bluuebunny/crossref_metadata_2025 huggingface dataset:
Models of chromosome aberration induction: an example based on radiation track structure
Authors: Ballarini F. , Ottolenghi A.
Published: May 2004

A few examples of models of chromosome aberration induction are summarised and discussed on the basis of the three main theories of aberration formation, that is “breakage-and-reunion”, “exchange” and “one-hit”. A model and code developed at the Universities of Milan and Pavia is then presented in detail. The model provides dose-response curves for different aberration types (dicentrics, translocations, rings, complex exchanges and deletions) induced in human lymphocytes by gamma rays, protons and alpha particles of different energies, both as monochromatic fields and as mixed fields. The main assumptions are that only clustered – and thus severe – DNA breaks (“Complex Lesions”, CL) can participate in the production of aberrations, and that only break free ends in neighbouring chromosome territories can interact and form exchanges. The yields of CLs induced by the various radiation types of interest are taken from a previous modelling work. These lesions are distributed within a sphere representing the cell nucleus according to the radiation track structure, e.g. randomly for gamma rays and along straight lines for light ions. Interphase chromosome territories are explicitly simulated and configurations are obtained in which each chromosome occupies an intranuclear domain with volume proportional to its DNA content. In order to allow direct comparisons with experimental data, small fragments can be neglected since usually they cannot be detected in experiments. The presence of a background level of aberrations is also taken into account. The results of the simulations are in good agreement with experimental dose-response curves available in the literature, that provides a validation of the model both in terms of the adopted assumptions and in terms of the simulation techniques. To address the question of “true” incompleteness, simulations were also run in which all fragments were assumed to be visible.
Virtual radiation biophysics: implications of nuclear structure
Authors: Kreth G. , Finsterle J. , Cremer C.
Published: May 2004

The non-random positioning of chromosome territories (CTs) in lymphocyte cell nuclei has raised the question whether systematic chromosome-chromosome associations exist which have significant influence on interchange rates. In such a case the spatial proximity of certain CTs or even of clusters of CTs is expected to increase the respective exchange yields significantly, in comparison to a random association of CTs. In the present study we applied computer simulated arrangements of CTs to calculate interchange frequencies between all heterologous CT pairs, assuming a uniform action of the molecular repair machinery. For the positioning of CTs in the virtual nuclear volume we assumed a) a statistical, and b) a gene density-correlated arrangement. The gene density-correlated arrangement regards the more experimentally observed interior localization of gene-rich and the more peripheral positioning of gene-poor CTs. Regarding one-chromosome yields, remarkable differences for single CTs were observed taking into account the gene density-correlated distribution of CTs.
Dose dependency of FISH-detected translocations in stable and unstable cells after 137Cs γ irradiation of human lymphocytes in vitro
Authors: Romm H. , Stephan G.
Published: May 2004

Human peripheral lymphocytes were exposed to 137Cs γ-rays (0–4.3 Gy) in order to check the impact of unstable cells on the dose-response curve for translocations. Chromosomes 2, 4 and 8 were FISH-painted. 17,720 first dividing cells were analysed. For the discrimination between stable and unstable cells the painted and the counter-stained chromosomes were analysed at doses of 1 Gy and higher. The cell distribution of translocations follows a Poisson distribution. The data were fitted to the linear-quadratic function, y = c + αD + βD2. As expected, the α coefficients of the dose-response curves for translocations in stable cells or in total cells do not differ. However, at doses >1 Gy, the frequency of all translocations in stable cells seems to be lower than the frequency in total cells. For the establishment of calibration curves for past dose assessment purposes, only complete translocations should be scored, in order to estimate reliable doses.
Potassium bromate but not X-rays cause unexpectedly elevated levels of DNA breakage similar to those induced by ultraviolet light in Cockayne syndrome (CS-B) fibroblasts
Authors: Mosesso P. , Penna S. , Pepe G. , Lorenti-Garcia C. , Palitti F.
Published: May 2004

It has been previously reported that the elevated accumulation of repair incision intermediates in cells from patients with combined characteristics of xeroderma pigmentosum complementation group D (XP-D) and Cockayne syndrome (CS) XP-D/CS fibroblasts following UV irradiation is caused by an “uncontrolled” incision of undamaged genomic DNA induced by UV-DNA-lesions which apparently are not removed. This could be an explanation for the extreme sensitivity of these cells to UV light. In the present study, we confirm the immediate DNA breakage following UV irradiation also for CS group B (CS-B) fibroblasts by DNA migration in the “comet assay” and extend these findings to other lesions such as 8-oxodeoxyguanosine (8-oxodG), selectively induced by KBrO3 treatment. In contrast, X-ray exposure does not induce differential DNA breakage. This indicates that additional lesions other than the UV-induced photoproducts (cyclobutane pyrimidine dimers, CPD, and 6-pyrimidine-4-pyrimidone products, 6-4 PP), such as 8-oxodG, specifically induced by KBrO3, are likely to trigger “uncontrolled” DNA breakage in the undamaged genomic DNA in the CS-B fibroblasts, thus accounting for some of the clinical features of these patients.
Distribution of breakpoints induced by etoposide and X-rays along the CHO X chromosome
Authors: Martínez-López W. , Folle G.A. , Cassina G. , Méndez-Acuña L. , Di-Tomaso M.V. , Obe G. , Palitti F.
Published: May 2004

