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S Petersen

Publications and source records attributed to S Petersen.

At least 19 recordsLinked to original sources
PubMed2001

Increased plasma homocysteine in liver cirrhosis.

Background: Homocysteine (Hcy), is an atherogenic and thrombogenic risk factor which has also been proposed to be involved in hepatic fibrinogenesis. Hcy metabolism, depends on the cofactors folate, vit. B12, and the vit. B6 vitamer pyridoxalphosphate (PLP). Metabolism of these vitamins is frequently disturbed in cirrhotics, but little is known about plasma Hcy levels in these patients. Methods: Plasma levels of Hcy, methionine, serine, cysteine, PLP, vit. B12 and folate, and standard clinical/biochemical parameters of liver disease were measured in 43 postabsorptive patients with biopsy proven cirrhosis of different origin. Results: 74% of the patients had elevated plasma Hcy levels defined as >13.4 µmol/l (mean+2SD of healthy age matched controls). Increased plasma Hcy concentrations were seen in alcoholic as well as in non-alcoholic cirrhosis. Excluding patients with impaired renal function (n=7), Hcy concentrations remained elevated in 69% of the patients. We found a high prevalence of pathological plasma vitamin concentrations of 33% for increased vit. B12 levels and 5% and 80% for decreased folate and vit. B6 levels, respectively. Mean plasma vitamin B12 concentrations increased, folate remained unchanged and PLP concentrations decreased with deteriorating liver function. Hcy concentrations were correlated with levels of creatinine (r=0.44, P<0.01), serine (r=-0.46, P<0.01), and cysteine (r=0.38, P<0.05), but showed no association with parameters of liver function and with plasma levels of folate, vit. B12 und vit. B6. This was contrary to data obtained in healthy individuals. In a stepwise multiple regression serine and cysteine best explained the variance in Hcy levels. Conclusions: Elevated basal Hcy-plasma levels are frequently seen cirrhotic patients. Variations of Hcy concentration in liver cirrhosis are not explained by plasma levels of cofactors of Hcy metabolism.

Journal Article↗
PubMed2001

Targeted disruption of the Nijmegen breakage syndrome gene NBS1 leads to early embryonic lethality in mice.

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive human disease whose clinical features include growth retardation, immunodeficiency, and increased susceptibility to lymphoid malignancies. Cells from NBS patients exhibit gamma-irradiation sensitivity, S-phase checkpoint defects, and genomic instability. Recently, it was demonstrated that this chromosomal breakage syndrome is caused by mutations in the NBS1 gene that result in a total loss of full-length NBS1 expression. Here we report that in contrast to the viability of NBS patients, targeted inactivation of NBS1 in mice leads to early embryonic lethality in utero and is associated with poorly developed embryonic and extraembryonic tissues. Mutant blastocysts showed greatly diminished expansion of the inner cell mass in culture, and this finding suggests that NBS1 mediates essential functions during proliferation in the absence of externally induced damage. Together, our results indicate that the complex phenotypes observed in NBS patients and cell lines may not result from a complete inactivation of NBS1 but may instead result from hypomorphic truncation mutations compatible with cell viability.

Animals↗
PubMed2001

A universal framework for 13C metabolic flux analysis.

A general methodology is presented for the modeling, simulation, design, evaluation, and statistical analysis of (13)C-labeling experiments for metabolic flux analysis. The universal software framework 13C-FLUX was implemented to support all steps of this process. Guided by the example of anaplerotic flux determination in Corynebacterium glutamicum, the technical details of the model setup, experimental design, and data evaluation are discussed. It is shown how the network structure, the input substrate composition, the assumptions about fluxes, and the measurement configuration are specified within 13C-FLUX. Based on the network model, different experimental designs are computed depending on the goal of the investigations. Finally, a specific experiment is evaluated and the various statistical methods used to analyze the results are briefly explained. The appendix gives some details about the software implementation and availability.

