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At least 541 records · Page 30Linked to original sources
PubMed2003

Radiation-induced genomic instability in immortalized haemopoietic stem cells.

PURPOSE: To investigate the expression of radiation-induced delayed reproductive death and chromosomal instability using an immortalized cell line (R-M26/2-1) with the characteristics of long-term repopulating haemopoietic stem cells established from the CBA mouse strain. MATERIALS AND METHODS: R-M26/2-1 cells were gamma-irradiated and maintained in culture for up to 41 population doublings. At intervals, measurements were made of cloning efficiency and cells were examined for cytogenetic aberrations at eight and 24 population doublings. The p53 status and p53 phosphorylation were investigated by Western analysis and immunocytochemistry and production of intracellular reactive oxygen species was investigated by use of the fluorescent probe DCFH-DA. RESULTS: The descendants of cells surviving 4Gy gamma-irradiation exhibited a reduced colony-forming efficiency and expressed chromosomal instability independent of p53 function and with no evidence of enhanced production of reactive oxygen species. The delayed reproductive death phenotype persisted at a constant rate of 12% clonogenic cell loss when colony formation was assessed in anchorage-dependent conditions on tissue culture substrates. However, R-M26/2-1 cells, like normal haemopoietic cells, can be cultured in anchorage-independent conditions and this type of assay demonstrated a 50% or greater persisting clonogenic cell loss. There was no significant delayed reproductive death or chromosomal instability in cultures established with 0.5 Gy gamma-irradiated R-M26/2-1 cells. CONCLUSIONS: A radiation-induced genomic instability phenotype, independent of p53 function and with no evidence of oxidative stress, was demonstrated in the descendants of 4Gy gamma-irradiated R-M26/2-1 cells and unstable aberrations characteristic of radiation-induced chromosomal instability may account for a component of the delayed reproductive death phenotype. Colony-forming efficiency and expression of the delayed death phenotype determined using an anchorage-independent assay was significantly greater than that determined using an anchorage-dependent assay indicating that some aspect of adherence influences these endpoints. The absence of significant instability in the descendants of 0.5 Gy gamma-irradiated cells implies a threshold for these endpoints in this haemopoietic stem cell line.

Animals↗
PubMed2003

Genomic instability and tumor-specific alterations in oral squamous cell carcinomas assessed by inter-(simple sequence repeat) PCR.

PURPOSE: Genomic instability plays a major role in the genesis and progression of tumors, and in the evolution of tumor heterogeneity. To determine the role of genomic instability in the genesis and progression of oral cancer, we assessed the extent of genomic alterations in oral squamous cell carcinomas (OSCCs). EXPERIMENTAL DESIGN: We used the recently developed inter-(simple sequence repeat) PCR technique to quantitate genomic instability using matched tumor and normal OSCC samples (n = 25). The inter-repeat region bands of similar molecular size observed to be altered in more than one case were sequenced and analyzed to identify probable OSSC-associated specific genetic lesions. RESULTS: Of the four base-anchored, dinucleotide repeat-based primers used for the study, the most informative profile in OSCCs was generated by the (CA)(8)RG primer. Measurement of genomic instability index using the (CA)(8)RG primer revealed a high incidence of genomic instability in OSCCs. No significant correlation between the extent of alterations and stage or location of the tumor was observed. Sequencing analysis of the altered bands revealed gains/losses in several chromosomal regions. Of the matched tumor and corresponding normal tissue DNA studied, hitherto unreported losses were seen in 11p15 and 17q25 chromosomal regions. Sequencing of some of the tumor-specific altered regions indicated that they code for regions of UDP-GalNAc and hRAD 17 genes, which were lost (deleted) in oral cancer. CONCLUSIONS: Our results indicate that the extent of genomic instability in OSCC is not correlated to the tumor stage or location. For the first time, we have shown that chromosomal alterations detected by inter-(simple sequence repeat) PCR could be correlated to genes associated with cancer development.

