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At least 775 records · Page 43Linked to original sources
PubMed2000

Meiotic instability of CAG repeat tracts occurs by double-strand break repair in yeast.

Expansion of trinucleotide repeats is associated with a growing number of human diseases. The mechanism and timing of expansion of the repeat tract are poorly understood. In humans, trinucleotide repeats show extreme meiotic instability, and expansion of the repeat tract has been suggested to occur in the germ-line mitotic divisions or postmeiotically during early divisions of the embryo. Studies in model organisms have indicated that polymerase slippage plays a major role in the repeat tract instability and meiotic instability is severalfold higher than the mitotic instability. We show here that meiotic instability of the CAG/CTG repeat tract in yeast is associated with double-strand break (DSB) formation within the repeated sequences, and that the DSB formation is dependent on the meiotic recombination machinery. The DSB repair results in both expansions and contractions of the CAG repeat tract.

Alcohol Oxidoreductases↗
PubMed1998

Chromosomal instability in the descendants of unirradiated surviving cells after alpha-particle irradiation.

We have demonstrated chromosomal instability in the clonal descendants of hemopoietic stem cells after irradiating murine bone marrow with alpha-particles. However, because cells that are irradiated by alpha-particles are defined by a Poisson distribution of individual particle traversals, there is an inevitable proportion of unirradiated cells in the surviving population. The calculated expected proportions of irradiated and nonirradiated cells indicate that the number of clonogenic cells transmitting chromosomal instability is greater than the number expected to be hit and survive. To investigate further this discrepancy, we studied the effects of interposing a grid between the cells and the alpha-particle source so that the surviving population consists predominantly of untraversed stem cells. Comparison with the same irradiation conditions without the grid reveals that the same level of instability is induced. The data confirm that alpha-particles induce chromosomal instability but instability is demonstrated in the progeny of nonirradiated stem cells and must be due to unexpected interactions between irradiated and nonirradiated cells. This untargeted effect has important implications for mechanistic studies of radiation action and for assessment of radiation risk.

Abnormalities, Radiation-Induced↗
PubMed2005

BetaIII-tubulin induces paclitaxel resistance in association with reduced effects on microtubule dynamic instability.

The development of resistance to paclitaxel in tumors is one of the most significant obstacles to successful therapy. Overexpression of the betaIII-tubulin isotype has been associated with paclitaxel resistance in a number of cancer cell lines and in tumors, but the mechanism of resistance has remained unclear. Paclitaxel inhibits cancer cell proliferation by binding to the beta-subunit of tubulin in microtubules and suppressing microtubule dynamic instability, leading to mitotic arrest and cell death. We hypothesized that betaIII-tubulin overexpression induces resistance to paclitaxel either by constitutively enhancing microtubule dynamic instability in resistant cells or by rendering the microtubules less sensitive to the suppression of dynamics by paclitaxel. Using Chinese hamster ovary cells that inducibly overexpress either betaI- or betaIII-tubulin, we analyzed microtubule dynamic instability during interphase by microinjection of rhodamine-labeled tubulin and time-lapse fluorescence microscopy. In the absence of paclitaxel, there were no differences in any aspect of dynamic instability between the two beta-tubulin-overexpressing cell types. However, in the presence of 150 nm paclitaxel, dynamic instability was suppressed to a significantly lesser extent (suppressed only 12%) in cells overexpressing betaIII-tubulin than in cells overexpressing similar levels of betaI-tubulin (suppressed 47%). The results suggest that overexpression of betaIII-tubulin induces paclitaxel resistance by reducing the ability of paclitaxel to suppress microtubule dynamics. The results also suggest that endogenous regulators of microtubule dynamics may differentially interact with individual tubulin isotypes, supporting the idea that differential expression of tubulin isotypes has functional consequences in cells.

Animals↗
PubMed2006

Adverse outcomes in patients with community acquired pneumonia discharged with clinical instability from Internal Medicine Department.

