Michelle; Hoyoux, Claire; Murray, Jayne; Noguera, Rosa; Pierron, Gaelle; Schleiermacher, Gudrun; Schulte, Johannes H.; Stallings, Ray L.; Tweddle, Deborah A.; De Preter, Katleen; Speleman, Frank; Vandesompele, Jo

    2016-01-01

    Accurate assessment of neuroblastoma outcome prediction remains challenging. Therefore, this study aims at establishing novel prognostic tumor DNA methylation biomarkers. In total, 396 low- and high-risk primary tumors were analyzed, of which 87 were profiled using methyl-CpG-binding domain (MBD) sequencing for differential methylation analysis between prognostic patient groups. Subsequently, methylation-specific PCR (MSP) assays were developed for 78 top-ranking differentially methylated regions and tested on two independent cohorts of 132 and 177 samples, respectively. Further, a new statistical framework was used to identify a robust set of MSP assays of which the methylation score (i.e. the percentage of methylated assays) allows accurate outcome prediction. Survival analyses were performed on the individual target level, as well as on the combined multimarker signature. As a result of the differential DNA methylation assessment by MBD sequencing, 58 of the 78 MSP assays were designed in regions previously unexplored in neuroblastoma, and 36 are located in non-promoter or non-coding regions. In total, 5 individual MSP assays (located in CCDC177, NXPH1, lnc-MRPL3-2, lnc-TREX1-1 and one on a region from chromosome 8 with no further annotation) predict event-free survival and 4 additional assays (located in SPRED3, TNFAIP2, NPM2 and CYYR1) also predict overall survival. Furthermore, a robust 58-marker methylation signature predicting overall and event-free survival was established. In conclusion, this study encompasses the largest DNA methylation biomarker study in neuroblastoma so far. We identified and independently validated several novel prognostic biomarkers, as well as a prognostic 58-marker methylation signature. PMID:26646589

  5. Evolving transcriptomic fingerprint based on genome‐wide data as prognostic tools in prostate cancer

    PubMed Central

    Schliekelman, Mark; Shin, Heesun; Erho, Nicholas; Davicioni, Elai

    2015-01-01

    Background Information Prostate cancer (PCa) is a common disease but only a small subset of patients are at risk of developing metastasis and lethal disease, and identifying which patients will progress is challenging because of the heterogeneity underlying tumour progression. Understanding this heterogeneity at the molecular level and the resulting clinical impact is a critical step necessary for risk stratification. Defining genomic fingerprint elucidates molecular variation and may improve PCa risk stratification, providing more accurate prognostic information of tumour aggressiveness (or lethality) for prognostic biomarker development. Therefore, we explored transcriptomic differences between patients with indolent disease outcome and patients who developed metastasis post‐radical prostatectomy using genome‐wide expression data in the post radical prostatectomy clinical space before metastatic spread. Results Based on differential expression analysis, patients with adverse pathological findings who are at higher risk of developing metastasis have a distinct transcriptomic fingerprint that can be detected on surgically removed prostate specimens several years before metastasis detection. Nearly half of the transcriptomic fingerprint features were non‐coding RNA highlighting their pivotal role in PCa progression. Protein‐coding RNA features in the fingerprint are involved in multiple pathways including cell cycle, chromosome structure maintenance and cytoskeleton organisation. The metastatic transcriptomic fingerprint was determined in independent cohorts verifying the association between the fingerprint and metastatic patients. Further, the fingerprint was confirmed in metastasis lesions demonstrating that the fingerprint represents early metastatic transcriptomic changes, suggesting its utility as a prognostic tool to predict metastasis and provide clinical value in the early radical prostatectomy setting. Conclusions Here, we show that transcriptomic

  6. Genetics Home Reference: ring chromosome 20 syndrome

    MedlinePlus

    ... Home Health Conditions ring chromosome 20 syndrome ring chromosome 20 syndrome Enable Javascript to view the expand/ ... Download PDF Open All Close All Description Ring chromosome 20 syndrome is a condition that affects the ...

  7. Genetics Home Reference: ring chromosome 14 syndrome

    MedlinePlus

    ... Home Health Conditions ring chromosome 14 syndrome ring chromosome 14 syndrome Enable Javascript to view the expand/ ... Download PDF Open All Close All Description Ring chromosome 14 syndrome is a condition characterized by seizures ...

  8. Bacterial chromosome organization and segregation

    PubMed Central

    Badrinarayanan, Anjana; Le, Tung BK; Laub, Michael T

    2016-01-01

    If fully stretched out, a typical bacterial chromosome would be nearly one millimeter long, or approximately 1000 times the length of a cell. Not only must cells massively compact their genetic material, but they must also organize their DNA in a manner that is compatible with a range of cellular processes, including DNA replication, DNA repair, homologous recombination, and horizontal gene transfer. Recent work, driven in part by technological advances, has begun to reveal the general principles of chromosome organization in bacteria. Here, drawing on studies of many different organisms, we review the emerging picture of how bacterial chromosomes are structured at multiple length-scales, highlighting the functions of various DNA-binding proteins and impact of physical forces. Additionally, we discuss the spatial dynamics of chromosomes, particularly during their segregation to daughter cells. Although there has been tremendous progress, we also highlight gaps that remain in understanding chromosome organization and segregation. PMID:26566111

  9. Chromosome choreography: the meiotic ballet.

    PubMed

    Page, Scott L; Hawley, R Scott

    2003-08-08

    The separation of homologous chromosomes during meiosis in eukaryotes is the physical basis of Mendelian inheritance. The core of the meiotic process is a specialized nuclear division (meiosis I) in which homologs pair with each other, recombine, and then segregate from each other. The processes of chromosome alignment and pairing allow for homolog recognition. Reciprocal meiotic recombination ensures meiotic chromosome segregation by converting sister chromatid cohesion into mechanisms that hold homologous chromosomes together. Finally, the ability of sister kinetochores to orient to a single pole at metaphase I allows the separation of homologs to two different daughter cells. Failures to properly accomplish this elegant chromosome dance result in aneuploidy, a major cause of miscarriage and birth defects in human beings.

  10. Microsatellite instability and loss of heterozygosity in gastric cancer

    SciTech Connect

    Schneider, B.G.; Pulitzer, D.R.; Moehlmann, R.D.

    1994-09-01

    In order to detect regions of DNA containing tumor suppressor genes involved in the development of gastric cancer, we evaluated loss of heterozygosity (LOH) in 78 gastric adenocarcinomas. A total of 46 microsatellite markers were employed, which detected at least one site per arm of each autosome in the human genome, including several markers linked to known tumor suppressor genes (TP53, APC, DCC, RB1, and BRCA1). We detected elevated rates of LOH at D3S1478 on chromosome 3p21 (44%, or 22 of 50 cases), at D12S78 at 12q14q24.33 (39%), and 37% at D9S157 on 9p, three sites not previously known to be affected in gastric cancer. Another locus on chromosome 12q, D12S97, showed LOH in 40% of informative cases. LOH was detected on chromosome 17p near TP53 in 66% of informative cases (23 of 35). Microsatellite instability (MI) was observed in 22% of the cancers. Tumors varied greatly in percentage of sites exhibiting MI, from 0% to 77% of sites tested. These findings expand the description of the genetic lesions occurring in gastric cancer.

  11. Schizophrenia and chromosomal deletions

    SciTech Connect

    Lindsay, E.A.; Baldini, A.; Morris, M. A.