Biomedical Engineering↗
PubMed2001

The results of colorectal cancer treatment by p53 status: treatment-specific overview.

PURPOSE: Both negative and positive influences of mutant p53 on treatment outcome have been reported, and we present here a meta-analysis of published studies where outcome was reported for defined treatment groups. METHODS: We identified articles on the effect of p53 status by treatment modality, excluding those not stratified by method of treatment. A common hazard ratio was estimated from studies that reported a multivariate analysis. We also estimated the numbers of patients expressing the endpoint at the mean or median follow-up time and calculated a pooled odds ratio. RESULTS: Twenty-eight articles were evaluable (23 using immunohistochemistry to detect overexpression of p53 and 8 using DNA sequencing), for a total of 4,416 patients. For patients treated with surgery only, the immunohistochemistry studies showed a significant influence of p53 status on disease-free survival and a marginally significant influence on overall survival. In the studies using DNA sequencing, by contrast, there was a significant influence of p53 mutations on overall survival, but not disease-free survival. For patients treated with surgery and radiotherapy, the influence of p53 status on disease-free survival was either insignificant or marginally significant, depending on test used; there was no influence on overall survival. CONCLUSIONS: Although this pooled analysis of published studies where treatment was accounted for shows that there is a borderline significant hazard associated with p53 overexpression or mutation vs. p53 wild-type, it is unlikely that p53 can be applied in a routine clinical setting alongside factors such as T stage, nodal status, and residual tumor, whose prognostic value is much stronger.

Adenocarcinoma↗
PubMed2001

The challenge of p53 as prognostic and predictive factor in Hodgkin's or non-Hodgkin's lymphoma.

The results of individual studies examining the role of p53 as a predictive and prognostic factor in lymphoid malignancies have varied considerably. In order to summarize the available data on the overexpression or mutation of p53 in Hodgkin's and non-Hodgkin's lymphoma, a systematic literature review was performed. Twenty-four studies met the eligibility criteria. With respect to non-Hodgkin's lymphoma, most studies seem to support the hypothesis that patients whose tumors contain wild-type p53 respond better to treatment and have increased survival rates. If true, the implication may be that patients with p53 mutated tumors could be selected for non-standard treatment. With respect to Hodgkin's lymphoma, comparable associations were rarely reported. However, techniques for assessing the inactivation of p53 varied widely. Furthermore, in most instances, the study design and/or statistical methods did not allow sufficient analyses of the influence of confounding factors such as histologic type, stage, first-line and salvage treatment, etc. Therefore, it remains unclear whether the apparent influence of p53 status on outcome in non-Hodgkin's lymphoma is independent of established parameters such as stage, performance status, etc. Further studies involving large numbers of specimens derived from patients treated in clinical trials with identical regimens, follow-up and salvage strategies are needed. These studies should also be stratified according to histologic subtypes.

Disease-Free Survival↗
PubMed2001

Overexpression of c-erbB2 protein correlates with disease-stage and chromosomal gain at the c-erbB2 locus in non-small cell lung cancer.

Overexpression of the c-erbB2 protein is observed in a variety of malignancies including non-small cell lung cancer (NSCLC). We aimed to determine the rate of c-erbB2-overexpression in our tumour collection and to clarify its correlation with the chromosomal status at the c-erbB2 locus 17q21 in NSCLC. Eighty-nine NSCLC were analysed immunohistochemically using a polyclonal c-erbB2 antibody (DAKO). The staining was scored according to the guidelines of the Clinical Trial Assay recommendations (0-3+). Of these, 44 cases were also analysed by comparative genomic hybridisation (CGH). Overexpression was observed in 37% of the cases (score>1) which was associated with higher disease stages and a positive nodal status in adenocarcinomas. Chromosomal gains at 17q21 were clearly correlated with overexpression of the gene (P=0.009). In addition, there was a highly significant correlation between the c-erbB2 expression comparing the whole section immunostaining analysis and a 127 lung tumour tissue array which included 74 of the 89 cases that were analysed by the classical procedure. We conclude that c-erbB2 is a marker of tumour progression in NSCLC which can be observed on protein level and reflects chromosomal alterations at 17q21.

