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At least 1,207 records · Page 67Linked to original sources
PubMed2003

Genomic instability in human osteoblast cells after exposure to depleted uranium: delayed lethality and micronuclei formation.

It is known that radiation can induce a transmissible persistent destabilization of the genome. We have established an in vitro cellular model using HOS cells to investigate whether genomic instability plays a role in depleted uranium (DU)-induced effects. Transmissible genomic instability, manifested in the progeny of cells exposed to ionizing radiation, has been characterized by de novo chromosomal aberrations, gene mutations, and an enhanced death rate. Cell lethality and micronuclei formation were measured at various times after exposure to DU, Ni, or gamma radiation. Following a prompt, concentration-dependent acute response for both endpoints, there was de novo genomic instability in progeny cells. Delayed reproductive death was observed for many generations (36 days, 30 population doublings) following exposure to DU, Ni, or gamma radiation. While DU stimulated delayed production of micronuclei up to 36 days after exposure, levels in cells exposed to gamma-radiation or Ni returned to normal after 12 days. There was also a persistent increase in micronuclei in all clones isolated from cells that had been exposed to nontoxic concentrations of DU. While clones isolated from gamma-irradiated cells (at doses equitoxic to metal exposure) generally demonstrated an increase in micronuclei, most clonal progeny of Ni-exposed cells did not. These studies demonstrate that DU exposure in vitro results in genomic instability manifested as delayed reproductive death and micronuclei formation.

Cell Culture Techniques↗
PubMed1998

Genomic instability and tumorigenic induction in immortalized human bronchial epithelial cells by heavy ions.

Carcinogenesis is postulated to be a progressive multistage process characterized by an increase in genomic instability and clonal selection with each mutational event endowing a selective growth advantage. Genomic instability as manifested by the amplification of specific gene fragments is common among tumor and transformed cells. In the present study, immortalized human bronchial (BEP2D) cells were irradiated with graded doses of either 1GeV/nucleon 56Fe ions or 150 keV/micrometer alpha particles. Transformed cells developed through a series of successive steps before becoming tumorigenic in nude mice. Tumorigenic cells showed neither ras mutations nor deletion in the p16 tumor suppressor gene. In contrast, they harbored mutations in the p53 gene and over-expressed cyclin D1. Genomic instability among transformed cells at various stage of the carcinogenic process was examined based on frequencies of PALA resistance. Incidence of genomic instability was highest among established tumor cell lines relative to transformed, non-tumorigenic and control cell lines. Treatment of BEP2D cells with a 4 mM dose of the aminothiol WR-1065 significantly reduced their neoplastic transforming response to 56Fe particles. This model provides an opportunity to study the cellular and molecular mechanisms involved in malignant transformation of human epithelial cells by heavy ions.

Alpha Particles↗
PubMed1999

Analysis of genomic instability in squamous cell carcinoma of the head and neck using the random amplified polymorphic DNA method.

Using the random amplified polymorphic DNA (RAPD) method, we identified genomic instability in head and neck squamous cell carcinoma (HNSCC) tissues. We extracted DNA from tumor and corresponding normal tissues of 30 HNSCC patients and amplified with ten random 10-mer arbitrary primers by the RAPD method. Genomic instabilities, which appeared as banding pattern changes between normal and tumor DNA, were detected by at least one primer in all tumor tissues. Moreover, there was significant correlation between the frequency of genomic instability and the degree of tumor differentiation. These results indicate a possible association of genomic instability with malignant potential of head and neck cancer.

Carcinoma, Squamous Cell↗
PubMed1998

Evaluating sensory conflict and postural instability. Theories of motion sickness.

