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PubMed2004

Genomic instability in histologically normal breast tissues: implications for carcinogenesis.

Breast cancer is an important contributor to morbidity and mortality in society, but factors that affect the cause of the disease are poorly defined. Genomic instability drives tumorigenic processes in invasive carcinomas and premalignant breast lesions, and might promote the accumulation of genetic alterations in apparently normal tissues before histological abnormalities are detectable. Evidence suggests that genomic changes in breast parenchyma affect the behaviour of epithelial cells, and ultimately might affect tumour growth and progression. Inherent instability in genes that maintain genomic integrity, as well as exogenous chemicals and environmental pollutants, have been implicated in breast-cancer development. Although molecular mechanisms of tumorigenesis are unclear at present, carcinogenic agents could contribute to fields of genomic instability localised to specific areas of the breast. Understanding the functional importance of genomic instability in early carcinogenesis has important implications for improvement of diagnostic and treatment strategies.

Breast Neoplasms↗
PubMed1996

Dynamic instability of microtubules assembled from microtubule-associated protein-free tubulin: neither variability of growth and shortening rates nor "rescue" requires microtubule-associated proteins.

The growth and shortening of microtubules in dynamic instability is known to be modulated by microtubule-associated proteins (MAPs). A full understanding of the mechanism of dynamic instability requires that one distinguish which of its aspects are mediated by microtubule-associated proteins (even in small residual concentrations) and which are intrinsic properties of the tubulin lattice itself. This paper addresses two of those aspects: whether MAPs cause the rescue events of dynamic instability (i.e., the transitions from shortening to growth) and whether MAPs are responsible for the marked variability of the rates at which microtubules grow and shorten. Very pure tubulin was prepared by sequential chromatographies on phosphocellulose and DEAE-Sephadex. Analysis by electrophoresis and immunoblotting showed it to be essentially MAP-free; it contained fewer than one MAP molecule per 10000 tubulin dimers. When its dynamic instability was studied by video-DIC microscopy, rescues were found to occur at a mean frequency of one per 4 microns of shortening. Variability of rates of growth and shortening, which is observed on the length scale of a few micrometers, was not changed by removal of MAPs. Because the mean distance between bound MAP molecules was calculated to be greater than 14 microns in these experiments, it is concluded that they cannot cause either rescue or variability of rates.

Animals↗
PubMed2006

Negative-tension instability of scroll waves and winfree turbulence in the oregonator model.

Excitable media support self-organized scroll waves which can be unstable and give rise to three-dimensional wave chaos. Winfree turbulence of scroll waves results from the negative-tension instability of scroll waves; it plays an important role in the cardiac tissue where it may lead to ventricular fibrillation. By numerical simulations of the Oregonator model, we show that this instability and, thus, the Winfree turbulence may also be observed in the Belousov-Zhabotinsky reaction. The region in the parameter space, where the instability takes place, is determined, and a relationship between the negative-tension instability and the meandering behavior of spiral waves is found. The application of global periodic forcing to control such turbulence in the Oregonator model is discussed.

Journal Article↗
PubMed1995

Accuracy and precision in the radiographic diagnosis of clinical instability in Brånemark dental implants.

The aim was to evaluate accuracy and precision in the radiographic diagnosis of clinical instability in Brånemark dental implants. In two clinics specialized in the Brånemark osseointegration technique we identified all patients in whom lack of clinical stability of one or more fixtures had been observed during a 5-year period. Radiographs of these fixtures (n=62) were mixed with radiographs of clinically stable fixtures (n=158). Eight observers were asked to determine whether or not a perifixtural radiolucency was seen by means of a 5-point rating scale expressing the confidence with which the presence or absence of a radiolucency was determined. Receiver operator characteristic analysis was used to calculate the A(z) values and the variability in A(z) values between and within observers was determined. In addition, we evaluated the agreement in rating codes within observers between repeat examinations. The A(z) values (mean=0.844 at the first reading and 0.856 at the second) indicated that the accuracy in radiographic diagnosis of clinical fixture instability was at least as good as that associated with other radiographic tasks such as approximal caries diagnosis and diagnosis of small periodontal bone lesions. Interobserver variability was larger than intraobserver variability. Intraobserver agreement in rating codes was relatively high and less than an average of 6% of all ratings differed with two rating codes or more. Despite the relatively good diagnostic accuracy, the probability of predicting clinical fixture instability from a radiographic examination can be low in populations with a low prevalence of fixtures showing clinical instability.