    1995-06-01

    Recent genetic linkage analysis studies have suggested the presence of a schizophrenia locus on the chromosomal region 22q11-q13. Schizophrenia has also been frequently observed in patients affected with velo-cardio-facial syndrome (VCFS), a disorder frequently associated with deletions within 22q11.1. It has been hypothesized that psychosis in VCFS may be due to deletion of the catechol-o-methyl transferase gene. Prompted by these observations, we screened for 22q11 deletions in a population of 100 schizophrenics selected from the Maryland Epidemiological Sample. Our results show that there are schizophrenic patients carrying a deletion of 22q11.1 and a mild VCFS phenotype that might remain unrecognized. These findings should encourage a search for a schizophrenia-susceptibility gene within the deleted region and alert those in clinical practice to the possible presence of a mild VCFS phenotype associated with schizophrenia. 9 refs.

  12. Chromosome fragility in New Zealand black mice: effect of ultraviolet and gamma radiations on fetal fibroblasts in vitro

    SciTech Connect

    Reddy, A.L.; Fialkow, P.J.

    1980-04-01

    The sensitivity of fibroblasts cultured from New Zealand Black (NZB) and BALB/c mouse fetuses to uv and gamma radiations was tested with two methods: (1) colony-forming ability and (2) chromosome abnormalities. When compared with BALB/c cells, NZB cells had reduced colony-forming ability and increased chromosome abnormalities after uv irradiation. However, no differences were seen in colony formation or frequency of chromosome abnormalities between NZB and BALB/c cells after exposure to gamma radiation. This apparent uv specificity strengthens the suggestion that NZB mice might be used as a model to study the relationship between chromosome abnormalities and cancer in human syndromes such as xeroderma pigmentosum, which is characterized by chromosome instability.

  13. Molecular Cytogenetic Approach to Characterize Novel and Cryptic Chromosome Abnormalities in Childhood Myeloid Malignances of Fanconi Anemia.

    PubMed

    Borges, Maria L R; Capela de Matos, Roberto R; Amaral, Bethânia D A Silva; Soares-Ventura, Eliane M; Leite, Edinalva P; Silva, Mariluze O D; Cornélio, Maria T M Nogueira; Silva, Maria L M; Liehr, Thomas; Marques-Salles, Terezinha D J

    2017-03-01

    Myeloid malignancies can be either primary or secondary, whether or not a specific cause can be determined. Fanconi anemia (FA), a rare constitutional bone marrow failure, usually presents an increased possibility of clonal evolution, due to the increase in chromosomal instability, TP53 activation, and cell death. The evolution of FA may include aplastic anemia by the progressive failure of the bone marrow and myelod neoplasias, such as acute myeloid leukemia and myelodysplastic syndrome. Chromosome abnormalities, particularly of chromosomes, 1, 3, and 7, during the aplastic phase of the disease are predictive of evolution to acute myeloid leukemia/myelodysplastic syndrome. Cytogenetic studies are indispensable to characterize chromosome abnormalities, and thus an important part of the clinical management, and for planning of therapeutic interventions. Here, clinical data and outcomes of 4 FA, 3 of them with myeloid malignances and 1 asymptomatic, and detailed characterization of their chromosome abnormalities using cytogenetics techniques are described.

  14. Advanced Ground Systems Maintenance Prognostics Project

    NASA Technical Reports Server (NTRS)

    Harp, Janicce Leshay

    2014-01-01

    The project implements prognostics capabilities to predict when a component, system or subsystem will no longer meet desired functional or performance criteria, called the "end of life." The capability also provides an assessment of the "remaining useful life" of a hardware component.

  15. Requirements Flowdown for Prognostics and Health Management

    NASA Technical Reports Server (NTRS)

    Goebel, Kai; Saxena, Abhinav; Roychoudhury, Indranil; Celaya, Jose R.; Saha, Bhaskar; Saha, Sankalita

    2012-01-01

    Prognostics and Health Management (PHM) principles have considerable promise to change the game of lifecycle cost of engineering systems at high safety levels by providing a reliable estimate of future system states. This estimate is a key for planning and decision making in an operational setting. While technology solutions have made considerable advances, the tie-in into the systems engineering process is lagging behind, which delays fielding of PHM-enabled systems. The derivation of specifications from high level requirements for algorithm performance to ensure quality predictions is not well developed. From an engineering perspective some key parameters driving the requirements for prognostics performance include: (1) maximum allowable Probability of Failure (PoF) of the prognostic system to bound the risk of losing an asset, (2) tolerable limits on proactive maintenance to minimize missed opportunity of asset usage, (3) lead time to specify the amount of advanced warning needed for actionable decisions, and (4) required confidence to specify when prognosis is sufficiently good to be used. This paper takes a systems engineering view towards the requirements specification process and presents a method for the flowdown process. A case study based on an electric Unmanned Aerial Vehicle (e-UAV) scenario demonstrates how top level requirements for performance, cost, and safety flow down to the health management level and specify quantitative requirements for prognostic algorithm performance.

  16. Prognostic Analysis of the Tactical Quiet Generator

    SciTech Connect

    Hively, Lee M

    2008-09-01

    The U.S. Army needs prognostic analysis of mission-critical equipment to enable condition-based maintenance before failure. ORNL has developed and patented prognostic technology that quantifies condition change from noisy, multi-channel, time-serial data. This report describes an initial application of ORNL's prognostic technology to the Army's Tactical Quiet Generator (TQG), which is designed to operate continuously at 10 kW. Less-than-full power operation causes unburned fuel to accumulate on internal components, thereby degrading operation and eventually leading to failure. The first objective of this work was identification of easily-acquired, process-indicative data. Two types of appropriate data were identified, namely output-electrical current and voltage, plus tri-axial acceleration (vibration). The second objective of this work was data quality analysis to avoid the garbage-in-garbage-out syndrome. Quality analysis identified more than 10% of the current data as having consecutive values that are constant, or that saturate at an extreme value. Consequently, the electrical data were not analyzed further. The third objective was condition-change analysis to indicate operational stress under non-ideal operation and machine degradation in proportion to the operational stress. Application of ORNL's novel phase-space dissimilarity measures to the vibration power quantified the rising operational stress in direct proportion to the less-than-full-load power. We conclude that ORNL's technology is an excellent candidate to meet the U.S. Army's need for equipment prognostication.

  17. EXPLOSIVE INSTABILITY AND CORONAL HEATING

    SciTech Connect

    Dahlburg, R. B.; Liu, J.-H.; Klimchuk, J. A.; Nigro, G.

    2009-10-20

    The observed energy-loss rate from the solar corona implies that the coronal magnetic field has a critical angle at which energy is released. It has been hypothesized that at this critical angle an 'explosive instability' would occur, leading to an enhanced conversion of magnetic energy into heat. In earlier investigations, we have shown that a shear-dependent magnetohydrodynamic process called 'secondary instability' has many of the distinctive features of the hypothetical 'explosive instability'. In this paper, we give the first demonstration that this 'secondary instability' occurs in a system with line-tied magnetic fields and boundary shearing-basically the situation described by Parker. We also show that, as the disturbance due to secondary instability attains finite amplitude, there is a transition to turbulence which leads to enhanced dissipation of magnetic and kinetic energy. These results are obtained from numerical simulations performed with a new parallelized, viscoresistive, three-dimensional code that solves the cold plasma equations. The code employs a Fourier collocation-finite difference spatial discretization, and uses a third-order Runge-Kutta temporal discretization.

  18. Interfacial Instabilities on a Droplet

    NASA Astrophysics Data System (ADS)

    Jalaal, Maziyar; Mehravaran, Kian

    2013-11-01

    The fragmentation of droplets is an essential stage of several natural and industrial applications such as fuel atomization and rain phenomena. In spite of its relatively long history, the mechanism of fragmentation is not clear yet. This is mainly due to small length and time scales as well as the non-linearity of the process. In the present study, two and three-dimensional numerical simulations have been performed to understand the early stages of the fragmentation of an initially spherical droplet. Simulations are performed for high Reynolds and a range of relatively high Weber numbers (shear breakup). To resolve the small-scale instabilities generated over the droplet, a second-order adaptive finite volume/volume of fluids (FV/VOF) method is employed, where the grid resolution is increased with the curvature of the gas-liquid interface as well as the vorticity magnitude. The study is focused on the onset and growth of interfacial instabilities. The role of Kelvin-Helmholtz instability (in surface wave formation) and Rayleigh-Taylor instability (in azimuthal transverse modulation) are shown and the obtained results are compared with the linear instability theories for zero and non-zero vorticity layers. Moreover, the analogy between the fragmentation of a single drop and a co-axial liquid jet is discussed. The current results can be used for the further development of the current secondary atomization models.

