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At least 19 recordsLinked to original sources
PubMed2005

O6-methylguanine-DNA methyltransferase, O6-benzylguanine, and resistance to clinical alkylators in pediatric primary brain tumor cell lines.

PURPOSE: Primary brain tumors are the leading cause of cancer death in children. Our purpose is (a) to assess the contribution of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) to the resistance of pediatric brain tumor cell lines to clinical alkylating agents and (b) to evaluate variables for maximal potentiation of cell killing by the MGMT inhibitor O6-benzylguanine, currently in clinical trials. Few such data for pediatric glioma lines, particularly those from low-grade tumors, are currently available. EXPERIMENTAL DESIGN: We used clonogenic assays of proliferative survival to quantitate cytoxicity of the chloroethylating agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and the methylating agent temozolomide in 11 glioma and five medulloblastoma lines. Twelve lines are newly established and characterized here, nine of them from low-grade gliomas including pilocytic astrocytomas. RESULTS: (a) MGMT is a major determinant of BCNU resistance and the predominant determinant of temozolomide resistance in both our glioma and medulloblastoma lines. On average, O(6)-benzylguanine reduced LD10 for BCNU and temozolomide, 2.6- and 26-fold, respectively, in 15 MGMT-expressing lines. (b) O6-Benzylguanine reduced DT (the threshold dose for killing) for BCNU and temozolomide, 3.3- and 138-fold, respectively. DT was decreased from levels higher than, to levels below, clinically achievable plasma doses for both alkylators. (c) Maximal potentiation by O6-benzylguanine required complete and prolonged suppression of MGMT. CONCLUSIONS: Our results support the use of O6-benzylguanine to achieve full benefit of alkylating agents, particularly temozolomide, in the chemotherapy of pediatric brain tumors.

Adolescent↗
PubMed2004

Apurinic endonuclease activity in adult gliomas and time to tumor progression after alkylating agent-based chemotherapy and after radiotherapy.

PURPOSE: Apurinic/apyrimidinic endonuclease (Ap endo) is a key DNA repair enzyme that cleaves DNA at cytotoxic abasic sites caused by alkylating agents and radiation. We have observed that human glioma cells deficient in Ap endo activity are hypersensitive to clinically used alkylators (Silber et al., Clin Cancer Res 2002;8:3008.). Here we examine the association of glioma Ap endo activity with clinical response after alkylating agent-based chemotherapy or after radiotherapy. EXPERIMENTAL DESIGN: Cox proportional hazards regression models were used to analyze the relationship of Ap endo activity with time to tumor progression (TTP). RESULTS: In a univariate model with Ap endo activity entered as a continuous variable, the hazard ratio (HR) for progression after alkylator therapy in 30 grade III gliomas increased by a factor of 1.061 for every 0.01 increase in activity (P = 0.013). Adjusting for age, gender, extent of resection, and prior treatment strengthened slightly the association (HR = 1.094; P = 0.003). Similarly, the HR for progression after radiotherapy in 44 grade II and III tumors increased by a factor of 1.069 (P = 0.008). Adjusting for the aforementioned variables had little effect on the association. In contrast, we observed no association between activity and TTP in grade IV gliomas after either alkylator therapy in 34 tumors or radiotherapy in 26 tumors. CONCLUSIONS: Our data suggest that Ap endo activity mediates resistance to alkylating agents and radiation and may be a useful predictor of progression after adjuvant therapy in a subset of gliomas.

Adult↗
PubMed2004

The Werner syndrome protein confers resistance to the DNA lesions N3-methyladenine and O6-methylguanine: implications for WRN function.

