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PubMed1998

Role of chromosome instability in long term effect of manned-space missions.

Astronauts are exposed to heavy ions during space missions and heavy ion induced-chromosome damages have been observed in their lymphocytes. This raises the problem of the consequence of longer space flights. Recent studies show that some alterations can appear many cell generations after the initial radiation exposure as a delayed genomic instability. This delayed instability is characterized by the accumulation of cell alterations leading to cell transformation, delayed cell death and mutations. Chromosome instability was shown in vitro in different model systems (Sabatier et al., 1992; Marder and Morgan, 1993, Kadhim et al., 1994 and Holmberg et al., 1993, 1995). All types of radiation used induce a chromosome instability, however, heavy ions cause the most damage. The period of chromosome instability followed by the formation of clones with unbalanced karyotypes seems to be shared by cancer cells. The shortening of telomere sequences leading to the formation of telomere fusions is an important factor in the appearance of this chromosome instability.

Animals↗

PubMed1980

Carpal dislocations: pathomechanics and progressive perilunar instability.

The pathomechanics, ligamentous damage, and degree of carpal instability in perilunate and lunate dislocations were analyzed by experimentally loading 32 cadaver wrists to failure. Thirteen perilunate and two lunate dislocations were produced. The mechanism of injury was extension, ulnar deviation, and intercarpal supination. These dislocations occurred in a sequential fashion due to progressive and specific ligamentous disruptions and were classified according to the degree of perilunar instability (PLI). Stage I perilunar instability (scapholunate diastasis) had the least degree of carpal instability. Lunate dislocations (stage IV PLI) had the highest degree of carpal instability. Radial styloid fractures were produced in seven as a result of avulsion. Scaphoid rotation was created in eight and was due to rupture of the radioscaphoid and scapholunate ligaments. Reduction was accomplished by reversing the mechanism of injury--that is, intercarpal pronation, radial deviation, and palmar flexion. Stress roentgenograms employing longitudinal carpal compression in radial and ulnar deviation were helpful in determining the degree of associated carpal instability.

Adolescent↗

PubMed1998

Hemodynamic instability following carotid endarterectomy does not affect early discharge.

Over the last few years, there has been increased emphasis on early discharge of patients following carotid endarterectomy in the United States. Recent studies have shown that short-stay hospitalization for carotid endarterectomy may be safe and cost-effective. However, this is not always possible because of reasons that are not clearly delineated. In order to optimize the early discharge of patients following carotid endarterectomy, an analysis of the causes of delayed discharges was performed in the present series. Since hemodynamic instability has been shown to be the most frequent complication following carotid endarterectomy, the authors investigated whether it was an important factor preventing early postoperative discharge. This study reviewed the data of 100 consecutive patients admitted for elective carotid endarterectomy. The incidence of post-carotid endarterectomy hemodynamic instability was 37% (n = 37), with hypertension occurring in 25 patients (68%) and hypotension occurring in 12 patients (32%). Hemodynamic instability tended to occur with the use of general anesthesia as compared with regional anesthesia. Hemodynamic instability did not correlate with pre-existent history of hypertension, nor with the type of drug used when general anesthesia was applied. All the patients were successfully treated either in the recovery room or in a monitored area. The average total length of stay was 1.65 days with 79% of the patients being discharged on the first postoperative day and 21% having delayed discharge ranging from 2 to 15 days (mean 4 days). The main reasons for delayed discharges were cardiac and urinary tract complications. Blood pressure instability accounted for only 2% of cases. Thus, these data show that hemodynamic instability does not significantly affect early discharge.

Aged↗

PubMed2002

A single low dose of X-rays induces high frequencies of genetic instability (aneuploidy) and heritable damage (apoptosis), dependent on cell type and p53 status.