Adult↗
PubMed2001

Predictors of homicidal ideation and intent in schizophrenia: an empirical study.

Correlations of age, gender, and psychosocial variables with ratings of current homicidal ideation and intent were investigated among psychiatric facility clients with schizophrenia. Multiple regression analyses revealed, irrespective of age or gender, significantly positive correlations of three psychosocial variables--manic symptoms, psychotic symptoms, and impaired global functioning--with homicidal ideation and intent. Implications for research are discussed.

Adolescent↗
PubMed2001

[Perfusion MR imaging of the heart with TrueFISP].

OBJECTIVE: Development and test of a saturation-recovery TrueFISP (SR-Trufi) pulse sequence for myocardial perfusion MR imaging (MRI) using improved gradient hardware. MATERIAL AND METHODS: Measurements were performed on a 1.5 T scanner with prototype gradients (50 mT/m, minimum rise time 300 microseconds). T1-weighted first-pass MRI of Gd-DTPA (0.025 mumol/kg) kinetics in the myocardium was performed using an SR-Trufi pulse sequence (TR/TE/alpha = 2.6 ms/1.4 ms/55 degrees) with a saturation preparation of TD = 30 ms before the TrueFISP readout. Measurements were performed in volunteers (n = 4) and in a pig model of chronic ischemia (n = 1). RESULTS: In phantoms, the signal intensity was linear with contrast concentration up to 0.9 mmol/kg Gd-DTPA. MR images obtained with SR-Trufi had a good image quality and high spatial resolution of 2.1 mm x 2.1 mm. Differences of the contrast agent's kinetics between a subendocardial perfusion deficit and neighboring myocardium were well visible on both MR images and signal-time curves derived from the region-of-interest analysis. CONCLUSION: SR-Trufi appears to be an interesting new technique for the assessment of myocardial microcirculation using dedicated cardiovascular MR systems.

Adult↗
PubMed2001

Deep prosthesis infection in incisional hernia repair: predictive factors and clinical outcome.

OBJECTIVE: To evaluate the incidence of prosthetic infection in incisional hernia repairs, to determine whether there are any factors associated with prosthetic infection and to describe the clinical outcome. DESIGN: Retrospective clinical study. SETTING: Teaching hospital, Germany. SUBJECTS: 121 consecutive patients who underwent incisional hernia repair in our department from December 1994 to December 1999. INTERVENTION: Hernia repair by implantation of an alloplastic prosthesis by the Stoppa-Rives technique. MAIN OUTCOME MEASURES: Postoperative deep prosthetic infection and associated factors. RESULTS: All 121 patients had the mesh implanted in the subfascial plane, 77 had a polypropylene mesh (Prolene) (64%), 7 had a polyester mesh (Mersilene) (6%), and 37 patients had a expanded polytetrafluoroethylene patch (ePTFE, Gore-Tex) (31%). Postoperatively the mesh became infected in 8 patients (7%), a mean of 4.5 months (range 0.5-16) after hernia repair. All three infected ePTFE patches had to be removed whereas drainage was sufficient treatment for the infected polypropylene and polyester meshes. CONCLUSION: Once a mesh infection is verified adequate drainage seems to be sufficient for polypropylene and polyester meshes but ePTFE patches should be removed.

Aged↗
PubMed2001

Towards a genetic-based classification of human lung cancer.