The Werner syndrome (WS) protein (WRN), a DNA helicase/exonuclease, is required for genomic stability and avoidance of cancer. Current evidence suggests that WRN is involved in the resolution of stalled and/or collapsed replication forks. This function is indicated, in part, by replication defects in WS cells and by hypersensitivity to agents causing major structural aberrations in DNA that block replication. We show here that antisense suppression of WRN in two human glioma cell lines reproduces hallmarks of the drug cytotoxicity profile of WS cells, namely, hypersensitivity to 4-nitroquinoline 1-oxide, camptothecin and hydroxyurea. We also show that antisense-treated cells are hypersensitive to methyl-lexitropsin, a site-specific alkylating agent that produces mainly N3-methyladenine, a cytotoxic and replication-blocking lesion. Antisense-treated cells are hypersensitive to O(6)-methylguanine adducts as well, but only when repair by O(6)-methylguanine-DNA methyltransferase is lacking. Our results illustrate the drug sensitivity caused by deficiency of WRN in a uniform genetic background. They extend the WRN DNA damage sensitivity spectrum to methyl base adducts that can result in blocked replication, and suggest that WRN may be required for resumption of processive replication when incomplete repair of DNA damage leaves blocking lesions at forks. The evidence that highly disparate lesions fall within the purview of WRN, and that abrogating DNA repair can reveal dependence on WRN, suggests that WRN may protect the genome from the lethal, mutagenic and carcinogenic effects of widely diverse DNA damage arising from endogenous processes and environmental agents.

4-Nitroquinoline-1-oxide↗
PubMed2002

The apurinic/apyrimidinic endonuclease activity of Ape1/Ref-1 contributes to human glioma cell resistance to alkylating agents and is elevated by oxidative stress.

Alkylating agents are standard components of adjuvant chemotherapy for gliomas. We provide evidence here that Ape1/Ref-1, the major mammalian apurinic/apyrimidinic endonuclease (Ap endo), contributes to alkylating agent resistance in human glioma cells by incising DNA at abasic sites. We show that antisense oligonucleotides directed against Ape1/Ref-1 in SNB19, a human glioma cell line lacking O(6)-methylguanine-DNA-methyltransferase, mediate both reduction in Ape1/Ref-1 protein and Ap endo activity and concurrent reduction in resistance to methyl methanesulfonate and the clinical alkylators temozolomide and 1,3-(2-chloroethyl)-1-nitrosourea. An accompanying increase in the level of abasic sites indicates that the DNA repair activity of Ape1/Ref-1 contributes to resistance. Conversely, we also show that exposure of SNB19 cells to HOCl, a generator of reactive oxygen species (ROS), results in elevated Ape1/Ref-1 protein and Ap endo activity, enhanced alkylator resistance, and reduced levels of abasic sites. Given current evidence that heightened oxidative stress prevails within brain tumors, the finding that ROS increase resistance to clinical alkylators in glioma cells may have significance for the response of gliomas to alkylating agent-based chemotherapy. Our results may also be relevant to the design of therapeutic regimens using concurrent ionizing radiation (a generator of ROS) and alkylating agent-based chemotherapy.

Antineoplastic Agents, Alkylating↗
PubMed2001

Apurinic/apyrimidinic endonuclease activity is elevated in human adult gliomas.

Apurinic/apyrimidinic endonuclease (Ap endo) is a key DNA repair activity that confers resistance to ionizing radiation and alkylating agents in human cell lines. The major Ap endo in human cells is Ape1, an abundant multi-functional protein also known as Ref-1, Hap-1, and Apex. In this work, we assayed Ap endo activity in human adult gliomas to establish correlates with tumor characteristics, and in histologically normal brain adjacent to tumors to characterize changes in activity accompanying neurocarcinogenesis. To our knowledge, this is the first available analysis of Ap endo activity in human brain tumors. Mean activity in 84 gliomas of different diagnostic types and grades was 0.072 +/- 0.095 fmol abasic sites incised/cell/min, ranging approximately 550-fold from 0.00077 to 0.42. The mean for high-grade gliomas was 3.5-fold greater than for low-grade tumors (P < or = 4.0 x 10(-5)), a difference observed within all diagnostic types. Activity was correlated with the fraction of S-phase cells in diploid gliomas (P < or = 0.02), suggesting that proliferation could be a determinant of activity in these tumors. Activity was also correlated with S-phase fraction in the majority of aneuploid gliomas (P < or = 0.03). Moreover, within the aneuploid tumors, there was a significant relationship between activity and the fraction of aneuploid cells (P < or = 4.0 x 10(-4)). In the 58 cases analyzed, mean activity was 7.3-fold higher in gliomas than in adjacent histologically normal brain (0.070 +/- 0.10 versus 0.0096 +/- 0.012 fmol/cell/min; P < or = 3.0 x 10(-5)). Increased tumor activity was observed in 93% of tumor/normal pairs, indicating that elevation of Ap endo activity is characteristic of human gliomagenesis. The elevation was large within most pairs, being 13-fold on average and > or = 10-fold in 43% of cases. A concomitant increase in Ape1 protein was observed by Western blotting in the subset of tumor/normal pairs examined. A clinically important consequence of the increase in Ap endo activity that accompanies neurocarcinogenesis may be enhanced resistance to the radiotherapy and alkylating agent-based chemotherapy that are mainstays of adjuvant therapy for malignant gliomas.

