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Items 1 - 18 of 18
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One page. |
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MLL gene alterations in
radiation-associated acute myeloid leukemia.
Klymenko
SV, Bink K, Trott KR, Bebeshko VG, Bazyka DA, Dmytrenko IV, Abramenko
IV, Bilous NI, Zitzelsberger H, Misurin AV, Atkinson MJ, Rosemann M.
Research Centre for Radiation Medicine, Academy of Medical Science of
Ukraine, Kyiv 04050, Ukraine. klymenko_sergiy@yahoo.co.uk.
AIM:
Although acute myelogenous leukemia (AML) arising after radiation
exposure is considered to be secondary, little is known about the
molecular mechanisms by which the radiation induces the leukemogenic
phenotype. The aim of the study was to analyze whether the MLL
translocations are as frequent in radiation-associated AML as in
spontaneous AML cases. METHODS: Sixty one AML samples obtained at
diagnosis were analyzed for the presence of MLL abnormalities using
fluorescent in situ hybridization and/or reverse transcription
polymerase chain reaction. Of these patients, 27 had experienced
radiation exposure due to the Chernobyl accident, 32 were
non-irradiated (spontaneous AML), and 2 developed therapy-related AML
after chemotherapy with topoisomerase II inhibitors. RESULTS: MLL gene
translocations were detected in both groups of spontaneous and
therapy-related AML (1/32 and 1/2 cases respectively). The sole MLL
rearrangement found in the group of radiation-associated AML patients
was a duplication of the gene. CONCLUSION: Our data preclude the
involvement of MLL gene translocations in radiation-induced
leukemogenesis, but support the assumption that loss and gain of
chromosomal material could be crucial in the leukemogenesis of AML
patients with the history of radiation exposure due to the Chernobyl
accident.
PMID: 15812362 [PubMed - in process]
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Profiling the molecular difference
between Patched- and p53-dependent rhabdomyosarcoma.
Kappler R, Bauer R, Calzada-Wack J, Rosemann M, Hemmerlein B, Hahn H.
Institute of Human Genetics, University of Gottingen,
Heinrich-Duker-Weg 12, Gottingen, Germany.
Rhabdomyosarcoma
(RMS) is a highly malignant tumor that is histologically related to
skeletal muscle, yet genetic and molecular lesions underlying its
genesis and progression remain largely unknown. In this study we have
compared the molecular profiles of two different mouse models of RMS,
each associated with a defined primary genetic defect known to play a
role in rhabdomyosarcomagenesis in man. We report that RMS of
heterozygous Patched1 (Ptch1) mice show less aggressive growth and a
greater degree of differentiation than RMS of heterozygous p53 mice. By
means of cDNA microarray analysis we demonstrate that RMS in Ptch1
mutants predominantly express a number of myogenic markers, including
myogenic differentiation 1, myosin heavy chain, actin, troponin and
tropomyosin, as well as genes associated with Hedgehog/Patched
signaling like insulin-like growth factor 2, forkhead box gene Foxf1
and the growth arrest and DNA-damage-inducible gene Gadd45a. In sharp
contrast, RMS in p53 mutants display higher expression levels of cell
cycle-associated genes like cyclin B1, cyclin-dependent kinase 4 and
the proliferation marker Ki-67. These results demonstrate that
different causative mutations lead to distinct gene expression profiles
in RMS, which appear to reflect their different biological
characteristics. Our results provide a first step towards a molecular
classification of different forms of RMS. If the described differences
can be confirmed in human RMS our results will contribute to a new
molecular taxonomy of this cancer, which will be critical for gene
mutation- and expression-specific therapy.
PMID: 15480423 [PubMed - indexed for MEDLINE]
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Genetic mapping of a Ptch1-associated
rhabdomyosarcoma susceptibility locus on mouse chromosome 2.
Hahn H, Nitzki F, Schorban T, Hemmerlein B, Threadgill
D, Rosemann M.