Alveolar Process↗
PubMed1998

Level and instability of day-to-day psychological well-being and risk for depression.

For 21 days, 123 undergraduates provided measures of their self-esteem, anxiety, causal uncertainty, perceived control over outcomes, and the three constructs comprising A. T. Beck's (1972) cognitive triad. Factor analyses of measures of the mean level and day-to-day instability of these constructs produced 2 factors, level of well-being and day-to-day instability of well-being. Participants also provided 4 measures of risk for depression over 2 1/2 months. For participants who were not at risk for depression, level of day-to-day well-being was negatively related to risk for depression, and this effect was not moderated by day-to-day instability. In contrast, for participants who were classified as at-risk for depression, day-to-day instability of well-being moderated the strength of the negative relationship between level of well-being and risk for depression. The relationship between level of well-being and depression was stronger for participants who were more unstable.

Cognition↗
PubMed2005

Instability of hierarchical cluster analysis due to input order of the data: the PermuCLUSTER solution.

Hierarchical agglomerative cluster analysis (HACA) may yield different solutions under permutations of the input order of the data. This instability is caused by ties, either in the initial proximity matrix or arising during agglomeration. The authors recommend to repeat the analysis on a large number of random permutations of the rows and columns of the proximity matrix and select a solution with the highest goodness-of-fit. This approach was implemented in an SPSS add-in, PermuCLUSTER, which can perform all HACA methods of SPSS. Analyses of 2 data sets show that (a) results are affected by input order, (b) instability in one method co-occurs with instability in other methods, and (c) some instability effects are more dramatic because they occur at higher agglomeration levels.

Cluster Analysis↗
PubMed1998

Genetic instabilities in human cancers.

Whether and how human tumours are genetically unstable has been debated for decades. There is now evidence that most cancers may indeed be genetically unstable, but that the instability exists at two distinct levels. In a small subset of tumours, the instability is observed at the nucleotide level and results in base substitutions or deletions or insertions of a few nucleotides. In most other cancers, the instability is observed at the chromosome level, resulting in losses and gains of whole chromosomes or large portions thereof. Recognition and comparison of these instabilities are leading to new insights into tumour pathogenesis.

Chromosome Aberrations↗
PubMed1999

Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice.

Huntington disease (HD), an autosomal dominant, progressive neurodegenerative disorder, is caused by an expanded CAG repeat sequence leading to an increase in the number of glutamine residues in the encoded protein. The normal CAG repeat range is 5-36, whereas 38 or more repeats are found in the diseased state; the severity of disease is roughly proportional to the number of CAG repeats. HD shows anticipation, in which subsequent generations display earlier disease onsets due to intergenerational repeat expansion. For longer repeat lengths, somatic instability of the repeat size has been observed both in human cases at autopsy and in transgenic mouse models containing either a genomic fragment of human HD exon 1 (ref. 9) or an expanded repeat inserted into the endogenous mouse gene Hdh (ref. 10). With increasing repeat number, the protein changes conformation and becomes increasingly prone to aggregation, suggesting important functional correlations between repeat length and pathology. Because dinucleotide repeat instability is known to increase when the mismatch repair enzyme MSH2 is missing, we examined instability of the HD CAG repeat by crossing transgenic mice carrying exon 1 of human HD (ref. 16) with Msh2-/- mice. Our results show that Msh2 is required for somatic instability of the CAG repeat.