There are well established admission criteria for patients suffering from community-acquired pneumonia, yet the clinical tool for decision to discharge the hospitalized patient is lacking. Continuous pressure to reduce hospital expenditures can lead to a premature discharge of unstable patients. The current study assessed the impact of clinical instability at discharge on short-term outcomes. Demographic data, background disease, laboratory tests results and PORT score were assessed prospectively. On the last day of the hospitalization 7 physiological parameters of instability were evaluated. 60 d composite mortality and readmission rate was a primary outcome measure. Of the 373 patients, 22% were discharged with 1 or more instabilities, of whom 26.8% reached primary outcome within 60 d, compared to 8.2% of patients with no instabilities. 60 d death rate was 2.1% in the former group, compared to 14.6% in the unstable patients (p<0.001). Instability on discharge remained a significant prognosticator of adverse outcome (odds ratio 3.5; 95% CI 1.8-6.8) after adjustment for pneumonia severity and baseline comorbidity. We concluded that discharging an unstable patient hospitalized with pneumonia is associated with elevated risk of death or readmission within 60 d. Pneumonia guidelines should include objective criteria for judging patients' stability and promptness for discharge.

Adolescent↗
PubMed2000

Coming of age: 'dysgenetics'--a theory connecting induction of persistent delayed genomic instability with disturbed cellular ageing.

INTRODUCTION: In recent years a new phenomenon has manifested itself: delayed, persistent genomic instability. When cells are treated with carcinogens not only direct induction of chromosome aberrations and mutations takes place, but there is also an indirect induction: in the distant progeny of treated cells persistently enhanced levels of new chromosome aberrations and enhanced mutation rates are found. This persistent enhanced genomic instability is not due to the presence of lesions in the DNA induced by the treatment because the response can be transmitted to untreated cells. Apparently it is caused by a persistent dysfunctioning of the cell as a whole. Due to these findings a new model for multistep carcinogenesis emerges. According to this model the initiation of carcinogenesis is the induction of a state of persistent genomic instability that not only is responsible for enhanced mutation rates of oncogenes and tumor suppressor genes, but also predisposes to immortalization. This view could lead to a radical change in our views on carcinogenesis. Therefore understanding the mechanism is of utmost importance. PURPOSE: Up to now, the mechanism responsible for this persistent delayed genomic instability remains completely elusive and has only been described as 'unknown'. In this review the phenomenon is connected with a recent theory on cellular ageing and immortalization. CONCLUSION: Although highly speculative this review provides a framework for further experimental approaches that will contribute to our understanding of delayed genomic instability and possibly even to a better understanding of cellular ageing also.

Animals↗
PubMed1998

Radiation-induced chromosomal instability in human fibroblasts: temporal effects and the influence of radiation quality.

PURPOSE: To determine whether chromosomal instability is induced in human diploid fibroblasts by ionizing radiation and to investigate the effects of radiation quality by comparing X-rays, neutrons and alpha-particles. MATERIALS AND METHODS: Cells from two human diploid fibroblast lines, HF12 and HF19, were irradiated and analysed cytogenetically at 3, 20 and 35 population doublings post-irradiation. RESULTS: Exposure of HF19 cells to neutrons and alpha-particles resulted in a consistently increased frequency of unstable aberrations, particularly chromatid-type aberrations, compared to control cultures. Aberration frequency after X-irradiation was not significantly greater than controls at 20 population doublings but was significantly increased after 35 population doublings, although not to the same level as that following neutron or alpha-irradiation. No chromosomal instability was demonstrated in the progeny of HF12 cells after X-, neutron or alpha-particle irradiation. CONCLUSIONS: The data are consistent with the progeny of irradiated HF19 cells expressing chromosomal instability. All three radiations are effective in inducing instability, but the expression of the phenotype is influenced by radiation quality. The absence of radiation-induced chromosomal instability in HF12 cells may reflect the influence of genetic factors.

Alpha Particles↗
PubMed1998

Chromosomal instability in human lymphocytes after low dose rate gamma-irradiation and delayed mitogen stimulation.