Institute
of Human Genetics, University of Gottingen, Heinrich-Duker-Weg 12,
37073 Gottingen, Federal Republic of Germany. hhahn@gwdg.de
Mutations
in the Patched (Ptch1) gene are responsible for various familial and
sporadic cancers. Ptch1(neo67/+) mice, in which exons 6 and 7 are
deleted, show genetic background-dependent susceptibility to the
development of muscle tumors resembling human rhabdomyosarcoma (RMS);
BALB/c (BALB) is a susceptible strain whereas C57BL/6 (B6) shows
resistance. A genome-wide linkage analysis was carried out using
Ptch1(neo67/+)mice produced from B6 x (BALB x B6) backcrosses to
identify loci involved in the control of RMS susceptibility.
Quantitative trait locus mapping with the censored tumor latency time
as the quantitative parameter was used to detect a significant RMS
susceptibility modifier locus, Parms1 (Patched-Associated RMS 1), on
chromosome 2 between D2Mit37 and D2Mit102 (LRS = 10). A Kaplan-Meier
survival curve revealed that mice with the B6/BALB genotype develop
tumors more frequently and much faster as compared to mice homozygous
for the B6 allele (P = 0.02). Additional loci not reaching linkage
significance were also detected for medulloblastoma resistance.
PMID: 15475264 [PubMed - indexed for MEDLINE]
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Mapping of a novel MEN-like syndrome
locus to rat chromosome 4.
Piotrowska K, Pellegata NS, Rosemann M, Fritz A, Graw J,
Atkinson MJ.
Institute of Pathology, GSF-National Research Center for Environment
and Health, D-85764 Neuherberg, Germany.
Multiple
endocrine neoplasia-like syndrome (MENX) is a hereditary cancer
syndrome in the rat characterized by inborn cataract and multiple
tumors affecting the neuroendocrine system developed within the first
year of life. The spectrum of affected organs is intermediate between
MEN type 1 (MEN1) and MEN type 2 (MEN2) syndromes in human, but, in
contrast to them, MENX is inherited in a recessive fashion. Here we
report the mapping of the MENX locus to rat Chromosome (Chr) 4 by a
genome-wide linkage analysis. This analysis was done in 41 animals
obtained from a (Wistar/Nhg x SDwe) x SDwe interstrain backcross, where
SDwe (Sprague-Dawley white eye) indicates the affected animals. The
MENX disease locus was ultimately mapped to a approximately 22-cM
interval on Chr 4 that includes the rat homolog of the human RET
proto-oncogene. As activating point mutations of RET are known to be
responsible for MEN2 in human, we analyzed several markers located in
the proximity of Ret for linkage to the disease phenotype. Our data
exclude Ret involvement in MENX and establish that a second gene,
playing a role in endocrine tumor formation, lies within the distal
part of rat Chr 4. Although heritable human endocrine tumors are quite
rare, sporadic tumors of MEN-affected tissues occur at a much higher
frequency, and their pathogenesis is poorly understood. The
identification of the MENX gene should contribute to our understanding
of the genetic mechanisms of neuroendocrine tissue tumorigenesis and
may assist in developing new and more appropriate therapeutic
strategies for these diseases.
PMID: 15058384 [PubMed - indexed for MEDLINE]
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The nature and identification of
quantitative trait loci: a community's view.
Abiola
O, Angel JM, Avner P, Bachmanov AA, Belknap JK, Bennett B, Blankenhorn
EP, Blizard DA, Bolivar V, Brockmann GA, Buck KJ, Bureau JF, Casley WL,
Chesler EJ, Cheverud JM, Churchill GA, Cook M, Crabbe JC, Crusio WE,
Darvasi A, de Haan G, Dermant P, Doerge RW, Elliot RW, Farber CR,
Flaherty L, Flint J, Gershenfeld H, Gibson JP, Gu J, Gu W, Himmelbauer
H, Hitzemann R, Hsu HC, Hunter K, Iraqi FF, Jansen RC, Johnson TE,
Jones BC, Kempermann G, Lammert F, Lu L, Manly KF, Matthews DB, Medrano
JF, Mehrabian M, Mittlemann G, Mock BA, Mogil JS, Montagutelli X,
Morahan G, Mountz JD, Nagase H, Nowakowski RS, O'Hara BF, Osadchuk AV,
Paigen B, Palmer AA, Peirce JL, Pomp D, Rosemann M, Rosen GD, Schalkwyk
LC, Seltzer Z, Settle S, Shimomura K, Shou S, Sikela JM, Siracusa LD,
Spearow JL, Teuscher C, Threadgill DW, Toth LA, Toye AA, Vadasz C, Van
Zant G, Wakeland E, Williams RW, Zhang HG, Zou F; Complex Trait
Consortium.