Two experiments were carried out to evaluate the sensory conflict and the postural instability theories of motion sickness. The central hypothesis of sensory conflict theory is that motion sickness is caused by conflict between the current pattern of sensory inputs about self-movement and the pattern that is expected on the basis of previous experience. A subsidiary hypothesis is that the degree of motion sickness is proportional to the magnitude of sensory conflict. The central hypothesis of postural instability theory is that motion sickness is caused by loss of postural control. A subsidiary hypothesis is that the degree of motion sickness is proportional to amount of postural instability, which can be manipulated by physical restraint. In both experiments there were two levels of sensory conflict and two levels of postural restraint. Dependent variables were latency of onset and severity of motion sickness. The widespread occurrence of motion sickness in both experiments clearly confirmed the main hypothesis of sensory conflict theory. The results from Experiment 1, that there was significantly more motion sickness in the restrained condition, and from Experiment 2, that there was no significant difference in symptoms between the two restraint conditions, provide no support for the subsidiary hypothesis of postural instability theory. Evidence relating to the subsidiary proposition of sensory conflict theory was inconsistent.

Adolescent↗
PubMed1981

Ulnar midcarpal instability-clinical and laboratory analysis.

Patients with ulnar midcarpal instability have a characteristic pattern of clinical signs and symptoms related to the midcarpal joint. The usual presenting complaint is a painful wrist click which can be reproduced by ulnar deviation, axial compression, and pronation of the wrist. Routine x-rays are usually normal, but cinefluoroscopy reveals sudden dissociation between the proximal and distal carpal rows resulting in a dorsiflexion collapse deformity. In six of our patients, conservative therapy sufficed to relieve symptoms. Four other patients required surgical stabilization. We close to stabilize the triquetrohamate joint because it was a relatively easy procedure and eliminated instability in most instances. Laboratory studies aided in understanding the pathomechanics of midcarpal instability, which consisted of dorsal subluxation of the capitate and hamate on the lunate and triquetrum. We believe that midcarpal instability is not a rare condition but may often be confused clinically with more common carpal dissociations.

Carpal Bones↗
PubMed1984

Intercarpal arthrodesis in the management of chronic carpal instability after trauma.

A retrospective review of five patients with chronic carpal instability resulting from trauma suggests that this condition can be successfully treated by intercarpal arthrodesis. Scaphoid-lunate fusion was used to treat chronic dorsal intercalary segment instability, while scaphoid-capitate-lunate fusion was used to treat chronic palmar intercalary segment instability. Results after intercarpal arthrodesis were consistently good, with restoration of painless function, preservation of grip strength, and a high degree of patient satisfaction. Although a fibrous union was obtained in two of the three scaphoid-lunate arthrodeses, this did not prejudice a good clinical outcome. These results compare favorably to those with other treatment modalities, including ligamentous reconstructions with tendons. Based on these findings, a more extensive clinical trial of intercarpal arthrodesis to treat chronic carpal instability appears warranted.

Adult↗
PubMed1997

Noninvasive measurement of distal radius instability.

Except for subjective clinical criteria, there is no formal definition of distal radius fracture instability in the literature. The purposes of this ex vivo biomechanical study were (1) to provide an objective mechanical definition of fracture instability and (2) to demonstrate a noninvasive method that allows for direct measurement of instability. The following 3 questions are addressed: (1) Can the stability of distal radius fractures be measured using computed tomography (CT)? (2) Are the stability measurements reproducible? (3) How does external fixation change stability? A CT technique is described that was used to measure displacement of fracture fragments and measure the compliance of ex vivo distal radius fractures before and after external fixation. Validation studies of the CT technique revealed a mean coefficient of variation of 0.38. There was a linear relationship between measured and known displacements for all 3 orthogonal planes (coefficient of determination 0.99; p < .01). There was significant fracture displacement with loads as small as 20 N. The slope of the load-displacement curve (structural compliance) provided a quantitative measure of fracture instability. Fracture compliance decreased up to 69% after application of an external fixator.

Biomechanical Phenomena↗
PubMed1996

Isolation of a mRNA instability sequence that is cis-dominant to the ompA stability determinant in Escherichia coli.

