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PubMed1997

Instability of highly expanded CAG repeats in mice transgenic for the Huntington's disease mutation.

Six inherited neurodegenerative diseases are caused by a CAG/polyglutamine expansion, including spinal and bulbar muscular atrophy (SBMA), Huntington's disease (HD), spinocerebellar ataxia type 1 (SCA1), dentatorubral pallidoluysian atrophy (DRPLA) Machado-Joseph disease (MJD or SCA3) and SCA2. Normal and expanded HD allele sizes of 6-39 and 35-121 repeats have been reported, and the allele distributions for the other diseases are comparable. Intergenerational instability has been described in all cases, and repeats tend to be more unstable on paternal transmission. This may present as larger increases on paternal inheritance as in HD, or as a tendency to increase on male and decrease on female transmission as in SCA1 (ref. 15). Somatic repeat instability is also apparent and appears most pronounced in the CNS. The major exception is the cerebellum, which in HD, DRPLA, SCA1 and MJD has a smaller repeat relative to the other brain regions tested. Of non-CNS tissues, instability was observed in blood, liver, kidney and colon. A mouse model of CAG repeat instability would be helpful in unravelling its molecular basis although an absence of CAG repeat instability in transgenic mice has so far been reported. These studies include (CAG) in the androgen receptor cDNA, (CAG) in the HD cDNA, (CAG) in the SCA1 cDNA, (CAG) in the SCA3 cDNA and as an isolated (CAG) tract.

Animals↗
PubMed1999

Microsatellite instability and mismatch repair gene inactivation in sporadic pancreatic and colon tumours.

Genomic instability has been proposed as a new mechanism of carcinogenesis involved in hereditary non-polyposis colorectal cancer (HNPCC) and in a large number of sporadic cancers like pancreatic and colon tumours. Mutations in human mismatch repair genes have been found in HNPCC patients, but their involvement in sporadic cancer has not been clarified yet. In this study we screened 21 pancreatic and 23 colorectal sporadic cancers for microsatellite instability by ten and six different microsatellite markers respectively. Microsatellite alterations were observed at one or more loci in 66.6% (14/21) of pancreatic cancers and in 26% (6/23) colon tumours, but all the pancreatic and half of the colon samples showed a low rate of microsatellite instability. All the unstable samples were further analysed for mutations in the hMLH1 and hMSH2 genes and for hypermethylation of the hMLH1 promoter region. Alterations in the hMLH1 gene were found only in colorectal tumours with a large presence of microsatellite instability. None of the pancreatic tumours showed any alteration in the two genes analysed. Our results demonstrate that microsatellite instability is unlikely to play a role in the tumorigenesis of sporadic pancreatic cancers and confirm the presence of mismatch repair gene alterations only in sporadic colon tumours with a highly unstable phenotype.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Chromosomal and extrachromosomal instability of the cyclin D2 gene is induced by Myc overexpression.

We examined the expression of cyclins D1, D2, D3, and E in mouse B-lymphocytic tumors. Cyclin D2 mRNA was consistently elevated in plasmacytomas, which characteristically contain Myc-activating chromosome translocations and constitutive c-Myc mRNA and protein expression. We examined the nature of cyclin D2 overexpression in plasmacytomas and other tumors. Human and mouse tumor cell lines that exhibited c-Myc dysregulation displayed instability of the cyclin D2 gene, detected by Southern blot, fluorescent in situ hybridization (FISH), and in extrachromosomal preparations (Hirt extracts). Cyclin D2 instability was not seen in cells with low levels of c-Myc protein. To unequivocally demonstrate a role of c-Myc in the instability of the cyclin D2 gene, a Myc-estrogen receptor chimera was activated in two mouse cell lines. After 3 to 4 days of Myc-ER activation, instability at the cyclin D2 locus was seen in the form of extrachromosomal elements, determined by FISH of metaphase and interphase nuclei and of purified extrachromosomal elements. At the same time points, Northern and Western blot analyses detected increased cyclin D2 mRNA and protein levels. These data suggest that Myc-induced genomic instability may contribute to neoplasia by increasing the levels of a cell cycle-regulating protein, cyclin D2, via intrachromosomal amplification of its gene or generation of extrachromosomal copies.