This white paper by eighty members of the
Complex Trait Consortium presents a community's view on the approaches
and statistical analyses that are needed for the identification of
genetic loci that determine quantitative traits. Quantitative trait
loci (QTLs) can be identified in several ways, but is there a
definitive test of whether a candidate locus actually corresponds to a
specific QTL?
Publication Types:
PMID: 14634638 [PubMed - indexed for MEDLINE]
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Allelic imbalance at intragenic markers
of Tbx18 is a hallmark of murine osteosarcoma.
Rosemann M,
Kuosaite V, Nathrath M, Strom TM, Quintanilla-Martinez L, Richter T,
Imai K, Atkinson MJ.
Institute of Pathology, GSF National Research Center for Environment
and Health, Neuherberg, Germany. rosemann@gsf.de
We
have recently identified a locus exhibiting a high frequency of allelic
imbalance (AI) in both spontaneous human (HSA 6q14.1-15) and radiogenic
murine (MMU9, 42 cM) osteosarcoma. Here we describe the fine mapping of
the locus in osteosarcoma arising in (BALB/cxCBA) F(1) hybrid mice.
These studies have allowed us to identify Tbx18, a member of the T-box
transcriptional regulator gene family, as a candidate gene. Three
intragenic Tbx18 polymorphisms were used to map the region of maximum
AI to within the gene itself; 16 of 17 tumours exhibited imbalances of
at least one of these markers. The highest frequency was found in exon
1, where 14 of 17 tumours were affected at a single nucleotide
polymorphism at 541 nt. Two polymorphic CA repeat markers in intron 2
and intron 5 demonstrated overlapping regions of imbalance in several
tumours. Both markers flanking the Tbx18 gene (D9Osm48 and D9Mit269)
revealed significantly lower frequencies of imbalance and confirmed the
limitation of the common interval to Tbx18. Examination of both the
mouse and human annotated genomic sequences indicated Tbx18 to be the
only gene within the interval. Sequence analysis of the Tbx18 coding
region did not reveal any evidence of mutation. Given the
haploinsufficiency phenotypes reported for other T-box genes, we
speculate that AI may influence the function of Tbx18 during
osteosarcomagenesis.
PMID: 12663494 [PubMed - indexed for MEDLINE]
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The genetics of radiation-induced and
sporadic osteosarcoma: a unifying theory?
Rosemann M,
Kuosaite V, Nathrath M, Atkinson MJ.
Institute of Pathology, GSF National Research Centre for Environment
and Health, Neuherberg, Germany.
Cancer
is a disease of the genome, with the neoplastic phenotype being passed
from one cell generation to the other. Radiation-induced cancer has
often been considered to represent a unique entity amongst neoplasia,
with the energy deposition being held responsible for both direct (gene
mutations) and indirect (bystander effects, induced instability etc)
alterations to the cellular genome. However, radiogenic tumours in man
and experimental animals appear to be physiologically and genetically
indistinguishable from their sporadic counterparts, suggesting that the
aetiologies of these two tumour types are in fact closely related. We
have conducted a general screen of the genetic alterations in
radiation-induced mouse osteosarcoma, a tumour that is
histopathologically indistinguishable from human sporadic osteosarcoma.
Comparison of the two tumour types indicates the existence of a common
set of genetic changes, providing additional evidence to support the
concept that the molecular pathology of radiation-induced malignancy is
no different to that of sporadic cancers.
PMID: 12400958 [PubMed - indexed for MEDLINE]
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Identification of cyclin D1 mRNA
overexpression
in B-cell neoplasias by real-time reverse transcription-PCR of
microdissected paraffin sections.
Specht K, Kremer M, Muller U, Dirnhofer S, Rosemann M, Hofler H,
Quintanilla-Martinez L, Fend F.
