Biomedical subjects

M Bache

Publications and source records attributed to M Bache.

At least 19 recordsLinked to original sources

PubMed2002

Gains of 12q are the most frequent genomic imbalances in adult fibrosarcoma and are correlated with a poor outcome.

Comparative genomic hybridization was used to analyze 41 adult fibrosarcomas from 34 patients. Thirty-one patients showed in their tumors DNA sequence copy number changes (mean 11, range 3-25). The minimal common regions for the most frequent gains were narrowed down to 12q21 (18 cases); 12q14-q15 and 14q22 (16 cases each); 4q22, 7q31, and 14q23-q24 (15 cases each); and 4q21, 4q23-q24, 8q22, and 12q22 (14 cases each). Twenty-five high-level amplifications were observed in 12 samples. 12q21 and 18p were affected three times each; and 1p21, 4q31.3, 7p21, 12q14-q15, Xp22.1-p22.2, and Xq22-q23 two times each. Losses were less frequent than gains. Early stages of adult fibrosarcomas were characterized by frequent gains of chromosomes 2, 4q, and 14q, whereas gains of chromosomes 7 and 8q were associated with progression. Gains of 12q were frequent in all of the developmental steps of this soft-tissue sarcoma. By investigation of several tumors of the same patient, a number of corresponding changes were always detected. Adult fibrosarcomas from patients who died during the observation time showed statistically significant more frequent gains of 8q, 12q, 13q, and 15q compared to the fibrosarcomas of patients who are alive. Gains and high-level amplifications of 12q14-q22, which were the most frequent genomic imbalances, partly reflected an MDM2 amplification, indicating the importance of this region in the tumorigenesis of sarcomas. In adult fibrosarcomas, a gain of 12q22 correlated significantly (P = 0.028) with a poor overall survival rate.

Abdominal Neoplasms↗

PubMed2002

Expression of cathepsin B, D and L protein in juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is the most common childhood autoimmune rheumatic disease and like rheumatoid arthritis (RA), it is characterized by inflammation and the progressive destruction of joints. In RA, cathepsins as proteinases play a major role in destroying synovial tissue and cartilage matrix. So far no data on cathepsin expression in pannus tissue of HA patients exist. The aim of this study was to characterize the expression levels of cathepsins B, D, H, and L in HA and to compare them with those in RA. Synovectomy tissue from 16 HA and 12 RA patients was investigated for cathepsin expression levels by Western blot analysis. Expression of cathepsins B, D and L was on comparable levels in the synovectomy tissue of HA and RA patients. The following graduation of expression was determined: cathepsin D > cathepsin L > cathepsin B. Cathepsin H was neither found to be expressed in HA nor in RA patients. The expression levels of cathepsins in pannus tissue showed no clear difference between patients with systemic JIA and patients with monoarticular JIA. In summary, the comparable expression of cathepsins B, D and L in RA and JIA synovectomy tissue suggests that they may play a similarly important role in destroying synovial tissue and cartilage matrix in the course of HA and RA.

Adolescent↗

PubMed2001

Increased survivin transcript levels: an independent negative predictor of survival in soft tissue sarcoma patients.

Survivin, a recently identified inhibitor of apoptosis protein (IAP), is expressed in diverse embryonic tissues and in various human cancers. We have investigated the quantitative expression of survivin mRNA by a sensitive TaqMan-based RT-PCR assay in tissue samples from 94 patients with soft tissue sarcomas (STS). Survivin transcript levels were measured and normalized to GAPDH transcripts. By using a multivariate Cox regression analysis, we found an inverse correlation between the level of survivin mRNA (ratio >2 zmol survivin/amol GAPDH) and the rate of overall survival (p = 0.009, RR = 2.7). Survivin transcript variants as detected by qualitative RT-PCR analysis were revealed in 36 of 56 STS patients (64%). Only survivin DeltaEx3 and/or full-length survivin variants but not survivin 2B were identified. Our results suggest that a higher level of survivin mRNA is an independent predictor of survival for STS patients.

Adolescent↗

PubMed2001

Cytogenetic characterization of six malignant peripheral nerve sheath tumors: comparison of karyotyping and comparative genomic hybridization.