Adolescent↗
PubMed2000

Thermus aquaticus DNA polymerase I mutants with altered fidelity. Interacting mutations in the O-helix.

Phe(667) in the conserved O-helix of Thermus aquaticus (Taq) DNA polymerase I (pol I) is known to be important for discrimination against dideoxy-NTPs. We show here that Phe(667) is also important for base selection fidelity. In a forward mutation assay at high polymerase concentration, wild type pol I catalyzed frequent A --> T and G --> T transversions and -1 frameshifts at nonreiterated sites involving loss of a purine immediately downstream of a pyrimidine. The mutants F667L and A661E,I665T,F667L exhibited large decreases in A --> T and G --> T transversions, and the triple mutant displayed reduction in the aforementioned -1 frameshifts as well. Kinetic analysis showed that the F667L and A661E,I665T,F667L polymerases discriminated against synthesis of A:A mispairs more effectively and catalyzed less extension of A:A mispairs than the wild type enzyme. These data indicate that Phe(667) functions in maintaining the error frequency and spectrum, and the catalytic efficiency, of wild type pol I. We also found that the strong general mutator activity conferred by the single A661E substitution was entirely suppressed in the A661E, I665T,F667L polymerase, exemplifying how interactions among O-helix residues can contribute to fidelity. We discuss the mutator and anti-mutator mutations in light of recently obtained three-dimensional structures of T. aquaticus pol I.

Amino Acid Sequence↗
PubMed2000

Filling factor of a paramagnetic sample in a rectangular cavity: theory and application.

A computational method is presented for calculating the filling factor of an electron paramagnetic resonance (EPR) tube in a rectangular TE102 cavity. The algorithm employs the conventional finite element method. In addition to the filling factor, the algorithm allows to calculate the quality factor and the reflection coefficient of the loaded cavity. This method allows calculating very accurately the EPR signal intensities from which the spin concentration of paramagnetic samples can be determined. A comparison between the predicted EPR signal intensities to several experimental results was found to be satisfactory. The method also allows optimizing the EPR tube dimensions and its glass quality to improve measurement sensitivity.

Algorithms↗
PubMed2000

Quantitative estimation of attenuation in ultrasound video images: correlation with histology in diffuse liver disease.