Animals↗
PubMedDate not supplied

The relationship between spontaneous telomere loss and chromosome instability in a human tumor cell line.

Chromosome instability plays an important role in cancer by promoting the alterations in the genome required for tumor cell progression. The loss of telomeres that protect the ends of chromosomes and prevent chromosome fusion has been proposed as one mechanism for chromosome instability in cancer cells, however, there is little direct evidence to support this hypothesis. To investigate the relationship between spontaneous telomere loss and chromosome instability in human cancer cells, clones of the EJ-30 tumor cell line were isolated in which a herpes simplex virus thymidine kinase (HSV-tk) gene was integrated immediately adjacent to a telomere. Selection for HSV-tk-deficient cells with ganciclovir demonstrated a high rate of loss of the end these "marked" chromosomes (10-4 events/cell per generation). DNA sequence and cytogenetic analysis suggests that the loss of function of the HSV-tk gene most often involves telomere loss, sister chromatid fusion, and prolonged periods of chromosome instability. In some HSV-tk-deficient cells, telomeric repeat sequences were added on to the end of the truncated HSV-tk gene at a new location, whereas in others, no telomere was detected on the end of the marked chromosome. These results suggest that spontaneous telomere loss is a mechanism for chromosome instability in human cancer cells.

Base Sequence↗
PubMed2001

Bias in detection of instability of the (C)8 mononucleotide repeat of MSH6 in tumours from HNPCC patients.

Recently, we and others reported instability in the (C)8 repeat in exon 5 of MSH6 as a preferential target for somatic mutations in tumours from MSH6 germline mutation carriers. Here, we report that in 45% of tumours from MLH1, MSH2 and MSH6 germline mutation carriers no sequence change in the (C)8 repeat of MSH6 was found upon DNA sequencing analysis of PCR products with a shift in electrophoresis mobility. Using "standard" PCR primers a high frequency of instability (50-86%) of the (C)8 repeat was found, but using a modified PCR reverse primer, accomplishing modulation of non-templated addition of adenine during in vitro PCR amplification by the Taq polymerase, a markedly lower frequency of instability was found in tumours from MLH1, MSH2 and MSH6 mutation carriers (6, 13 and 40%, respectively). Furthermore, a significant difference of the frequency of instability of the (C)8 repeat in tumours from MSH6 mutation carriers was found compared to MLH1, MSH2 mutation carriers. These results might have important implications for the detection of instability of other short mononucleotide repeats, e.g. TGFbetaRII, BAX, IGFRII, PTEN, BRCA2.

Adaptor Proteins, Signal Transducing↗
PubMed2002

c-MYC overexpression in Ba/F3 cells simultaneously elicits genomic instability and apoptosis.

Overexpression of c-Myc in tumors is usually associated with cell proliferation and increased susceptibility to apoptosis. Concomitantly, c-Myc contributes to tumorigenesis by its ability to destabilize the cellular genome. Here, we examined whether c-Myc induces genomic instability and apoptosis in c-Myc-activated cells. Wild-type Myc (wt-Myc) and two mutated Myc myc box II proteins (mt-Myc) were overexpressed in IL3-dependent murine Ba/F3 cells. As expected, wt-Myc triggered apoptosis in absence of IL3. Standard karyotyping, spectral karyotyping, and fluorescent in situ hybridization (FISH) were performed before and after c-Myc activation. Structural and numerical genomic instability was detected 48 h after wt-Myc activation and included gene amplification, the formation of extrachromosomal elements (EEs), chromosome breakage, deletions, increased aneuploidy, and polyploidization. Interestingly, some cells simultaneously displayed genomic instability and apoptosis. Both wt- and mt-Myc proteins were equally potent promoters of genomic instability. However, only wt-Myc simultaneously induced genomic instability and apoptosis. Mt-Myc proteins failed to induce apoptosis, thereby generating a strong imbalance towards the survival of genomically unstable cells.

Aneuploidy↗
PubMed2002

Heterozygosity for p53 promotes microsatellite instability and tumorigenesis on a Msh2 deficient background.

