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M van Vliet

Publications and source records attributed to M van Vliet.

At least 37 records · Page 2Linked to original sources
PubMed1995

Rapid detection of BRCA1 mutations by the protein truncation test.

More than 75% of the reported mutations in the hereditary breast and ovarian cancer gene, BRCA1, result in truncated proteins. We have used the protein truncation test (PTT) to screen for mutations in exon 11, which encodes 61% of BRCA1. In 45 patients from breast and/or ovarian cancer families we found six novel mutations: two single nucleotide insertions, three small deletions (1-5 bp) and a nonsense mutation identified two unrelated families. Furthermore, we were able to amplify the remaining coding region by RT-PCR using lymphocyte RNA. Combined with PTT, we detected aberrantly spliced products affecting exons 5 and 6 in one of two BRCA1-linked families examined. The protein truncation test promises to become a valuable technique in detecting BRCA1 mutations.

BRCA1 Protein↗
PubMed1995

Unbalanced haemostatic changes following strenuous physical exercise. A study in young sedentary males.

During acute exercise both coagulant and fibrinolytic potential increase. Since strenuous exertion is associated with an enhanced risk for cardiac events, especially in untrained individuals, it is important to determine whether the initial haemostatic balance is maintained during exercise. Twenty-nine sedentary males (20-30 years) were subjected to a standardized cycle ergometer test. Blood samples were obtained at two exercise levels, 70% VO2max (submaximal), 100% VO2max (maximal) and during 25 min recovery. Both during submaximal and maximal performance, tissue type plasminogen activator antigen, urokinase plasminogen activator antigen and tissue type plasminogen activator activity were increased. A concomitant enhancement of clotting activity of factors VII, VIII, IX, XII and fibrinogen resulted in a shortening of clotting times. Following correction for changes in plasma volume, the results for factor VII:c were reversed, and factor XII:c and fibrinogen no longer demonstrated exercise-related changes. Increases in coagulant (activated partial thromboplastin time) and fibrinolytic (tissue type plasminogen activator activity) potential proceeded in parallel during exercise. However, during recovery while there was a sustained increase in coagulant potential, fibrinolytic potential demonstrated a sharp fall. We conclude that during physical activity, while parallel changes in coagulant and fibrinolytic activity occur, this haemostatic balance is not maintained during recovery. This phenomenon could constitute an enhanced risk for coronary artery thrombosis which may contribute to exercise-related cardiovascular events.

Blood Coagulation Factors↗
PubMed1995

Changes in haemostatic factors and activation products after exercise in healthy subjects with different ages.

We studied exercise-induced changes in coagulation and fibrinolytic factors and activation products in different age categories. Thirty-eight sedentary males, divided in three age categories (cats I-III; 20-30, 35-45 and 50-60 y) were subjected to a standardized exercise test. Pre-exercise levels (cats I-III resp) of FVII:c (105 +/- 5, 121 +/- 6 and 123 +/- 7% NP), fibrinogen (2.35 +/- 0.12, 2.55 +/- 0.10 and 2.66 +/- 0.09 mg/ml), prothrombin activation fragment F1 + 2 (0.80 +/- 0.10, 0.80 +/- 0.11 and 1.22 +/- 0.16 nM), t-PA (5.2 +/- 0.6, 9.2 +/- 1.0, 8.6 +/- 1.2 ng/ml) and PAI-I (42.8 +/- 7.5, 67.6 +/- 7.6, 62.2 +/- 10.9 ng/ml) showed differences that seemed related to age. Regression analysis revealed associations with anthropometry (FVII:c, fibrinogen, F1+2, t-PA, PAI-1) rather than with age. Exercise-induced changes in coagulation (increase in von Willebrand factor and FVIII:c and a shortening of APTT) and fibrinolytic potential (increase in t-PA and u-PA) were of comparable magnitude for the three age categories. Hardly any change in F1 + 2 (6%) was observed, while thrombin-antithrombin complexes (93%), plasmin-antiplasmin complexes (79%) and D-dimer (77%) almost doubled during maximal exercise. We conclude that anthropometric differences play a more significant role than age on constitutive levels of haemostatic factors in participants up to 60 years of age. The magnitude of exercise-induced changes is comparable in the age categories under study, and simply super-imposed on constitutive (pre-exercise) levels. Clear evidence for prothrombin activation is lacking, but plasmin formation is enhanced during exercise.