Transcriptional fusions with ompA and bla have been used to identify a novel mRNA instability element. A 287-nucleotide (nt) sequence containing a repetitive extragenic palindrome (REP) from the chloramphenicol acetyltransferase (cat) gene was inserted into the 3' untranslated region (UTR) of the ompA gene. In one orientation, the insert had no effect on the half-life of the ompA-cat chimeric transcript. In the other orientation, however, the sequence functioned as a destabilizing element and was dominant to the 5'-UTR ompA and REP stability elements. The orientation-dependent effect of the instability sequence suggests that sequence rather than structure alone is important to the function of the instability determinant. In addition, the instability sequence also destabilized an ompA-bla fusion construct when fused to its 3'-UTR region. A sensitive RNA ligation/PCR amplification technique was developed and used to analyze RNA decay intermediates. The results indicated that degradation of the chimeric transcript initiated within the 287-nt inserted sequence.

Bacterial Outer Membrane Proteins↗
PubMed2000

Genomic instability in multistage carcinogenesis.

For a normal cell to accumulate multiple genetic changes during multistage carcinogenesis, the induction of genomic instability is considered advantageous. Since most human cancers are associated with exposure to environmental carcinogens, it is likely that environmental carcinogens interact with genomic instability. Our results indeed suggest that carcinogens contribute to the induction of microsatellite instability and induce more mutations in those cells which show microsatellite instability. We have recently developed a sensitive method to clearly detect changes in simple repeats of coding sequences of cancer genes and the results suggest that such sequences of different genes are mutated in different tumors.

Animals↗
PubMed1999

Instability, stabilization, and formulation of liquid protein pharmaceuticals.

One of the most challenging tasks in the development of protein pharmaceuticals is to deal with physical and chemical instabilities of proteins. Protein instability is one of the major reasons why protein pharmaceuticals are administered traditionally through injection rather than taken orally like most small chemical drugs. Protein pharmaceuticals usually have to be stored under cold conditions or freeze-dried to achieve an acceptable shelf life. To understand and maximize the stability of protein pharmaceuticals or any other usable proteins such as catalytic enzymes, many studies have been conducted, especially in the past two decades. These studies have covered many areas such as protein folding and unfolding/denaturation, mechanisms of chemical and physical instabilities of proteins, and various means of stabilizing proteins in aqueous or solid state and under various processing conditions such as freeze-thawing and drying. This article reviews these investigations and achievements in recent years and discusses the basic behavior of proteins, their instabilities, and stabilization in aqueous state in relation to the development of liquid protein pharmaceuticals.

Animals↗
PubMed1998

Analytical techniques used to study the degradation of proteins and peptides: chemical instability.

Instability of peptides and proteins can be divided into two forms: chemical and physical instability. Chemical instability is due to modification/alteration of amino acid residues. There are several types of degradation reactions responsible for this instability. Most frequently described reactions are oxidation, reduction, deamidation, hydrolysis, arginine conversion, beta-elimination and racemisation. However, any study of the degradation of a chemical substance lacks reliability when the analytical methodology, that is used is not properly validated. Especially in the investigation, where degradation processes lead to their parent compounds, validation of the analysis is pivotal for the correct interpretation of the results. It is therefore appropriate and useful to assemble an overview of degradation processes in relation to the analytical methods to monitor them. An overview like this can help investigators to make the right choices in their analytical approach of stability problems. The degradation reactions involved in peptide/protein degradation as well as the methods to monitor them are summarized and discussed.

Arginine↗
PubMedDate not supplied

Induction of genetic instability by ionizing radiation.

Evidence is presented to support the hypothesis that radiation may induce a heritable, genome-wide process of instability that leads to an enhanced frequency of genetic changes occurring among the progeny of the original irradiated cell. This instability is transmissible over many generations of cell replication. Mutational instability is induced in a relatively large fraction (approximately 10%) of the cell population, and may be modulated by factors acting in vivo. Thus, it cannot be a targeted event involving a specific gene or set of genes. There is no dose-response relationship in the range 2-12 Gy, suggesting that the instability phenotype may be induced by quite low radiation doses. The molecular mechanisms associated with the genesis of mutations in unstable populations differ from those for direct X-ray-induced mutations. These results suggest that it may not be possible to predict the nature of the dose-response relationship for the ultimate genetic effects of radiation based on a qualitative or quantitative analysis of the original DNA lesions.

Alpha Particles↗
PubMed2001

Attenuation of radiation-induced genomic instability by free radical scavengers and cellular proliferation.