RATIONALE AND OBJECTIVES: To determine the relationship between the attenuation of backscatter intensity in B-scan images of the liver and diffuse liver disease in order to assess the usefulness of this method in providing quantitative objective characterization of diffuse liver diseases in general and in fatty liver in particular. METHODS: Twenty-four healthy volunteers and 28 patients with elevated liver enzyme levels who underwent liver biopsy were included in this study. An automatic far-field slope (FFS) algorithm that estimates the decrease in amplitude of the backscattered echo as a function of beam depth was implemented on the noncompensated image that was acquired on a commercial phased-array ultrasound system fitted to a custom-built interface card. The images were processed at a work-station. All scans were acquired repeatedly, read, and graded blindly by experienced ultrasound radiologists. Histology obtained via needle biopsy was reviewed without knowledge of the ultrasound findings. RESULTS: Analysis of the FFS data for fatty infiltration in all patient groups yielded a sensitivity of 67%, a specificity of 77%, a positive predictive value (PPV) of 77%, negative predictive value (NPV) of 67%, and an accuracy of 71%. The mean score of the ultrasound reviewers showed a sensitivity of 82%, a specificity of 66%, a PPV% of 68%, an NPV of 81%, and an accuracy of 72%. Normal FFS values (false-negative) were found in five patients with proved fatty infiltration. All of these patients had coexistent moderate to severe hepatic inflammation. However, FFS data in patients with uncomplicated (pure) fatty infiltration revealed a sensitivity of 100%, a specificity of 80%, a PPV of 89%, an NPV of 100%, and an accuracy of 92%. The best ultrasound score yielded a sensitivity of 100%, a specificity of 60%, a PPV of 80%, an NPV of 100%, and an accuracy of 85% in the same patients. CONCLUSIONS: The data demonstrate an excellent sensitivity (100%) of the FFS values in patients with uncomplicated fatty infiltration. This was also the only group of patients in whom the FFS score was superior to the radiologists' best score. The FFS method can be used as a tool to follow up the response to a clinical or research treatment and to obtain standardization of pattern interpretation independently of the individual reader.

Adolescent↗
PubMed1999

Eosinophilic, polymorphic, and pruritic eruption associated with radiotherapy.

OBJECTIVE: To characterize the epidemiological, clinical, and histopathological features of patients with cancer who develop widespread polymorphic and pruritic skin lesions following radiotherapy. PATIENTS, DESIGN, AND INTERVENTIONS: During phase 1, epidemiological and clinical features of 103 patients with cancer, 83 treated with radiotherapy (71 women and 12 men) and 20 controls who did not undergo radiotherapy (16 women and 4 men), were explored during 3 months (October 1995 to January 1996). During phase 2, in 30 additional patients with cancer who were treated with telecobalt or linear accelerator, 18 with skin lesions (15 women and 3 men) and 12 without lesions (10 women and 2 men), the following were investigated: (1) hematoxylin-eosin-stained sections for routine histopathological examination and direct immunofluorescence, and lymphocytic markers; (2) blood, skin, and primary tumor eosinophilia; and (3) the presence of antiepidermal autoantibodies. Patients were examined during 5 months (February 1996 to June 1996). SETTING: A dermatology department at a university hospital. RESULTS: During phase 1, 14 (17%) of the 83 patients undergoing radiotherapy developed an eruption. Acral excoriations, erythematous papules, vesicles, and bullae were the most frequent lesions. During phase 2, in 18 patients, a superficial and deep lymphocytic perivascular infiltrate with numerous eosinophils, intraepidermal and interstitial eosinophilic infiltrates, eosinophilic panniculitis, IgM and C3 perivascular deposits, and slightly predominant CD4+ cells were observed. No antiepidermal autoantibodies were found. CONCLUSIONS: The clinical, histopathological, and immunopathologic features in patients with cancer undergoing radiotherapy are described. To our knowledge, this condition has not been well characterized. Because of its unique presentation, the denomination "eosinophilic, polymorphic, and pruritic eruption associated with radiotherapy" is suggested.

Adult↗
PubMed1999

Lundh meal: a single non-invasive challenge test for evaluation of exocrine and endocrine pancreatic function in cystic fibrosis patients.

