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PubMed1990

The effect of retinoids, carotenoids and phenolics on chromosomal instability of bovine papillomavirus DNA-carrying cells.

Antioxidants were found to protect against the genotoxic effects of chemical and physical mutagenic and clastogenic agents. This study focused on the capacity of antioxidants to reduce an intrinsic and persistent chromosome instability. As a model system, strains of C127 cells, which were transformed by bovine papillomavirus (BPV) DNA and which carry BPV DNA varying from 20 to 160 copies, were used. Transformed cells of 10 different strains showed a persistently high incidence of mitotic irregularities detectable at anaphase and telophase (27.3-58.9%), an elevated frequency of cells with micronuclei (6.6-34.7%), and a broad spectrum of nuclear sizes, as measured by image analysis. A 3-day exposure to retinoic acid, retinol, beta-carotene, canthaxanthin, ascorbic acid and ellagic acid greatly reduced the degree of chromosome instability, whereas catechin, eugenol and pyrogallol showed a smaller inhibitory effect, and curcumin had no detectable effect on the frequency of mitotic irregularities. After withdrawal of retinoic acid treatment, the high levels of chromosome instability reappeared. The possibility that the protective effect of the retinoids and carotenoids examined in the model system points to their beneficial administration to human cells with an intrinsic or acquired chromosome instability is discussed.

Antioxidants↗
PubMed1996

Lack of microsatellite instability in giant cell tumor of bone.

Microsatellite instability was searched for at six different loci on chromosome arms 5q, 18q, 15q, 17p, 19q, and 11p in 22 patients (12 men and 10 women; average age of 31.8 years, range of 20-55 years) with giant cell tumor of bone (GCT). These loci were chosen because of their use in microsatellite instability studies in other tumors such as colorectal cancer (e.g., 5q, 18q, 17p) or because of the presence of chromosomal abnormalities such as telomeric associations commonly occurring at 19q and 11p termini (thus the reason for including the 19q and 11p termini microsatellites in our study of GCT). No microsatellite instability or loss of heterozygosity were detected when comparing normal and tumor cells from any of the GCT patients. Unlike several other tumors, our study indicates that microsatellite instability does not appear to play a role in the tumorigenesis of GCT although other abnormal cytogenetic, biochemical, and molecular genetics data do exist for this musculoskeletal tumor.

Adult↗
PubMed2006

Fragile self-esteem and affective instability in posttraumatic stress disorder.

Temporal fluctuations in self-esteem and affect are prominent features of several clinical conditions (e.g., depression), but there is an absence of empirical work examining their role in posttraumatic stress disorder (PTSD). Individuals who experience large fluctuations in self-evaluations and affect are considered more vulnerable to psychopathology than individuals able to adequately modulate their self-image and emotional responses. We examined the relevance of self-esteem and affective instability to PTSD. Veterans with and without PTSD completed 14 daily ratings of self-esteem, positive affect, negative affect, and gratitude. Compared to veterans without PTSD, veterans with PTSD exhibited more temporal fluctuations in self-esteem, negative affect, and gratitude, with a smaller effect for positive affect. For all veterans, self-esteem and negative affective instability was associated with diminished well-being. Except for self-esteem instability, most findings were substantially reduced after accounting for variance attributable to PTSD diagnoses and mean intensity levels over the 14-day monitoring period. These data suggest self-esteem instability is important in understanding the lives of veterans with and without PTSD.

Affect↗
PubMed2004

Double-Jump migration and diffusive instability.

In order to look into the stability consequences of a particular migration process in which individuals choose to settle, we formulated a continuous-time multi-species multi-patch model in which individuals migrate by one or two instantaneous jumps while making the second jump with a certain probability that possibly depends on the conditions at the end point of the first jump. It turned out that a second jump has some quantitative effects on diffusive instability even when it occurs in the absence of density-dependent mechanisms. When a second jump happens as a natural interspecific response of individuals, and such a response is sufficiently strong, it has crucial effects on diffusive instability: it leads to diffusive instability in the case of competitive interactions, whereas it annihilates diffusive instability in the case of prey-predator interactions. We demonstrated these results in the context of two specific examples.

Animals↗
PubMed2005

Coupled analysis of bacterial transformants and ligation mixture by duplex PCR enables detection of fatal instability of a nascent recombinant plasmid.

When a DNA cloning experiment fails, it is often difficult to distinguish between an inadequate cloning protocol and instability of the new recombinant plasmid. The identification of plasmid instability is particularly challenging when the instability is fatal and no DNA of the expected construct can be isolated. We have effectively addressed this problem by employment of duplex PCR (insert-insert, vector-insert) to analyse both the ligation mixture and the resultant bacterial transformants. Using this approach we found a fatal maintenance instability of one of the plasmids generated during subcloning of the cDNA for human LDLR in Escherichia coli STBL2. The described duplex PCR screening method allows monitoring of the fate of nascent recombinant plasmid from ligation, through the initial bacterial colony and the subsequent overnight culture.