Institute of Pathology, GSF-National Research Centre for Environment
and Health, D-85764 Neuherberg, Germany.
PURPOSE:
Overexpression of cyclin D1 mRNA and protein as a result of the
chromosomal translocation t(11;14)(q13;q32) is a highly specific
molecular marker of mantle cell lymphoma, but cyclin D1 dysregulation
can also be found in other B-cell neoplasias. The aim of the study was
to develop a precise and reliable tool for quantitation of cyclin D1
mRNA suitable for archival clinical specimens. EXPERIMENTAL DESIGN: A
real-time reverse transcription-PCR (RT-PCR) assay was used to
quantitate cyclin D1 mRNA copy numbers. Using 2000 microdissected cells
as template, 104 formalin-fixed, paraffin-embedded lymph node, spleen,
and decalcified bone marrow biopsies from a panel of 95 cases of B-cell
non-Hodgkin's lymphomas (B-NHLs) were analyzed. In addition, cyclin D1
protein expression was assessed by immunohistochemistry. RESULTS:
Strong cyclin D1 mRNA overexpression was detected in mantle cell
lymphomas (23 of 23), hairy cell leukemias (5 of 19), and multiple
myelomas (7 of 23) with particularly high levels in 2 of the latter
cases. Intermediate transcript levels were found in 5 of 23 multiple
myelomas and 7 of 19 hairy cell leukemias. B-cell chronic lymphocytic
leukemias (10 of 10), follicular lymphomas (9 of 9), mucosa-associated
lymphoid tissue lymphomas (5 of 5) and reactive lymphoid tissues with
the exception of normal spleen had no or very low cyclin D1 expression.
In comparison with real-time RT-PCR, immunohistochemistry showed a
lower level of sensitivity, more variability, and did not allow
accurate quantitation. CONCLUSIONS: Real-time RT-PCR for cyclin D1 mRNA
is an excellent tool for the differential diagnosis of B-NHLs and, in
combination with microdissection, a powerful approach for retrospective
trials using archival clinical specimens as tissue source. Furthermore,
real-time RT-PCR may help to identify subgroups of B-NHLs according to
cyclin D1 mRNA copy numbers and to investigate the possible influence
of different chromosomal breakpoints on cyclin D1 expression.
PMID: 12231535 [PubMed - indexed for MEDLINE]
-
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The genetics of radiation-induced
osteosarcoma.
Rosemann M,
Kuosaite V, Nathrath M, Atkinson MJ.
GSF-Institut fur Pathologie Ingolstaedter Landstrasse 1 D85764
Neuherberg, Germany.
Individual
genetic variation can influence susceptibility to the carcinogenic
effects of many environmental carcinogens. In radiation-exposed
populations those individuals with a greater genetically determined
susceptibility would be at greater risk of developing cancer. To
include this modification of risk into radiation protection schemes it
is necessary to identify the genes responsible for determining
individual sensitivity. Alpha-particle-induced osteosarcoma in the
mouse has been adopted as a model of human radiation carcinogenesis,
and genome-wide screens have been conducted for allelic imbalance and
genetic linkage. These studies have revealed a series of genes involved
in determining the sensitivity to radiogenic osteosarcoma formation.
PMID: 12194300 [PubMed - indexed for MEDLINE]
-
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Two novel tumor suppressor gene loci on
chromosome 6q and 15q in human osteosarcoma identified through
comparative study of allelic imbalances in mouse and man.
Nathrath MH, Kuosaite V, Rosemann M, Kremer M, Poremba C,
Wakana S, Yanagi M, Nathrath WB, Hofler H, Imai K, Atkinson MJ.