The determination of endocrine and exocrine pancreatic function in cystic fibrosis patients is clinically important. Recently, a new non-invasive test, in which pancreatic stimulation by a Lundh meal is followed by sequential serum lipase measurements, was found to be a good indicator of exocrine pancreatic status. Since the Lundh meal also contains glucose, the present study assessed whether it also might be suitable for evaluation of the pancreatic endocrine axis. After an overnight fast, 10 healthy non-diabetic subjects and 14 cystic fibrosis patients ingested a Lundh meal. Glucose, insulin, and C peptide levels were measured at various time intervals following the meal. For purposes of comparison, the oral glucose tolerance test was also performed on the cystic fibrosis patients. All healthy subjects demonstrated an increase in glucose levels post Lundh meal, peaking at 45 min (mean 140+/-21 mg/dl) and then gradually declining and reaching the normal range at 120 min. Concordant peaks of insulin (46.3+/-20 IU/ml) and C peptide (5.8+/-1. 5 ng/ml) levels were noted at 60 min. All 14 cystic fibrosis patients had normal basal glucose levels: in 8, the pattern of glucose, insulin, and C peptide post Lundh meal was similar to that of the healthy controls. These 8 patients also had a normal oral glucose tolerance test, and their hemoglobin A(1C) levels were within the normal range. The other 6 cystic fibrosis patients demonstrated glucose levels above 200 mg/dl 30-60 min post Lundh meal, and all also had an impaired oral glucose tolerance test. Of these 6, 4 had high levels of hemoglobin A(1C). This study demonstrates that the Lundh meal challenges the endocrine pancreas as well as the oral glucose tolerance test. Thus, determination of both exocrine and endocrine pancreatic status can be achieved by a single non-invasive test.

Adolescent↗
PubMed1999

O6-methylguanine-DNA methyltransferase-deficient phenotype in human gliomas: frequency and time to tumor progression after alkylating agent-based chemotherapy.

The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) contributes to the resistance of human brain tumor cell lines and xenografts to methylating and chloroethylating agents. We assayed MGMT in 174 newly diagnosed or recurrent gliomas to (a) quantitate changes in MGMT activity associated with alkylating agent-based chemotherapy; and (b) assess the contribution of MGMT to clinical outcome. Glioma MGMT activity ranged 300-fold, averaging 3,800+/-7,200 molecules/cell. Twenty-four percent of tumors lacked detectable activity [Methyl repair-deficient (Mer-) phenotype, defined here as <151 molecules/cell or <0.25 fmol/10(6) cells]. Tumors treated with surgery alone and tumors recurring after surgery and radiotherapy did not differ significantly in frequency of the Mer- phenotype (29% versus 24%). However, the frequency of the Mer- phenotype among tumors recurring after surgery, radiation, and alkylating agent-based chemotherapy was 7-fold lower than in tumors treated with surgery alone (4.3% versus 29%; P < or = 0.02) and 6-fold lower than in tumors recurring after surgery and radiation (4.3% versus 24%; P < or = 0.05). In contrast to gliomas, there was no relationship of alkylating agent-based therapy with the frequency of the Mer- phenotype in paired histologically normal brain. These data suggest that alkylating agents, either alone or synergistically with radiotherapy, selectively kill Mer- glioma cells in situ. Importantly, Mer- and Mer+ tumors did not differ in time to tumor progression following treatment with alkylating agents, indicating that although Mer- glioma cells may be differentially killed by alkylators, factors other than Mer phenotype were the principal determinants of time to clinical progression. Nonetheless, our results support the possibility that complete ablation of glioma MGMT with substrate analogue inhibitors could improve the efficacy of alkylating agent-based chemotherapy.

Adolescent↗
PubMed1999

Solubility and fluoride release in ionomers and compomers.

OBJECTIVE: The degree of solubility and the fluoride release of glass-ionomer cements and "compomers" were determined as a function of time. METHOD AND MATERIALS: Three conventional glass-ionomer cements, three hybrid ionomers, and two compomers were included in the study. Disk-shaped specimens were prepared and immersed in a lactic acid solution. Solubility was evaluated from determinations of loss of mass as a function of time. To evaluate fluoride release, similar specimens were immersed in 50 mL of deionized water to which 50 mL of buffer solution was added. A fluoride ion detector was used to read the concentration of fluoride ion in the overall solution at different times after immersion. RESULTS: Material and time factors had a significant influence on results. The compomers showed less corrosion and fluoride release than the ionomers. Some correlation was found between solubility and fluoride leakage values. CONCLUSION: Components of both the ionomers and compomers that were studied can dissolve in water. The materials leak fluoride ions in amounts that differ according to the characteristics of the individual products.