We harvested and analyzed cells from four different non-transformed cell lines surviving a single X-ray exposure. Evidence of radiation-induced karyotype instability was observed in 100% of C3H 10T1/2 fibroblast clones and 11.3% of V79 fibroblast clones. Heritable damage: predisposition to apoptosis, but not karyotype instability, was induced in TK6 (p53(wt/wt)) and WTK1 (p53(mut/mut)) human B-lymphoblastoid cell clones. The studies indicate: (1) genetic instability and/or heritable damage are induced in cells exposed to radiation at a high frequency, and induction of genetic instability is not limited to morphologically transformed cells [Radiat. Res. 138 (1994) S105; Radiat. Environ. Biophys. 36 (1998) 255]; (2) sensitivity to genetic instability and heritable damage depend on cell type; (3) checkpoint stringency and p53 status significantly influence the frequency of radiation-induced genetic instability and heritable damage; (4) in some cell lines, damage induced by low doses of radiation (below 2 Gy) leads to heritable cytotoxic and genotoxic effects in 100% of cells exposed. The data suggest that mammalian cells misinterpret damage induced by ionizing radiation as if it were a physiological cell signal. This contrasts strongly with the response of mammalian cells to damage induced by other types of DNA-toxic agents where damage-specific repair mechanisms are activated.

Aneuploidy↗

PubMed2007

State affective instability in borderline personality disorder assessed by ambulatory monitoring.

BACKGROUND: Although affective instability is an essential criterion for borderline personality disorder (BPD), it has rarely been reported as an outcome criterion. To date, most of the studies assessing state affective instability in BPD using paper-pencil diaries did not find indications of this characteristic, whereas in others studies, the findings were conflicting. Furthermore, the pattern of instability that characterizes BPD has not yet been identified. METHOD: We assessed the affective states of 50 female patients with BPD and 50 female healthy controls (HC) during 24 hours of their everyday life using electronic diaries. RESULTS: In contrast to previous paper-and-pencil diary studies, heightened affective instability for both emotional valence and distress was clearly exhibited in the BPD group but not in the HC group. Inconsistencies in previous papers can be explained by the methods used to calculate instability (see Appendix). In additional, we were able to identify a group-specific pattern of instability in the BPD group characterized by sudden large decreases from positive mood states. Furthermore, 48% of the declines from a very positive mood state in BPD were so large that they reached a negative mood state. This was the case in only 9% of the HC group, suggesting that BPD patients, on average, take less time to fluctuate from a very positive mood state to a negative mood state. CONCLUSION: Future ambulatory monitoring studies will be useful in clarifying which events lead to the reported, sudden decrease in positive mood in BPD patients.

Adult↗

PubMed2002

Chromosome instability in malignant astrocytic tumors detected by fluorescence in situ hybridization.

Malignant tumors intrinsically manifest genetic instability, and consequently genetic aberrations successively accumulate in tumor cells as the tumor progresses. However, the relationship of genetic instability and biological behavior still remains to be investigated in malignant tumors. In the present investigation, the relationship between chromosomal instability and patient prognosis was studied in 19 malignant gliomas. Chromosomal instability was estimated by numerical variation in chromosomes 7, 10 and 17 which was measured by fluorescence in situ hybridization (FISH), and DNA ploidy was determined by laser scanning cytometry. The mean number of fractions was significantly higher in cases with DNA aneuploidy than in those with DNA diploidy. The tendency toward higher fractions in glioblastomas existed, although it did not reach statistical significance. Kaplan-Meier survival rate analysis demonstrated significantly lower survival rates in patients with higher fractions of chromosome 7 (>5) than others. Our results suggest that DNA aneuploidy in malignant gliomas reflects an underlying chromosomal instability, and that this instability is associated with clinical behavior.

Adult↗

PubMedDate not supplied

Genomic instability and colon cancer.