In colorectal tumorigenesis, loss of function of the mismatch repair genes is closely associated with genomic instability at the nucleotide level whereas p53 deficiency has been linked with gross chromosomal instability. We have addressed the contribution of these two forms of genetic instability to tumorigenesis using mice mutant for Msh2 and p53. As previously reported, deficiency of both genes leads to rapid lymphomagenesis Here we show that heterozygosity for p53 also markedly reduces survival on an Msh2 null background. We characterized the patterns of genomic instability in a small set of tumours and showed that, as predicted p53 deficiency predisposes to aneuploidy and Msh2 deficiency leads to microsatellite instability (MSI). However, heterozygosity for p53 in the absence of Msh2 resulted in increased MSI and not aneuploidy. This implied role for p53 in modulating MSI was confirmed using a large cohort of primary fibroblast clones. The differences observed were highly significant (P<0.01) in both the fibroblast clones (which all retained p53 functionality) and the tumours, a proportion of which retained p53 functionality. Our results therefore demonstrate a dose sensitive role for p53 in the maintenance of genomic integrity at the nucleotide level.

Animals↗
PubMed1997

Rarity of microsatellite genomic instability in B-cell non-Hodgkin's lymphomas in hepatitis C virus-infected patients.

Several groups have emphasized the likely implication of the hepatitis C virus (HCV) in a fraction of B-cell non-Hodgkin's lymphomas. Since only a minority of patients with HCV infection and monoclonal mixed cryoglobulinaemia develop overt lymphoma, the identification of predisposing factors has relevant clinical implications. The replication error phenotype (RER+), as revealed by widespread microsatellite instability, is caused by defects in DNA mismatch repair genes, and has been frequently disclosed in subsets of B-cell lymphomas with underlying infection and chronic inflammation. We therefore investigated the occurrence of the RER+ phenotype in a series of eight consecutive B-cell NHLs in patients with chronic infection by HCV. A polymerase chain reaction-based assay was used to analyse an extended panel of 15 microsatellite loci. Microsatellite instability was not observed in six tumour samples in any locus; the two remaining cases showed instability at only one locus. Therefore genetic instability by defects in DNA mismatch repair genes should not represent the general mechanism predisposing to overt lymphoma in HCV-infected patients. Although a clearer definition of HCV-related B-cell disorders should better address future studies on genetic instability in larger series, we recommend additional oncogenetic pathways as the target of further research.

Adult↗
PubMed1997

Differences in detrusor contractile function in women with neuropathic and idiopathic detrusor instability.

OBJECTIVE: To compare urodynamic indices of isometric and isotonic detrusor contractile function between patients with idiopathic detrusor instability and patients with multiple sclerosis (MS) and detrusor hyper-reflexia and thus determine whether the different types of detrusor instability share a common pathophysiological pathway. PATIENTS AND METHODS: Two groups of women were studied; 1139 neurologically normal patients with detrusor instability (mean age 55 years, SD 17) and 141 with multiple sclerosis (MS) and detrusor hyper-reflexia (mean age 45 years, SD 11). Patients were assessed using static water cystometry, examining storage function, isometric and isotonic detrusor contractile function and voiding outflow function. RESULTS: Bladder capacities were lower in the MS group, with a median of 357 mL, 95% confidence interval (CI) 305-400 mL, compared with the neurologically normal patients (median 450 mL, 95% CI 425-450, P < 0.001, Mann-Whitney U-test). Voiding was incomplete in the MS group, with a median (95% CI) residual volume of 100 (100-125) mL, but complete in the normal group, at 10 (10-10) mL. Higher median (95% CI) detrusor pressures at urethral opening (P(det open)) and closing (P(det close)) were recorded in the MS group than in the neurologically normal group, at 35.5 (33.2-46.6) cmH2O and 30 (27.6-31.6) cmH2O for P(det open), respectively (P = 0.003), and 25.3 (20.9-31.6)cmH2O and 16.6 (15.0-18.1) for P(det close), respectively, (P = 0.001). In the MS group, the median (95% CI) isometric unstable contractions were less well maintained, but were more powerful, at 17.6 (15.6-18.9) N, compared to the neurologically intact group at 14.4 (14.0-14.9) N (P = 0.002). In the MS group, contractions frequently did not relax back to baseline, whereas in the group with detrusor instability, full relaxation after contraction was more usual. There was no significant difference in the maximum speed of detrusor shortening (isotonic activity), measured by the velocity constant Q*, between the groups (median for both groups 20 mL/s, 95% CI 17-23). CONCLUSION: These results show differences in storage function, isometric detrusor contractile function and voiding outflow function between detrusor instability and detrusor hyper-reflexia, indicating that the two conditions may not share a common pathophysiological pathway.