PURPOSE: To study the possibility that radiation induced chromosomal instability in human lymphocytes is promoted by a conflict between mitogen-induced growth stimulation and radiation-induced genotoxic stress. MATERIALS AND METHODS: Peripheral blood lymphocytes were exposed to low LET-irradiation at: (1) low-dose rate (LDR, 1-3 Gy, 0.024 Gy h[-1]) in order to minimize genotoxic stress; (2) high dose rate (HDR, 1-3 Gy, 45 Gy h[-1]) followed by immediate mitogen stimulation; and (3) HDR followed by a recovery period of 5 days before mitogen stimulation. Subsequent analyses included cell viability and clonogenic cell survival, chromosome aberrations at the first post-irradiation mitosis, and karyotype analysis of long term cultured cells, 11-57 days after mitogen stimulation. RESULTS: Dose (1-3 Gy) and dose rate (LDR and HDR) effects on the frequency of dicentric chromosomes at the first post-irradiation mitosis were in agreement with published data, with a pronounced dose rate effect of 2 and 3 Gy exposures. G-handed karyotypes after 11 days of growth in vitro showed increased frequencies of chromosome breaks and rearrangements in all irradiated cell cultures. Clones with complex karyotype abnormalities and increased frequencies of de novo aberrations developed in the irradiated cultures during extended growth for 22-57 days. These results show that: (1) LDR-irradiation induces chromosomal instability in primary human lymphocytes; (2) mitogen stimulation rescues HDR-irradiated cells from death at the expense of an increased level of chromosome aberrations; and (3) HDR-irradiated cells that are allowed 5 days of recovery before mitogen stimulation develop chromosomal instability during subsequent long-term proliferation. CONCLUSIONS: Neither the acute genotoxic stress of HDR-irradiation compared with LDR-irradiation, nor the hypothesized conflict between mitogen-induced growth stimulation and irradiation-induced growth arrest, seem to be critical conditions for the development of chromosomal instability in primary human T lymphocytes. Post-irradiation incubation allowing apoptotic processes to remove damaged cells does not prevent the subsequent development of chromosomal instability during long-term cell proliferation.

Cells, Cultured↗
PubMed2000

Mechanisms of dinucleotide repeat instability in Escherichia coli.

The high level of polymorphism of microsatellites has been used for a variety of purposes such as positional cloning of genes associated with diseases, forensic medicine, and phylogenetic studies. The discovery that microsatellites are associated with human diseases, not only as markers of risk but also directly in disease pathogenesis, has triggered a renewed interest in understanding the mechanism of their instability. In this work we have investigated the role of DNA replication, long patch mismatch repair, and transcription on the genetic instability of all possible combinations of dinucleotide repeats in Escherichia coli. We show that the (GpC) and (ApT) self-complementary sequence repeats are the most unstable and that the mode of replication plays an important role in their instability. We also found that long patch mismatch repair is involved in avoiding both short deletion and expansion events and also in instabilities resulting from the processing of bulges of 6 to 8 bp for the (GpT/ApC)- and (ApG/CpT)- containing repeats. For each dinucleotide sequence repeat, we propose models for instability that involve the possible participation of unusual secondary structures.

DNA Replication↗
PubMed1997

Human minisatellite MS32 (D1S8) displays somatic but not germline instability in transgenic mice.

Human minisatellite MS32 (D1S8) shows instability both in the germline and, at much lower levels, in somatic DNA. To investigate factors that influence somatic and germline mutation, large cosmid-based constructs containing MS32 were introduced into mice, bred to homozygosity and tested for instability in blood and sperm. Analysis of single copy and multicopy transgenic lines revealed somatic mutants occurring at a frequency comparable with that seen in man. As in humans, these mutants arose mainly by simple intra-allelic duplications and deletions. In contrast, analysis of sperm DNA from four different transgenic lines showed no trace of the complex recombination-based germline instability seen in man, even using PCR-based approaches capable of detecting very rare mutants. These data provide further evidence that germline and somatic mutation at human minisatellite MS32 occur via distinct pathways, that a major barrier exists to the transfer of germline instability from humans to mice and that the mouse germline appears to be protected from mitotic instability of the type seen in blood.