  19. Additional chromosome abnormalities in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy

    PubMed Central

    Cervera, José; Montesinos, Pau; Hernández-Rivas, Jesús M.; Calasanz, María J.; Aventín, Anna; Ferro, María T.; Luño, Elisa; Sánchez, Javier; Vellenga, Edo; Rayón, Chelo; Milone, Gustavo; de la Serna, Javier; Rivas, Concha; González, José D.; Tormo, Mar; Amutio, Elena; González, Marcos; Brunet, Salut; Lowenberg, Bob; Sanz, Miguel A.

    2010-01-01

    Background Acute promyelocytic leukemia is a subtype of acute myeloid leukemia characterized by the t(15;17). The incidence and prognostic significance of additional chromosomal abnormalities in acute promyelocytic leukemia is still a controversial matter. Design and Methods Based on cytogenetic data available for 495 patients with acute promyelocytic leukemia enrolled in two consecutive PETHEMA trials (LPA96 and LPA99), we analyzed the incidence, characteristics, and outcome of patients with acute promyelocytic leukemia with and without additional chromosomal abnormalities who had been treated with all-trans retinoic acid plus anthracycline monochemotherapy for induction and consolidation. Results Additional chromosomal abnormalities were observed in 140 patients (28%). Trisomy 8 was the most frequent abnormality (36%), followed by abn(7q) (5%). Patients with additional chromosomal abnormalities more frequently had coagulopathy (P=0.03), lower platelet counts (P=0.02), and higher relapse-risk scores (P=0.02) than their counterparts without additional abnormalities. No significant association with FLT3/ITD or other clinicopathological characteristics was demonstrated. Patients with and without additional chromosomal abnormalities had similar complete remission rates (90% and 91%, respectively). Univariate analysis showed that additional chromosomal abnormalities were associated with a lower relapse-free survival in the LPA99 trial (P=0.04), but not in the LPA96 trial. However, neither additional chromosomal abnormalities overall nor any specific abnormality was identified as an independent risk factor for relapse in multivariate analysis. Conclusions The lack of independent prognostic value of additional chromosomal abnormalities in acute promyelocytic leukemia does not support the use of alternative therapeutic strategies when such abnormalities are found. PMID:19903674

  20. Chromosome number evolution in Hymenophyllum (Hymenophyllaceae), with special reference to the subgenus Hymenophyllum.

    PubMed

    Hennequin, Sabine; Ebihara, Atsushi; Dubuisson, Jean-Yves; Schneider, Harald

    2010-04-01

    With about 100 species distributed worldwide, Hymenophyllum subg. Hymenophyllum is the largest subgenus of filmy ferns. It also displays morphological disparity and extreme chromosome numbers variation, with n=11, 12, 13, 14, 18, 21, 22, 26, 28, and 34. We use DNA sequences from the genes rbcL, part of accD, rps4, and the intergenic spacers rbcL-accD, rps4-trnS, and trnG-trnR to infer relationships within Hymenophyllum, with a focus on this subgenus. In the subgenus Hymenophyllum, two main clades are retrieved together with several minor clades whose placement within the subgenus remains ambiguous. We then investigate the evolution of chromosome numbers in the genus and the subgenus, using a maximum likelihood approach taking into account phylogenetic uncertainty. We provide evidence that Hymenophyllum experienced descending aneuploidy during its evolutionary history, especially within the subgenus Hymenophyllum. Reduction in chromosome numbers is particularly extreme in one clade of the subgenus, with the lowest number reported for homosporous ferns. In addition, this group of species displays a high instability in its chromosome number. Both the reduction and the instability in chromosome number may coincide with the distribution of these species in either temperate areas or at high elevations.

  1. Karyotyping of Chromosomes in Human Bronchial Epithelial Cells Transformed by High Energy Fe Ions

    NASA Technical Reports Server (NTRS)

    Yeshitla, Samrawit; Zhang, Ye; Park, Seongmi; Story, Michael T.; Wilson, Bobby; Wu, Honglu

    2014-01-01

    Lung cancer induced from exposure to space radiation is believed to be one of the most significant health risks for long-term space travels. In a previous study, normal human bronchial epithelial cells (HBECs), immortalized through the expression of Cdk4 and hTERT, were exposed to gamma rays and high energy Fe ions for the selection of transformed clones induced by low- and high-LET radiation. In this research, we analyzed chromosome aberrations in these selected clones for genomic instability using the multi-color fluorescent in situ hybridization (mFISH), as well as the multi-banding in situ hybridization (mBAND) techniques. In most of the clones, we found chromosomal aberrations involving translocations between different chromosomes, with several of the breaks occurred in the q-arm of chromosome 3. We also identified copy number variations between the transformed clones and the parental HBEC cells regardless of the exposure condition. Our results indicated that the chromosomal aberrations in low- and high radiation-induced transformed clones are inadequately different from spontaneous soft agar growth. Further analysis is underway to reveal the genomic instability in more transformed clones

  2. Evaluation of Genomic Instability as an Early Event in the Progression of Breast Cancer

    DTIC Science & Technology

    2007-04-01

    Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL, Shay JW. Specific associa- tion of human telomerase...LeFeuvre CE, Stewart NG, Greider CW, Harley CB, Bacchetti S: Telomere shortening associated with chromosome instability is arrested in immortal cells...Piatyszek MA, Shay JW, Harley CB: Telomere shortening is associated with cell division in vitro and in vivo. Exp Cell Res 220: 194–200, 1995 14. Karlseder J

  3. A New Methodology for Early Anomaly Detection of BWR Instabilities

    SciTech Connect

    Ivanov, K. N.

    2005-11-27

    The objective of the performed research is to develop an early anomaly detection methodology so as to enhance safety, availability, and operational flexibility of Boiling Water Reactor (BWR) nuclear power plants. The technical approach relies on suppression of potential power oscillations in BWRs by detecting small anomalies at an early stage and taking appropriate prognostic actions based on an anticipated operation schedule. The research utilizes a model of coupled (two-phase) thermal-hydraulic and neutron flux dynamics, which is used as a generator of time series data for anomaly detection at an early stage. The model captures critical nonlinear features of coupled thermal-hydraulic and nuclear reactor dynamics and (slow time-scale) evolution of the anomalies as non-stationary parameters. The time series data derived from this nonlinear non-stationary model serves as the source of information for generating the symbolic dynamics for characterization of model parameter changes that quantitatively represent small anomalies. The major focus of the presented research activity was on developing and qualifying algorithms of pattern recognition for power instability based on anomaly detection from time series data, which later can be used to formulate real-time decision and control algorithms for suppression of power oscillations for a variety of anticipated operating conditions. The research being performed in the framework of this project is essential to make significant improvement in the capability of thermal instability analyses for enhancing safety, availability, and operational flexibility of currently operating and next generation BWRs.