SORB (selected observed residual breakpoints) induced by ionizing radiation or endonucleases are often non-randomly distributed in mammalian chromosomes. However, the role played by chromatin structure in the localization of chromosome SORB is not well understood. Anti-topoisomerase drugs such as etoposide are potent clastogens and unlike endonucleases or ionizing radiation, induce DNA double-strand breaks (DSB) by an indirect mechanism. Topoisomerase II (Topo II) is a main component of the nuclear matrix and the chromosome scaffold. Since etoposide leads to DSB by influencing the activity of Topo II, this compound may be a useful tool to study the influence of the chromatin organization on the distribution of induced SORB in mammalian chromosomes. In the present work, we compared the distribution of SORB induced during S-phase by etoposide or X-rays in the short euchromatic and long heterochromatic arms of the CHO9 X chromosome. The S-phase stage (early, mid or late) at which CHO9 cells were exposed to etoposide or X-rays was marked by incorporation of BrdU during treatments and later determined by immunolabeling of metaphase chromosomes with an anti-BrdU FITC-coupled antibody. The majority of treated cells were in late S-phase during treatment either with etoposide or X-rays. SORB induced by etoposide mapped preferentially to Xq but random localization was observed for SORB produced by X-rays. Possible explanations for the uneven distribution of etoposide-induced breakpoints along Xq are discussed.
Ionizing radiation-induced instant pairing of heterochromatin of homologous chromosomes in human cells
Authors: Abdel-Halim H.I. , Imam S.A. , Badr F.M. , Natarajan A.T. , Mullenders L.H.F. , Boei J.J.W.A.
Published: May 2004

Using fluorescence in situ hybridization with human band-specific DNA probes we examined the effect of ionizing radiation on the intra-nuclear localization of the heterochromatic region 9q12→q13 and the euchromatic region 8p11.2 of similar sized chromosomes 9 and 8 respectively in confluent (G1) primary human fibroblasts. Microscopic analysis of the interphase nuclei revealed colocalization of the homologous heterochromatic regions from chromosome 9 in a proportion of cells directly after exposure to 4 Gy X-rays. The percentage of cells with paired chromosomes 9 gradually decreased to control levels during a period of one hour. No significant changes in localization were observed for chromosome 8. Using 2-D image analysis, radial and inter-homologue distances were measured for both chromosome bands. In unexposed cells, a random distribution of the chromosomes over the interphase nucleus was found. Directly after irradiation, the average inter-homologue distance decreased for chromosome 9 without alterations in radial distribution. The percentage of cells with inter-homologue distance <3 µm increased from 11% in control cells to 25% in irradiated cells. In contrast, irradiation did not result in significant changes in the inter-homologue distance for chromosome 8. Colocalization of the heterochromatic regions of homologous chromosomes 9 was not observed in cells irradiated on ice. This observation, together with the time dependency of the colocalization, suggests an underlying active cellular process. The biological relevance of the observed homologous pairing remains unclear. It might be related to a homology dependent repair process of ionizing radiation induced DNA damage that is specific for heterochromatin. However, also other more general cellular responses to radiation-induced stress or change in chromatin organization might be responsible for the observed pairing of heterochromatic regions.
G2 chromatid damage and repair kinetics in normal human fibroblast cells exposed to low- or high-LET radiation
Authors: Kawata T. , Ito H. , Uno T. , Saito M. , Yamamoto S. , Furusawa Y. , Durante M. , George K. , Wu H. , Cucinotta F.A.
Published: May 2004

Radiation-induced chromosome damage can be measured in interphase using the Premature Chromosome Condensation (PCC) technique. With the introduction of a new PCC technique using the potent phosphatase inhibitor calyculin-A, chromosomes can be condensed within five minutes, and it is now possible to examine the early damage induced by radiation. Using this method, it has been shown that high-LET radiation induces a higher frequency of chromatid breaks and a much higher frequency of isochromatid breaks than low-LET radiation. The kinetics of chromatid break rejoining consists of two exponential components representing a rapid and a slow time constant, which appears to be similar for low- and high-LET radiations. However, after high-LET radiation exposures, the rejoining process for isochromatid breaks influences the repair kinetics of chromatid-type breaks, and this plays an important role in the assessment of chromatid break rejoining in the G2 phase of the cell cycle.
Cytogenetic effects of densely ionising radiation in human lymphocytes: impact of cell cycle delays
Authors: Nasonova E. , Ritter S.
Published: May 2004

The classical cytogenetic assay to estimate the dose to which an individual has been exposed relies on the measurement of chromosome aberrations in lymphocytes at the first post-irradiation mitosis 48 h after in vitro stimulation. However, evidence is accumulating that this protocol results in an underestimation of the cytogenetic effects of high LET radiation due to a selective delay of damaged cells. To address this issue, human lymphocytes were irradiated with C-ions (25-mm extended Bragg peak, LET: 60–85 keV/µm) and aberrations were measured in cells reaching the first mitosis after 48, 60, 72 and 84 h and in G2-phase cells collected after 48 h by calyculin A induced premature chromosome condensation (PCC). The results were compared with recently published data on the effects of X-rays and 200 MeV/u Fe-ions (LET: 440 keV/µm) on lymphocytes of the same donor (Ritter et al., 2002a). The experiments show clearly that the aberration yield rises in first-generation metaphase (M1) with culture time and that this effect increases with LET. Obviously, severely damaged cells suffer a prolonged arrest in G2. The mitotic delay has a profound effect on the RBE: RBE values estimated from the PCC data were about two times higher than those obtained by conventional metaphase analysis at 48 h. Altogether, these observations argue against the use of single sampling times to quantify high LET induced chromosomal damage in metaphase cells.
Cytogenetic analyses in peripheral lymphocytes of persons living in houses with increased levels of indoor radon concentrations
Authors: Oestreicher U. , Braselmann H. , Stephan G.
Published: May 2004