Adult↗
PubMed1994

Evidence for a gene on 17p13.3, distal to TP53, as a target for allele loss in breast tumors without p53 mutations.

In breast cancer, loss of heterozygosity (LOH) on 17p is a frequent event and a likely target is the p53 gene on 17p13.1. However, several LOH mapping studies have indicated that, in some breast tumors, LOH affects only the most distal 17p markers, suggestive of a second tumor suppressor locus in 17p13.3. In order to distinguish which gene has most probably served as the target for LOH on 17p, we have screened 141 breast tumors for somatic mutations in the p53 gene in conjunction with detailed LOH mapping on the short arm of chromosome 17. A total of 32 mutations were detected in 31 tumors, 15 of which have never been reported in breast cancer before. The majority are point mutations leading to an amino acid change in the protein. In addition, we have stained a subset of 87 tumors for the p53 protein by immunohistochemistry. In 21 of these tumors (24%), nuclear staining was detected in over 25% of the tumor cells with the anti-p53 antibody DO7. A positive correlation was found between p53-positive staining and p53 mutation (P < 0.001). A strong association was observed between p53 mutation and LOH at the TP53 locus but not between p53 expression and LOH on 17p. In breast tumors without a detectable p53 mutation but with LOH on 17p, the 17p13.3 region is always involved and, in some cases, even exclusively involved. These results suggest that a second tumor suppressor gene, located distal to TP53, is targeted by LOH on 17p in some breast tumors and that a substantial number of breast tumors stabilize p53 through mechanisms other than mutation.

Alleles↗
PubMed1994

Differences in u-PA and t-PA increase during acute exercise: relation with exercise parameters.

Plasma levels of urokinase-type (u-PA Ag) and tissue-type (t-PA Ag) plasminogen activator are both enhanced during physical exercise. Whether, the extent of the increase and the post-exercise clearance rate of the two activators are comparable is not known. We studied the changes in u-PA Ag, t-PA Ag and t-PA activity during a standardized exercise test comprising submaximal and maximal exercise intensity. During submaximal (recreational) exercise, increases in u-PA are mainly due to changes in plasma volume, submaximal exercise demonstrates a continuous rise in level of t-PA Ag. During maximal performance peak levels of u-PA and t-PA Ag do not coincide in time and magnitude, moreover, u-PA Ag rather than t-PA Ag is related to t-PA Act. From these results we conclude that independent mechanisms regulate the exercise-induced plasma levels of u-PA and t-PA.

Adult↗
PubMed1993

Linkage to markers for the chromosome region 17q12-q21 in 13 Dutch breast cancer kindreds.

We have performed linkage analysis with five markers for the chromosome region 17q12-q21 in 13 Dutch breast cancer kindreds in order to find support for the claim by Hall et al. that a gene in this region, termed "BRCA1," is associated with predisposition to early-onset familial breast cancer. This work is part of a collaborative study, the results of which are published elsewhere in this issue. Best evidence for linkage was observed with the marker CMM86 (D17S74) in pedigrees with an average age at onset of < or = 47 years (LOD score = 1.77 at 1% recombination). In one breast-ovarian cancer family with a high probability of being linked to 17q, we observed one putative recombinant between D17S250 and D17S579, which suggests that BRCA1 is proximal to D17S579.

Adult↗
PubMed1993

Allele loss patterns on chromosome 17q in 109 breast carcinomas indicate at least two distinct target regions.

Loss of heterozygosity (LOH) of markers for chromosome 17 is the most frequent genetic change observed in breast cancer to date. To assess whether the location of several candidate target genes is compatible with patterns of allele losses in the individual tumors, we examined the LOH status of chromosome 17 in 109 primary breast tumors with 15 polymorphic DNA markers (three for 17p and 12 for 17q). Allelic imbalance (AI) at 17q was observed in 44 of the 97 informative cases. A significant correlation was found between AI at the long arm and AI at the short arm of chromosome 17. The patterns of AI on 17q in the tumors differed and were highly complex in some cases. A number of tumors showed AI distal to the growth hormone locus, whereas others showed AI exclusively proximal of this marker. These results indicate that there are at least two different regions of allele loss on 17q.