Cloning, Molecular↗
PubMedDate not supplied

Suture anchors for treatment of sternoclavicular joint instability.

Instability of the sternoclavicular joint is a difficult problem to treat and can present with gross limitation in activities. Eight sternoclavicular joint stabilization procedures were performed over an 8-year period. The patients' ages ranged from 16 to 48 years (mean, 23.5 years). The indication for stabilization was pain associated with instability of the sternoclavicular joint. The joint was stabilized by use of suture anchors on the manubrium and capsular plication. The functional outcome was evaluated by use of the Constant score and patient-based Oxford Shoulder Questionnaire. At a mean follow-up of 4.5 years (range, 1-7.6 years), none of the patients had instability at the sternoclavicular joint, and all except one had returned to their previous employment. The Oxford score was 16 (range, 12-38). The mean Constant score was 74.88 (range, 33-87). We had only 1 poor result (Constant score of 33). Stabilization of the sternoclavicular joint can safely be performed by use of suture anchors. The technique is recommended for symptomatic sternoclavicular joint instability.

Adolescent↗
PubMed2004

Advances in the application of germline tandem repeat instability for in situ monitoring.

Alterations in tandem repetitive DNA sequences such as minisatellite DNA and expanded simple tandem repeats (ESTRs) may provide useful biomarkers of induced germline effects. In this review, I describe the differences between ESTRs and minisatellites with respect to their structure and mutational mechanisms, and discuss field applications measuring induced germline instability. It is evident that both types of loci have high rates of mutation that facilitate the measurement of induced mutation measured in relatively small numbers of samples following environmentally relevant exposures. Several research groups have used these loci to demonstrate a significant increase in germline mutation in humans and animals exposed to radioactive or chemical pollutants in their natural environment. Mutations are manifested as gains or losses in repeat units and are detected either by pedigree screening or by PCR amplification of sperm DNA. Mutations at both ESTRs and minisatellites appear to arise via indirect mechanisms rather than by direct damage to the repeat locus itself. Most interestingly, ESTR instability following radiation has been shown to be heritable and transmitted to subsequent generations. An understanding of the mechanisms involved in induced instability is required in order to begin to decipher the potential biological implications of increased germline tandem repeat mutation. Furthermore, relatively few studies have investigated the ability of different genotoxins to induce tandem repeat instability. Such laboratory-based experiments will be crucial in clarifying the particular environmental or occupational exposures that should be targeted for future studies and for isolating and subsequently identifying the putative mutagens in complex environmental matrices.

Animals↗
PubMed2003

Chromosomal imbalances in the colorectal carcinomas with microsatellite instability.

Recent molecular genetic studies have revealed that two major types of genomic instabilities, chromosomal instability and microsatellite instability, exist in the colorectal carcinomas. To clarify the relationship between chromosomal abnormalities and mismatch repair gene defects in colorectal carcinomas, we performed a chromosomal analysis on 39 colorectal carcinomas with high-microsatellite instability (MSI-H) and compared the results obtained with those of 20 right-sided microsatellite-stable (MSS) colorectal carcinomas. Chromosomal imbalances (CIs) in MSS colorectal carcinomas were more frequent than in MSI-H colon carcinomas by comparative genomic hybridization analysis (70% versus 31%, P = 0.004). The CI patterns of MSI-H and MSS carcinomas were different. Frequent CIs in MSI-H colon carcinomas were gains of 4q (15%) and 8q (8%), and losses of 9q (21%), 1p (18%), and 11q (18%). In contrast, frequent CIs in right-sided MSS colon carcinomas were gains of 8q (50%), 13q (35%), and 20q (25%), and losses of 18q (55%), 15q (35%), and 17p (30%). We compared the mutation status of 45 target genes and CIs in our MSI-H tumors. Among these 45 target genes, mutation of hRAD50, a member of the DNA repair genes, and FLJ11383 were significantly related to MSI-H colorectal carcinomas with CIs (P = 0.01 and P = 0.02, respectively). Our findings indicate that unique CIs were present in a subset of MSI-H colorectal carcinomas and that these CIs are related to the mutation of several target genes, especially of hRAD50.

Acid Anhydride Hydrolases↗
PubMed1999

Polymorphic variation at the BAT-25 and BAT-26 loci in individuals of African origin. Implications for microsatellite instability testing.