Institute of Pathology, GSF-National Research Center for Environment
and Health, 85764 Neuherberg, Germany. nathrath@gsf.de
We
have performed a comparative study of allelic imbalances in human and
murine osteosarcomas to identify genetic changes critical for
osteosarcomagenesis. Two adjacent but discrete loci on mouse chromosome
9 were found to show high levels of allelic imbalance in
radiation-induced osteosarcomas arising in (BALB/cxCBA/CA) F1 hybrid
mice. The syntenic human chromosomal regions were investigated in 42
sporadic human osteosarcomas. For the distal locus (OSS1) on mouse
chromosome 9 the syntenic human locus was identified on chromosome 6q14
and showed allelic imbalance in 77% of the cases. Comparison between
the human and mouse syntenic regions narrowed the locus down to a 4 Mbp
fragment flanked by the marker genes ME1 and SCL35A1. For the proximal
locus (OSS2) on mouse chromosome 9, a candidate human locus was mapped
to chromosome 15q21 in a region showing allelic imbalance in 58% of
human osteosarcomas. We have used a combination of synteny and
microsatellite mapping to identify two potential osteosarcoma
suppressor gene loci. This strategy represents a powerful tool for the
identification of new genes important for the formation of human tumors.
PMID: 12185601 [PubMed - indexed for MEDLINE]
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Recessive transmission of a multiple
endocrine neoplasia syndrome in the rat.
Fritz A, Walch A, Piotrowska K, Rosemann M, Schaffer E, Weber K,
Timper A, Wildner G, Graw J, Hofler H, Atkinson MJ.
Institute
of Pathology, GSF-National Research Center for Environment and Health,
Ingolstaedter Landstrasse 1, D-85764 Neuherberg, Germany.
We
describe a novel hereditary cancer syndrome in the rat that is
transmitted by a recessive gene mutation. Animals exhibiting the mutant
phenotype develop multiple neuroendocrine malignancies within the first
year of life. The endocrine neoplasia is characterized by bilateral
adrenal pheochromocytoma, multiple extra-adrenal pheochromocytoma,
bilateral medullary thyroid cell neoplasia, bilateral parathyroid
hyperplasia, and pituitary adenoma. The appearance of neoplastic
disease is preceded by the development of bilateral juvenile cataracts.
Although the spectrum of affected tissues is reminiscent of human forms
of multiple endocrine neoplasia (MEN), no germ-line mutations were
detected in the Ret or Menin genes that are responsible for the
dominantly inherited MEN syndromes in humans. Segregation studies in F1
and F2 crosses yielded frequencies of affected animals entirely
consistent with a recessive autosomal mode of inheritance. The lack of
the phenotype in F1 animals effectively excludes a germ-line tumor
suppressor gene mutation as the causal event. The absence of mutation
of known MEN genes and the unique constellation of affected tissues,
plus the recessive mode of inheritance, lead us to conclude that the
mutation of an as yet unknown gene is responsible for this syndrome of
inherited neuroendocrine cancer.
PMID: 12036912 [PubMed - indexed for MEDLINE]
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Unbalanced overexpression of the mutant
allele in murine Patched mutants.
Calzada-Wack J, Kappler R, Schnitzbauer U, Richter T,
Nathrath M, Rosemann M,
Wagner SN, Hein R, Hahn H.
Institute of Pathology, Technical University Munich, Munich, Federal
Republic of Germany.
Inherited
mutations of Patched (PTCH) in the nevoid basal cell carcinoma syndrome
(NBCCS) lead to several developmental defects and contribute to tumor
formation in a variety of tissues. PTCH mutations have been also
identified in sporadic tumors associated with NBCCS including basal
cell carcinoma (BCC) and medulloblastoma. Mice heterozygous for Ptch
recapitulate the typical developmental symptoms of NBCCS and develop
rhabdomyosarcoma (RMS) and medulloblastoma. PTCH is assumed to act as a
tumor suppressor gene although inactivation of both alleles has been
demonstrated only in a fraction of tumors. We have investigated the
status of Ptch in RMS of heterozygous Ptch neo67/+ mice. Although the
wild-type Ptch allele was retained in tumor tissue, the high levels of
Ptch mRNA in these tumors result from overexpression of the mutant Ptch
transcript. Our results suggest that the wild-type Ptch allele might be
selectively silenced in RMS tissue or, alternatively, that
haploinsufficiency of Ptch is sufficient to promote RMS formation in
mice.
PMID: 12016144 [PubMed - indexed for MEDLINE]
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Bone tumorigenesis induced by
alpha-particle radiation: mapping of genetic loci influencing
predisposition in mice.