  4. Taurodontism, an isolated trait associated with syndromes and X-chromosomal aneuploidy.

    PubMed Central

    Jaspers, M T; Witkop, C J

    1980-01-01

    A review of the literature on teeth with enlarged pulp chambers and apical displacement of the bifurcation or trifurcation of roots (taurodontism) and investigation of the association of this trait with X-chromosomal aneuploidy shows that: (1) Taurodontism is not a rare trait in modern man, as indicated by the majority of recent reports, but occurs in approximately 2.5% of adult Caucasians. (2) Taurodontism occurs in syndromes, particularly in those having an ectodermal defect. (3) Among 12 patients showing taurodontic teeth radiographically, all had normal karyotypes. (4) Among 12 patients showing various combinations of X-chromosomal aneuploidy, 11 had taurodontic molars. (5) Patients with a female habitus and X-chromosomal aneuploidy as well as patients with a male habitus and X-chromosomal states have taurodontic teeth. (6) There is no simple association of the degree of taurodontism and the number of X chromosomes, but, in general, patients with the more severe forms of the trait--meso- or hypertaurodontism--are more likely to have X-chromosomal aneuploidy. While taurodontism may be viewed as an extension of a continuous trait of pulp chamber size, the extreme shape may arise when conditions disturbing the epithelial-derived root sheath produce a generalized amplified instability of development, as has been suggested from tissue culture studies of X-chromosomal aneuploid cells. Images Fig. 1 Fig. 3 Fig. 4 Fig. 5 PMID:6992564

  5. CHROMOSOMAL MAPPING IN STRAINS OF STAPHYLOCOCCUS AUREUS,

    DTIC Science & Technology

    STAPHYLOCOCCUS AUREUS , CHROMOSOMES), (*CHROMOSOMES, MAPPING), NITROSO COMPOUNDS, GUANIDINES, GENETICS, MUTATIONS, DRUGS, TOLERANCES(PHYSIOLOGY), TEST METHODS, DEOXYRIBONUCLEIC ACIDS, INHIBITION, RESISTANCE(BIOLOGY).

  6. Mitotic chromosome condensation in vertebrates

    SciTech Connect

    Vagnarelli, Paola

    2012-07-15

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

  7. Chondral Injury in Patellofemoral Instability

    PubMed Central

    Lustig, Sébastien; Servien, Elvire; Neyret, Philippe

    2014-01-01

    Objective: Patellofemoral instability is common and affects a predominantly young age group. Chondral injury occurs in up to 95%, and includes osteochondral fractures and loose bodies acutely and secondary degenerative changes in recurrent cases. Biomechanical abnormalities, such as trochlear dysplasia, patella alta, and increased tibial tuberosity-trochlear groove distance, predispose to both recurrent dislocations and patellofemoral arthrosis. Design: In this article, we review the mechanisms of chondral injury in patellofemoral instability, diagnostic modalities, the distribution of lesions seen in acute and episodic dislocation, and treatments for articular cartilage lesions of the patellofemoral joint. Results: Little specific evidence exists for cartilage treatments in patellofemoral instability. In general, the results of reparative and restorative procedures in the patellofemoral joint are inferior to those observed in other compartments of the knee. Conclusion: Given the increased severity of chondral lesions and progression to osteoarthritis seen with recurrent dislocations, careful consideration should be given to early stabilisation in patients with predisposing factors. PMID:26069693

  8. Hydrodynamick instabilities on ICF capsules

    SciTech Connect

    Haan, S.W.

    1991-06-07

    This article summarizes our current understanding of hydrodynamic instabilities as relevant to ICF. First we discuss classical, single mode Rayleigh-Taylor instability, and nonlinear effects in the evolution of a single mode. Then we discuss multimode systems, considering: (1) the onset of nonlinearity; (2) a second order mode coupling theory for weakly nonlinear effects, and (3) the fully nonlinear regime. Two stabilization mechanisms relevant to ICF are described next: gradient scale length and convective stabilization. Then we describe a model which is meant to estimate the weakly nonlinear evolution of multi-mode systems as relevant to ICF, given the short-wavelength stabilization. Finally, we discuss the relevant code simulation capability, and experiments. At this time we are quite optimistic about our ability to estimate instability growth on ICF capsules, but further experiments and simulations are needed to verify the modeling. 52 refs.

  9. Compressive Instability Phenomena During Springback

    NASA Astrophysics Data System (ADS)

    Kim, J.-B.; Yoon, J. W.; Yang, D. Y.

    2007-05-01

    Springback in sheet metal product makes difficulties in die design because small strain causes large displacement. Especially for the sheet metal product having small geometric constraints, springback displacement may become severe. After first stage of stamping of outer case of washing machine, a large amount of springback is observed. The stamping depth of the outer case is small while stamping area is very large compared to the stamping depth, and therefore, there exists small geometric constraints in the formed part. Also, a compressive instability during the elastic recovery takes place and this instability enlarged the elastic recovery and dimensional error. In this paper, the compressive instability during the elastic recovery is analyzed using bifurcation theory. The final deformed shape after springback is obtained by bifurcating the solution path from primary to secondary. The deformed shapes obtained by the finite element analysis are in good agreement with the experimental data. The bifurcation behavior and the springback displacement for different forming depth are investigated.

  10. Compressive Instability Phenomena During Springback

    SciTech Connect

    Kim, J.-B.; Yoon, J. W.; Yang, D. Y.

    2007-05-17

    Springback in sheet metal product makes difficulties in die design because small strain causes large displacement. Especially for the sheet metal product having small geometric constraints, springback displacement may become severe. After first stage of stamping of outer case of washing machine, a large amount of springback is observed. The stamping depth of the outer case is small while stamping area is very large compared to the stamping depth, and therefore, there exists small geometric constraints in the formed part. Also, a compressive instability during the elastic recovery takes place and this instability enlarged the elastic recovery and dimensional error. In this paper, the compressive instability during the elastic recovery is analyzed using bifurcation theory. The final deformed shape after springback is obtained by bifurcating the solution path from primary to secondary. The deformed shapes obtained by the finite element analysis are in good agreement with the experimental data. The bifurcation behavior and the springback displacement for different forming depth are investigated.

  11. Interfacial Instability during Granular Erosion.

    PubMed

    Lefebvre, Gautier; Merceron, Aymeric; Jop, Pierre

    2016-02-12

    The complex interplay between the topography and the erosion and deposition phenomena is a key feature to model granular flows such as landslides. Here, we investigated the instability that develops during the erosion of a wet granular pile by a dry dense granular flow. The morphology and the propagation of the generated steps are analyzed in relation to the specific erosion mechanism. The selected flowing angle of the confined flow on a dry heap appears to play an important role both in the final state of the experiment, and for the shape of the structures. We show that the development of the instability is governed by the inertia of the flow through the Froude number. We model this instability and predict growth rates that are in agreement with the experiment results.

  12. Faraday instability in deformable domains

    NASA Astrophysics Data System (ADS)

    Pucci, Giuseppe; Ben Amar, Martine; Couder, Yves

    2014-11-01

    We investigate the Faraday instability in floating liquid lenses, as an example of hydrodynamic instability that develops in a domain with flexible boundaries. We show that a mutual adaptation of the instability pattern and the domain shape occurs, as a result of the competition between the wave radiation pressure and the capillary response of the lens border. Two archetypes of behaviour are observed. In the first, stable shapes are obtained experimentally and predicted theoretically as the exact solutions of a Riccati equation, and they result from the equilibrium between wave radiation pressure and capillarity. In the second, the radiation pressure exceeds the capillary response of the lens border and leads to non-equilibrium behaviours, with breaking into smaller domains that have a complex dynamics including spontaneous propagation. The authors are grateful to Université Franco-Italienne (UFI) for financial support.

  13. Gravitational instabilities in protostellar disks

    NASA Technical Reports Server (NTRS)

    Tohline, J. E.

    1994-01-01

    The nonaxisymmetric stability of self-gravitating, geometrically thick accretion disks has been studied for protostellar systems having a wide range of disk-to-central object mass ratios. Global eigenmodes with four distinctly different characters were identified using numerical, nonlinear hydrodynamic techniques. The mode that appears most likely to arise in normal star formation settings, however, resembles the 'eccentric instability' that was identified earlier in thin, nearly Keplerian disks: It presents an open, one-armed spiral pattern that sweeps continuously in a trailing direction through more than 2-pi radians, smoothly connecting the inner and outer edges of the disk, and requires cooperative motion of the point mass for effective amplification. This particular instability promotes the development of a single, self-gravitating clump of material in orbit about the point mass, so its routine appearance in our simulations supports the conjecture that the eccentric instability provides a primary route to the formation of short-period binaries in protostellar systems.