Alleles↗
PubMed1998

Somatic instability of the CTG repeat in mice transgenic for the myotonic dystrophy region is age dependent but not correlated to the relative intertissue transcription levels and proliferative capacities.

A (CTG)nexpansion in the 3'-untranslated region (UTR) of the DM protein kinase gene ( DMPK ) is responsible for causing myotonic dystrophy (DM). Major instability, with very large expansions between generations and high levels of somatic mosaicism, is observed in patients. There is a good correlation between repeat size (at least in leucocytes), clinical severity and age of onset. The trinucleotide repeat instability mechanisms involved in DM and other human genetic diseases are unknown. We studied somatic instability by measuring the CTG repeat length at several ages in various tissues of transgenic mice carrying a (CTG)55expansion surrounded by 45 kb of the human DM region, using small-pool PCR. These mice have been shown to reproduce the intergenerational and somatic instability of the 55 CTG repeat suggesting that surrounding sequences and the chromatin environment are involved in instability mechanisms. As observed in some of the tissues of DM patients, there is a tendency for repeat length and somatic mosaicism to increase with the age of the mouse. Furthermore, we observed no correlation between the somatic mutation rate and tissue proliferation capacity. The somatic mutation rates in different tissues were also not correlated to the relative inter-tissue difference in transcriptional levels of the three genes (DMAHP , DMPK and 59) surrounding the repeat.

Age Factors↗
PubMed1999

Length-dependent gametic CAG repeat instability in the Huntington's disease knock-in mouse.

The CAG repeats in the human Huntington's disease (HD) gene exhibit striking length-dependent intergenerational instability, typically small size increases or decreases of one to a few CAGs, but little variation in somatic tissues. In a subset of male transmissions, larger size increases occur to produce extreme HD alleles that display somatic instability and cause juvenile onset of the disorder. Initial efforts to reproduce these features in a mouse model transgenic for HD exon 1 with 48 CAG repeats revealed only mild intergenerational instability ( approximately 2% of meioses). A similar pattern was obtained when this repeat was inserted into exon 1 of the mouse Hdh gene. However, lengthening the repeats in Hdh to 90 and 109 units produced a graded increase in the mutation frequency to >70%, with instability being more evident in female transmissions. No large jumps in CAG length were detected in either male or female transmissions. Instead, size changes were modest increases and decreases, with expansions typically emanating from males and contractions from females. Limited CAG variation in the somatic tissues gave way to marked mosaicism in liver and striatum for the longest repeats in older mice. These results indicate that gametogenesis is the primary source of inherited instability in the Hdh knock-in mouse, as it is in man, but that the underlying repeat length-dependent mechanism, which may or may not be related in the two species, operates at higher CAG numbers. Moreover, the large CAG repeat increases seen in a subset of male HD transmissions are not reproduced in the mouse, suggesting that these arise by a different fundamental mechanism than the small size fluctuations that are frequent during gametogenesis in both species.

Age Factors↗
PubMed2000

Transgenic mice carrying large human genomic sequences with expanded CTG repeat mimic closely the DM CTG repeat intergenerational and somatic instability.

Myotonic dystrophy (DM) is caused by a CTG repeat expansion in the 3'UTR of the DM protein kinase (DMPK) gene. A very high level of instability is observed through successive generations and the size of the repeat is generally correlated with the severity of the disease and with age at onset. Furthermore, tissues from DM patients exhibit somatic mosaicism that increases with age. We generated transgenic mice carrying large human genomic sequences with 20, 55 or >300 CTG, cloned from patients from the same affected DM family. Using large human flanking sequences and a large amplification, we demonstrate that the intergenerational CTG repeat instability is reproduced in mice, with a strong bias towards expansions and with the same sex- and size-dependent characteristics as in humans. Moreover, a high level of instability, increasing with age, can be observed in tissues and in sperm. Although we did not observe dramatic expansions (or 'big jumps' over several hundred CTG repeats) as in congenital forms of DM, our model carrying >300 CTG is the first to show instability so close to the human DM situation. Our three models carrying different sizes of CTG repeat provide insight on the different factors modulating the CTG repeat instability.