Adult↗
PubMed2004

[Instability of repetitive units of foreign centromeric satellite DNA in transgenic mice and transfected cells].

Cytologically detectable instability of centromeric satellite DNA may cause hereditary disorders in human. To study the mechanisms of such instability, two transgenic mouse lines and 11 clones of transfected F9 mouse embryonic teratocarcinoma cells were obtained with the 3.8-kb repetitive unit (Sat) of Bos taurus satellite DNA IV. Intergeneration and somatic instability of exogenous satellite DNA (satDNA) was observed in transgenic mice and transfected cells as a change in nucleotide sequence of an internal Sat region approximately 1000 bp in size. Since Sat was in the hemizygous state in both cases by the experimental protocol, the instability was attributed to intra-allelic processes. Intergeneration instability probably took place in the premeiotic period of gametogenesis or in early embryo development and led to prenatal death of transgenic embryos after at least one generation. No direct or inverse correlation was observed between methylation and instability of Sat. The results testify that submicroscopic changes in highly repetitive noncoding DNA sequences may already affect the genome function in higher eukaryotes.

Animals↗
PubMed2005

Wood smoke inhalation causes alveolar instability in a dose-dependent fashion.

BACKGROUND: Wood smoke inhalation causes severe ventilation and oxygenation abnormalities. We hypothesized that smoke inhalation would cause lung injury by 2 mechanisms: (1) direct tissue injury by the toxic chemicals in the smoke and (2) a mechanical shear-stress injury caused by alveolar instability (ie, alveolar recruitment/derecruitment). We further postulated that alveolar instability would increase with the size of the cumulative smoke dose. METHODS: Anesthetized pigs were ventilated and instrumented for hemodynamic and blood-gas measurements. After baseline readings, the pigs were exposed to 5 separate doses of wood smoke, each dose lasting 1 min. Factors studied included hemodynamics, pulmonary variables, and in vivo photomicroscopy of alveolar mechanics (ie, the dynamic change in alveolar size with ventilation). RESULTS: Smoke inhalation significantly increased alveolar instability with 4 min and 5 min of smoke exposure. Significant rises in carboxyhemoglobin levels and in pulmonary shunt were also observed at 4 min and 5 min of smoke exposure. Lung histology demonstrated severe damage characteristic of acute lung injury. CONCLUSIONS: We demonstrated that wood smoke inhalation causes alveolar instability and that instability increases with each dose of smoke. These data suggest that smoke inhalation may cause a "2-hit" insult: the "first hit" being a direct toxic injury and the "second hit" being a shear-stress injury secondary to alveolar instability.

Animals↗
PubMed1990

[Rotational instability of the lumbar spine--a three-dimensional motion study using bi-plane X-ray analysis system].

The purpose of this study is to investigate the rotational instability of the lumbar spine using bi-plane X-ray analysis system and to clarify mechanical etiology of the lumbar instability. The following results were obtained. (1) The range of rotational motion was about 2 to 3 degrees at each motion segment in the normal lumbar spine. The rotational motion was significantly large in spondylolysis, spondylolisthesis, and degenerative spondylolisthesis. (2) The rotational instability and the flexion-extension instability correlated to each other in spondylolysis and spondylolisthesis. However, in degenerative spondylolisthesis, the rotational instability and the antero-posterior instability were correlated to each other. (3) Instantaneous axis of rotation (IAR) was located at the posterior part of the intervertebral disc in the normal L4 vertebra, and more posteriorly in the L5 vertebra, while the IAR was located anteriorly in spondylolysis, and posteriorly in degenerative spondylolisthesis. (4) When the trunk was twisted, the lumbar lordotic angle was generally decreased, and the lumbar spine showed scoliotic curvature convex to the twisted direction. The apex was located at the L4/5 intervertebral level. Highly significant increases in flexion motion associated with rotation were observed at the pathological levels of spondylolysis and degenerative spondylolisthesis.