Alleles↗
PubMed1992

Fractional allelic imbalance in human breast cancer increases with tetraploidization and chromosome loss.

We have previously reported a complete allelotype study of 86 primary breast carcinomas, in which each non-acrocentric chromosome arm was studied with at least one polymorphic DNA-marker for the presence of allelic imbalance (AI, allelic loss or allelic gain) in the tumor. Here we report the statistical analysis of this data set, investigating the relationships between AI, DNA aneuploidy and several clinico-pathological parameters of tumor progression. AI on 13 different chromosome arms, including 3p, 11p, and 17p, correlated significantly with the total number of AI events at other sites, suggesting that they are progression-related events. AI at 1q and 16q did not show such a correlation and may thus represent earlier events. Mean fractional allelic imbalance (FAI) was significantly higher in flow cytometrically aneuploid tumors than in diploid tumors (0.27 vs. 0.17, p = 0.007), and was highest in hypotetraploid tumors (0.37). This suggests that tetraploidization followed by chromosome segregation may underlie the development of AI at multiple sites. No correlation was found between mean FAI and clinico-pathological variables such as lymph-node involvement, stage, age, estrogen-receptor content and development of distant metastases, although there was a noticeable trend towards impaired survival for those patients with a higher-than-median FAI value.

Alleles↗
PubMed1992

A prospective, controlled multicenter study on the obstetric risks of pregnant women with antiphospholipid antibodies.

OBJECTIVES: A prospective, controlled multicenter study was performed to estimate the obstetric risks of antiphospholipid antibodies (the lupus anticoagulant and anticardiolipin antibodies). In addition, the risks of prior thrombosis, obstetric history, systemic lupus erythematosus, and high-dose prednisone treatment were evaluated. STUDY DESIGN: After screening for antiphospholipid antibodies in patients with lupus erythematosus or women with prior fetal loss(es), 59 subsequent pregnancies with and 54 without these antibodies were followed. RESULTS: The presence of the lupus anticoagulant and a history of at least three spontaneous abortions could predict fetal loss (p = 0.032 and 0.001, respectively). In live born infants, a low birth weight could be predicted by the presence of anticardiolipin antibodies (p = 0.034), prior intrauterine fetal death (p = 0.025), and treatment with high-dose prednisone (p = 0.002). No relationships were seen between antiphospholipid antibodies and small-for-gestational-age newborns and pregnancy-induced hypertension or preeclampsia. The disappearance of antiphospholipid antibodies during pregnancy was not correlated with live birth. CONCLUSION: It is concluded that the presence of antiphospholipid antibodies is a risk factor for adverse pregnancy outcome.

Abortion, Spontaneous↗
PubMed1992

A gene subject to genomic imprinting and responsible for hereditary paragangliomas maps to chromosome 11q23-qter.

Paragangliomas of the head and neck are slow growing tumors which rarely show malignant progression. Familial transmission has been described consistent with an autosomal dominant mode of inheritance. Clinical manifestations of hereditary paragangliomas are determined by the sex of the transmitting parent. All affected individuals have inherited the disease gene from their father, expression of the phenotype is not observed in the offspring of an affected female until subsequent transmittance of the gene through a male carrier. This finding strongly suggests that genomic imprinting is involved. We report the results of a linkage study on a large Dutch pedigree with hereditary paragangliomas. Highly significant evidence for genetic linkage to chromosome 11q23-qter with the anonymous DNA marker D11S147 was detected with a peak lod score of 6.0 at a recombination fraction theta = 0.0. Likelihood calculations yielded an odds ratio of 2.7 x 10(6) in favor of genomic imprinting versus the absence of genomic imprinting.

Chromosome Mapping↗
PubMed1992

Prospective study of fluctuations of lupus anticoagulant activity and anticardiolipin antibody titre in patients with systemic lupus erythematosus.