To investigate the mechanisms of radiation-induced chromosomal instability, cells were irradiated in the presence of the free radical scavengers DMSO, glycerol, or cysteamine, in the presence of DMSO while frozen, or held in confluence arrest post-irradiation to permit cells to repair potentially lethal DNA damage. Clones derived from single progenitor cells surviving each treatment were then analyzed for the subsequent development of chromosomal instability. The presence of scavengers (+/- freezing) during irradiation, and the recovery from potentially lethal damage after irradiation led to an increase in cell survival that was accompanied by a decrease in the initial yield of chromosomal rearrangements. Furthermore, analysis of over 400 clones and 80,000 metaphases indicates that these same treatments reduced the incidence of instability at equitoxic doses when compared to controls irradiated in the absence of scavengers at ambient temperature. Results suggest that preventing reactive species from damaging DNA, promoting chemical repair of ionized DNA intermediates, or allowing enzymatic removal of genetic lesions, represent measures that reduce the total burden of DNA damage and reduce the subsequent onset of radiation-induced genomic instability.

Animals↗
PubMed2002

The effectiveness of combined clinical-sonographic screening in the treatment of neonatal hip instability.

OBJECTIVE: The early diagnosis of neonatal hip instability is well recognized in preventing possible late developmental dysplasia of the hip. The optimal scheme of its diagnosis is essential. The role of combined approach of clinical and ultrasonographic evaluation of hip instability in newborns is evaluated in the present study. METHODS: Hips of 9030 consecutive neonates were examined independently by clinical and ultrasonographic means, separately by neonatologists and orthopedic surgeons, without initial sharing of information. When hip pathology was diagnosed by one of the modalities and missed by another, re-examination was performed. The rate of initially undiagnosed, clinically or ultrasonographically unstable hips and the 1-year follow up of the effected newborns were recorded. RESULTS: Instability was diagnosed in 1.4% of all hips, but only 63% of unstable hips were diagnosed on the initial clinical examination. In the remainder, the clinical pathology was established on clinical re-examination after the sonographic abnormality was recognized. Similarly, but to a much lesser extent, sonographic pathology was detected only on the re-examination in 5% of the clinically unstable hips. Although the overall initial under-diagnosis rate of hip instability was 0.6% of all hips, the rate for treated hips was 0.1%. CONCLUSION: These data should be taken into consideration in planning an efficient DDH screening policy.

Hip Dislocation, Congenital↗
PubMed2003

A prospective evaluation of hemodynamic instability during off-pump coronary artery bypass surgery.

OBJECTIVE: Despite recognized hemodynamic derangements during cardiac displacement, most patients appear to tolerate the off-pump procedure well. However, some patients unpredictably become hemodynamically unstable requiring emergency cardiopulmonary bypass or intra-aortic balloon pump support. After an experience of 5306 multivessel off-pump coronary artery bypasses (OPCABs), this study was undertaken to determine the factors that would identify the patients who were at a higher risk for the procedure. DESIGN: Prospective clinical investigation. SETTING: Tertiary care academic cardiac care center. PARTICIPANTS: Five hundred consecutive patients undergoing multivessel OPCAB from September to December 2001. INTERVENTIONS: Various cardiac and extracardiac factors were charted in prespecified data-entry forms. Multiple logistic regression analysis was done to determine if any identifiable factors were predictors of a higher risk of unacceptable hemodynamic instability during OPCAB. Institution of IABP support or conversion to CPB were the endpoints of the study. MEASUREMENTS AND MAIN RESULTS: Of the 500 patients studied, significant hemodynamic instability developed in 24 (4.8%) patients. IABP support was instituted in 16 (3.2%) patients, and 8 (1.6%) were converted to CPB. Stepwise logistic regression identified ejection fraction <25% (p < 0.001), myocardial infarction of <1-month duration (p = 0.009), congestive heart failure (p = 0.016), and preoperative hemodynamic instability (p = 0.057) as predictors of conversion during OPCAB. CONCLUSIONS: Patients with low left ventricular ejection fraction <25%, myocardial infarction of <1-month duration, congestive heart failure, or preoperative hemodynamic instability constitute the high-risk group for OPCAB.