Instability in the repeat size of microsatellite sequences has been described in both hereditary nonpolyposis and sporadic colorectal cancers. Tumors expressing microsatellite instability are identified through the comparison of the repeat sizes at multiple microsatellite loci between tumor and matched normal tissue DNA. The use of a five-marker panel including two mononucleotide repeat microsatellites, BAT-25 and BAT-26, has recently been suggested for the clinical determination of tumor microsatellite instability. The BAT-25 and BAT-26 loci included in this panel have both demonstrated sensitivity to microsatellite instability and normal quasimonomorphic allelic patterns, which has simplified the distinction between normal and unstable alleles. However, in this study, we identified allelic variations in the size of the poly(A) tract at BAT-26 in 12.6% of 103 healthy African-Americans screened. In addition, 18.4% exhibited allelic size variations in the poly(T) tract at BAT-25. Finally, 2.9% showed variant alleles at both BAT-25 and BAT-26 loci. Screening a small population of Nigerians confirmed the polymorphic nature of both loci and the ethnic origin of alleles not identified in other populations studied thus far. Our results dispute the quasimonomorphic nature of both BAT-25 and BAT-26 in all populations and support the need for thorough population studies to define the different allelic profiles and frequencies at microsatellite loci.

Adenocarcinoma↗
PubMed1999

On the meaning and measurement of affective instability: clues from chaos theory.

BACKGROUND: "Affective instability" describes affective shifts occurring over hours to days that are associated with clinically significant impairment or distress. Since patients with this condition are clinically "chaotic," we undertook to study affective instability relative to normal affective variability using the tools of chaos theory. METHODS: Patients and controls generated time series data over 90 days using a visual analog mood scale to capture daily affective means and extremes. The series were analyzed using the Mean Squared Successive Difference (MSSD), Power Spectral Density (PSD), and Fractal Dimension (FD). RESULTS: Patients demonstrated substantially more variability than controls on the MSSD, but less complexity as measured by the FD. The PSD revealed that power varied with frequency (f) in a 1 [corrected] alpha relationship, wherein the alpha for patients was double that for controls. CONCLUSIONS: Despite the "chaotic" clinical presentation of affective instability patients, affective instability itself was found to be less complex from a chaos-theoretic perspective than normal affective variability. Of particular interest is the alpha ratio of order 2 between patients and controls seen in both our study and a similar but much longer study of mood in rapid-cycling bipolar disorder; an observation suggesting that pathological affect may be distinguishable from normal affective variability by a scale-invariant parameter.

Adolescent↗
PubMed1998

MR imaging of suspected acute spinal instability.

Twenty-two patients with suspected acute vertebral instability were imaged within 48 h of injury using a 0.5 Tesla magnet. In all patients plain radiographs, T1 weighted gradient echo (GE) and STIR sequences were performed. Two radiologists blindly evaluated the magnetic resonance imaging (MRI) scans defining injuries with bony or soft tissue disruption of both columns as unstable. Indirect signs of instability such as soft tissue haemorrhage were recorded and correlated where possible with operative findings. Sixteen patients were radiologically unstable on MRI, five more than on plain films alone. Instability was confirmed operatively in 10 patients. The six other patients with unstable injuries were treated conservatively. Two of these patients had evidence of increased deformity before fracture union. The radiologically stable patients were treated as such and at 6-month review showed no evidence of progressive instability. The presence of soft tissue haemorrhage in the interspinous gap was not associated with ligament rupture unless actual discontinuity was demonstrated at that level. We conclude that using MRI acutely, most unstable spinal injuries can be rapidly and accurately evaluated without the need for further imaging.

Acute Disease↗
PubMed1983

Factors that influence the incidence of detrusor instability in women.

Detrusor instability was examined in 108 women with urinary incontinence. The presence of instability correlated with the symptoms of urge incontinence in 81 of 99 patients. The technique of the cystometrogram also proved important and minor variations significantly altered the incidence. Finally, there seems to be a significant correlation between reduced urethral closure as measured by the urethral pressure profile and instability, suggestive of a causal relationship. An understanding of the factors that affect the incidence of detrusor instability will help to place it in the right perspective in terms of its diagnostic value and pathogenesis.

Female↗
PubMed2002

Bystander effects in radiation-induced genomic instability.

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

Animals↗
PubMed2002

Single nucleotide instability: a wide involvement in human and rat mammary carcinogenesis?

Genetic instability plays important roles in carcinogenesis. In two cell lines which we established from mammary carcinomas induced in lacI-transgenic rats by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), spontaneous point mutation rates (MRs) of the endogenous hypoxanthine-guanine phosphoribosyltransferase (hprt) gene and lacI transgene were found to be increased. The two rat mammary carcinoma cell lines lacked microsatellite instability (MSI), and nuclear extracts from them were proficient in G/T mismatch binding. The increase of spontaneous point MRs was considered to be due to a mechanism(s) different from mismatch repair insufficiency, and this type of genetic instability was termed as single nucleotide instability (SNI). SNI in the rat mammary carcinoma cell lines was characterized by the elevation of A:T to C:G transversions of the hprt and lacI genes, which were rarely observed in normal mammary epithelial cells. The elevation of A:T to C:G transversions was also present in the lacI gene of the primary carcinomas of the two cell lines, which suggested that the molecular abnormality present in the cell lines was already present in their primary carcinomas. Mth1 mutation, which is known to cause elevation of A:T to C:G transversions, was analyzed in the 2 cell lines and in 11 primary PhIP-induced mammary carcinomas, but no mutations were observed. Finally, spontaneous point MRs of the hprt gene were measured in six human breast cancer cell lines, and increase was found in five of them. These human breast cancer cell lines were proficient in G/T mismatch binding, and were reported to lack MSI. SNI was suggested to play a wide involvement in human and rat mammary carcinogenesis.