3' Untranslated Regions↗
PubMed1998

Targeted breakage of paracentromeric heterochromatin induces chromosomal instability.

Current models suggest that genomic instability is crucial in the accumulation of the multiple alterations required for tumorigenesis. However, the nature of the initial damage responsible for the origin of genomic instability remains poorly understood. In this investigation we demonstrate that the nucleotide analog 2,6-diaminopurine (DAP) can be used to induce highly focused damage to the large blocks of paracentromeric heterochromatin on chromosomes 1, 9 and 16. A large fraction of cells exposed to DAP exhibit undercondensation of alpha and classical heterochromatin which persists into metaphase. Subsequent chromosome breakage was observed for one of the target chromosomes by preferential exclusion of chromosome 16 fragments into micronuclei (P < 0.0001). The specificity of DAP-induced chromosomal breakage enabled us to utilize it as a reagent to demonstrate that paracentromeric heterochromatin is a sensitive target for the induction of persistent genomic instability. We observed a 100-fold increase in mutagenesis affecting a chromosome 16 marker (APRT) compared with marker loci on chromosomes 17 (TK) or X (HPRT). We previously reported that APRT- mutants were recovered at a high rate upon selection in DAP in a process involving recombinationally mediated loss of heterozygosity that extends from the telomere to the boundary region of the paracentromeric heterochromatin. Karyotypic analysis of DAP-resistant APRT- mutant clones demonstrated extensive genomic instability, particularly evidence of multiple and sequential events affecting chromosome 16. These data suggest that the heterochromatic breakage observed cytogenetically immediately following DAP exposure is also responsible for the initiation of persistent genomic instability.

2-Aminopurine↗
PubMed2002

Measurement and analysis of the chemotherapy-induced genetic instability in pediatric cancer patients.

Bleomycin sensitivity has been proven to be a useful biomarker for environmental carcinogenesis and tumor genetic instability. We have previously reported a significant increase in the chromosomal aberrations induced by chemotherapy regimens. This study aimed to test whether there is an inherent increased genetic instability in cancer patients at diagnosis, to determine the increase and time course of the chemotherapy-induced instability and to test whether bleomycin sensitivity can be used as a predictor of tumor evolution or relapse. The analysis included 99 pediatric cancer patients with four different tumor types (Ewing's sarcoma, osteosarcoma, lymphoma and CNS tumors) and 25 controls. Blood samples (n = 171) were obtained before and at the end of treatment, during clinical remission and at relapse and bleomycin tests on lymphocyte cultures were performed. We detected a significant increase (P = 0.004) in mutagen sensitivity in patients at the end of treatment compared with untreated patients, regardless of the tumor type. In both the longitudinal and cross-sectional analyses maximal and similar values of mutagen sensitivity were found in patients during treatment (1.84 +/- 0.82) and at relapse (1.78 +/- 0.52); minimum and similar values were found in controls (0.93 +/- 0.23), untreated patients (1.15 +/- 0.65) and in those who had fulfilled the chemotherapy protocols for at least 2 years before their sample was collected (1.09 +/- 0.53). From this preliminary data we can conclude that cytostatic drugs induce a transient increase in chromosomal instability in pediatric cancer patients that can be monitored by bleomycin-induced sensitivity tests and that the genetic instability indices should be further investigated as predictors of relapse.

Adolescent↗
PubMed2002

The structural nature of chromosomal instability in colon cancer cells.

Biological and genetic cell heterogeneity is a landmark of most colorectal cancers and provides a frame for tumor progression as an evolutional process. Classical models have hypothesized that increased genetic instability may contribute to modulating and shaping malignant transformation. This is true for the small subset of colorectal cancers displaying microsatellite instability. For the rest of colorectal tumors, numerical and/or structural chromosomal alterations are the most prominent outcome of genetic disruption. These observations have prompted some investigators to hypothesize about the presence of chromosomal instability in these cells. To characterize chromosomal instability in cancer cells, we have analyzed genetic clonal divergence in three colorectal cancer cell lines considered to be archetypes in cancer research (HCT116, LoVo, and SW480). A dynamic setting was designed to allow the calculation of mutation rates. Comprehensive analyses at the chromosomal level revealed distinctive patterns of genetic divergence. Aneuploid SW480 cells displayed high rates of structural alterations (>100-fold) as compared with near diploid LoVo cells. Numerical alterations also occurred more frequently in SW480 cells but at low rates as compared with rearrangements in the chromosomically unstable SW480 cells. These results strengthen the role of structural instability in the generation of genetic heterogeneity in colorectal cancer.