We analysed six malignant peripheral nerve sheath tumors (MPNSTs) from four patients using metaphase preparations and compared the results with those obtained by using comparative genomic hybridization (CGH). All six tumors showed structural and numerical chromosomal aberrations, mostly of chromosomes 1, 5, 7-10, 14-17, 19, 21, and 22. The number of chromosomes per tumor cell ranged from 42 to 104. We could not find a recurrent specific pattern of structural changes after comparing the MPNSTs of different patients. However, aberrations of different tumors from the same patient were nearly identical. In the four patients, we found a total of 117 breakpoints, mostly in 21q11.2 (seven times), in 8q11.2 and 14q10 (six times each), in 5q11.2 and 15q26 (four times each), in 8p11.2, 10q11.2, 16q22, 19q13.3, and 22q10 (three times each). In three MPNSTs, double minute chromosomes (dmin) we detected with metaphase investigations and high-level amplifications by using CGH, respectively. C-MYC gene amplification and loss of the P53 gene could be ruled out by locus-specific probes for the common gain of 8q and for losses of 17p. When comparing the CGH results with those of karyotyping an overlap in the most frequent gains in 7q, 8q, 15q, and 17q was observed. However, we found more frequent losses in 19q in the metaphase investigations.

Aged↗

PubMed2001

Amplification of the MDM2 gene, but not expression of splice variants of MDM2 MRNA, is associated with prognosis in soft tissue sarcoma.

The MDM2 gene encodes a 90-kDa oncoprotein that is overexpressed in several human carcinomas, osteosarcomas, gliomas and soft tissue sarcomas (STSs). This overexpression is the result of several mechanisms, for example, enhanced transcription or translation, gene amplification and alternative splicing. We found that 19 of 67 (28.4%) STS specimens contained an amplified MDM2 gene. The amplification was more likely to be present in grade 1 tumors than in grade 2 or 3 tumors (58% of grade 1 tumors vs. 15% of grade 2 or 3 tumors, p = 0.001, chi(2) test). Furthermore, patients with tumors that contained an amplified MDM2 gene had a survival estimate (87 months) that was longer than that of patients with tumors that lacked an amplified gene (40 months; p = 0.02, log-rank test). Alternatively and aberrantly spliced MDM2 mRNAs were detected in human STSs by a highly sensitive reverse transcription-polymerase chain reaction method. Of 71 tumor samples, 38 (54%) showed evidence of the spliced forms, which included MDM2-A, MDM2-B and several variants exclusively expressed in STSs. A common feature of all forms was the absence of the MDM2 N-terminal region, which includes the TP53-binding region. Furthermore, the presence of the spliced forms was associated with elevated levels of TP53 (p = 0.01, chi(2) test). Although the presence of spliced forms was associated with late-stage tumor phenotypes (p = 0.05, chi(2) test), we observed no relationship between the presence of splice variants and patient outcome.

Alleles↗

PubMed2001

Loss of G2/M arrest correlates with radiosensitization in two human sarcoma cell lines with mutant p53.

We have examined the modulation of radiosensitivity by using caffeine in two human sarcoma cell lines both with a p53 mutation (US8-93 and LMS6-93). In both cell lines a strong irradiation-induced G2/M arrest was coupled with a low rate of apoptosis. Incubation with caffeine resulted in a low percentage of S and G2/M cells, associated with an accumulation in G1. With a higher caffeine concentration, we detected a lower clonogenic survival with IC(50) at 2 mM. In both cell lines incubation with caffeine completely prevents the irradiation-induced G2/M arrest. This was connected to radiosensitization, but without direct correlation to an induction of apoptosis. The effect of radiosensitization rose with higher irradiation doses. However, in comparison with LMS6-93, it was stronger in cell line US8-93. A higher radiosensitization in US8-93 correlated with the prevention of strong irradiation-induced G2/M response and higher initial DNA damage. Results of Western hybridization reveal a p53-independent mechanism of radiosensitization caused by caffeine. Our findings suggest that modulation in G2/M regulation may affect a common checkpoint for tumor cells with defective p53 function. Furthermore, our results show that the enhancer effect of caffeine is dependent on a strong reduction in the number of G2/M arrested cells and on an inhibition of DNA damage repair after irradiation.

Adenocarcinoma↗

PubMed2000

A MboII polymorphism in exon 11 of the human MDM2 gene occuring in normal blood donors and in soft tissue sarcoma patients: an indication for an increased cancer susceptibility?

The human MDM2 oncogene, well known as the tumor suppressor gene p53's partner, plays an important role in tumorigenesis whether it is dependent on or independent of TP53. In this study, we investigated in a PCR-sequencing analysis the exon 11 of the human MDM2 gene for gene alterations. A MboII polymorphism occurs in 8% of normal blood donors (8 out of 100 probands) and in 13% of the soft tissue sarcoma patients (11 out of 82 patients). Of note was that two STS patients carried the gene alteration only in the tumor specimens heterozygously but not in normal tissue. In a Kaplan-Meier analysis, patients without the polymorphism, indicated a median survival rate of 57 months, whereas, patients with the polymorphism survived on average only 38 months. We suggest that this polymorphism might be associated with an increased cancer susceptibility.