Fluctuations of lupus anticoagulant activity and anticardiolipin antibody titres were studied in 53 patients with systemic lupus erythematosus (SLE). The median study time was 26 months with a median number of 12 samples. Lupus anticoagulant was measured by the kaolin clotting time (KCT) and dilute Russell viper venom time (dRVVT) assays; anticardiolipin antibodies were assayed by an enzyme linked immunosorbent assay (ELISA). Normal and increased KCTs or dRVVTs were seen during follow up in 13 and 12 patients, respectively. IgG anticardiolipin antibodies changed from negative to positive or positive to negative in 26 patients and IgM anticardiolipin antibodies in 16 patients. Disease activity and treatment with prednisone could account for these fluctuations in the kaolin clotting time (KCT) in 7 of 13 patients and in the dRVVT in 2 of 12 patients. Whole group analysis showed that the KCT, dRVVT, and IgM anticardiolipin antibodies were not associated with disease activity, in contrast with IgG anticardiolipin antibodies. During treatment with prednisone normal KCT and dRVVT results were obtained more easily than normal anticardiolipin antibody levels. It is recommended that lupus patients should not be classified as antiphospholipid antibody positive or negative on the basis of only one sample.

Adolescent↗
PubMed1991

In vitro studies of antiphospholipid antibodies and its cofactor, beta 2-glycoprotein I, show negligible effects on endothelial cell mediated protein C activation.

The effect of sera and purified IgG isolated from plasma of 46 patients with systemic lupus erythematosus (SLE) and 9 healthy donors on the endothelial cell (EC) mediated protein C activation was investigated. Out of the 46 SLE sera used, 19 were antiphospholipid antibodies (aPL) positive. From 12 patients IgG was isolated, of which 6 contained aPL. EC were first incubated with IgG (7 mg/ml) or serum (1:1 diluted) for 1 h and then tested for their ability to promote protein C activation by thrombin, with the cells either in a monolayer or in a suspension. The normal range (mean of control values +/- 2 SD) of protein C activation was 80-120%. In contrast to others, we could not detect an inhibition of protein C activation by any of the patient IgG's or sera. The recently described cofactor for binding of antiphospholipid antibodies to phospholipids, beta 2-glycoprotein I, was purified and added to the purified IgG's. A combination of these two components did not inhibit the EC mediated protein C activation by thrombin. This study suggests that the inhibition of the protein C activation, mediated by EC, is not a general mechanism by which aPL related thrombosis can be explained.

Adolescent↗
PubMed1991

Antibodies to platelets in patients with anti-phospholipid antibodies.

Binding of anti-phospholipid antibodies to circulating platelets and its consequences on platelet activation and aggregation was investigated in 11 patients with anti-phospholipid antibodies. Seven patients had mild thrombocytopenia. Nine healthy donors served as controls. Binding to platelets was investigated by performing enzyme-linked immunosorbent assays (ELISAs) with phospholipids as antigen on platelet eluates. Platelet activation was measured by flow cytofluorometry using monoclonal antibodies to an activation-specific lysosomal membrane protein. Findings in ELISA were compared with results of a conventional immunofluorescence method to detect platelet autoantibodies. In seven patients antibodies to negatively charged phospholipids were present in platelet eluates. In all thrombocytopenic patients and controls the platelets were not activated and aggregation was not impaired. There was a positive concordance of 50% between the results of immunofluorescence and ELISA. No apparent relation was found between the results of ELISA or immunofluorescence and platelet counts. It is concluded that anti-phospholipid antibodies can bind to circulating platelets. This binding is not associated with measurable aggregation abnormalities nor with platelet activation characterized by exposure of lysosomal membrane proteins. More studies are necessary to determine the exact role of anti-phospholipid antibodies in the pathogenesis of thrombocytopenia and thrombosis.

Adult↗
PubMed1991

Frequent somatic imbalance of marker alleles for chromosome 1 in human primary breast carcinoma.

Loss of heterozygosity at particular chromosomal loci in the tumor cell, as evidenced by restriction fragment length polymorphism analysis, has been taken as a hallmark of the presence of tumor suppressor genes. Recent studies of breast carcinoma have suggested that such genes might be located on the short as well as on the long arm of chromosome 1. We report here that comparison of constitutional and tumor genotypes of 84 breast tumors at 7 polymorphic chromosome 1 loci indicates a frequent imbalance of alleles on both 1p (12 of 61 informative patients) and 1q (37 of 71 informative patients). In about one-half of these cases, however, this imbalance was consistent with a gain in copy number of one allele in tumor DNA relative to normal DNA, rather than loss of the other. In 10 tumors we performed chromosome 1 enumeration in the interphase nucleus using in situ hybridization with a probe detecting the heterochromatin region at 1q12. These experiments confirmed the supernumerary presence of region 1q12 in those tumors showing an allelic copy number gain of 1q. We suggest that there are several genes on chromosome 1 serving as targets for these changes, some of them associated with breast cancer development through their deletion and others through an increase in copy number.