Analysis of Variance↗
PubMed1998

O6-methylguanine-DNA methyltransferase activity in adult gliomas: relation to patient and tumor characteristics.

The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) confers resistance to therapeutic methylating and chloroethylating agents in human brain tumor-derived cell lines. In this work, we assayed MGMT activity in 152 adult gliomas to establish correlates with patient and tumor characteristics. We also assayed MGMT in histologically normal brain adjacent to 87 tumors to characterize changes in activity accompanying neurocarcinogenesis. MGMT activity was detectable in 76% (115 of 152) of tumors, ranging approximately 300-fold from 0.30 to 89 fmol/10(6) cells (180-57,000 molecules/cell). Mean activity was 6.6 +/- 13 fmol/10(6) cells and varied 4-fold among diagnostic groups. The mean for oligodendrogliomas was 2-fold lower (P < 0.03), and for mixed oligodendroglioma-astrocytomas, the mean was 4-fold lower (P < 0.006) than for astroglial tumors. Twenty-five % of gliomas had no detectable MGMT activity (Mer- phenotype; < 0.25 fmol/10(6) cells or 150 molecules/cell). Glioma MGMT was inversely correlated with age (P < 0.01), consistent with the observed age dependence in the progenitor tissue of brain tumors (J. R. Silber et al., Proc. Natl. Acad. Sci. USA, 93: 6941-6946, 1996). Neither MGMT activity nor proportion of Mer- tumors differed by sex. Glioma MGMT was correlated with degree of aneuploidy (P < 0.006) but not with fraction of S-phase cells. Mean activity in tumors was 5-fold higher than in adjacent histologically normal brain (5.0 +/- 7.6 versus 1.1 +/- 1.9 fmol/10(6) cells; P < 0.001). Notably, elevation of tumor activity was observed in 62% of tissue pairs, ranging from 2-fold to > 105-fold. Moreover, 64% of Mer- normal tissue was accompanied by Mer+ tumor. These observations indicate that expression of MGMT activity is frequently activated and/or increased during human neurocarcinogenesis, and that the enhancement is not related to proliferation per se. Significantly, enhanced MGMT activity may heighten the resistance of brain tumors to therapeutic alkylating agents.

Adolescent↗
PubMed1998

Mastodynon(R) bei weiblicher Sterilität.

Mastodynon(R) for Female Infertility. Randomized, Placebo-Controlled, Clinical Double-Blind Study OBJECTIVE AND DESIGN: The effects of Mastodynon(R), an Agnus castus-containing preparation, were investigated in 96 women with fertility disorders in a prospective, randomized, placebo-controlled, double-blind study. PATIENTS AND METHODS: 38 women with secondary amenorrhoea, 31 women with luteal insuffciency and 27 women with idiopathic infertility received 30 drops of Mastodynon or placebo twice a day over a period of 3 months. OUTCOME MEASURE AND RESULTS: The outcome measure, which was pregnancy or spontaneous menstruation in women with amenorrhoea and pregnancy or improved concentrations of luteal hormones in both other groups, was achieved in 31 out of 66 women who were suitable for evaluation. It was achieved more often in the Mastodynon group compared to the placebo group (57.6% versus 36.0%, p = 0.069). 15 women conceived during the observation period (n = 7 with amenorrhoea, n = 4 with idiopathic infertility, n = 4 with luteal insufficiency). In women with amenorrhoea or luteal insufficiency, pregnancy occurred in the Mastodynon group more than twice as often as in the placebo group. Under therapy no hormonal changes were found at a 5% significance level. Only very few undesirable drug effects were observed. CONCLUSION: In women with sterility due to secondary amenorrhoea and luteal insufficiency, a treatment with Mastodynon can be recommended over a period of 3 to 6 months.

Journal Article↗
PubMed1998

Comorbidity and course of psychiatric disorders in a community sample of former prisoners of war.