Base Sequence↗

PubMed2000

Spiral intensity patterns in the internally pumped optical parametric oscillator

We describe a nonlinear optical system that supports spiral pattern solutions in the field intensity. This new spatial structure is found to bifurcate above a secondary instability in the internally pumped optical parametric oscillator. The analytical predictions of threshold and spatial scale for the instability are supplemented by detailed numerical investigations of the formation of spiral patterns.

Journal Article↗

PubMed2000

Gains in chromosomes 7, 8q, 15q and 17q are characteristic changes in malignant but not in benign peripheral nerve sheath tumors from patients with Recklinghausen's disease.

In order to investigate typical genomic alterations in patients with Recklinghausen's disease (NF1) we studied one from each of the six patients with NF1 several benign and/or malignant tumors. By means of comparative genomic hybridization (CGH) gained results from six benign neurofibromas and 14 malignant peripheral nerve sheath tumors (MPNSTs) were compared with four benign peripheral nerve sheath tumors (BPNSTs) from patients without NF1. In all 14 MPNSTs DNA sequence copy number changes were detected with a mean value of 13.5 imbalances per sample. The most frequent gains were in 8q, 17q (12 tumors each), 7p, 15q (ten tumors each), and 7q (nine tumors). We found ten high-level amplifications in nine of the 14 samples. In two cases, the high-level amplification involved 7p14-pter and 17q24-qter as well. The most frequent loss was in 17p (seven tumors). The benign neurofibromas from NF1-patients and the sporadic BPNSTs revealed only partially DNA sequence copy number changes without any distinct pattern. The gains of #7, 8q, 15q, and 17q were found exclusively in MPNSTs but not in neurofibromas and are supposed to be associated with malignant tumor progression. In comparison of the results of the 14 MPNSTs from NF1-patients with the results of previously published 20 sporadic MPNSTs, we found that the gain of 8q occurs most frequently in both tumor groups. Of course additionally in the sporadic MPNSTs there were more frequent gains of 5p, #6, and statistically significant gains of 20q. On the other hand in the MPNSTs from NF1-patients the most frequent gains were found in #7, and statistically significant in 15q, and 17q.

Adult↗

PubMed2000

Colony formation of soft tissue sarcoma cells is inhibited by lipid-mediated antisense oligodeoxynucleotides targeting the human mdm2 oncogene.

More than one third of human soft tissue sarcoma (STS) have elevated levels of the MDM2 oncoprotein, resulting either from gene amplification or alternate mechanisms. MDM2 functions as a negative feedback regulator of the tumor suppressor p53. The aim of the present study was to investigate whether mdm2-antisense oligodeoxyribonucleotides (AS-ODNs) can influence the growth characteristics of two MDM2-overexpressing STS cell lines (US8-93, LMS6-93) where both have heterozygous p53 non-missense mutations. Cells were treated with lipofectamine-complexed mdm2 AS-ODNs complementary to a sequence of the mdm2 cDNA initiation site in comparison to sense control ODNs. After seeding and cultivation of a defined cell number the clonogenic survival was performed. The treatment of US8-93 cells with AS-ODNs, but not with sense ODNs, decreased the number of colonies up to > 80%. Western blot analysis demonstrated a significant decreasing of MDM2 protein level in AS-ODN transfected cells indicating an AS-specific inhibition of mdm2 transcription in US8-93 cells. Additionally, an increase of the G2/M population was found. In contrast, in the LMS6-93 cells treated with AS-ODNs only a decrease in clonogenic survival up to 26%, no change in MDM2 protein level and no cell cycle alterations were seen. All these factors taken together into consideration can be suggest that lipid-mediated mdm2 AS-ODNs could be as an effective therapeutic strategy for STS with an abnormal mdm2 overexpression.

Cell Division↗

PubMed2000

The p53 status in juvenile chronic arthritis and rheumatoid arthritis.

The aim of this study was to investigate the p53 status in two autoimmune diseases; juvenile chronic arthritis (JCA) and rheumatoid arthritis (RA). In a PCR-sequencing analysis of exons 4-9 of the p53 gene, no mutation was identified, except for the case of an RA synovectomy sample with two mutations of intron 7. p53 gene polymorphisms for codons 36, 47, and 213 were not detected. Codon 72 polymorphism showed an indication of an increased occurrence of the Pro/Pro allelotype in JCA. Expression of P53 protein was comparable for JCA and RA synovectomy samples. For all RA samples P53 protein was detectable, whereas one sample of a JCA patient failed to express P53 protein.