  14. SURGICAL TREATMENT OF PATELLOFEMORAL INSTABILITY

    PubMed Central

    de Andrade, Marco Antônio Percope; de Abreu e Silva, Guilherme Moreira; Freire, Marcelo Machado; Teixeira, Luiz Eduardo Moreira

    2015-01-01

    Objective: To describe functional outcomes following surgical treatment of patients with patellofemoral instability submitted to patellar realignment. Methods: This was a retrospective study evaluating 34 operated knees for patellofemoral instability between 1989 and 2004. The patients were evaluated in the late postoperative period when a functional questionnaire was applied. Results: After a mean follow-up time of 6 years and 5 months, the mean score was 82.94 in the surgical group (p=0.00037). The results of this investigation showed pain relief in 97.05% and low rate of recurrent dislocation (5.88%), although lower scores were seen in intense articular activities (squatting, running and jumping). No patient developed osteoarthritis while being followed up. Conclusion: The procedure for joint described in this paper was shown to be effective for treating patients with recurrent patellofemoral instability. PMID:27077065

  15. Conceptualizing prognostic awareness in advanced cancer: A systematic review

    PubMed Central

    Applebaum, Allison J; Kolva, Elissa A; Kulikowski, Julia R; Jacobs, Jordana D; DeRosa, Antonio; Lichtenthal, Wendy G; Olden, Megan E; Rosenfeld, Barry; Breitbart, William

    2015-01-01

    This systematic review synthesizes the complex literature on prognostic awareness in cancer. A total of 37 studies examining cancer patients’ understanding of their prognosis were included. Prognostic awareness definitions and assessment methods were inconsistent across studies. A surprisingly high percentage of patients (up to 75%) were unaware of their poor prognosis, and in several studies, even their cancer diagnosis (up to 96%), particularly in studies conducted outside of North America. This review highlights surprisingly low rates of prognostic awareness in patients with advanced cancer as well as discrepancies in prognostic awareness assessment, suggesting the need for empirically validated measures of prognostic awareness. PMID:24157936

  16. Conceptualizing prognostic awareness in advanced cancer: a systematic review.

    PubMed

    Applebaum, Allison J; Kolva, Elissa A; Kulikowski, Julia R; Jacobs, Jordana D; DeRosa, Antonio; Lichtenthal, Wendy G; Olden, Megan E; Rosenfeld, Barry; Breitbart, William

    2014-09-01

    This systematic review synthesizes the complex literature on prognostic awareness in cancer. A total of 37 studies examining cancer patients' understanding of their prognosis were included. Prognostic awareness definitions and assessment methods were inconsistent across studies. A surprisingly high percentage of patients (up to 75%) were unaware of their poor prognosis, and in several studies, even their cancer diagnosis (up to 96%), particularly in studies conducted outside of North America. This review highlights surprisingly low rates of prognostic awareness in patients with advanced cancer as well as discrepancies in prognostic awareness assessment, suggesting the need for empirically validated measures of prognostic awareness.

  17. Prognostic value of the International Neuroblastoma Pathology Classification in Neuroblastoma (Schwannian stroma-poor) and comparison with other prognostic factors: a study of 182 cases from the Spanish Neuroblastoma Registry.

    PubMed

    Burgues, Octavio; Navarro, Samuel; Noguera, Rosa; Pellín, Antonio; Ruiz, Amparo; Castel, Victoria; Llombart-Bosch, Antonio

    2006-10-01

    In addition to clinical and biological factors, further valuable prognostic information in neuroblastoma (Schwannian stroma-poor) (NB) patients is provided by the histopathologic analysis and the application of the International Neuroblastoma Pathology Classification (INPC) system. The objective of this study was to assess the prognostic impact of the INPC classification in a series of NB (Schwannian stroma-poor) and its relation with other prognostic factors. One hundred eighty-two cases of NB were collected from the files of the Spanish Neuroblastoma Registry. Slides were reviewed, and NB cases were grouped into favorable and unfavorable categories according to INPC criteria, taking into account morphological features (mitosis-karyorrhexis index, histological subtype) and patient's age at diagnosis. Other pathological [presence of calcifications, tissular components, and number of mitotic cells per 10 high-power field (HPF)], immunohistochemical (P-glycoprotein and Ki-67 protein expression) and genetic (MYCN amplification and chromosome 1p deletion) features were also studied. Statistical analyses of overall survival with Kaplan-Meier curves and a multivariate study using Cox regression were performed (40.3% of NBs were considered favorable and 59.7% unfavorable). Unfavorable NB showed a mean survival time of 57 months compared with 89 months in favorable cases. Advanced stage, more than ten mitoses per 10 HPF, Ki-67 expression in more than 30% of tumor cells, MYCN oncogene amplification and chromosome 1p deletion were observed more frequently in unfavorable NB. The Cox regression analysis demonstrated that clinical stage (International Neuroblastoma Staging System stage 4) and histological subtype (undifferentiated NB) were the most important factors that influence the overall survival (p<0.001). INPC classification results are major prognostic indicators in NB and should be considered in the therapeutic stratification of NB patients.

  18. Tethering telomerase to telomeres increases genome instability and promotes chronological aging in yeast

    PubMed Central

    Liu, Jun; He, Ming-Hong; Peng, Jing; Duan, Yi-Min; Lu, Yi-Si; Wu, Zhenfang; Gong, Ting; Li, Hong-Tao; Zhou, Jin-Qiu

    2016-01-01

    Chronological aging of the yeast Saccharomyces cerevisiae is attributed to multi-faceted traits especially those involving genome instability, and has been considered to be an aging model for post-mitotic cells in higher organisms. Telomeres are the physical ends of eukaryotic chromosomes, and are essential for genome integrity and stability. It remains elusive whether dysregulated telomerase activity affects chronological aging. We employed the CDC13-EST2 fusion gene, which tethers telomerase to telomeres, to examine the effect of constitutively active telomerase on chronological lifespan (CLS). The expression of Cdc13-Est2 fusion protein resulted in overlong telomeres (2 to 4 folds longer than normal telomeres), and long telomeres were stably maintained during long-term chronological aging. Accordingly, genome instability, manifested by accumulation of extra-chromosomal rDNA circle species, age-dependent CAN1 marker-gene mutation frequency and gross chromosomal rearrangement frequency, was significantly elevated. Importantly, inactivation of Sch9, a downstream kinase of the target of rapamycin complex 1 (TORC1), suppressed both the genome instability and accelerated chronological aging mediated by CDC13-EST2 expression. Interestingly, loss of the CDC13-EST2 fusion gene in the cells with overlong telomeres restored the regular CLS. Altogether, these data suggest that constitutively active telomerase is detrimental to the maintenance of genome stability, and promotes chronological aging in yeast. PMID:27855118

  19. Correlations of Dynamic Contrast-Enhanced Magnetic Resonance Imaging with Morphologic, Angiogenic, and Molecular Prognostic Factors in Rectal Cancer

    PubMed Central

    Hong, Hye-Suk; Kim, Se Hoon; Park, Hae-Jeong; Park, Mi-Suk; Kim, Won Ho; Kim, Nam Kyu; Lee, Jae Mun; Cho, Hyeon Je