Adult↗
PubMedDate not supplied

Anterolateral rotary instability associated with chronic anterior cruciate insufficiency.

Patients with anterior cruciate tears identified by previous surgery were examined for anterolateral rotary instability of the knee. Twenty-four of 30 patients returning for examination had positive tests for anterolateral rotary instability using the techniques described by both Slocum and MacIntosh. The presence of anterolateral rotary instability was directly related to the attainment of full extension of the operative knee. Inherent ligamentous laxity and the degree of combined instabilities were thought to amplify the anterolateral rotary instability tests. Quadriceps rehabilitation, pes anserines transfers and semimembranosus transfers were thought not to influence anterolateral rotary instability.

Adult↗
PubMed1981

[Intraclonal heterogeneity and instability of CHO-K1 Chinese hamster cells in sensitivity to ultraviolet light and resistance to 8-azaguanine].

The phenotypic instability of a 8-azaguanine (AG)-resistant clone A14--2c-1 was previously reported (Abramyan et al., 1979) to be determined by genetic (replicative) instability. Further, phenotype gene activity changes are characteristic of genetically instable "mutant", which may be "passed" from one locus to another. In the present work, some clones were isolated from clone A14-2c-1 differing in their sensitivity to lethal UV-radiation, lethal dose D37 differences being almost 6 times. During a further cultivation through 90 passages (300 cell generations), two of four clones changed their D37 values: for clone 2c-15 it increased by 3 times, for clone 2c-16 it decreased more than twice. Besides, subclones of 2c-15 and 2c-16 clones had also different D37 values. With respect to AG-resistance, clone 2s-15 was shown to have LD50 to AG, similar to that of the parental one-while in 3 other clones LD50 was 3 times as much. These differences are associated with variations in hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity: in clones A14-2c-1 and 2c-15 this activity is two times higher than in other clones. All the clones have the same value of the Michaelis constant for hypoxanthine and phosphoribosylpyrophosphate. It can be outlined that difference in HPRT activity and quantity in cells are closely related. Thus, phenotypic instability of A14-2c-1 clone offers characteristic features of genetic (replicative) instability: instability in AG-resistance and UV-sensitivity coincides with interclonal heterogeneity according to unstable markers; the unstable property may be transmitted from one locus (responsible for AG-resistance) to be another one (UV-sensitivity); and different level of AG-resistance in clones is probably determined by changes in gene activity, which lead to differences in HPRT quantity in cells.

Animals↗
PubMedDate not supplied

Extra-articular stabilization of the knee joint for anterior instability.

The results after one year or longer were evaluated in 76 patients with extra-articular reconstruction for functionally disabling anterior instability of the knee joint. The reconstruction was performed by a modification of the Ellison procedure for treatment of anterolateral rotatory instability. The various superimposed components of knee instability were managed by a variety of methods. Postoperatively,objective stability correlated well with subjective improvement. Patients with 2+ or greater anterior instability preoperatively had disappointing results in both subjective symptoms and objective signs. although extra-articular reconstruction may be sufficient for lesser grades of functionally disabling instability, knees with grade 2-3+ instability may require direct anterior cruciate ligament reconstruction in addition to the extra-articular surgical procedure.

Evaluation Studies as Topic↗
PubMed1980

Intra-articular volume and hip joint instability in dogs with hip dysplasia.