Adolescent↗

PubMed2000

mdm2 mRNA level is a prognostic factor in soft tissue sarcoma.

BACKGROUND: The oncogenic properties of murine double minute-2 (mdm2) protein over-expression, which mostly results from the interaction with the tumor suppressor p53, are well described and their negative impacts on the prognosis of affected patients is well characterized. However, clinical relevance of mdm2 mRNA expression is poorly investigated. MATERIALS AND METHODS: In this study, 65 soft tissue sarcoma (STS) samples were analyzed for mdm2 mRNA expression by a quantitative reverse transcription polymerase chain reaction (RT-PCR) approach using available validated ready-to-use assays based on the TaqMan technology (PE Applied Biosystems, Weiterstadt, Germany). Mdm2 data were correlated to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression calculated from the same sample. RESULTS: For patients with a mdm2/GAPDH mRNA ratio below 50 zmol/amol the survival was strikingly reduced in comparison to patients with a ratio of > or =50 (p = 0.0241). Multivariate Cox analysis showed that the difference in prognosis for patients with tumor stage 2 and 3 became even more pronounced between patients with a ratio of <50 zmol/amol and patients with a ratio of > or =50 (p = 0.0041; RR = 5.6). To test if the group with an mdm2 mRNA expression > or =50 is homogenous concerning the prognosis, the group was divided into three subgroups with values of 50 to <100, 100 to <500 and > or =500. The subgroup with values of 100 to <500 showed the best prognosis (p = 0.0164); whereas, the one with values of 50 to <100 showed the worst prognosis in this group and, in between, was the one with values of > or =500. After omitting patients of stage 1 and 4, the subgroup with values of 100 to <500 showed an even more striking best prognosis (p = 0.0015); the other subgroups remained in the same sequence. The risk of tumor-related death over 5 years was most conspicuous in patients with mdm2 mRNA expression <50 than in those with ratios of 100 to <500 displaying a 13.3-fold higher risk. In a comparison between mdm2 mRNA levels and P53 protein expression or p53 mutational status, no relationship was found. CONCLUSIONS: In our study, the mdm2 mRNA level appears to be an independent prognostic factor for STS patients, marking its role in STS genesis and as a potential factor for gene therapeutical approaches.

DNA Mutational Analysis↗

PubMed1999

Clinical relevance of pRb and p53 co-overexpression in soft tissue sarcomas.

The goal of this study was to examine the relationship between immunohistochemical pRb detectability and p53 overexpression in 198 soft tissue sarcomas (STS) with regard to its clinical relevance. Distinct pRb detectability multivariately shows a correlation to survival rate (relative risk (RR)=1.59, P=0.037). p53 positivity was also multivariately correlated to poor prognosis (RR=2.17, P=0.0014). Stratification of pRb staining to p53 results shows a prognostical graduation. Patients with negativity for both proteins have the most favorable prognosis (projected 5-year survival rate (psr)=54.5%). In contrast to this, positivity for both antibodies has the highest risk (RR=2.48, P=0.02) and the poorest prognosis (psr=17.4%). To conclude, these results explain that the clinical relevance of immunohistochemical pRb positivity in STS is connected with p53 in the form of having an increasing effect on the known prognostic relevance of p53 overexpression.

Adolescent↗

PubMed1999

Stationary space-periodic structures with equal diffusion coefficients.

The paper investigates a chemical reaction-diffusion model in an open flow system. It is shown that such a system may, with particular boundary conditions, exhibit stationary space-periodic structures even in the case of equal diffusion coefficients. This is confirmed through numerical simulations.

Journal Article↗

PubMed1999

Genomic imbalances of 7p and 17q in malignant peripheral nerve sheath tumors are clinically relevant.