Animals↗
PubMed1997

Microsatellite instability and loss of heterozygosity in mammary carcinoma and its probable precursors.

Microsatellite instability is a form of genetic damage that may be due to defective mismatch repair genes and may be a marker of processes leading to malignancy. We have analysed a series of epithelial hyperplasia of usual type, carcinomas in situ and invasive and metastatic carcinomas from the mammary gland on the assumption that they represent stages in the evolution of mammary carcinoma. Eight markers on chromosomes 3p, 4q, 9p, 11p, 14q, 17p, 17q and Xq were examined for microsatellite instability and loss of heterozygosity. High rates of loss on chromosomes 17p, 17q and Xq indicate that these chromosomal arms contain genes important in mammary carcinogenesis. The rate of microsatellite instability observed in this study was uniformly low, irrespective of the lesion. This implies that microsatellite instability is not a marker of malignancy in most instances of mammary neoplasia.

Breast↗
PubMed1998

Microsatellite instability in squamous cell carcinomas of the head and neck related to field cancerization phenomena.

Patients affected by squamous cell carcinoma of the head and neck (HNSCC) show frequent occurrence of multiple cancers and widespread precancerous lesions in the mucosa of the upper respiratory tract, a phenomenon known as field cancerization. In this study, we investigated the role of genetic instability in the development of HNSCC and in particular in tumour multiplicity phenomena of the upper respiratory tract. For this purpose, we analysed microsatellite instability (MI) and loss of heterozygosity (LOH) at 20 loci mapping on five chromosomal arms in 67 HNSCC patients, 45 of whom had a single cancer and 22 had multiple primary tumours. The possible involvement of the hMLH1 gene in genetic instability and as a potential target of 3p21 deletion phenomena in head and neck cancers was also investigated. Our data indicate that mismatch repair-related genetic instability plays a minor role in the carcinogenesis of HNSCC and in tumour multiplicity of the head and neck region. Moreover, our results exclude a role for the hMLH1 gene as a determinant of MI and as a specific gene target of deletion at 3p21 in HNSCC. We conclude that presumably other genetic mechanisms, such as those hypothesized for MI-negative hereditary non-polyposis colorectal cancer patients, may play a major role in the carcinogenesis of the mucosa of the upper respiratory tract.

Alleles↗
PubMed2006

Dynamical fracture instabilities due to local hyperelasticity at crack tips.

As the speed of a crack propagating through a brittle material increases, a dynamical instability leads to an increased roughening of the fracture surface. Cracks moving at low speeds create atomically flat mirror-like surfaces; at higher speeds, rougher, less reflective ('mist') and finally very rough, irregularly faceted ('hackle') surfaces are formed. The behaviour is observed in many different brittle materials, but the underlying physical principles, though extensively debated, remain unresolved. Most existing theories of fracture assume a linear elastic stress-strain law. However, the relation between stress and strain in real solids is strongly nonlinear due to large deformations near a moving crack tip, a phenomenon referred to as hyperelasticity. Here we use massively parallel large-scale atomistic simulations--employing a simple atomistic material model that allows a systematic transition from linear elastic to strongly nonlinear behaviour--to show that hyperelasticity plays a governing role in the onset of the instability. We report a generalized model that describes the onset of instability as a competition between different mechanisms controlled by the local stress field and local energy flow near the crack tip. Our results indicate that such instabilities are intrinsic to dynamical fracture and they help to explain a range of controversial experimental and computational results.

Journal Article↗
PubMed2006

Radiation-pressure cooling and optomechanical instability of a micromirror.