Adult↗
PubMedDate not supplied

Microsatellite instability in uterine sarcomas.

Studies have shown a 15-30% frequency of microsatellite instability in endometrial cancer. In addition, we found a 21% frequency of microsatellite instability in endometrial cancer. Our aim was to investigate the presence of microsatellite instability and loss of heterozygosity in uterine sarcomas. The records of 69 women referred to Kalafong Academic and Pretoria Academic Hospital with a primary diagnosis of uterine sarcoma were reviewed. At histological review of 43 cases with a primary diagnosis of leiomyosarcoma, diagnosis of mitotically active leiomyoma was made in 21. Diagnosis of carcinosarcoma was made in 21 cases and endometrial stromal sarcoma in five. In all cases, genomic DNA was extracted from normal myometrium and tumor and analyzed for microsatellite instability and loss of heterozygosity. High-frequency microsatellite instability was absent in leiomyosarcoma, endometrial stromal sarcoma, and mitotically active leiomyomas and was observed in 1 (5%) carcinosarcoma. Loss of heterozygosity for chromosome 11 was present in 8/48 (17%) of uterine sarcomas, equally distributed between leiomyosarcomas (4/22 = 18%) and carcinosarcomas (4/21 = 19%). There was no loss of alleles in endometrial stromal sarcoma nor mitotically active leiomyomas. In conclusion, it is suggested that tumor suppressor genes may play a role in the tumorigenesis of uterine mesenchymal cells, whereas mismatch repair genes contribute to the carcinogenesis of endometrial cancer.

Carcinosarcoma↗
PubMed2001

Genomic instability in chronic viral hepatitis and hepatocellular carcinoma.

Chronic hepatitis may progress to cirrhosis and hepatocellular carcinoma (HCC). Progressive accumulation of mutations and genomic instability in chronic viral hepatitis might flag an increased risk of HCC development. Genomic instability at dinucleotide microsatellite loci in chromosomes 2, 13, and 17 and at 2 mononucleotide repeat loci was examined in liver tissues from 41 patients, including 30 without HCC (18 patients with chronic hepatitis and 12 with cirrhosis) and 11 with HCC. Genomic instability was detected in 51% of the 41 cases. Allelic imbalance at informative dinucleotide loci occurred in 37% of the cases. In 14 cases (34%), allelic imbalance was detected in chronic hepatitis or cirrhosis without HCC. Allelic imbalance at the chromosome 13 locus was detected in 50% of the cases of chronic hepatitis C. Allelic imbalance at the TP53 chromosome locus and/or at the chromosome 13 locus was significantly more frequent than alterations at the chromosome 2 locus (P =.026). Low-level microsatellite instability was found in 20% of all cases examined and high-level microsatellite instability in 3 patients (7.5%), including 2 cases of chronic hepatitis and 1 case of cirrhosis. Our results show that allelic imbalance occurs frequently in hepatitis-related HCC as well as in chronic hepatitis in patients without HCC. Allelic imbalance at the D13S170 chromosome 13 locus (13q31.2) occurs frequently in chronic hepatitis, suggesting that genomic alterations affecting the long arm of chromosome 13 might be used to monitor the natural progression of chronic hepatitis-associated liver carcinogenesis.

Adult↗
PubMedDate not supplied

[Dorsal lumbar interbody implantation of cages for stabilizing segmental spinal instabilities].