Published data concerning the effects of indoor radon exposure on the frequency of chromosome aberrations in peripheral lymphocytes of residents are contradictory. Possible reasons for this may be the low radon concentration in dwellings and/or the limited number of investigated persons. We therefore studied the relationship of domestic radon exposure and the occurrence of chromosome aberrations in peripheral lymphocytes in 61 persons living in houses with radon concentrations from 80 up to 13,000 Bq/m3. We analyzed 60,000 cells from fluorescence plus Giemsa (FPG)-stained slides. It could be clearly demonstrated that in groups of persons living in dwellings with indoor radon concentrations >200 Bq/m3 the number of cells containing dicentrics and/or centric rings (Cdic + cr) (2.45 ± 0.50 × 10–3) was significantly increased (p < 0.05) in comparison to the control level (1.03 ± 0.15 × 10–3). However, there was no difference in the mean frequency of Cdic + cr between the groups living in dwellings with higher radon concentrations. Using the fluorescence in situ hybridization (FISH) technique for the detection of translocations, we analyzed 23,315 cells in 16 persons of the highest exposed group (>5,000 Bq/m3). The observed frequency of translocations was 3.9 ± 0.64 × 10–3. In comparison to the control group (2.02 ± 0.18 × 10–3), there was a slight but not statistically significant increase in the exposed group (P = 0.055). If, however, the age of the examined persons is taken into account, the values are significantly increased (P < 0.05) in the exposed persons older than 40 years in comparison to the age-matched controls. Since most of the translocations were found in stable cells, it is concluded that translocations are also induced in blood-forming tissue and are transmitted to peripheral blood.
Complex chromosomal rearrangements induced in vivo by heavy ions
Authors: Durante M. , Ando K. , Furusawa Y. , Obe G. , George K. , Cucinotta F.A.
Published: May 2004

It has been suggested that the ratio complex/simple exchanges can be used as a biomarker of exposure to high-LET radiation. We tested this hypothesis in vivo, by considering data from several studies that measured complex exchanges in peripheral blood from humans exposed to mixed fields of low- and high-LET radiation. In particular, we studied data from astronauts involved in long-term missions in low-Earth-orbit, and uterus cancer patients treated with accelerated carbon ions. Data from two studies of chromosomal aberrations in astronauts used blood samples obtained before and after space flight, and a third study used blood samples from patients before and after radiotherapy course. Similar methods were used in each study, where lymphocytes were stimulated to grow in vitro, and collected after incubation in either colcemid or calyculin A. Slides were painted with whole-chromosome DNA fluorescent probes (FISH), and complex and simple chromosome exchanges in the painted genome were classified separately. Complex-type exchanges were observed at low frequencies in control subjects, and in our test subjects before the treatment. No statistically significant increase in the yield of complex-type exchanges was induced by the space flight. Radiation therapy induced a high fraction of complex exchanges, but no significant differences could be detected between patients treated with accelerated carbon ions or X-rays. Complex chromosomal rearrangements do not represent a practical biomarker of radiation quality in our test subjects.
Chromosome aberrations of clonal origin are present in astronauts’ blood lymphocytes
Authors: George K. , Durante M. , Willingham V. , Cucinotta F.A.
Published: May 2004

Radiation-induced chromosome translocations remain in peripheral blood cells over many years, and can potentially be used to measure retrospective doses or prolonged low-dose rate exposures. However, several recent studies have indicated that some individuals possess clones of cells with balanced chromosome abnormalities, which can result in an overestimation of damage and, therefore, influence the accuracy of dose calculations. We carefully examined the patterns of chromosome damage found in the blood lymphocytes of twelve astronauts, and also applied statistical methods to screen for the presence of potential clones. Cells with clonal aberrations were identified in three of the twelve individuals. These clonal cells were present in samples collected both before and after space flight, and yields are higher than previously reported for healthy individuals in this age range (40–52 years of age). The frequency of clonal damage appears to be even greater in chromosomes prematurely condensed in interphase, when compared with equivalent analysis in metaphase cells. The individuals with clonal aberrations were followed-up over several months and the yields of all clones decreased during this period. Since clonal aberrations may be associated with increased risk of tumorigenesis, it is important to accurately identify cells containing clonal rearrangements for risk assessment as well as biodosimetry.
Transgenerational transmission of radiation- and chemically induced tumors and congenital anomalies in mice: studies of their possible relationship to induced chromosomal and molecular changes
Authors: Nomura T. , Nakajima H. , Ryo H. , Li L.Y. , Fukudome Y. , Adachi S. , Gotoh H. , Tanaka H.
Published: May 2004