We investigated 31 malignant peripheral nerve sheath tumors (MPNSTs) from 23 patients by means of comparative genomic hybridization (CGH) in order to study quantitative genomic aberrations of these tumors. Twenty-one of the 23 patients revealed changes, with a mean value of 11 aberrations per sample (range 2-29). The minimal common regions of the most frequent gains were 8q23-q24.1 (12 cases), 5p14 (11 cases), and 6p22-pter, 7p15-p21, 7q32-q35, 8q21.1-q22, 8q24.2-qter, and 17q22-qter (10 cases each). Seventeen high-level amplifications were detected in eight of the 21 samples. In three cases, the high-level amplifications involved 8q24.1-qter, and in two cases each the high-level amplifications involved regions 5p14, 7p14-pter, 8q21.1-q23, and 13q32-q33. The minimal common region of frequent losses was 14q24.3-qter (five cases). The gain of 8q as a single common change in the primary tumor, the recurrence, and the metastasis from the same patient suggests that this aberration is an early change in the tumorigenesis of MPNSTs. Comparable aberrations were observed in separate tumors of the same patients affected by Recklinghausen's disease, indicating a limited number of accidental secondary changes. In sporadic MPNSTs, the most frequent gains were narrowed down predominantly to 5p, 6, 8q, and 20q, whereas in MPNSTs from patients with Recklinghausen's disease, there was most often a gain in 7q, 8q, 15q, and 17q. The occurrence of gain of both 7p15-p21 and 17q22-qter was associated with a statistically significant poor overall survival rate (P = 0.0096).

Adolescent↗

PubMed1998

No p16INK4A/CDKN2/MTS1 mutations independent of p53 status in soft tissue sarcomas.

The p16INK4A/CDKN2/MTS1 gene encodes a specific inhibitor of cyclin-dependent kinases (CDKs) 4 and 6. This study investigates p16INK4A gene status and expression in mesenchymal tumours, in particular soft tissue sarcomas (STSs). Employing non-radioactive polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) sequencing, no p16INK4A mutation was found in 86 samples taken from 74 mesodermal tumours with known p53 gene status. This suggests that p16INK4A gene alterations, inc contrast to p53, are not involved in the progression of STS. This finding is supported by the reports of a low frequency of deletions and intragenic mutations in STS. Furthermore, by immunohistochemistry (IHC), an inverse correlation was established between p16INK4A and RB positivity for 62 per cent of the frozen tumour samples investigated. However, alterations in other components of the pRh/p16INK4A/ CDK4/cyclin D1/E2F pathway have been proven crucial for tumourigenesis in human sarcomas.

Cyclin-Dependent Kinases↗

PubMed1998

p53 status in radiation-induced soft-tissue sarcomas.

BACKGROUND: Following therapeutic irradiation after a latency period of many years radiation-induced tumors, often sarcomas, can arise. Results of radiation-induced DNA damage can be 1. p53 over-expression, inducing growth arrest or apoptosis, and 2. occurrence of mutations, frequently including the p53 gene, as one molecular promotor for carcinogenesis. We were interested whether radiation-induced sarcomas are associated with alterations of the p53 status. MATERIAL AND METHODS: Samples from 11 radiation-induced soft-tissue sarcomas (STS) were studied by a non-radioactive PCR-SSCP sequencing analysis and by immunohistochemistry with five antibodies for their p53 status. RESULTS: A tumor of one patient possessed a G->A transition in codon 280 (exon 8). Of 11 tumors, 9 showed nuclear p53 positivity, detected by monoclonal antibody DO-1. Of these 9 patients, 7 died during the observation period, whereas the 2 patients with DO-1 negative tumor samples are still alive. CONCLUSIONS: p53 over-expression and p53 mutation occur in radiation-induced STS. p53 status is expected to have prognostic impact for radiation-induced STS.

Adult↗

PubMed1998

Significance of retinoblastoma and mdm2 gene expression as prognostic markers for soft-tissue sarcoma.

The growth regulatory function of the retinoblastoma protein (RB) can be suppressed by mdm2 via RB/mdm2 interaction by perturbation of the RB suppression of the E2F function. The goal of this study was to examine the clinical value of immunohistochemical (IHC) RB detection and its relationship to mdm2 overexpression in a cohort of 198 adult primary soft-tissue sarcomas (STS). RB overexpression reveals, multivariately, a correlation with survival (RR=1.59, P=0.037) as well as mdm2 positivity (RR=2.32, P=0.0035). Stratification of RB results to mdm2 staining shows a prognostic graduation in four levels. Patients with positivity for both antibodies have the highest risk (RR=3.30, P=0.002) and the poorest prognosis (projected 5-year survival rate, 18.6%); those with negativity for both antibodies show the most favourable prognosis (projected 5-year survival rate, 63.4%). Intermediately, an isolated RB overexpression (projected 5-year survival rate, 46.1%) is more favourable than an isolated mdm2 positivity (projected 5-year survival rate, 33.5%). To sum up, this study proves that RB and mdm2 overexpression have an individual and also an additive effect on prognosis in STS.

Adult↗