Colorectal cancer affected approximately 135,000 people in the United States in 2001, resulting in 57,000 deaths. At the cellular level, colorectal cancer results from the progressive accumulation of genetic and epigenetic alterations that lead to the transformation of normal colonic epithelial cells to colon adenocarcinoma cells. The loss of genomic stability appears to be a key molecular and pathogenetic step that occurs early in the tumorigenesis process and serves to create a permissive environment for the occurrence of alterations in tumor suppressor genes and oncogenes. At least three forms of genomic instability have been identified in colon cancer: (1) microsatellite instability (MSI), (2) chromosome instability (i.e. aneusomy, gains and losses of chromosomal regions) (CIN), and (3) chromosomal translocations. Microsatellite instability occurs in approximately 15% of colon cancers and results from inactivation of the mutation mismatch repair (MMR) system by either MMR gene mutations or hypermethylation of the MLH1 promoter. MSI promotes tumorigenesis through generating mutations in target genes that possess coding microsatellite repeats, such as TGFBR2 and BAX. CIN is found in the majority of colon cancers and leads to a different pattern of gene alterations that contribute to tumor formation. CIN appears to result primarily from deregulation of the DNA replication checkpoints and mitotic-spindle checkpoints. The mechanisms that induce and influence genomic instability in cancer in general and more specifically in colon cancer are only partly understood and are consequently under intense investigation. These studies have revealed mutation of the mitotic checkpoint regulators BUB1 and BUBR1 and amplification of STK15 in a subset of CIN colon cancers. The etiology of CIN in the other unexplained cases of colon cancer remains to be determined. Hopefully, discovery of the cause and specific role of genomic instability in colon cancer will yield more effective chemotherapy strategies that take advantage of this unique characteristic of cancer cells.

Base Pair Mismatch↗

PubMed1999

Microsatellite instability is absent in liver and biliary mucosa of patients with primary sclerosing cholangitis.

Microsatellite instability occurs in the colonic mucosa of patients with inflammatory bowel disease and may predispose the mucosa to neoplastic transformation. It is unknown whether microsatellite instability also plays a role in the neoplastic risk associated with primary sclerosing cholangitis. We examined 134 tissue samples from 21 patients with sclerosing cholangitis for microsatellite instability at eight loci. All tissues were also stained immunohistochemically using an antibody to the proliferation marker Ki-67. Microsatellite instability did not occur in any samples from the intrahepatic or extrahepatic biliary system, although one patient demonstrated instability in the colon. Ki-67 indices ranged from 0 to 2.5 in nondysplastic biliary epithelium and from 1.5 to 29.4 in areas of dysplasia. The absence of microsatellite instability in sclerosing cholangitis suggests that the genetic basis of neoplastic progression in chronic inflammatory disease of the bile ducts differs from that of intestinal cancers arising in the setting of chronic inflammatory bowel disease and may relate to differences in the microenvironment in these two sites.

Adult↗

PubMed1996

Microsatellite instability in early sporadic breast cancer.

We have studied the incidence of microsatellite instability at three trinucleotide repeats and seven dinucleotide repeats from five chromosomal regions, in a group of 30 mammographically detected 'early' invasive breast cancers and correlated its occurrence with clinicopathological parameters. The myotonic dystrophy (DM-1) trinucleotide repeat was analysed in 48 additional cases. In 4 out of 78 (5%) paired tumour-normal DNA samples we found evidence of somatic microsatellite instability at DM-1: a novel allele of a different size was seen in the tumour DNA which was not present in the normal DNA sample. All four tumours that showed evidence of instability were from the core group of 30 cases (13%) and were well or moderately differentiated, oestrogen receptor-positive, infiltrating ductal carcinomas. Two of these tumours were unstable at nine of ten loci studied, both trinucleotide and dinucleotide repeats. DNA prepared from different normal tissues showed no evidence of instability, for all four instability cases. These data indicate that microsatellite instability is specific to the tumour DNA and is an early event in the genesis of some sporadic breast cancers.

Breast Neoplasms↗

PubMed1997

Infrequent microsatellite instability in oesophageal cancers.

Alterations of microsatellites have been found at relatively high frequency in hereditary and sporadic colorectal cancer and gastric and pancreatic cancers and at lower frequency in some other cancers. We determined the frequency of instability at 39 poly-CA microsatellite loci in 20 squamous cell carcinomas and 26 Barrett's adenocarcinomas of the oesophagus. None of the tumours presented instability for a high percentage of the tested loci. Four squamous cell carcinomas and six Barrett's adenocarcinomas showed microsatellite instability at one locus, and three Barrett's adenocarcinomas showed microsatellite instability at two loci. The presence of few loci showing microsatellite instability could be due to an instability background. We conclude that genetic defects in the DNA mismatch repair system do not play an important role in oesophageal cancers.

Adenocarcinoma↗

PubMed1995

Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability.