This article provides a broad overview of our earlier studies on the induction of tumors and congenital anomalies in the progeny of X-irradiated or chemically treated mice and our subsequent (published, hitherto unpublished and on-going) investigations aimed at identifying potential relationships between genetic changes induced in germ cells and the adverse effects manifest as tumors and congenital anomalies using cytogenetic and molecular approaches. The earlier studies document the fact that tumors and congenital anomalies can be induced by irradiation or treatment with certain chemicals such as urethane and that these phenotypes are heritable i.e., transmitted to generations beyond the first generation. These findings support the view that transmissible induced genetic changes are involved. The induced rates of congenital abnormalities and tumors are about two orders of magnitude higher than those recorded in the literature from classical mutation studies with specific locus mutations. The cytogenetic studies addressed the question of whether there were any relationships between induced translocations and induced tumors. The available data permit the inference that gross chromosomal changes may not be involved but do not exclude smaller induced genetic changes that are beyond the resolution of the techniques used in these studies. Other work on possible relationship between visible chromosomal anomalies (in bone marrow preparations) and tumors were likewise negative. However, there were indications that some induced cytogenetic changes might underlie induced congenital anomalies, i.e., trisomies, deletions and inversions were observed in induced and transmissible congenital anomalies (such as dwarfs, tail anomalies). Studies that explored possible relationships between induction of minisatellite mutations at the Pc-3 locus and tumors were negative. However, gene expression analysis of tumor (hepatoma)-susceptible offspring of progeny descended from irradiated male mice showed abnormal expression of many genes. Of these, only very few were oncogenes. This lends some support to our hypothesis that cumulative changes in gene expression of many genes, which perform normal cellular functions, may contribute to the occurrence of tumors in the offspring of irradiated or chemically treated mice.
Investigations into the biological relevance of in vitro clastogenic and aneugenic activity
Authors: Parry J.M. , Fowler P. , Quick E. , Parry E.M.
Published: May 2004

In the current study we present a view of events leading to chemically induced DNA damage in vitro from both a cytogenetic and molecular aspect, focusing on threshold mediated responses and the biological relevance of DNA damaging events that occur at low and high cellular toxicity levels. Current regulatory mechanisms do not take into account chemicals that cause significant DNA damage only at high toxicity. Our results demonstrate a defined threshold for micronucleus induction after insult with the alkylating agent MMS. Other results define a significant change in gene expression following treatment with chemicals that give rise to structural DNA damage only at high toxicity. Pairs of chemicals with a similar mode of action but differing toxicity levels were chosen, the chemicals that demonstrated structural DNA damage only at high levels of toxicity showed an increase in heat shock protein gene expression whereas the chemicals causing DNA damage events at all levels of toxicity did not induce changes in heat shock gene expression at identical toxicity levels. The data presented indicates that there are a number of situations where the linear dose response model is not appropriate for risk estimation. However, deviation from linear risk models should be dependent upon the availability of appropriate experimental data such as that shown here.
A liver micronucleus assay using young rats exposed to diethylnitrosamine: methodological establishment and evaluation
Authors: Suzuki H. , Shirotori T. , Hayashi M.
Published: May 2004

We have developed a simple liver micronucleus assay using young rats (up to 4 weeks old) to assess cytogenetic damage of chemicals in liver cells. Diethylnitrosamine (DEN) was used as a model rodent hepatocarcinogen in this study. Compared to the partial hepatectomy method most commonly used for the liver micronucleus assay, the present assay method showed equal or even higher practicability. The young rat liver micronucleus assay was also characterized for rat strain differences, sampling time after treatment, single treatment vs. split treatment, age of animals, administration route, and staining method. Although based on one model chemical, we propose an acceptable protocol for the micronucleus assay using young rat liver as follows: Up to 4-week-old rats should be used; oral or intraperitoneal administration can be used; single or repeated treatment protocols can be applied; sampling time is 3–5 days after the last treatment; hepatocytes are prepared by the collagenase perfusion method; and cells are stained with the AO-DAPI double staining method.
Insights into the mechanisms of sister chromatid exchange formation
Authors: Wojcik A. , Bruckmann E. , Obe G.
Published: May 2004

The DNA lesions responsible for the formation of sister chromatid exchanges (SCEs) have been the object of research for a long time. SCEs can be visualized by growing cells for either two rounds of replication in the presence of 5-bromo-2′-deoxyuridine (BrdU) or for one round with BrdU and the next without. If BrdU is added after cells were treated with a DNA-damaging agent, the effect on SCEs can only be analyzed in the second post-treatment mitosis. If one wishes to analyze the first post-treatment mitosis, cells unifilarily labeled with BrdU must be treated. Due to the highly reactive bromine atom, BrdU interacts with such agents like ionizing and UV radiation enhancing the frequency of SCEs. However, its precise role in this process was difficult to assess for a long time, because no alternative technique existed that allowed differential staining of chromatids. We have recently developed a method to differentially label sister chromatids with biotin-16-2′-deoxyuridine-5′-triphosphate (biotin-dUTP) circumventing the disadvantage of BrdU. This technique was applied to study the SCEs induced by ionizing and UV radiation as well as by mitomycin C, DNaseI and AluI. This article is a review of the results and conclusions of our previous studies.
Frequent occurrence of UVB-induced sister chromatid exchanges in telomere regions and its implication to telomere maintenance
Authors: Jin G. , Ikushima T.
Published: May 2004