UNLABELLED: The nature of the instability of the hip joint in dogs with dysplasia of the hip was investigated. In the experimental canine model, instability of the joint, as shown by subluxation of the femoral head on a roentgenogram, was accompanied by an increase in the volume of the synovial fluid and of the ligamentum teres and, therefore, an increase in the intra-articular volume. Injection of a buffered solution of hyaluronic acid into non-subluxated hip joints in situ increased subluxation, whereas withdrawal of synovial fluid from one joint with severe subluxation reduced the degree of subluxation. The withdrawal of varying amounts of synovial fluid from excised but intact joints resulted in a decrease in the lateral displacement of the femoral heads. Injection of the hyaluronic acid solution into excised joints resulted in increased lateral displacement of the femoral heads. The results suggest that the joint instability associated with canine hip dysplasia is related to increased intra-articular volume. CLINICAL RELEVANCE: Instability of the hip joint (abnormal laxity) is a feature of hip dysplasia in dogs and congenital dislocation of the hip in children. The canine disease can provide a valuable model in which to examine the pathogenesis of hip instability. The model may be useful to test prophylactic procedures to prevent joint instability and thus ameliorate disease.

Animals↗
PubMed1994

Instability of short tandem repeats (microsatellites) in human gliomas.

OBJECTIVE: Microsatellite instability implying multiple replication errors (RER) characterizes a proportion of familial and sporadic carcinomas. The purpose of this report is to analyze whether microsatellite instability occurred during the development of human gliomas. EXPERIMENTAL DESIGN: We checked prospectively 16 central nervous system tumors, including 10 glioblastomas and 6 astrocytomas of different malignancy grades, for genetic microsatellite instability. Fifteen different microsatellites, located on 6 different chromosomes, were investigated. All microsatellites are dinucleotide CA, repeats except for D11S956,P23 (CTAT) and CYP 19, which are tetranucleotide repeats and P23 (GTTTT) which is a pentanucleotide repeat. The repeats were analysed by PCR amplification, followed by electrophoresis on denaturing 6% polyacrylamide gels. MEASURES: We looked for all kinds of microsatellite alterations. Only microsatellite shifts were considered to represent microsatellite instability. RESULTS: Three out of 10 glioblastomas showed mobility shifts on gel electrophoresis in tumor, compared to corresponding normal DNA samples. In contrast, no microsatellite instability was found in any of the astrocytomas. Besides the presence of larger or smaller alleles, an imbalance in the ratio between alleles was noticed in one astrocytoma and in one glioblastoma multiforme. In addition, loss of heterozygosity (LOH) is observed without a fixed pattern in 3 glioblastomas. CONCLUSIONS: We conclude that genetic instability of microsatellites may be demonstrated in high grade gliomas rather than in their low grade precursors and should be regarded as an evolution in tumor progression rather than as a new mechanism for tumor initiation in gliomas.

Astrocytoma↗
PubMed1995

Microsatellite instability in colorectal adenocarcinoma cell lines that have full-length adenomatous polyposis coli protein.

Almost 20% of colon cancers are characterized by genomic instability at simple repeated sequences. This instability is the result of a deficient DNA mismatch repair system. Sporadic, as well as hereditary carcinomas of the proximal colon display this effect. In this study, we examined colorectal adenocarcinoma cell lines, with or without wild-type adenomatous polyposis coli (APC) protein, for the presence of microsatellite instability. The three cell lines that maintained full-length APC protein also displayed the highest level of instability, suggesting a negative correlation between APC mutations and microsatellite instability. This data, in addition to other studies that show a negative correlation between microsatellite instability and mutations in p53 and K-ras, support the idea of a second pathway for colorectal cancer development.

Adenocarcinoma↗
PubMed1995

Association of minisatellite instability with c-myc amplification and K-ras mutation in methylcholanthrene-induced mouse sarcomas.