Recent table-top optical interferometry experiments and advances in gravitational-wave detectors have demonstrated the capability of optical interferometry to detect displacements with high sensitivity. Operation at higher powers will be crucial for further sensitivity enhancement, but dynamical effects caused by radiation pressure on the interferometer mirrors must be taken into account, and the appearance of optomechanical instabilities may jeopardize the stable operation of the next generation of interferometers. These instabilities are the result of a nonlinear coupling between the motion of the mirrors and the optical field, which modifies the effective dynamics of the mirror. Such 'optical spring' effects have already been demonstrated for the mechanical damping of an electromagnetic waveguide with a moving wall, the resonance frequency of a specially designed flexure oscillator, and the optomechanical instability of a silica microtoroidal resonator. Here we present an experiment where a micromechanical resonator is used as a mirror in a very high-finesse optical cavity, and its displacements are monitored with unprecedented sensitivity. By detuning the laser frequency with respect to the cavity resonance, we have observed a drastic cooling of the microresonator by intracavity radiation pressure, down to an effective temperature of 10 kelvin. For opposite detuning, efficient heating is observed, as well as a radiation-pressure-induced instability of the resonator. Further experimental progress and cryogenic operation may lead to the experimental observation of the quantum ground state of a micromechanical resonator, either by passive or active cooling techniques.

Journal Article↗
PubMed2002

Chromosomal instability in ulcerative colitis is related to telomere shortening.

Ulcerative colitis, a chronic inflammatory disease of the colon, is associated with a high risk of colorectal carcinoma that is thought to develop through genomic instability. We considered that the rapid cell turnover and oxidative injury observed in ulcerative colitis might accelerate telomere shortening, thereby increasing the potential of chromosomal ends to fuse, resulting in cycles of chromatin bridge breakage and fusion and chromosomal instability associated with tumor cell progression. Here we have used quantitative fluorescence in situ hybridization to compare chromosomal aberrations and telomere shortening in non-dysplastic mucosa taken from individuals affected by ulcerative colitis, either with (UC progressors) or without (UC non-progressors) dysplasia or cancer. Losses, but not gains, of chromosomal arms and centromeres are highly correlated with telomere shortening. Chromosomal losses are greater and telomeres are shorter in biopsy samples from UC progressors than in those from UC non-progressors or control individuals without ulcerative colitis. A mechanistic link between telomere shortening and chromosomal instability is supported by a higher frequency of anaphase bridges--an intermediate in the breakage and fusion of chromatin bridges--in UC progressors than in UC non-progressors or control individuals. Our study shows that telomere length is correlated with chromosomal instability in a precursor of human cancer.

Adult↗
PubMed1995

Microsatellite instability in primary neoplasms from HIV + patients.

AIDS is associated with a high risk of certain malignancies, notably Kaposi's sarcoma (KS) and B-cell non-Hodgkin's lymphoma (NHL). The pathogenesis of these malignancies is not fully understood. One mechanism of malignant transformation recently described in colon tumorigenesis results from defects in DNA mismatch repair, manifest as widespread microsatellite instability. We demonstrate a high rate of microsatellite instability in KS and aggressive lymphomas obtained from HIV-infected patients, whereas there is no evidence of instability in similar lesions from HIV-negative patients. Further elucidation of the underlying mechanisms responsible for HIV-associated instability in primary tumours may provide insight into the pathogenesis of these AIDS-related neoplasms.

DNA Repair↗
PubMed1995

Genetic instability occurs in the majority of young patients with colorectal cancer.

Replication errors (RER) associated with genetic instability have been found in cancers of several different types and particularly in the tumours of patients with hereditary non-polyposis colorectal cancer (HNPCC). We have here determined the prevalence of such instability in relation to age among patients without HNPCC. Colorectal cancers (CRCs) in the majority of patients 35 years of age or younger exhibited instability (58% of 31 patients), whereas CRCs from patients older than 35 uncommonly did (12% of 158, p < 0.0001). Twelve of the patients under 35 with instability were evaluated for alterations of mismatch repair genes, and five were found to harbour germline mutations. These data suggest that the mechanisms underlying tumour development in young CRC patients differ from those in most older patients, regardless of HNPCC status. The results have important implications for genetic testing and management of young CRC patients and their families.