Aged↗
PubMed2002

Chromosomal biomarkers of genomic instability relevant to cancer.

It is generally acknowledged that a crucial event in the initiation and evolution of cancer is the acquisition of a genomic instability phenotype. This review focuses on mechanisms of chromosomal instability including aneuploidy, chromosome rearrangement and breakage-fusion-bridge cycles. The role of micronutrient deficiency, such as folate deficiency, in the causation of chromosomal instability is briefly reviewed and the concept of recommended dietary allowances for genomic stability is introduced. In addition, the techniques for measuring the various chromosomal instability events are discussed with a focus on the cytokinesis-block micronucleus assay as an almost complete system for measuring these various genetic mishaps.

Animals↗
PubMed1998

A novel missense mutation and frameshift mutations in the type II receptor of transforming growth factor-beta gene in sporadic colon cancer with microsatellite instability.

Microsatellite instability of DNA samples of 79 sporadic colon cancer patients were analyzed. These samples were also screened to search mutations in the repeat sequences in the gene for the type II receptor of transforming growth factor-beta (TGF-beta RII) using polymerase chain reaction (PCR), electrophoresis with urea gel, and PCR-single strand conformation polymorphism (PCR-SSCP) method. The incidence of microsatellite instability, defined as severe replication error phenotype (RER) with microsatellite alterations in more than three loci, was 6%. Deletion and insertion of an A residue in the (A)10 region, which cause frameshift mutation, were found in four samples and their incidence in the samples with microsatellite instability was 80%. A novel nucleotide substitution of T for G at 1918, which causes missense mutation of arginine to leucine at codon 528, was found in a sample with microsatellite instability. The mutation at 1918 was in highly conservative amino acid residue.

Colonic Neoplasms↗
PubMed2001

Mitochondrial genome instability in human cancers.

Malfunction of mismatch repair (MMR) genes produces nuclear genome instability (NGI) and plays an important role in the origin of some hereditary and sporadic human cancers. The appearance of non-inherited microsatellite alleles in tumor cells (microsatellite instability, MSI) is one of the expressions of NGI. We present here data showing mitochondrial genome instability (mtGI) in most of the human cancers analyzed so far. The mtDNA markers used were point mutations, length-tract instability of mono- or dinucleotide repeats, mono- or dinucleotide insertions or deletions, and long deletions. Comparison of normal and tumoral tissues from the same individual reveals that mt-mutations may show as homoplasmic (all tumor cells have the same variant haplotype) or as heteroplasmic (tumor cells are a mosaic of inherited and acquired variant haplotypes). Breast, colorectal, gastric and kidney cancers exhibit mtGI with a pattern of mt-mutations specific for each tumor. No correlation between NGI and mtGI was found in breast, colorectal or kidney cancers, while a positive correlation was found in gastric cancer. Conversely, germ cell testicular cancers lack mtGI. Damage by reactive oxygen species (ROS), slipped-strand mispairing (SSM) and deficient repair are the causes explaining the appearance of mtGI. The replication and repair of mtDNA are controlled by nuclear genes. So far, there is no clear evidence linking MMR gene malfunction with mtGI. Polymerase gamma (POLgamma) carries out the mtDNA synthesis. Since this process is error-prone due to a deficiency in the proofreading activity of POLgamma, this enzyme has been assumed to be involved in the origin of mt-mutations. Somatic cells have hundreds to thousands of mtDNA molecules with a very high rate of spontaneous mutations. Accordingly, most somatic cells probably have a low frequency of randomly mutated mtDNA molecules. Most cancers are of monoclonal origin. Hence, to explain the appearance of mtGI in tumors we have to explain why a given variant mt-haplotype expands and replaces part of (heteroplasmy) or all (homoplasmy) wild mt-haplotypes in cancer cells. Selective and/or replicative advantage of some mutations combined with a severe bottleneck during the mitochondrial segregation accompanying mitosis are the mechanisms probably involved in the origin of mtGI.

Base Pair Mismatch↗