Instability of microsatellite sequences are frequently found in human tumors. In addition, minisatellite sequences, another group of highly unstable sequences, serve as sensitive markers of genetic instability. We have studied minisatellite instability in methylcholanthrene-induced mouse sarcomas. These sarcomas frequently carry the amplified c-myc gene. Seven sarcomas without the amplification and seven others with the amplification were selected randomly. Regardless of the state of the c-myc gene amplification, these sarcomas exhibited a varying degree of transplantability in syngeneic mice. The hypervariable mouse minisatellite locus Ms6hm was found to be highly unstable, specifically among sarcomas with the amplified c-myc gene. However, chromosome instability, as analyzed by micronucleus assay, was observed similarly for two groups of sarcomas. In addition, transversion of G to C and A to T was detected at the K-ras gene in four of the seven sarcomas with the amplified c-myc gene, and these mutations are thought to be induced directly by methylcholanthrene. Thus, concomitant occurrence was observed for three seemingly unrelated mutations, amplification of the c-myc locus, point mutation of the K-ras gene, and instability at the hypervariable mouse minisatellite locus. The present study indicates a possible involvement of K-ras mutation and c-myc amplification in induction of genetic instability in methylcholanthrene-induced mouse sarcomas.

Animals↗
PubMed1995

Multiple mechanisms account for genomic instability and molecular mutation in neoplastic transformation.

Neoplastic cells typically possess numerous genomic mutations and chromosomal aberrations, including point mutations, gene amplifications and deletions, and replication errors. Acquisition of such genomic instability may represent an early step in the process of carcinogenesis. Proteins involved in DNA replication, DNA repair, cell cycle progression, and others are all components of complex overlapping biochemical pathways that function to maintain cellular homeostasis. Therefore, mutational alteration of genes encoding proteins involved in these cellular processes could contribute to genomic instability. Loss of normal cellular mechanisms that guard against genomic mutation and the ensuing genomic instability might lead to accumulation of multiple stable mutations in the genome of affected cells, perhaps resulting in neoplastic transformation when some critical number of transformation-related target genes become damaged. Thus, interactions of fundamental cellular processes play significant roles in sustaining cellular normality, and alteration of any of these homeostatic processes could entrain cells to the progressive genomic instability and phenotypic evolution characteristic of carcinogenesis. Here, we discuss possible molecular mechanisms governing DNA mutation and genomic instability in genetically normal cells that might account for the acquisition of genomic instability in somatic cells, leading to the development of neoplasia. These include (a) molecular alteration of genes encoding DNA repair enzymes, (b) molecular alteration of genes responsible for cell-cycle control mechanisms, and (c) direct molecular alteration of dominantly transforming cellular protooncogenes. We also discuss normal cellular processes involved with DNA replication and repair that can contribute to the mutational alteration of critical genes: e.g., slow repair of damaged DNA in specific genes, and the timing of normal gene-specific replication.

Animals↗
PubMed1994

Microsatellite instability in ulcerative colitis-associated colorectal dysplasias and cancers.

Microsatellites are short nucleotide repeat sequences present throughout the human genome. Alterations of microsatellites, comprising extra or missing copies of these sequences, have been termed microsatellite instability. This abnormality occurs in sporadic and hereditary adenocarcinomas of the proximal colon, as well as in many other tumor types. We determined whether microsatellite instability occurred in ulcerative colitis-associated cancers or precancerous dysplasias. Sixty-three patients were evaluated, consisting of 188 samples of genomic DNA (63 normal controls, 68 cancers, 52 dysplasias, and 5 adjacent tissues) at loci D2S119, D2S123, D2S147, D10S197, and D11S904. Multiplex polymerase chain reaction was performed using one radiolabeled nucleotide, and the products were electrophoresed on denaturing polyacrylamide gels. Seventeen of the 63 patients (27%) possessed lesions showing instability at 1 or more loci. Fourteen of 68 tumor samples (21%) and ten of 52 dysplasias (19%) displayed instability. There was no tendency for a greater number of loci to manifest instability in more advanced lesions. Neither anatomic location nor loss of heterozygosity at the p53 locus were associated with microsatellite instability by 2-way table analysis. These data support a role for defective DNA repair in the generation of a subset of both early and advanced ulcerative colitis-associated colorectal neoplastic lesions.

Colitis, Ulcerative↗
PubMed1994

Genetic instability of microsatellite sequences in many non-small cell lung carcinomas.