Sister chromatid exchanges (SCEs) are symmetrical exchanges between newly replicated chromatids and their sisters. While homologous recombination may be one of the principal mechanisms responsible for SCEs, the full details of their molecular basis and biological significance remain to be elucidated. Following exposure to ultraviolet light B (UVB), mitomycin C (MMC) and cisplatin, we analyzed the location of SCEs on metaphase chromosomes in Chinese hamster CHO cells. The frequency of SCEs increased over the spontaneous level in proportion to the agent’s dose. UVB-induced SCEs occurred frequently in telomere regions, as cisplatin-induced SCEs did, differing from MMC-induced ones. The remarkable difference of intrachromosomal distribution among the three mutagens may be attributed to the specificity of induced DNA lesions and structures of different chromosome regions. Telomeric DNA at the end of chromosomes is composed of multiple copies of a repeated motif, 5′-TTAGGG-3′ in mammalian cells. Telomeric repeats may be potential targets for UVB and cisplatin, which mainly form pyrimidine dimers and intrastrand d(GpG) cross-links, respectively, resulting in SCE formation. UVB irradiation shortened telomeres and augmented the telomerase activity. The possible implications of the frequent occurrence of SCEs in telomere regions are discussed in connection with the maintenance of telomere integrity.
X chromosome inactivation-mediated cellular mosaicism for the study of the monoclonal origin and recurrence of mouse tumors: a review
Authors: Tanooka H.
Published: May 2004

X chromosome inactivation-mediated cellular mosaicism was applied to study the clonal nature of experimental and human tumors and to judge whether apparently recurrent tumors which appear after therapeutic treatment are truly due to recurrence or due to new induction of a second tumor. Results show that the majority of experimental and human tumors, including benign tumors, are monoclonal and that the majority of apparently recurrent tumors are due to true recurrence. A series of experimental studies on this topic are reviewed.
Quantitative PCR analysis reveals a high incidence of large intragenic deletions in the FANCA gene in Spanish Fanconi anemia patients
Authors: Callén E. , Tischkowitz M.D. , Creus A. , Marcos R. , Bueren J.A. , Casado J.A. , Mathew C.G. , Surrallés J.
Published: May 2004

Fanconi anaemia is an autosomal recessive disease characterized by chromosome fragility, multiple congenital abnormalities, progressive bone marrow failure and a high predisposition to develop malignancies. Most of the Fanconi anaemia patients belong to complementation group FA-A due to mutations in the FANCA gene. This gene contains 43 exons along a 4.3-kb coding sequence with a very heterogeneous mutational spectrum that makes the mutation screening of FANCA a difficult task. In addition, as the FANCA gene is rich in Alu sequences, it was reported that Alu-mediated recombination led to large intragenic deletions that cannot be detected in heterozygous state by conventional PCR, SSCP analysis, or DNA sequencing. To overcome this problem, a method based on quantitative fluorescent multiplex PCR was proposed to detect intragenic deletions in FANCA involving the most frequently deleted exons (exons 5, 11, 17, 21 and 31). Here we apply the proposed method to detect intragenic deletions in 25 Spanish FA-A patients previously assigned to complementation group FA-A by FANCA cDNA retroviral transduction. A total of eight heterozygous deletions involving from one to more than 26 exons were detected. Thus, one third of the patients carried a large intragenic deletion that would have not been detected by conventional methods. These results are in agreement with previously published data and indicate that large intragenic deletions are one of the most frequent mutations leading to Fanconi anaemia. Consequently, this technology should be applied in future studies on FANCA to improve the mutation detection rate.
Analysis of ETV6/RUNX1 fusions for evaluating the late effects of cancer therapy in ALL (acute lymphoblastic leukemia) cured patients
Authors: Brassesco M.S. , Camparoto M.L. , Tone L.G. , Sakamoto-Hojo E.T.
Published: May 2004

Acute Lymphoblastic Leukemia (ALL) is the most common malignancy in childhood. The improvements of therapies have increased the number of long-term survivors. However, an increased incidence of secondary neoplasias has been observed in this cohort. Our purpose was to evaluate the late effects of cancer therapy in cured patients previously treated for ALL, considering previous reports on the occurrence of gene fusions as putative markers of chromosomal instability. Twelve ALL patients (aged 5 to 16 years) and twelve healthy subjects (aged 18 to 22 years) were studied for the presence of ETV6/RUNX1 (TEL/AML1) translocations, which were detected by FISH (fluorescence in situ hybridization). The blood samples were collected months or years after completion of the therapy, and the frequencies of gene fusions in lymphocytes were compared with those obtained retrospectively for bone marrow samples at the time of diagnosis, and also for the control group. It was demonstrated that ETV6/RUNX1 gene fusion was a frequent event (0.59–1.84/100 cells) in peripheral blood lymphocytes from normal individuals and the ALL patients who underwent chemotherapy showed significantly (P = 0.0043) increased frequencies (0.62–3.96/100 cells) of the rearrangement when compared with the control groups (patients at diagnosis and healthy subjects). However, a significant difference was not found between the groups of patients at diagnosis and healthy subjects, when the two patients who were positive for the rearrangement were excluded. Therefore, increased frequencies of ETV6/RUNX1 fusions in ALL cured patients indicate the influence of previous exposure to anti-cancer drugs, and they may represent an important genetic marker for estimating the risk of relapse, or development of secondary neoplasias.
Comparative genomic hybridization (CGH): ten years of substantial progress in human solid tumor molecular cytogenetics
Authors: Gebhart E.
Published: May 2004