    2013-01-01

    Purpose To investigate the correlations between parameters of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and prognostic factors in rectal cancer. Materials and Methods We studied 29 patients with rectal cancer who underwent gadolinium contrast-enhanced, T1-weighted DCE-MRI with a three Tesla scanner prior to surgery. Signal intensity on DCE-MRI was independently measured by two observers to examine reproducibility. A time-signal intensity curve was generated, from which four semiquantitative parameters were calculated: steepest slope (SLP), time to peak (Tp), relative enhancement during a rapid rise (Erise), and maximal enhancement (Emax). Morphologic prognostic factors including T stage, N stage, and histologic grade were identified. Tumor angiogenesis was evaluated in terms of microvessel count (MVC) and microvessel area (MVA) by morphometric study. As molecular factors, the mutation status of the K-ras oncogene and microsatellite instability were assessed. DCE-MRI parameters were correlated with each prognostic factor using bivariate correlation analysis. A p-value of <0.05 was considered significant. Results Erise was significantly correlated with N stage (r=-0.387 and -0.393, respectively, for two independent data), and Tp was significantly correlated with histologic grade (r=0.466 and 0.489, respectively). MVA was significantly correlated with SLP (r=-0.532 and -0.535, respectively) and Erise (r=-0.511 and -0.446, respectively). MVC was significantly correlated with Emax (r=-0.435 and -0.386, respectively). No significant correlations were found between DCE-MRI parameters and T stage, K-ras mutation, or microsatellite instability. Conclusion DCE-MRI may provide useful prognostic information in terms of histologic differentiation and angiogenesis in rectal cancer. PMID:23225808

  20. Political instability and illegal immigration.

    PubMed

    Campos, J E; Lien, D

    1995-01-01

    "Economic theory suggests that transnational migration results from the push-pull effect of wage differentials between host and source countries. In this paper, we argue that political instability exacerbates the migration flow, with greater instability leading to relatively larger flows. We conclude then that an optimal solution to the illegal immigration problem requires proper coordination of immigration and foreign policies by the host country. A narrow preoccupation with tougher immigration laws is wasteful and may be marginally effective." Emphasis is on the United States as a host country.

  1. Beam instabilities in hadron synchrotrons

    DOE PAGES

    Metral, E.; T. Argyropoulos; Bartosik, H.; ...

    2016-04-01

    Beam instabilities cover a wide range of effects in particle accelerators and they have been the subjects of intense research for several decades. As the machines performance was pushed new mechanisms were revealed and nowadays the challenge consists in studying the interplays between all these intricate phenomena, as it is very often not possible to treat the different effects separately. Furthermore, the aim of this paper is to review the main mechanisms, discussing in particular the recent developments of beam instability theories and simulations.

  2. Mechanical Instabilities of Biological Tubes

    NASA Astrophysics Data System (ADS)

    Hannezo, Edouard; Prost, Jacques; Joanny, Jean-François

    2012-07-01

    We study theoretically the morphologies of biological tubes affected by various pathologies. When epithelial cells grow, the negative tension produced by their division provokes a buckling instability. Several shapes are investigated: varicose, dilated, sinuous, or sausagelike. They are all found in pathologies of tracheal, renal tubes, or arteries. The final shape depends crucially on the mechanical parameters of the tissues: Young’s modulus, wall-to-lumen ratio, homeostatic pressure. We argue that since tissues must be in quasistatic mechanical equilibrium, abnormal shapes convey information as to what causes the pathology. We calculate a phase diagram of tubular instabilities which could be a helpful guide for investigating the underlying genetic regulation.

  3. Research on aviation fuel instability

    NASA Technical Reports Server (NTRS)

    Baker, C. E.; Bittker, D. A.; Cohen, S. M.; Seng, G. T.

    1984-01-01

    The problems associated with aircraft fuel instability are discussed. What is currently known about the problem is reviewed and a research program to identify those areas where more research is needed is discussed. The term fuel instability generally refers to the gums, sediments, or deposits which can form as a result of a set of complex chemical reactions when a fuel is stored for a long period at ambient conditions or when the fuel is thermally stressed inside the fuel system of an aircraft.

  4. Method of detecting genetic deletions identified with chromosomal abnormalities

    DOEpatents

    Gray, Joe W; Pinkel, Daniel; Tkachuk, Douglas

    2013-11-26

    Methods and compositions for staining based upon nucleic acid sequence that employ nucleic acid probes are provided. Said methods produce staining patterns that can be tailored for specific cytogenetic analyzes. Said probes are appropriate for in situ hybridization and stain both interphase and metaphase chromosomal material with reliable signals. The nucleic acids probes are typically of a complexity greater tha 50 kb, the complexity depending upon the cytogenetic application. Methods and reagents are provided for the detection of genetic rearrangements. Probes and test kits are provided for use in detecting genetic rearrangements, particlularly for use in tumor cytogenetics, in the detection of disease related loci, specifically cancer, such as chronic myelogenous leukemia (CML) and for biological dosimetry. Methods and reagents are described for cytogenetic research, for the differentiation of cytogenetically similar ut genetically different diseases, and for many prognostic and diagnostic applications.

  5. Chromosome-specific staining to detect genetic rearrangements

    DOEpatents

    Gray, Joe W.; Pinkel, Daniel; Tkachuk, Douglas; Westbrook, Carol

    2013-04-09

    Methods and compositions for staining based upon nucleic acid sequence that employ nucleic acid probes are provided. Said methods produce staining patterns that can be tailored for specific cytogenetic analyzes. Said probes are appropriate for in situ hybridization and stain both interphase and metaphase chromosomal material with reliable signals. The nucleic acid probes are typically of a complexity greater than 50 kb, the complexity depending upon the cytogenetic application. Methods and reagents are provided for the detection of genetic rearrangements. Probes and test kits are provided for use in detecting genetic rearrangements, particularly for use in tumor cytogenetics, in the detection of disease related loci, specifically cancer, such as chronic myelogenous leukemia (CML) and for biological dosimetry. Methods and reagents are described for cytogenetic research, for the differentiation of cytogenetically similar but genetically different diseases, and for many prognostic and diagnostic applications.

  6. Method of detecting genetic translocations identified with chromosomal abnormalities

    DOEpatents

    Gray, Joe W.; Pinkel, Daniel; Tkachuk, Douglas

    2001-01-01

    Methods and compositions for staining based upon nucleic acid sequence that employ nucleic acid probes are provided. Said methods produce staining patterns that can be tailored for specific cytogenetic analyses. Said probes are appropriate for in situ hybridization and stain both interphase and metaphase chromosomal material with reliable signals. The nucleic acid probes are typically of a complexity greater than 50 kb, the complexity depending upon the cytogenetic application. Methods and reagents are provided for the detection of genetic rearrangements. Probes and test kits are provided for use in detecting genetic rearrangements, particularly for use in tumor cytogenetics, in the detection of disease related loci, specifically cancer, such as chronic myelogenous leukemia (CML) and for biological dosimetry. Methods and reagents are described for cytogenetic research, for the differentiation of cytogenetically similar but genetically different diseases, and for many prognostic and diagnostic applications.

  7. Chromosome specific repetitive DNA sequences

    DOEpatents

    Moyzis, Robert K.; Meyne, Julianne

    1991-01-01

    A method is provided for determining specific nucleotide sequences useful in forming a probe which can identify specific chromosomes, preferably through in situ hybridization within the cell itself. In one embodiment, chromosome preferential nucleotide sequences are first determined from a library of recombinant DNA clones having families of repetitive sequences. Library clones are identified with a low homology with a sequence of repetitive DNA families to which the first clones respectively belong and variant sequences are then identified by selecting clones having a pattern of hybridization with genomic DNA dissimilar to the hybridization pattern shown by the respective families. In another embodiment, variant sequences are selected from a sequence of a known repetitive DNA family. The selected variant sequence is classified as chromosome specific, chromosome preferential, or chromosome nonspecific. Sequences which are classified as chromosome preferential are further sequenced and regions are identified having a low homology with other regions of the chromosome preferential sequence or with known sequences of other family me This invention is the result of a contract with the Department of Energy (Contract No. W-7405-ENG-36).