We have analyzed DNA obtained from 38 lung tumors and normal lung or blood DNA for microsatellite instability. Instability was examined at 10 different microsatellite loci on chromosome 3p, as well as loci on 3q, 11p, 11q, and 13q, and two on Xq. We observed microsatellite instability at one or more loci in 13 of the lung tumors analyzed, and this instability ranged from tumors showing instability in only a single microsatellite to two adenocarcinomas that had alterations in all 16 tested microsatellites. Microsatellite instability could therefore play a significant role in the development of a sizable portion of lung tumors.

Alleles↗
PubMed1994

In vivo enhancement of genomic instability in minisatellite sequences of mouse C3H/10T1/2 cells transformed in vitro by X-rays.

The level of genomic instability was determined during tumor development in vivo. Genomic rearrangements, a marker of genomic instability, was measured in mouse C3H/10T1/2 cells transformed in vitro by X-rays with a DNA fingerprinting assay. Three transformed clones isolated from type III foci were divided into two groups. Cells from the first group were injected s.c. into syngeneic and nonimmunosuppressed C3H mice. After 3 to 5 months, the tumors were excised, and the neoplastic cells were isolated and subcloned. Cells from the second group were incubated in vitro for 25 passages (about 6 months) to approximate the number of cell divisions occurring in the tumor, and then they were subcloned. DNA was extracted from subclones grown in vitro and in vivo and analyzed with the DNA fingerprinting assay. A high frequency of genomic rearrangements (50-100%) was found in subclones derived from tumors that arose in vivo, whereas the frequency was very low (< 10%) among subclones passaged in vitro, suggesting that genetic instability may be enhanced by factors present in the C3H mouse. In one clone (F-17) genomic instability appeared to be activated and down regulated. The high frequency of instability found in tumor cell subclones did not appear to result from an in vivo selection of a more tumorigenic subpopulation of cells present in the original clone prior to injection in the animal. This enhancement of genomic instability occurring in vivo could be required to complete the process of transformation to tumorigenicity and allow the neoplastic cells to adapt to a new environment.

Animals↗
PubMed1996

Role of induced genetic instability in the mutagenic effects of chemicals and radiation.

Recent studies have demonstrated that cells exposed to ionizing radiation or alkylating agents can develop prolonged genetic instability. Induced genetic instability is manifested in multiple ways, including delayed reproductive death, an increased rate of point mutations, and an increased rate of chromosome rearrangements. In many respects these changes are similar to the genetic instability associated with cancer and some human genetic diseases. Therefore, as with cancer cells, multiple mechanisms may be involved, some occurring in the early stages and some in the later stages. The high percentage of cells that develop induced genetic instability after exposure to stress, and the prolonged period over which the instability occurs, indicates that the instability is not in response to residual damage in the DNA or mutations in specific genes. Instead, changes affecting most of the exposed cells, such as epigenetic alterations in gene expression or chain reactions of chromosome rearrangements, are a more likely explanation. Learning more about the mechanisms involved in this process is essential for understanding the consequences of exposure of cells to ionizing radiation or alkylating agents.

Alkylating Agents↗
PubMed1995

Microsatellite instability is infrequent in neuroblastoma.

Neuroblastoma (NB) is a childhood cancer of the autonomic nervous system. The molecular pathology of NB is not yet well understood. Both amplification of the proto-oncogene N-myc and loss of heterozygosity of several chromosomal loci occur in NB, representing genetic instability. In this study, we examined another type of genetic instability, microsatellite instability. Five chromosomal loci known to exhibit this alteration in colon, gastric, and pancreatic cancers were used in a PCR-based assay to examine 30 matched normal and tumor DNAs, which included all stages of tumor progression. Among these 30, only 2 (7%) manifested microsatellite instability. There was no correlation between the occurrence of microsatellite instability and the amplification of the N-myc gene. These data show that microsatellite instability is infrequent in neuroblastoma tumors.

Case-Control Studies↗