Microsatellite instability has been observed in both sporadic and hereditary forms of colorectal cancer. In the hereditary form, this instability is generally due to germline mutations in mismatch repair (MMR) genes. However, only one in ten patients with sporadic tumours exhibiting microsatellite instability had a detectable germline mutation. Moreover, only three of seven sporadic tumour cell lines with microsatellite instability had mutations in a MMR gene, and these mutations could occur somatically. These results demonstrate that tumours can acquire somatic mutations that presumably do not directly affect cell growth but result only in genetic instability. They also suggest that many sporadic tumours with microsatellite instability have alterations in genes other than the four now known to participate in MMR.

Adult↗

PubMed1999

Environmentally responsive temperature instability in pediatric spinal cord injury.

OBJECTIVE: To study the frequency and clinical implications of environmentally responsive temperature instability in hospitalized pediatric patients with spinal cord injury (SCI). SETTING: A tertiary level SCI rehabilitation unit located in a free standing children's hospital in Wilmington, DE, USA. STUDY DESIGN: Temperature data and corresponding clinical responses were collected prospectively between January 1991 and June 1993. Fifty-four consecutive patients with SCI levels at or above T6 were admitted to the pediatric spinal cord injury rehabilitation unit over that time (4059 SCI days). METHODS: Hypothermic events were defined as oral temperatures less than 35.0 degrees C or rectal temperatures less than 35.6 degrees C. Hyperthermic events were defined as oral temperatures greater than 38.0 degrees C or rectal temperatures greater than 38.4 degrees C. The events and the clinical responses were reviewed retrospectively and were used for subsequent analysis if there was evidence of clinical response to environmental manipulation within 4 hours of case identification, and other potential etiologies of temperature fluctuation could be excluded. RESULTS: Sixty-five events of hypothermia (1.60%) and 14 events of hyperthermia (0.34%) were analyzed. Twelve patients (22%) accounted for all 79 events. Subjects with environmentally responsive temperature instability were more recently injured (P<0.001), had longer lengths of stay (P<0.001) and were more likely to be ventilator dependent (P<0.002) than those who did not have environmentally responsive temperature instability. There was no significant difference between the two groups in age, gender, level or etiology of the SCI. There were no adverse clinical outcomes as a result of the environmentally responsive temperature instability. CONCLUSIONS: Environmentally responsive temperature instability affects a select subset of pediatric aged spinal cord injured persons. Early recognition of the potential contribution of the environment to temperature fluctuation in this group has led to the successful utilization of a temperature instability protocol on our SCI unit.

Adolescent↗

PubMed2002

The relationship between gastric cancer cells circulating in the blood and microsatellite instability positive gastric carcinomas.

BACKGROUND: Cancers characterized by microsatellite instability may be biologically different from their counterparts with stable microsatellite sequences. Circulating cancers cell present in blood prior to surgery may constitute an adverse prognostic finding. AIM: To correlate these two phenomena with morphological features and survival in advanced gastric cancer. METHODS: We examined 76 cases of resected sporadic, advanced gastric cancer by means of routine morphology and a panel of microsatellite markers. Sixty-six cases were screened for presence of cancer cells circulating in blood prior to the surgery using combined morphological and immunocytochemical approach. RESULTS: Twenty-one (27.6%) cases demonstrated microsatellite instability in at least one locus. Among them 11 (14.5%) showed microsatellite instability in more than 30% (4/12) examined loci, and they were therefore designated as replication error positive (RER+). Circulating cancer cells were detected in 2/19 microsatellite instability and in 11/47 remaining cases (difference not significant). The survival of the microsatellite instability cases was significantly better. The presence of circulating cancer cells did not correlate with survival. CONCLUSION: It is possible that the microsatellite instability status, but not circulating cancer cells, constitutes a prognostic predictive factor in advanced gastric carcinoma. Confirmation of this hypothesis requires continuation of patient follow-up.

Adult↗

PubMed2001

Arthroscopic treatment of multidirectional glenohumeral instability: 2- to 5-year follow-up.