Chromosome Aberrations↗
PubMed1995

Transcatheter closure of ventricular septal defects: hemodynamic instability and anesthetic management.

The technique of transcatheter ventricular septal defect (VSD) device closure may be associated with significant hemodynamic instability. The anesthetic records and catheterization data of 70 consecutive transcatheter VSD closures between February 1989 and September 1992 were reviewed, and risk factors associated with hemodynamic instability evaluated. In 28 of 70 procedures (40%), hypotension (> 20% decrease in systolic blood pressure from baseline) occurred; 12 responded to administration of fluids intravascularly alone, whereas 16 patients required additional acute resuscitation. Significant dysrhythmias occurred during 20 (28.5%) anesthetics associated with hypotension and requiring treatment or catheter withdrawal. ASA physical status, precatheterization indication for device placement, and patient size were not predictive of hemodynamic instability during the procedure. Blood transfusions were necessary in 38 (54.4%) cases and were size-related, with patients weighing less than 10 kg requiring a significantly larger transfusion volume (25.1 +/- 12.4 mL/kg). After 35 procedures (50%) patients were admitted directly to the intensive care unit (ICU) due primarily to hemodynamic instability or procedure duration; 24 (68%) required mechanical ventilation. No deaths occurred; there was no late morbidity due to catheterization-related events. Intravenous sedation was used for the initial catheterizations, maintained with a combination of midazolam, ketamine, and morphine. Subsequently general intravenous or inhaled anesthesia was predominantly used during transesophageal echocardiography and internal jugular vein cannulation. We conclude that hemodynamic instability is common during device closure of VSDs, and is likely to be an inescapable feature of these procedures in many patients because of the technique necessary for device placement.

Anesthesia↗
PubMed2000

Genomic instability and colorectal cancer.

Colon cancer results from the accumulation of genetic alterations. Genomic instability creates a permissive state in which a potential cancer cell is allowed to acquire enough mutations to become a cancer cell. Several forms of genomic instability are common in colon cancer: microsatellite instability (MSI), chromosome instability (CIN), and chromosome translocations. MSI occurs in approximately 15% of colon cancers and results from inactivation of the mutation mismatch repair (MMR) system secondary to either MMR gene mutations or hypermethylation of the hMLH1 promoter. It promotes tumorigenesis by generating mutations in target genes that possess coding microsatellite repeats, such as the transforming growth factor-beta receptor type II gene. CIN occurs in most other colon cancers and leads to a different pattern of gene alterations that culminate in tumor formation. It seems to result from mutations in genes that control mitosis, DNA damage repair, centrosome structure and function, and other fundamental processes in DNA replication. The clinical significance of genomic instability is now under investigation, and it is hoped that this research will soon yield results that have an immediate effect on the treatment of colon cancer.

Journal Article↗
PubMed1989

Residential instability in adolescent inpatients.

The case records of 225 randomly selected adolescent psychiatric inpatients were reviewed to determine prevalence of residential instability. The study also examined the demographic, family composition, life event, and behavior characteristics associated with residential instability. Approximately 30% of the sample had experienced a high rate of residential instability (i.e., from 5 to 20 domicile moves). Analyses indicated that residential instability was associated with a set of characteristics that included caregiver neglect, caregiver abuse, parental separation, multiple hospitalizations, lower IQ, indices of poor impulse control, and antisocial behavior. The possible contribution of residential instability to treatment resistance and the development of antisocial behaviors in some adolescents is discussed.

Adolescent↗