PURPOSE: The technique of posterior lumbar interbody fusion (PLIF) has been critically discussed due to a high degree of complications, including the development of pseudarthrosis. With the recent establishment of intercorporeal implants new aspects have to be contemplated in surgical techniques, especially concerning the posterior approach. In this study we present our first results after intercorporeal stabilisation of segmental spinal instabilities utilising carbon and titanium cages. METHOD: 45 spinal instabilities were surgically stabilised in 42 patients who were evaluated on average for 2.8 years post-operatively. 12 patients had isthmic and 19 patients degenerative instabilities while 11 patients suffered from instabilities resulting from prior spinal surgery. RESULTS: Assessed according to the Hambly-score, 69% of the patients had an excellent or good result; 2 (4.8%) patients were subjectively worse off than before surgical treatment. After implantation of cages precise radiological evaluation of bony ingrowth is frequently impaired by artefacts. We found that three months after implantation of a titanium cage, which had to be removed after incorrect placement, no bony consolidation was visible. Persisting or recurrent instabilities in fused segments were not recorded. CONCLUSION: By means of PLIF and implantation of cages the interbody space is reconstructed and jeopardized neural structures are decompressed. In addition to this, the frequently osteochondrotically degenerated segment is immobilized. The posterior approach allows decompression of neural structures and, with comparable results concerning stability, the considerable risks of the ventral approach are avoided.

Adult↗
PubMed2004

Dynamical multiple-time stepping methods for overcoming resonance instabilities.

Current molecular dynamics simulations of biomolecules using multiple time steps to update the slowly changing force are hampered by instabilities beginning at time steps near the half period of the fastest vibrating mode. These "resonance" instabilities have became a critical barrier preventing the long time simulation of biomolecular dynamics. Attempts to tame these instabilities by altering the slowly changing force and efforts to damp them out by Langevin dynamics do not address the fundamental cause of these instabilities. In this work, we trace the instability to the nonanalytic character of the underlying spectrum and show that a correct splitting of the Hamiltonian, which renders the spectrum analytic, restores stability. The resulting Hamiltonian dictates that in addition to updating the momentum due to the slowly changing force, one must also update the position with a modified mass. Thus multiple-time stepping must be done dynamically.

Journal Article↗
PubMed1999

Segregation induced instabilities of granular fronts.

Experimental investigation of granular flows containing particles of several sizes and moving down slopes shows that segregation of coarse-grained, irregularly shaped particles induces a fingering instability at the propagating front. The size-segregation mechanism involves percolation of small particles downward and a corresponding migration of large ones toward the flow surface. Large particles at the flow surface experience velocities that are greater than average so that they migrate forward and begin to collect at the flow front. In the case of dry cohesionless flows, the instability depends upon these large particles at the flow perimeter being more angular and thus more resistant to flow than the smaller rounder ones in the interior. A simple analytical model predicts the fingering instability when friction of the flow front is greater than that of the following flow. The presence of viscous liquid inhibits both size-segregation and the development of the instability. Fluidization of dry flows permits segregation of large particles to flow perimeters, thus increasing permeability and permitting a similar instability that owes its development to the dry frictional perimeter that surrounds a partly fluidized interior. (c) 1999 American Institute of Physics.

Journal Article↗
PubMedDate not supplied

Chiropractic management of a professional hockey player with recurrent shoulder instability.

OBJECTIVE: To describe the clinical management of recurrent shoulder instability in a professional hockey player by using chiropractic management and rehabilitation exercises. CLINICAL FEATURES: A 23-year-old professional hockey player with recurrent left shoulder pain and instability. He had two previous unsuccessful shoulder operations to correct the instability. He reported that the shoulder "slips out" in positions of abduction and external rotation or when the left arm is moved suddenly above shoulder height. The patient was still playing hockey professionally at the time of the initial visit and did not want to have to take time off for another surgery, so he chose to attempt a conservative approach. INTERVENTION AND OUTCOME: The patient had undergone strength training for rehabilitation after each of the previous two shoulder operations and had very strong rotator cuff and scapular musculature. Proprioceptive testing revealed a poor response in the left shoulder compared with the right shoulder. Two subjective outcome measures were used to determine the effectiveness of the treatment protocol in reducing the symptoms of recurrent shoulder instability. Much of the treatment focused on proprioceptive training, soft tissue mobilization, and improving joint function. CONCLUSION: This case demonstrates the potential benefit of chiropractic management and proprioceptive exercises to decrease the symptoms of recurrent shoulder instability.