PURPOSE: We present the results of a prospective study evaluating arthroscopic technique in repairing multidirectional glenohumeral instability. Type of Study: Case series. METHODS: The 47 patient study group consisted of 26 men and 21 women. Inclusion criteria were multidirectional glenohumeral instability diagnosed on physical examination and at arthroscopy. Exclusion criteria were unidirectional anterior or posterior instability and prior instability operation. Four patients declined to participate in the study. The average age at the time of operation was 30 years (range, 15 to 56 years). The average interval from operation to final evaluation was 35 months (range 26 to 67 months). The American Shoulder and Elbow Surgeons (ASES) Shoulder Index, Constant, Rowe, and UCLA scores were recorded preoperatively and at final evaluation. RESULTS: Preoperatively, no patients were rated overall as good to excellent according to the Rowe scale; at final follow-up 94% (44 of 47 patients) were rated as good to excellent. One patient was considered a failure of the index operation due to persistent instability and underwent a second operative procedure. One patient noted a loss of strength during sports, and 2 patients had pain that limited their throwing ability. The ASES Shoulder Index improved to 94.7 from 45.4 (P =.001). The absolute Constant score improved to 91.7 from 60 (P =.001). The Rowe score improved to 93.7 from 14.2 (P =.001). The UCLA total score improved to 33.1 from 17.4 (P =.001). Average passive external rotation at 90 degrees abduction measured 88.2 degrees. Twenty-two of 26 patients (85%) returned to their desired levels of sports following the operations. CONCLUSIONS: Patients with multidirectional glenohumeral instability have multiple lesions within the shoulder and the surgeon must individualize the operative treatment. Arthroscopic surgery produced successful results in 44 of 47 patients.

Journal Article↗

PubMed2006

Dynamic contact angle in rim instability of dewetting holes.

The effects of dynamic contact angle (thetad), between a substrate and the melt of a dewetting polymer thin film, on the evolution of rim instabilities of dewetting holes were reported. Various thetad's were achieved by covering SiOx surfaces with different coverage of octadecyltrichlorosilane. On each surface, the morphology of the dewetting holes was examined in detail as the hole grew to a certain size. Rim instabilities, in terms of undulations in both r and z directions, became more pronounced as thetad increased, under which condition, narrower and higher rims were also observed. Experimentally, atomic force microscopic scans of the rim were used to obtain the rim profile, which was predicted using thetad. The predicted rim profile was used, in combination with the analysis of Rayleigh instability of a cylindrical fluid, to interpret the rim instability. The model captures the basic trend of the rim instability dependency on thetad. The study demonstrates the importance of the substrate properties on the rim instability and the destabilization of polymer thin films during hole growth.

Journal Article↗

PubMed2001

p53 Mutations and microsatellite instability in ovarian cancer: Yin and yang.

OBJECTIVE: We tested the hypothesis that p53 frameshift mutations in ovarian cancer occur as a result of genomic instability rather than as a proximal cause of this process. STUDY DESIGN: Sequencing of the p53 tumor suppressor gene has been carried out on 305 ovarian, fallopian tube, and peritoneal cancers. Two groups of p53 null mutations were identified: (1) those caused by frameshift insertion or deletion mutations (n = 31) and (2) those caused by nonsense mutations (n = 28). As a control group 59 tumors with p53 missense mutations were selected by matching with the p53 null tumors on the basis of patient age at diagnosis, stage and grade of cancer, cancer site, and year of diagnosis. Microsatellite instability was determined from paired normal and tumor tissue deoxyribonucleic acid by means of the following different markers: D2S123, D5S346, D17S250, BAT25, and BAT26. Amplimers from polymerase chain reactions were evaluated on 7% polyacrylamide gels. RESULTS: The p53 null tumors were more likely to be of higher stage and grade. Fallopian tube cancers were more common (P =.02) in the p53 frameshift group. The overall incidence of microsatellite instability was 39%, 36%, and 25% for tumors with p53 frameshift nonsense and missense mutations (P =.30). Microsatellite instability was seen almost exclusively with ovarian cancer (P =.04). CONCLUSIONS: Microsatellite instability is a relatively common event in ovarian cancer and is dependent on marker selection. The p53 frameshift mutations do not appear to occur as a consequence of genomic instability.

Adult↗

PubMed1998

Genetic instability of cancer cells is proportional to their degree of aneuploidy.