Animals↗
PubMed1997

The reliability of performing a screening cystometrogram using a fetal monitoring device for the detection of detrusor instability.

OBJECTIVE: To determine if a cystometrogram performed using the intrauterine pressure channel of a fetal monitor can be used to screen for detrusor instability in women undergoing evaluation for urinary incontinence. METHODS: Sixty-six women with primary complaints of urinary incontinence were randomized to have a cystometrogram performed at their initial visit with a multichannel electronic cystometer or with the intrauterine pressure channel of a fetal monitor. Subjects underwent a second cystometrogram 1-4 weeks later with the alternative technique. The results were analyzed with chi 2 analysis and correlation coefficients. RESULTS: Twenty-two subjects had detrusor instability diagnosed by the multichannel electronic cystometer. The fetal monitor cystometrogram was 91% sensitive and 86% specific in detecting detrusor instability, and had a 77% positive predictive value and a 95% negative predictive value. The correlation coefficients between the two examinations for bladder volume at first sensation, maximum capacity, volume at first contraction, and intensity of uninhibited detrusor contraction were r = 0.51, r = 0.69, r = 0.87, and r = 0.79, respectively; all of these were statistically significant. CONCLUSION: The intrauterine pressure channel of a fetal monitor can be used reliably to perform a cystometrogram to screen for detrusor instability in patients presenting with complaints of urinary incontinence.

Cross-Over Studies↗
PubMed2001

DNA amplification and chromosomal translocations are accompanied by chromosomal instability: analysis of seven human colon cancer cell lines by comparative genomic hybridization and spectral karyotyping.

Genetic instability in human cancers is classified as chromosomal instability (CIN) or microsatellite instability (MIN). DNA amplification and translocations are observed frequently in various cancers. We used comparative genomic hybridization (CGH) and spectral karyotyping (SKY) to study seven human colon cancer cell lines and investigate the relations among genetic instability, DNA amplification, and chromosomal translocations. DNA amplification was found in five cell lines (COLO320DM, COLO201, WiDr, CoCM-1, and CACO-2), and all were aneuploid. In these five cell lines, segments of chromosomes were translocated to other chromosomes. In contrast, cell lines with MIN, DLD-1, and LoVo did not show DNA amplification. The LoVo cells with MIN were considered near diploid and contained translocations. These findings suggest that DNA amplification and chromosomal translocations are accompanied by CIN.

Colonic Neoplasms↗
PubMed2001

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

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

Aneuploidy↗
PubMed1999

Microsatellite instability associated with hepatocarcinogenesis.

BACKGROUND/AIMS: The biological and clinicopathological significance of microsatellite instability in hepatocellular carcinoma still remains to be determined. The aim of this study was to assess the role of microsatellite instability in hepatocarcinogenesis. METHODS: Genomic DNA extracted from 38 fresh samples of hepatocellular carcinoma was amplified by polymerase chain reaction using 29 fluorescence-labeled microsatellite markers and analyzed using a semi-automated laser scanning system. Associations between the incidence of replication error and the clinicopathological features of hepatocellular carcinoma were evaluated. Since reference DNA was extracted from corresponding fresh samples of non-cancerous liver tissue, the incidence of microsatellite instability in non-cancerous liver tissues was not assessed in this study. RESULTS: Four (11%) hepatocellular carcinomas had a replication error in one or two microsatellite markers; they were all poorly differentiated hepatocellular carcinomas. The incidence of replication error correlated significantly with the histological differentiation of the tumor (p<0.05) and with portal vein involvement (p<0.05). All four hepatocellular carcinomas with replication errors showed loss of heterozygosity in one or more of the 29 markers we examined. No replication errors were detected in six markers in the coding regions of the BAX, insulin-like growth factor II receptor, transforming growth factor-beta type II receptor, E2F-4, hMSH3 and hMSH6 genes. CONCLUSIONS: The results of this study indicate that: (1) microsatellite instability is a rare event during hepatocarcinogenesis and may be specifically associated with progression of hepatocellular carcinoma; and (2) frame-shift mutation in the above six genes is not a common mechanism involved in progression of this cancer.

Aged↗