Data from ten years of research using comparative genomic hybridization (CGH) for the detection of chromosomal alterations in human solid tumors are concisely reviewed. By use of a basic methodology with some variations more or less specific patterns of genomic imbalances were found in a large number of tumors of various entities. Specific gains and losses of genomic material have not only opened the way to the detection of a series of cancer-related genes but also to clinical implications. Not only several areas of basic oncogenetic research, but also differential diagnosis, prognosis of disease progression, and therapeutic decisions have profited by CGH.
Chromosomal aberrations in arsenic-exposed human populations: a review with special reference to a comprehensive study in West Bengal, India
Authors: Mahata J. , Chaki M. , Ghosh P. , Das L.K. , Baidya K. , Ray K. , Natarajan A.T. , Giri A.K.
Published: May 2004

For centuries arsenic has played an important role in science, technology, and medicine. Arsenic for its environmental pervasiveness has gained unexpected entrance to the human body through food, water and air, thereby posing a great threat to public health due to its toxic effect and carcinogenicity. Thus, in modern scenario arsenic is synonymous with “toxic” and is documented as a paradoxical human carcinogen, although its mechanism of induction of neoplasia remains elusive. To assess the risk from environmental and occupational exposure of arsenic, in vivo cytogenetic assays have been conducted in arseniasis-endemic areas of the world using chromosomal aberrations (CA) and sister chromatid exchanges (SCE) as biomarkers in peripheral blood lymphocytes. The primary aim of this report is to critically review and update the existing in vivo cytogenetic studies performed on arsenic-exposed populations around the world and compare the results on CA and SCE from our own study, conducted in arsenic-endemic villages of North 24 Parganas (district) of West Bengal, India from 1999 to 2003. Based on a structured questionnaire, 165 symptomatic (having arsenic induced skin lesions) subjects were selected as the exposed cases consuming water having a mean arsenic content of 214.96 µg/l. For comparison 155 age-sex matched control subjects from an unaffected district (Midnapur) of West Bengal were recruited. Similar to other arsenic exposed populations our population also showed a significant difference (P < 0.01) in the frequencies of CA and SCE between the cases and control group. Presence of substantial chromosome damage in lymphocytes in the exposed population predicts an increased future carcinogenic risk by this metalloid.
Cytogenetic studies in mice treated with the jet fuels, Jet-A and JP-8
Authors: Vijayalaxmi V , Kligerman A.D. , Prihoda T.J. , Ullrich S.E.
Published: May 2004

The genotoxic potential of the jet fuels, Jet-A and JP-8, were examined in mice treated on the skin with a single dose of 240 mg/mouse. Peripheral blood smears were prepared at the start of the experiment (t = 0), and at 24, 48 and 72 h following treatment with jet fuels. Femoral bone marrow smears were made when all animals were sacrificed at 72 h. In both tissues, the extent of genotoxicity was determined from the incidence of micronuclei (MN) in polychromatic erythrocytes. The frequency of MN in the peripheral blood of mice treated with Jet-A and JP-8 increased over time and reached statistical significance at 72 h, as compared with concurrent control animals. The incidence of MN was also higher in bone marrow cells of mice exposed to Jet-A and JP-8 as compared with controls. Thus, at the dose tested, a small but significant genotoxic effect of jet fuels was observed in the blood and bone marrow cells of mice treated on the skin.
Chromosomal aberrations and risk of cancer in humans: an epidemiologic perspective
Authors: Bonassi S. , Znaor A. , Norppa H. , Hagmar L.
Published: May 2004

The pioneering papers published more than one century ago by Theodor Boveri opened the way to extensive research on the mechanism linking chromosomal abnormalities to the pathogenesis of cancer. As a result of this effort, robust theoretical and empirical evidence correlating cytogenetic damage to early stages of cancer in humans was consolidated, and an increased cancer risk was postulated in healthy subjects with high levels of chromosomal aberrations (CA). The first epidemiological investigation aimed at validating CA as predictor of cancer risk was carried out in the early 1990s. In that report the Nordic Study Group described an 80% increased risk of cancer in healthy subjects with high frequencies of CA. The results of this first study were replicated a few years later in a parallel research initiative carried out in Italy, and the subsequent pooled analysis of these two cohorts published in 1998 contributed to refine the quantitative estimate of the CA/cancer association. A small case-control study nested in a cohort of subjects screened for CA in Taiwan found an increased risk in subjects with high frequency of chromosome-type CA, while in 2001 a significant increase of cancer incidence associated with high levels of CA was described in a new independent cohort of radon exposed workers from the Czech Republic. Despite some common limitations affecting study design, the studies cited above have provided results of great interest both for the understanding of mechanisms of early stages of carcinogenesis, and for their potential implication for cancer prevention. The recent evolution of molecular techniques and the refinement of high throughput techniques have the potential to improve the knowledge about the role of specific sub-types of CA and to provide further insight into the mechanisms. Finally, the most challenging perspective in the field is the passage from research to regulation, with the implementation of preventive policies based on the accumulated knowledge.
mBAND: a high resolution multicolor banding technique for the detection of complex intrachromosomal aberrations
Authors: Chudoba I. , Hickmann G. , Friedrich T. , Jauch A. , Kozlowski P. , Senger G.
Published: May 2004