OBJECTIVE: The authors assessed DSM-III-R disorders among American former prisoners of war. Comorbidity, time of onset, and the relationship of trauma severity to complicated versus uncomplicated posttraumatic stress disorder (PTSD) were examined. METHOD: A community sample (N=262) of men exposed to combat and imprisonment was assessed by clinicians using the Structured Clinical Interview for DSM-III-R. RESULTS: The rates of comorbidity among the men with PTSD were lower than rates from community samples assessed by lay interviewers. Over one-third of the cases of lifetime PTSD were uncomplicated by another axis I disorder; over one-half of the cases of current PTSD were uncomplicated. PTSD almost always emerged soon after exposure to trauma. Lifetime PTSD was associated with increased risk of lifetime panic disorder, major depression, alcohol abuse/dependence, and social phobia. Current PTSD was associated with increased risk of current panic disorder, dysthymia, social phobia, major depression, and generalized anxiety disorder. Relative to PTSD, the onset of the comorbid disorders was as follows: major depression, predominantly secondary; alcohol abuse/dependence and agoraphobia, predominantly concurrent (same year); social phobia, equal proportions primary and concurrent; and panic disorder, equal proportions concurrent and secondary. Trauma exposure was comparable in the subjects with complicated and uncomplicated PTSD. CONCLUSIONS: The types of comorbid diagnoses and their patterns of onset were comparable to the diagnoses and patterns observed in other community samples. The findings support the validity of the PTSD construct; PTSD can be distinguished from comorbid disorders. Uncomplicated PTSD may be more common than previous studies suggest, particularly in clinician-assessed subjects exposed to severe trauma.

Agoraphobia↗
PubMed1998

Microsatellite instability is infrequent in sporadic adult gliomas.

Microsatellite instability (MSI) is a form of genomic instability in tumors that may reflect mechanisms underlying carcinogenesis. Assessment of MSI in various types of sporadic tumors is therefore relevant to an understanding of molecular pathogenesis. In the case of sporadic adult gliomas, destabilization of mononucleotide, dinucleotide, and longer repeat sequences has been reported in high-grade tumors, though published estimates of the frequency of MSI vary widely. In the present work, we quantitated the frequency of length alterations at three microsatellite loci in 26 glioma/normal tissue pairs and at nine additional loci in 16 of the pairs. We analyzed di- and tetranucleotide markers, including five previously reported to be unstable in gliomas. and examined mostly high-grade tumors, both diploid and aneuploid. A large proportion of the tumor and normal brain specimens had no detectable activity of the DNA repair protein O6-methylguanine-DNA methyltransferase, a prevalent phenotypic trait in these tissues that we thought might be associated with MSI. We observed no length alterations in 222 sequence analyses, and estimate the frequency of MSI in our tumor sample as < 0.45% unstable sequences among all sequences examined, or < 3.9% gliomas with unstable sequences. We conclude that microsatellite length alterations are infrequent in our tumor population, and interpret currently available literature to indicate that the frequency of MSI is low in sporadic adult gliomas.

Adult↗
PubMed1997

The Werner syndrome protein is a DNA helicase.

Werner syndrome (WS) is an uncommon autosomal recessive disorder characterized by premature aging. The clinical manifestations of WS, including atherosclerosis and osteoporosis, appear early in adulthood, and death in the fourth to sixth decade commonly ensues from myocardial infarction or cancer. In accord with the aging phenotype, cells from WS patients have a reduced replicative life span in culture. Genomic instability is observed at the cytogenetic level in the form of chromosome breaks and translocations and at the molecular level by multiple large deletions. The Werner syndrome gene (WRN) has recently been cloned. The predicted product is a 1,432-amino-acid protein whose central domain is homologous to members of the RecQ family of DNA helicases. Such homology does not necessarily mean that WRN encodes an active helicase. For example, the Saccharomyces cerevisiae RAD26 gene protein and the human transcription-repair coupling factor CSB (Cockayne syndrome 8) are highly homologous to known helicases, yet neither encodes an active helicase. Moreover, the Bloom's syndrome gene (BLM), discovered before WRN, is also homologous to the RecQ family of DNA helicases, though we still await demonstration that it encodes an active helicase. Here we report that the WS protein does indeed catalyze DNA unwinding.

Adult↗