Adult↗
PubMed2002

Patient characteristics that are associated with urodynamically diagnosed detrusor instability and genuine stress incontinence.

OBJECTIVE: We sought to compare characteristics of patients with urodynamically diagnosed detrusor instability or genuine stress incontinence. STUDY DESIGN: A retrospective audit of 293 consecutive women who were referred to a urogynecologist for evaluation of urinary incontinence between June 1996 and April 2000. RESULTS: Of the 293 patients, 289 women had a physical examination and urodynamic testing, which revealed genuine stress incontinence (35%), detrusor instability (32%), mixed incontinence (29%), or normal urodynamic function (4%). Compared with patients with detrusor instability, those women with genuine stress incontinence were more likely to be white than African American (P <.0001) and to have a cystocele(P =.027), rectocele (P <.0001), or paravaginal defect (P =.004). No differences in age, gravidity, parity, estrogen treatment, or previous anti-incontinence procedure were identified between women with detrusor instability and women with genuine stress incontinence. CONCLUSION: In a tertiary referral center, the distribution of urinary incontinence is evenly divided among genuine stress incontinence, detrusor instability, and mixed incontinence. Patients with genuine stress incontinence are more likely to be white and to have pelvic floor prolapse and symptoms of pure stress incontinence.

Adult↗
PubMed2002

Microsatellite instability in cancer: what problems remain unanswered?

Analyses of microsatellite instability have been prevalent, particularly in the field of oncology. However, the literature on this subject is diverse. The discrepancies may derive from methodological problems in the conventional techniques used for analysis. Problems include low quantitativity in the detection systems, inaccurate migration in electrophoresis, and Taq polymerase-mediated modifications of polymerase chain reaction products. Indeed, use of a new fluorescent technique where these problems have been overcome has elucidated various intriguing and previously unrecognized aspects of microsatellite instability in human cancers. Patterns of microsatellite changes observed in various human cancers can be classified into 2 subtypes, those showing relatively small changes within 6 base pairs (type A) and those exhibiting drastic changes over 8 base pairs (type B). Although type A microsatellite instability has been connected to defective mismatch repair phenotype, the relationship between type B microsatellite instability and defective mismatch repair phenotype remains unclear. Nevertheless, as symbolized in cases of hereditary nonpolyposis colorectal cancer, connections between type B microsatellite instability and familial predisposition have been suggested in some cancers. The molecular background of type B microsatellite changes warrants particular attention.

Colorectal Neoplasms↗
PubMed2002

Centrosome amplification drives chromosomal instability in breast tumor development.

Earlier studies of invasive breast tumors have shown that 60-80% are aneuploid and approximately 80% exhibit amplified centrosomes. In this study, we investigated the relationship of centrosome amplification with aneuploidy, chromosomal instability, p53 mutation, and loss of differentiation in human breast tumors. Twenty invasive breast tumors and seven normal breast tissues were analyzed by fluorescence in situ hybridization with centromeric probes to chromosomes 3, 7, and 17. We analyzed these tumors for both aneuploidy and unstable karyotypes as determined by chromosomal instability. The results were then tested for correlation with three measures of centrosome amplification: centrosome size, centrosome number, and centrosome microtubule nucleation capacity. Centrosome size and centrosome number both showed a positive, significant, linear correlation with aneuploidy and chromosomal instability. Microtubule nucleation capacity showed no such correlation, but did correlate significantly with loss of tissue differentiation. Centrosome amplification was detected in in situ ductal carcinomas, suggesting that centrosome amplification is an early event in these lesions. Centrosome amplification and chromosomal instability occurred independently of p53 mutation, whereas p53 mutation was associated with a significant increase in centrosome microtubule nucleation capacity. Together, these results demonstrate that independent aspects of centrosome amplification correlate with chromosomal instability and loss of tissue differentiation and may be involved in tumor development and progression. These results further suggest that aspects of centrosome amplification may have clinical diagnostic and/or prognostic value and that the centrosome may be a potential target for cancer therapy.

Aneuploidy↗