  8. Reference-assisted chromosome assembly.

    PubMed

    Kim, Jaebum; Larkin, Denis M; Cai, Qingle; Asan; Zhang, Yongfen; Ge, Ri-Li; Auvil, Loretta; Capitanu, Boris; Zhang, Guojie; Lewin, Harris A; Ma, Jian

    2013-01-29

    One of the most difficult problems in modern genomics is the assembly of full-length chromosomes using next generation sequencing (NGS) data. To address this problem, we developed "reference-assisted chromosome assembly" (RACA), an algorithm to reliably order and orient sequence scaffolds generated by NGS and assemblers into longer chromosomal fragments using comparative genome information and paired-end reads. Evaluation of results using simulated and real genome assemblies indicates that our approach can substantially improve genomes generated by a wide variety of de novo assemblers if a good reference assembly of a closely related species and outgroup genomes are available. We used RACA to reconstruct 60 Tibetan antelope (Pantholops hodgsonii) chromosome fragments from 1,434 SOAPdenovo sequence scaffolds, of which 16 chromosome fragments were homologous to complete cattle chromosomes. Experimental validation by PCR showed that predictions made by RACA are highly accurate. Our results indicate that RACA will significantly facilitate the study of chromosome evolution and genome rearrangements for the large number of genomes being sequenced by NGS that do not have a genetic or physical map.

  9. Cytogenetic analysis of B chromosomes in one population of the fish Moenkhausia sanctaefilomenae (Steindachner, 1907) (Teleostei, Characiformes)

    PubMed Central

    Voltolin, Diogo Teruo Hashimoto Tatiana Aparecida; Paes, Ana Danyelle Noitel Valim de Arruda; Foresti, Fausto; Bortolozzi, Jehud; Porto-Foresti, Fábio

    2012-01-01

    Abstract The aim of this study was to characterize cytogenetically one population of the fish Moenkhausia sanctaefilomenae (Steindachner, 1907), with emphasis on the analysis of B chromosomes. The nucleolar activity in the B microchromosomes was characterized, and an analysis of mitotic instability of these microchromosomes was accomplished. The results showed a diploid chromosome number of 50 chromosomes. In all individuals, we observed the presence of B microchromosomes with intra- and inter-individual variability. The analysis of the nucleolus organizing regions (NORs) by silver nitrate staining demonstrated multiple NORs. We observed active sites of ribosomal DNA in the B microchromosomes, with a frequency of 20% in the analyzed cells, which shows gene activity in these chromosomal elements. The analysis of constitutive heterochromatin patterns showed that the B microchromosomes are heterochromatic or euchromatic, which demonstrates differentiation of DNA composition between these genomic elements. The calculation of the mitotic instability index implied that B chromosomes in this species might be in a final stage of instability. PMID:24260658

  10. The interplay between chromosome stability and cell cycle control explored through gene–gene interaction and computational simulation

    PubMed Central

    Frumkin, Jesse P.; Patra, Biranchi N.; Sevold, Anthony; Ganguly, Kumkum; Patel, Chaya; Yoon, Stephanie; Schmid, Molly B.; Ray, Animesh

    2016-01-01

    Chromosome stability models are usually qualitative models derived from molecular-genetic mechanisms for DNA repair, DNA synthesis, and cell division. While qualitative models are informative, they are also challenging to reformulate as precise quantitative models. In this report we explore how (A) laboratory experiments, (B) quantitative simulation, and (C) seriation algorithms can inform models of chromosome stability. Laboratory experiments were used to identify 19 genes that when over-expressed cause chromosome instability in the yeast Saccharomyces cerevisiae. To better understand the molecular mechanisms by which these genes act, we explored their genetic interactions with 18 deletion mutations known to cause chromosome instability. Quantitative simulations based on a mathematical model of the cell cycle were used to predict the consequences of several genetic interactions. These simulations lead us to suspect that the chromosome instability genes cause cell-cycle perturbations. Cell-cycle involvement was confirmed using a seriation algorithm, which was used to analyze the genetic interaction matrix to reveal an underlying cyclical pattern. The seriation algorithm searched over 1014 possible arrangements of rows and columns to find one optimal arrangement, which correctly reflects events during cell cycle phases. To conclude, we illustrate how the molecular mechanisms behind these cell cycle events are consistent with established molecular interaction maps. PMID:27530428

  11. Chromosome substitution strain assessment of a Huntington's disease modifier locus.

    PubMed

    Ramos, Eliana Marisa; Kovalenko, Marina; Guide, Jolene R; St Claire, Jason; Gillis, Tammy; Mysore, Jayalakshmi S; Sequeiros, Jorge; Wheeler, Vanessa C; Alonso, Isabel; MacDonald, Marcy E

    2015-04-01

    Huntington's disease (HD) is a dominant neurodegenerative disorder that is due to expansion of an unstable HTT CAG repeat for which genome-wide genetic scans are now revealing chromosome regions that contain disease-modifying genes. We have explored a novel human-mouse cross-species functional prioritisation approach, by evaluating the HD modifier 6q23-24 linkage interval. This unbiased strategy employs C57BL/6J (B6J) Hdh(Q111) knock-in mice, replicates of the HD mutation, and the C57BL/6J-chr10(A/J)/NaJ chromosome substitution strain (CSS10), in which only chromosome 10 (chr10), in synteny with the human 6q23-24 region, is derived from the A/J (AJ) strain. Crosses were performed to assess the possibility of dominantly acting chr10 AJ-B6J variants of strong effect that may modulate CAG-dependent Hdh(Q111/+) phenotypes. Testing of F1 progeny confirmed that a single AJ chromosome had a significant effect on the rate of body weight gain and in Hdh(Q111) mice the AJ chromosome was associated subtle alterations in somatic CAG instability in the liver and the formation of intra-nuclear inclusions, as well as DARPP-32 levels, in the striatum. These findings in relatively small cohorts are suggestive of dominant chr10 AJ-B6 variants that may modify effects of the CAG expansion, and encourage a larger study with CSS10 and sub-strains. This cross-species approach may therefore be suited to functional in vivo prioritisation of genomic regions harbouring genes that can modify the early effects of the HD mutation.

  12. Distributed Prognostic Health Management with Gaussian Process Regression

    NASA Technical Reports Server (NTRS)

    Saha, Sankalita; Saha, Bhaskar; Saxena, Abhinav; Goebel, Kai Frank

    2010-01-01

    Distributed prognostics architecture design is an enabling step for efficient implementation of health management systems. A major challenge encountered in such design is formulation of optimal distributed prognostics algorithms. In this paper. we present a distributed GPR based prognostics algorithm whose target platform is a wireless sensor network. In addition to challenges encountered in a distributed implementation, a wireless network poses constraints on communication patterns, thereby making the problem more challenging. The prognostics application that was used to demonstrate our new algorithms is battery prognostics. In order to present trade-offs within different prognostic approaches, we present comparison with the distributed implementation of a particle filter based prognostics for the same battery data.

  13. Gametocidal chromosomes enhancing chromosome aberration in common wheat induced by 5-azacytidine.

    PubMed

    Su, W-Y; Cong, W-W; Shu, Y-J; Wang, D; Xu, G-H; Guo, C-H

    2013-07-08

    The gametocidal (Gc) chromosome from Aegilops spp induces chromosome mutation, which is introduced into common wheat as a tool of chromosome manipulation for genetic improvement. The Gc chromosome functions similar to a restriction-modification system in bacteria, in which DNA methylation is an important regulator. We treated root tips of wheat carrying Gc chromosomes with the hypomethylation agent 5-azacytidine; chromosome breakage and micronuclei were observed in these root tips. The frequency of aberrations differed in wheat containing different Gc chromosomes, suggesting different functions inducing chromosome breakage. Gc chromosome 3C caused the greatest degree of chromosome aberration, while Gc chromosome 3C(SAT) and 2C caused only slight chromosome aberration. Gc chromosome 3C induced different degrees of chromosome aberration in wheat varieties Triticum aestivum var. Chinese Spring and Norin 26, demonstrating an inhibition function in common wheat.