Rosemann M,
Lintrop M, Favor J, Atkinson MJ.
Institute of Pathology at the GSF National Research Center for
Environment and Health, Neuherberg, Germany. rosemann@gsf.de
The
present study was carried out to determine the extent to which genetic
factors modify the incidence of radiation-induced bone tumorigenesis in
mice, and to map putative susceptibility genes. We conducted a
genome-wide linkage analysis in a cohort of 47 interstrain backcrossed
mice. After the mice were injected with the bone-seeking
alpha-particle-emitting radionuclide (227)Th, 21 of the mice developed
osteosarcomas. Two loci, one on chromosome 7 close to D7Mit145 and a
second on chromosome 14 (D14Mit125), exhibited suggestive linkage to
osteosarcoma predisposition, with LOD scores of 1.37 and 1.05,
respectively. The LOD score increased considerably when interaction
between these two loci was taken into account (LOD = 3.48). Nine of 12
mice inheriting a susceptibility allele at both loci developed
osteosarcomas after (227)Th injection, compared to only four
osteosarcomas in 18 animals that did not inherit either of the
susceptibility alleles. Variance component analysis revealed that these
genetic factors determine approximately one-fifth of the total
incidence of osteosarcomas. This study demonstrates the presence of a
genetic component that modulates predisposition to radiation-induced
osteosarcoma.
PMID: 11893245 [PubMed - indexed for MEDLINE]
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DNA structures and radiation injury.
Erzgraber G, Rosemann
M, Regel K, Abel H.
Central Institute for Molecular Biology, Berlin, Germany.
In
the present paper experimental results from radiobiological
investigations of the sedimentation behaviour of damaged and restored
DNA-subunits attached to the nuclear membrane have been summarized. The
studies were carried out preferably with Chinese Hamster cells V79-4
irradiated with different kinds of radiation (gamma-rays, neutrons and
carbon ions) using the nucleoid sedimentation technique. Single-strand
breaks relax the supercoiled DNA in the subunits resulting in a
decreased sedimentation velocity. Rejoining leads to a correct
restoration of the structure as can be studied by means of
postincubation irradiation. Double-strand breaks release DNA fragments,
again leading to an increased sedimentation velocity. If the average
number of the induced double-strand breaks per subunit increases to a
number higher than one, the measured results suggest that the
structures should not be restored completely. The results are
compatible with a new repair model developed in our laboratory on the
assumption that, firstly, the single DNA subunits are the sensitive
target rather than the whole DNA and, secondly, the repair of DNA
damage takes place independently in each subunit.
PMID: 11537053 [PubMed - indexed for MEDLINE]
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Chromosomal instability in haemopoietic
cells of
the foetus, mother and offspring after in utero irradiation of the
CBA/Ca mouse.
Rosemann M,
Milner A, Lambert BE.
Institute of Pathology, GSF Forschungszentrum fur Umwelt und
Gesundheit, Neuherberg, Germany. rosemann@gsf.de
PURPOSE:
The present study was conducted to test the susceptibility of the mouse
foetus to transmit chromosomal instability to the haemopoietic stem
cells of offspring after in utero X-or plutonium-239-irradiation.
MATERIALS AND METHODS: Pregnant CBA/Ca-mice were injected with 80
kBq/kg 239Pu or X-irradiated with 1 Gy X-rays on days 13 or 14 of
gestation. CFU-A cultures were grown from haemopoietic stem cells
sampled from foetal liver and the bone marrow from the offspring and
from the mother. Non-clonal, unstable chromosomal aberrations were
scored in metaphases from individual stem cell colonies. RESULTS: The
relative excess (RE) of unstable chromosomal aberrations in foetal
liver cells irradiated with 1 Gy X-rays increased from 1.6 at day 2 up
to 2.7 at day 4 after irradiation. In the bone marrow cells from the
mother, this value was 1.8 (average from cells sampled at days 3 and 14
after irradiation). After injection of the pregnant mice with 235Pu,
the yield of unstable chromosomal aberrations per cell was 0.14+/-0.03
(RE approximately 10) in descendants of bone marrow cells from the
mother, 0.11+/-0.02 (RE = 10) in descendants of foetal liver cells and
0.16+/-0.05 (RE = 10) in descendants of bone marrow cells from the
offspring. CONCLUSIONS: From the numerical analysis of non-clonal,
unstable aberrations in haemopoietic cells from the foetus, the mother
and the offspring after in utero irradiation, it was concluded that in
utero irradiation of the CBA/Ca mouse was not more efficient in
inducing chromosomal instability in the offspring than in the foetus or
the mother. All three cell populations exhibited a similar degree of
unstable aberrations, both in terms of the absolute numbers of
non-clonal aberrations and in terms of relative excess compared with
unexposed controls.