Alleles↗
PubMed1991

Improved interpretation of complex chromosomal rearrangements by combined GTG banding and in situ suppression hybridization using chromosome-specific libraries and cosmid probes.

Chromosome aberrations of a hypodiploid ovarian carcinoma cell line (modal chromosome number 38) having a complex karyotype were analyzed using biotinylated DNA library probes that specifically hybridize to chromosomes 3, 6, 7, 8, 11, 13, and 16 from telomere (pter) to telomere (qter). A series of cosmid probes localized to the short arm of chromosome 16 were used to further investigate one of the two aberrant chromosomes 16 present in this cell line. The competitive in situ suppression (CISS) hybridization of DNA-libraries was mostly performed subsequent to GTG-banding of the same metaphase cell in order to interpret the hybridization signals optimally. This combined approach made it possible to detect the origin of chromosomal material that could not be identified using GTG-banding. Furthermore, the in situ hybridization techniques appeared to be helpful in the characterization of complex translocations and for accurate breakpoint determination.

Adenocarcinoma↗
PubMed1991

The role of different types of corticosteroids on the inflammatory mediators in cardiopulmonary bypass.

In a placebo-controlled double-blind study on patients undergoing cardiopulmonary bypass (CPB) we studied the inhibiting effects of dexamethasone, a high dose of methylprednisolone, and a low dose of prednisolone on the inflammatory reaction induced by CPB. During CPB two episodes of blood activation were noticed. First, the blood-material interaction caused a significant increase in complement C3a and elastase concentrations after the start of bypass (p less than 0.01). Secondly, the reperfusion of the ischemic heart, lungs, and peripheral tissue, after release of the aortic cross-clamp, caused an additional increase in C3a and elastase concentration and a statistically significant increase in leukotriene B4 (LTB4) concentration and tissue plasminogen activator (t-PA) activity (p less than 0.01, p less than 0.05, respectively). Dexamethasone treatment effectively inhibited the increase in LTB4 concentration and t-PA activity after release of the cross-clamp (significant differences to the placebo group, p less than 0.01, p less than 0.05, respectively). High-dose methylprednisolone treatment was almost as effective as dexamethasone treatment, whereas low-dose prednisolone treatment was less effective than methylprednisolone in the inhibition of the inflammatory mediators (DM greater than MP greater than P). None of the corticosteroid regimens was able to inhibit the increase in complement C3a and elastase. We therefore conclude that corticosteroids do not have an effect on complement activation during CPB. However, leukocyte activation and t-PA activity after release of the aortic cross-clamp are effectively inhibited by corticosteroid treatment, in a dose-dependent way. The inhibition of this inflammatory reaction will have a favourable effect on the postoperative course in patients who have undergone CPB.

Acute-Phase Proteins↗
PubMed1991

Prevalence of antiphospholipid antibodies in patients with fetal loss.

The prevalence of antiphospholipid and antinuclear antibodies in 102 patients with at least three unexplained miscarriages before a gestational age of 12 weeks, or at least one intrauterine fetal death after 12 weeks, was investigated and compared with the prevalence in 102 normal pregnant controls. Six patients had a history of thrombosis and six had 'lupus-like' disease. Twenty one patients had anticardiolipin antibodies compared with 10 controls. Serum samples of nine patients and one control contained antinuclear antibodies. The lupus anticoagulant was present in the plasma of five patients with anticardiolipin antibodies. The influence of patient selection on the results was illustrated by the finding that antiphospholipid antibodies and antinuclear antibodies were mainly detected in patients with lupus-like disease or a history of thrombosis. When these patients were excluded there was no significant difference in the prevalence of anticardiolipin and antinuclear antibodies between patients and controls. Therefore, in the absence of lupus-like disease or a history of thrombosis, screening for antiphospholipid antibodies in patients with adverse pregnancy outcomes seems not to be indicated.

Abortion, Habitual↗