  14. Disease-associated repeat instability and mismatch repair.

    PubMed

    Schmidt, Monika H M; Pearson, Christopher E

    2016-02-01

    Expanded tandem repeat sequences in DNA are associated with at least 40 human genetic neurological, neurodegenerative, and neuromuscular diseases. Repeat expansion can occur during parent-to-offspring transmission, and arise at variable rates in specific tissues throughout the life of an affected individual. Since the ongoing somatic repeat expansions can affect disease age-of-onset, severity, and progression, targeting somatic expansion holds potential as a therapeutic target. Thus, understanding the factors that regulate this mutation is crucial. DNA repair, in particular mismatch repair (MMR), is the major driving force of disease-associated repeat expansions. In contrast to its anti-mutagenic roles, mammalian MMR curiously drives the expansion mutations of disease-associated (CAG)·(CTG) repeats. Recent advances have broadened our knowledge of both the MMR proteins involved in disease repeat expansions, including: MSH2, MSH3, MSH6, MLH1, PMS2, and MLH3, as well as the types of repeats affected by MMR, now including: (CAG)·(CTG), (CGG)·(CCG), and (GAA)·(TTC) repeats. Mutagenic slipped-DNA structures have been detected in patient tissues, and the size of the slip-out and their junction conformation can determine the involvement of MMR. Furthermore, the formation of other unusual DNA and R-loop structures is proposed to play a key role in MMR-mediated instability. A complex correlation is emerging between tissues showing varying amounts of repeat instability and MMR expression levels. Notably, naturally occurring polymorphic variants of DNA repair genes can have dramatic effects upon the levels of repeat instability, which may explain the variation in disease age-of-onset, progression and severity. An increasing grasp of these factors holds prognostic and therapeutic potential.

  15. Condensin II mutation causes T-cell lymphoma through tissue-specific genome instability

    PubMed Central

    Woodward, Jessica; Taylor, Gillian C.; Soares, Dinesh C.; Boyle, Shelagh; Sie, Daoud; Read, David; Chathoth, Keerthi; Vukovic, Milica; Tarrats, Nuria; Jamieson, David; Campbell, Kirsteen J.; Blyth, Karen; Acosta, Juan Carlos; Ylstra, Bauke; Arends, Mark J.; Kranc, Kamil R.; Jackson, Andrew P.; Bickmore, Wendy A.

    2016-01-01

    Chromosomal instability is a hallmark of cancer, but mitotic regulators are rarely mutated in tumors. Mutations in the condensin complexes, which restructure chromosomes to facilitate segregation during mitosis, are significantly enriched in cancer genomes, but experimental evidence implicating condensin dysfunction in tumorigenesis is lacking. We report that mice inheriting missense mutations in a condensin II subunit (Caph2nes) develop T-cell lymphoma. Before tumors develop, we found that the same Caph2 mutation impairs ploidy maintenance to a different extent in different hematopoietic cell types, with ploidy most severely perturbed at the CD4+CD8+ T-cell stage from which tumors initiate. Premalignant CD4+CD8+ T cells show persistent catenations during chromosome segregation, triggering DNA damage in diploid daughter cells and elevated ploidy. Genome sequencing revealed that Caph2 single-mutant tumors are near diploid but carry deletions spanning tumor suppressor genes, whereas P53 inactivation allowed Caph2 mutant cells with whole-chromosome gains and structural rearrangements to form highly aggressive disease. Together, our data challenge the view that mitotic chromosome formation is an invariant process during development and provide evidence that defective mitotic chromosome structure can promote tumorigenesis. PMID:27737961

  16. Analysis of chromosome 21 yeast artificial chromosome (YAC) clones

    SciTech Connect

    Tassone, F. A. Gemelli School of Medicine, Rome ); Cheng, S.; Gardiner, K. )

    1992-12-01

    Chromosome 21 contains genes relevant to several important diseases. Yeast artificial chromosome (YAC) clones, because they span >100 kbp, will provide attractive material for initiating searches for such genes. Twenty-two YAC clones, each of which maps to a region of potential relevance either to aspects of the Down syndrome phenotype or to one of the other chromosome 21-associated genetic diseases, have been analyzed in detail. Clones total [approximately]6,000 kb and derive from all parts of the long arm. Rare restriction-site maps have been constructed for each clone and have been used to determine regional variations in clonability, methylation frequency, CpG island density, and CpG island frequency versus gene density. This information will be useful for the isolation and mapping of new genes to chromosome 21 and for walking in YAC libraries. 48 refs., 3 figs., 4 tabs.

  17. Analysis of chromosome 21 yeast artificial chromosome (YAC) clones.

    PubMed Central

    Tassone, F; Cheng, S; Gardiner, K

    1992-01-01

    Chromosome 21 contains genes relevant to several important diseases. Yeast artificial chromosome (YAC) clones, because they span > 100 kbp, will provide attractive material for initiating searches for such genes. Twenty-two YAC clones, each of which maps to a region of potential relevance either to aspects of the Down syndrome phenotype or to one of the other chromosome 21-associated genetic diseases, have been analyzed in detail. Clones total approximately 6,000 kb and derive from all parts of the long arm. Rare restriction-site maps have been constructed for each clone and have been used to determine regional variations in clonability, methylation frequency, CpG island density, and CpG island frequency versus gene density. This information will be useful for the isolation and mapping of new genes to chromosome 21 and for walking in YAC libraries. Images Figure 2 Figure 1 PMID:1463009

  18. Bacterial Chromosome Organization and Segregation

    PubMed Central

    Toro, Esteban; Shapiro, Lucy

    2010-01-01

    Bacterial chromosomes are generally ∼1000 times longer than the cells in which they reside, and concurrent replication, segregation, and transcription/translation of this crowded mass of DNA poses a challenging organizational problem. Recent advances in cell-imaging technology with subdiffraction resolution have revealed that the bacterial nucleoid is reliably oriented and highly organized within the cell. Such organization is transmitted from one generation to the next by progressive segregation of daughter chromosomes and anchoring of DNA to the cell envelope. Active segregation by a mitotic machinery appears to be common; however, the mode of chromosome segregation varies significantly from species to species. PMID:20182613

  19. [Chromosome analysis and genetic testing].

    PubMed

    Isobe, Yasushi; Miura, Ikuo

    2014-03-01

    Chromosomal and genetic tests are essential to establish correct diagnoses of the lymphoma. When the tissue examination is planned, these should be done simultaneously with the morphological and immunophenotypic evaluations. Chromosome analyses can identify the genomic alterations of tumor cells. Some chromosome abnormalities define disease subtypes. For example, recurrent 14q32 translocations involving the immunoglobulin heavy chain locus support the diagnosis of B-cell lymphoma, and their translocation partners identify the types. In contrast, genetic testings are performed to confirm the presence of certain abnormalities including gene rearrangements, mutations, amplifications and deletions in each case. These results provide us detailed information for diagnosis, prognosis, and choice of therapy.

  20. Chromosome Segregation in Vibrio cholerae

    PubMed Central

    Ramachandran, R.; Jha, J; Chattoraj, DK

    2014-01-01

    The study of chromosome segregation is currently one of the most exciting research frontiers in cell biology. In this review, we discuss our current knowledge of the chromosome segregation process in Vibrio cholerae, based primarily on findings from fluorescence microscopy experiments. This bacterium is of special interest because of its eukaryotic feature of having a divided genome, a feature shared with 10% of known bacteria. We also discuss how the segregation mechanisms of V. cholerae compare with those in other bacteria, and highlight some of the remaining questions regarding the process of bacterial chromosome segregation. PMID:25732338