Precise breakpoint definition of chromosomal rearrangements using conventional banding techniques often fails, especially when more than two breakpoints are involved. The classic banding procedure results in a pattern of alternating light and dark bands. Hence, in banded chromosomes a specific chromosomal band is rather identified by the surrounding banding pattern than by its own specific morphology. In chromosomal rearrangements the original pattern is altered and therefore the unequivocal determination of breakpoints is not obvious. The multicolor banding technique (mBAND, see Chudoba et al., 1999) is able to identify breakpoints unambiguously, even in highly complex chromosomal aberrations. The mBAND technique is presented and illustrated in a case of intrachromosomal rearrangement with seven breakpoints all having occurred on one chromosome 16, emphasizing the unique analyzing power of mBAND as compared to conventional banding techniques.
Peroxisome Proliferator-Activated Receptor γ Regulates Eosinophil Functions: A New Therapeutic Target for Allergic Airway Inflammation
Authors: Ueki Shigeharu , Matsuwaki Yoshinori , Kayaba Hiroyuki , Oyamada Hajime , Kanda Akira , Usami Atsuko , Saito Norihiro , Chihara Junichi
Published: May 2004

Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that regulates lipid metabolism and glucose homeostasis. PPARγ is not only highly expressed in adipose tissue but also in cells involved in the immune system, and it exerts anti-inflammatory activities. We showed that eosinophils, a major inflammatory cell in allergic inflammation, express PPARγ. PPARγ negatively modulates eosinophil functions, such as survival, chemotaxis, antibody-dependent cellular cytotoxicity and degranulation. Recently, three independent groups have demonstrated that PPARγ agonists inhibit airway inflammation in an animal model of asthma. This evidence suggests that PPARγ agonists may be a new therapeutic modality for the treatment of allergic diseases including asthma.
The Quantification of Endolymphatic Hydrops in an Experimental Animal Model with Guinea Pigs
Authors: Chi Fang-Lu , Liang Qin
Published: May 2004

To better quantify endolymphatic hydrops in experimental guinea pigs, endolymphatic hydrops was induced by endolymphatic sac obliteration through an extradural posterior cranial fossa approach in the right ear. The area of the scala vestibuli and scala media of each turn on both cochlear midmodiolar sections was measured, using an automated computer-aided design (AutoCAD R14) software combined with a digital camera. No endolymphatic hydrops was observed in all nonoperated ears; however, various degrees of hydrops were present in all operated ears. The average maximum SMA (scala media area) ratio in the 4-week group (2.22 ± 0.20) was greater than that in the control group (1.10 ± 0.06). The average maximum SMA ratio of the 8-week group (4.04 ± 0.52) was greater than that of the 4-week group (p < 0.05). This study provides a reliable methodologic base for the experimental study of Ménière’s disease.
Cyclo-Oxygenase 2 Expression in Laryngeal Squamous Cell Carcinoma and Its Clinical Correlates
Authors: Bayazıt Yıldırım A. , Buyukberber Suleyman , Sarı İbrahim , Camcı Celalettin , Ozer Enver , Sevinc Alper , Karakok Metin , Kanlıkama Muzaffer , Mumbuc Semih
Published: May 2004

Objective: To assess the significance of cyclo-oxygenase 2 (COX-2) in laryngeal squamous cell carcinoma (LSCC). Study Design: An immunohistochemical study in which 39 patients with LSCC were included. Methods: Immunohistochemical staining of the paraffin-embedded tumour tissues was performed using isoform-specific COX-2 polyclonal antisera (Santa Cruz, Calif., USA). COX-2 results were compared with the clinical parameters of the patients. Results: COX-2 was detected in all tumour tissues. In the normal laryngeal tissue around the tumour area, which served as control, there was no COX-2 staining. There was no relationship between the COX-2 results and the location of the primary tumour, T stage and N stage, survival, recurrence or pulmonary metastases. Conclusion: The absence of a relation between COX-2 positivity and clinical parameters may suggest an involvement of COX-2 in laryngeal carcinogenesis. Since COX-2 positivity could be detected in all LSCC specimens studied, COX-2 could serve as a therapeutic target in LSCC.
Acoustic and Perceptual Parameters Relating to Connected Speech Are More Reliable Measures of Hoarseness than Parameters Relating to Sustained Vowels
Authors: Halberstam Benjamin
Published: May 2004

This report investigates the correlations between acoustic parameters and the perception of hoarseness by trained listeners. Both sustained vowels and connected speech were examined. Fourteen acoustic parameters from samples of sustained vowels and 2 from connected speech were measured. The results show that jitter, shimmer and cepstral peak prominence (CPP) are correlated with the perception of hoarseness in sustained vowels. CPP is strongly correlated with the perception of hoarseness in connected speech. Some evidence is seen that perception of hoarseness in connected speech is more valid than the perception of hoarseness in sustained vowels. It is concluded that CPP for connected speech is a more valid objective measure of hoarseness than jitter, shimmer or CPP for sustained vowels and that perception of hoarseness may be most accurate in connected speech, rather than isolated vowels.
Cochlear Administration of Adenosine Triphosphate Facilitates Recovery from Acoustic Trauma (Temporary Threshold Shift)
Authors: Sugahara Kazuma , Shimogori Hiroaki , Okuda Takeshi , Takemoto Tsuyoshi , Hashimoto Makoto , Yamashita Hiroshi
Published: May 2004