PMID: 10374942 [PubMed - indexed for MEDLINE]
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Molecular mechanisms of radiation
carcinogenesis and the linear, non-threshold dose response model of
radiation risk estimation.
Trott KR, Rosemann
M.
Department
of Radiation Biology, St. Bartholomew's and the Royal London School of
Medicine and Dentistry, Queen Mary & Westfield College, UK.
Recent
research in molecular radiation carcinogenesis is reviewed with the
specific aim of exploring the implications this research may have on
the dose response relationship of radiation-induced cancer at low doses
and low dose rates. It is concluded that the linear non-threshold dose
response hypothesis may be used in radiation protection planning as a
simple, convenient method to optimize procedures and regulations, but
should not be mistaken as a stringent scientific conclusion directly
derived from the present state of knowledge of the processes involved
in radiation carcinogenesis.
Publication Types:
PMID: 10929376 [PubMed - indexed for MEDLINE]
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Chromatin structure and cellular
radiosensitivity: a comparison of two human tumour cell lines.
Woudstra EC, Roesink JM, Rosemann M, Brunsting JF,
Driessen C, Orta T, Konings AW, Peacock JH, Kampinga HH.
Department of Radiobiology, University of Groningen, The Netherlands.
The
role of variation in susceptibility to DNA damage induction was studied
as a determinant for cellular radiosensitivity. Comparison of the
radiosensitive HX142 and radioresistant RT112 cell lines previously
revealed higher susceptibility to X-ray-induced DNA damage in the
sensitive cell line using non-denaturing elution, but not when using
alkaline unwinding. The present data also show that no difference in
the amount of initial damage is seen when pulsed-field gel
electrophoresis (PFGE) or comet analysis are used for DNA damage
assessment. However, using the halo assay or a modified version of PFGE
in which the higher DNA architecture remained partially intact, the
radiosensitive cells showed steeper dose-response curves for initial
DNA damage than the radioresistant cells. Analysis of the protein
composition, of DNA-nucleoid structures revealed substantial
differences when isolated from HX142 or RT112 cells. From our data, it
is concluded that HX142 and RT112 differ in their structural
organization of chromatin. As no differences in the kinetics of DNA
damage rejoining were found, it is hypothesized that the same amount of
lesions have a different impact in the two cell lines in that the
'presentation' of DNA damage alters the ratio of repairable to
non-repairable DNA damage.
PMID: 8980667 [PubMed - indexed for MEDLINE]
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An image analysis technique for
detection of radiation-induced DNA fragmentation after CHEF
electrophoresis.
Rosemann M,
Kanon B, Konings AW, Kampinga HH.
Department of Radiobiology, State University of Groningen, The
Netherlands.
CHEF-electrophoresis
was used as a technique to detect radiation-induced DNA breakage with
special emphasis to biological relevant X-ray doses (0-10 Gy).
Fluorescence detection of DNA-fragments using a sensitive image
analysis system was directly compared with conventional scintillation
counting of 3H-thymidine prelabelled DNA in HeLa S3 cells. It is shown
that the image analysis-based fluorescence detection of fragmented DNA
after ionizing radiation is as sensitive and reproducible as detection
using radioactively prelabelled cells without the putative shortcomings
of fluorescence detection methods described earlier (Blocher and Kuhni
1990). Therefore, the image analysis-based detection of
radiation-induced DNA fragmentation after CHEF electrophoresis seems to
be the most reliable method for applications to non-cycling cells and
biopsy material.
PMID: 8103550 [PubMed - indexed for MEDLINE]
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