Genetic and phenotypic instability are hallmarks of cancer cells, but their cause is not clear. The leading hypothesis suggests that a poorly defined gene mutation generates genetic instability and that some of many subsequent mutations then cause cancer. Here we investigate the hypothesis that genetic instability of cancer cells is caused by aneuploidy, an abnormal balance of chromosomes. Because symmetrical segregation of chromosomes depends on exactly two copies of mitosis genes, aneuploidy involving chromosomes with mitosis genes will destabilize the karyotype. The hypothesis predicts that the degree of genetic instability should be proportional to the degree of aneuploidy. Thus it should be difficult, if not impossible, to maintain the particular karyotype of a highly aneuploid cancer cell on clonal propagation. This prediction was confirmed with clonal cultures of chemically transformed, aneuploid Chinese hamster embryo cells. It was found that the higher the ploidy factor of a clone, the more unstable was its karyotype. The ploidy factor is the quotient of the modal chromosome number divided by the normal number of the species. Transformed Chinese hamster embryo cells with a ploidy factor of 1.7 were estimated to change their karyotype at a rate of about 3% per generation, compared with 1.8% for cells with a ploidy factor of 0.95. Because the background noise of karyotyping is relatively high, the cells with low ploidy factor may be more stable than our method suggests. The karyotype instability of human colon cancer cell lines, recently analyzed by Lengnauer et al. [Lengnauer, C., Kinzler, K. W. & Vogelstein, B. (1997) Nature (London) 386, 623-627], also corresponds exactly to their degree of aneuploidy. We conclude that aneuploidy is sufficient to explain genetic instability and the resulting karyotypic and phenotypic heterogeneity of cancer cells, independent of gene mutation. Because aneuploidy has also been proposed to cause cancer, our hypothesis offers a common, unique mechanism of altering and simultaneously destabilizing normal cellular phenotypes.

Aneuploidy↗

PubMed2000

Dose- and time-response relationships for lethal mutations and chromosomal instability induced by ionizing radiation in an immortalized human keratinocyte cell line.

PURPOSE: To investigate the relationship between two well-established delayed effects of ionizing radiation, experiments were conducted to determine the induction and expression of lethal mutations (delayed reproductive death) and chromosomal instability with respect to dose and time in a human immortalized keratinocyte cell line. METHODS: HPV-G cells were gamma- or alpha-irradiated and maintained in culture for up to 72 population doublings. At intervals, measurements were made of cloning efficiency and the cells examined for apoptosis and cytogenetic aberrations. RESULTS: The descendants of cells surviving 1 or 3 Gy gamma-irradiation, but not 0.5 Gy gamma-irradiation, exhibited a reduced colony-forming efficiency. The reduction persisted at a constant rate of 15-20% clonogenic cell loss per population doubling for up to 72 population doublings. Apoptosis was demonstrated in all colonies in the 1 and 3 Gy groups at 30 and 72 population doublings post-irradiation but not in the 0.5 Gy group. A significant persistent reduction in colony-forming ability (approximately 80%) was demonstrated in the progeny of cells irradiated with 0.5 Gy alpha-particles. After 30 population doublings, the proportion of chromosomally aberrant cells was significantly greater than control values for all doses of both high- and low-LET radiations. The major cytogenetic aberrations (chromatid breaks, chromosome fragments and minutes) were consistent with the transmission of chromosomal instability. The expression of instability declined between 30 and 72 population doublings in the 0.5 Gy and 3 Gy gamma-irradiation groups, but persisted up to 72 population doublings in the 1 Gy group. The expression of chromosomal instability was greater in the descendants of alpha-irradiated cells and showed little evidence of reduction with time. CONCLUSIONS: Unstable aberrations characteristic of radiation-induced chromosomal instability may commonly result in apoptosis and account for a component of the delayed reproductive death/lethal mutation phenotype in HPV-G cells. However, the absence of lethal mutations in the descendants of 0.5 Gy gamma-irradiated cells indicates a low-LET threshold effect for this particular endpoint. Overall, and particularly at low doses, there is no direct correlation between the two endpoints, indicating the absence of a simple relationship between these manifestations of radiation-induced genomic instability.

Alpha Particles↗