Background: Adenosine triphosphate (ATP) has often been used in the treatment of acoustic trauma although evidence supporting its clinical use was lacking. The aim of this study was to evaluate the chronic effects of ATP on acoustic trauma in guinea pigs. Methods: We infused ATP into the perilymph of the guinea pig cochlea concurrently with intense noise exposure to investigate the effect of ATP on the process of recovery after acoustic trauma. We assessed auditory brainstem response (ABR) thresholds to evaluate cochlear function. Results: After noise exposure (120 dB SPL, 5 h), ABR thresholds showed an increase of approximately 50 dB SPL that returned to normal after 14 days. Cochlear function in ATP-treated ears recovered more quickly than in control ears. The effect of ATP was inhibited by the administration of the ATP receptor antagonist: pyridoxal- phosphate-6-azophenyl-2′,4′-disulfonic acid. Conclusion: These results suggest that ATP mitigates the effects of noise trauma through the ATP receptor.
Sinonasal Malignancy: What’s New?
Authors: Götte Karl , Hörmann Karl
Published: May 2004

Tumors of the nasal cavity are located at a complex anatomic site and show a huge histological diversity. Although dealing with a rare malignancy, the last decade has brought – besides new histological and clinical classifications – a variety of new insights into etiological agents, tumor biology and therapeutic concepts as well as valuable overviews of rare histological subtypes. This review tries to disentangle the different medical and scientific aspects of the most frequently encountered histological types of tumors in the nasal cavity and the paranasal sinuses. We concentrate on epidemiology, classification, etiology, cytogenetics and molecular genetics, outcome and prognosis as well as treatment modalities, as far as the past few years have brought considerable new insights. Our principal aim is to provide the clinician with important data from publications of the last decade.
Influence of a Long-Term, High-Dose Volume Therapy with 6% Hydroxyethyl Starch 130/0.4 or Crystalloid Solution on Hemodynamics, Rheology and Hemostasis in Patients with Acute Ischemic Stroke
Authors: Woessner Ralph , Grauer Markus T. , Dieterich Hans-Jürgen , Bepperling Frank , Baus Daniela , Kahles Timo , Georgi Sven , Bianchi Oliver , Morgenthaler Martin , Treib Johannes
Published: May 2004

Background: This study was performed to investigate the clinical effects of a 4-day volume therapy with a newly developed, 6% hydroxyethyl starch (HES) 130/0.4 versus crystalloid solution, with particular regard to systemic and cerebral hemodynamics, rheology and safety. Methods: In a randomized, double-blind study, 40 patients suffering from an acute ischemic stroke received either 6% HES 130/0.4 or crystalloid solution as continuous infusion over 4 days with a total dose of 6.5 liters. Efficacy parameters studied included hemodynamics (cardiac output, blood pressure, flow velocity with transcranial Doppler) and rheology (hematocrit and plasma viscosity). Safety parameters examined included laboratory, hemostaseology (including factor VIII) and an adverse event questionnaire (including pruritus). Results: In both groups, a small, but not significant increase in cardiac output was observed. There were no significant changes regarding the remaining efficacy or safety parameters, except for the well-known increase in serum alpha-amylase through the infusion of HES. Conclusion: In our study with patients suffering from acute ischemic stroke, continuous infusion (1 ml/min) of HES 130/0.4 or crystalloid solution did not differ regarding safety or hemodynamic efficacy.
High Intensity Exercise Enhances Platelet Reactivity to Shear Stress and Coagulation during and after Exercise
Authors: Ikarugi Hideo , Shibata Masashi , Shibata Shiori , Ishii Hiromitsu , Taka Tomomi , Yamamoto Junichiro
Published: May 2004

Platelets play a crucial role in the pathogenesis of acute cardiac events, such as angina, myocardial infarction and sudden death. It is believed that regular low-intensity exercise can reduce, while high-intensity exercise may provoke acute cardiac events. The aim of the present study was to investigate the effect of acute exercise both at low and high intensities on the ventilatory threshold (VT), platelet reactivity and coagulation before and after exercise. Platelet reactivity and coagulation were measured under flow condition, using native blood, by hemostatometry. Seven healthy young men (age: 20–29 years) performed bicycle ergometer exercise for 30 min at intensities of 90% (Ex-VT90% or approximately 55% VO2max) and 130% (Ex-VT130% or 80% VO2max) of individual VT. Blood cell counts, hematocrit, blood lactic acid and plasma catecholamine levels were slightly but significantly increased after Ex-VT90% and markedly after Ex-VT130% after 30 min exercise. Subsequent to the exercise, the elevated blood cell counts decreased to the resting levels both at Ex-VT90% and at Ex-VT130%. Platelet reactivity to shear stress and dynamic coagulation were significantly enhanced immediately and 30 min after Ex-130%VT. In contrast, no significant changes occurred in those of Ex-90%VT. The present study suggests that high-intensity exercise-induced platelet hyperreactivity and hypercoagulable state may pose an increased risk for acute, sometimes fatal cardiac event. On the other hand, our findings support the view that low-intensity exercise does not present a risk of thrombosis.