Adult↗
PubMed2003

Genomic instability--the engine of tumorigenesis?

Human cancers harbour numerous mutations and it has been proposed that these result from some form of inherent genomic instability. Some cancers have proven genomic instability or features that are indicative of this. Inherited cancer syndromes exist that are caused by deficient DNA repair or chromosomal integrity. By contrast, theoretical analysis and experimental data from sporadic colorectal tumours provide little general evidence of genomic instability in early lesions. These apparently conflicting data raise the question of whether or not genomic instability is necessary for driving tumour growth, and whether or not it is the usual initiating event in tumorigenesis.

Cell Transformation, Neoplastic↗
PubMed1999

Frequent allelic imbalance but infrequent microsatellite instability in gastric lymphoma.

Specific defects in DNA repair pathways are reflected by DNA microsatellite instability (MSI) and play an important role in carcinogenesis. Reported frequencies in gastric non-Hodgkin's lymphomas (NHL) vary from 14% to as high as 90%. Another form of genetic instability in tumours is allelic imbalance (AI) due to loss or gain of genetic material at a specific chromosomal region. This might point to the presence of a tumour suppressor gene or oncogene. We examined both MSI and AI in 26 gastric lymphomas (10 low-grade and 13 high-grade MALT lymphomas and three cases lacking MALT features and categorised as diffuse large B cell lymphoma (DLCL)). Tumour components and normal cells (epithelium, muscle) were microdissected from paraffin-embedded resection samples. Contrary to other studies we did not observe frequent MSI when investigating 18 different loci distributed over 12 chromosomes. Microsatellite instability of a single locus was found in 1/10 (10%) low-grade MALT lymphomas and 2/13 (15%) high-grade MALT lymphomas. These data indicate that DNA mismatch repair genes do not play a role in the pathogenesis of these lymphomas. Allelic imbalance was detected in 60% (6/10) of low-grade MALT lymphomas, in 62% (8/13) of high-grade MALT lymphoma and in 67% (2/3) of DLCL. In high-grade lymphomas more loci showed AI (one to seven loci, with a mean of 2.5 loci per case) than in the low-grade lymphomas (one to two loci, with a mean of 1.3 loci per case), possibly reflecting an increased genomic instability.

DNA Mutational Analysis↗
PubMed2000

Genetic instability is associated with histological transformation of follicle center lymphoma.

Follicle center lymphoma (FCL) is an indolent B cell non-Hodgkin's lymphoma (NHL) characterized genetically by the t(14;18) translocation. Histological transformation and clinical progression of FCLs are frequently associated with secondary genetic alterations at both nucleic acid and chromosomal levels. To determine the type and pattern of genomic instability occurring in histological transformation of FCLs and the role of DNA mismatch repair defects in this procedure, we have performed microsatellite analysis, comparative genomic hybridization (CGH) and mutational analysis of hMLH1 and hMSH2 genes on serial biopsy specimens from patients with FCL transformed to diffuse large cell lymphoma (DLCL). Paired biopsy samples of eight patients were analyzed for microsatellite instability and structural alterations for hMLH1 and hMSH2 genes, and tumor samples of five patients were subjected to CGH analysis. A high level of microsatellite instability was associated with histological transformation of two cases of FCL, but no mutations of the hMLH1 and hMSH2 genes were detected in any of the lymphoma samples. In the five cases subjected to CGH analysis, the histological transformation of FCLs was associated with genomic imbalances at 21 chromosomal regions. The genomic abnormalities found were rather heterogeneous and none of the genetic changes were overrepresented in the transformed DLCLs. These data suggest that histological transformation of FCLs to DLCL is frequently associated with genome wide instability at both nucleic acid and chromosomal levels, although mutations of the hMSH1 and hMLH2 genes are not involved in this process.

Adaptor Proteins, Signal Transducing↗