Lung cancer is a highly aggressive neoplasm which is reflected by a multitude of genetic aberrations being detectable on the chromosomal and molecular level. In order to understand this seemingly genetic chaos, we performed Comparative Genomic Hybridisation (CGH) in a large collective of human lung carcinomas investigating different tumor entities as well as multiple individual tumour specimens of single patients. Despite the considerable genetic instability being reflected by the well known morphological heterogeneity of lung cancer the comparison of different tumour groups using custom made computer software revealed recurrent aberration patterns and highlighted chromosomal imbalances that were significantly associated with morphological histotypes and biological phenotypes. Specifically we identified imbalances in NSCLC being associated with metastasis formation which are typically present in SCLC thus explaining why the latter is such an aggressive neoplasm characterized by widespread tumor dissemination. Based on the genetic data a new model for the development of SCLC is presented. It suggests that SCLC evolving from the same stem cell as NSCLC should be differentiated into primary and secondary tumors. Primary SCLC corresponding to the classical type evolved directly from an epithelial precursor cell. In contrast, secondary SCLC correlating with the combined SCLC develops via an NSCLC intermediate. In addition, we established libraries of differentially expressed genes from different human lung cancer types to identify new candidate genes for several of the chromosomal subregions identified by CGH. In this review, we summarise the status of our results aiming at a refined classification of lung cancer based on the pattern of genetic aberrations.

Carcinoma, Non-Small-Cell Lung↗
PubMed2001

Enhancement of tumor radioresponse by docetaxel: Involvement of immune system.

Docetaxel, a potent chemotherapeutic drug and a strong enhancer of tumor radioresponse, possesses immunomodulating properties. We previously reported that 40% of murine tumors responding to docetaxel by growth delay showed heavy infiltration with macrophages or lymphocytes. The present study explored the effect of whole body irradiation on antitumor action of docetaxel alone or docetaxel plus tumor irradiation. Mice bearing 8-mm MCa-K mammary carcinoma in the leg received 33 mg/kg docetaxel i.v., 5 to 65 Gy tumor irradiation, or both (radiation given 24 h after docetaxel). Docetaxel delayed tumor growth and enhanced the efficacy of radiation: it dramatically reduced TCD50 (radiation dose yielding 50% tumor cure) from the control value of 38.6 Gy to 11.8 Gy, for an enhancement factor of 3.27. In addition to enhancing tumor radioresponse, docetaxel decreased the lung metastatic rate in mice with local tumor control from 26% in mice receiving radiation alone to 11% in mice receiving docetaxel plus radiation. Docetaxel induced heavy infiltration of tumors with lymphocytes, determined 2-4 days after treatment: the percentage of lymphocytes increased from the control value of <2% to 27% in mice that received docetaxel 3 days earlier. This increase was due to the influx of helper/inducer T-lymphocytes and natural killer cells. Immunosuppression of tumor-bearing mice with 6 Gy whole-body irradiation prior to tumor isotransplantation reduced docetaxel-induced lymphocyte infiltration of tumors, antitumor and anti-metastatic action of docetaxel, and docetaxel-induced enhancement of tumor radioresponse. Thus, our results showed that docetaxel stimulates tumor infiltration with immune cells, which then participate in antitumor action of docetaxel alone or when combined with radiotherapy.

Animals↗
PubMed2001

Characterization of the phosphoenolpyruvate carboxykinase gene from Corynebacterium glutamicum and significance of the enzyme for growth and amino acid production.

Corynebacterium glutamicum possesses phosphoenolpyruvate (PEP) carboxykinase, oxaloacetate decarboxylase and malic enzyme, all three in principle being able to catalyze the first step in gluconeogenesis. To investigate the role of PEP carboxykinase for growth and amino acid production, the respective pck gene was isolated, characterized and used for construction and analysis of mutants and overexpressing strains. Sequence analysis of the pck gene predicts a polypeptide of 610 amino acids showing up to 64% identity with ITP-/GTP-dependent PEP carboxykinases from other organisms. C. glutamicum cells harbouring pck on plasmid showed about tenfold higher specific PEP carboxykinase activities than the wildtype. Inactivation of the chromosomal pck gene led to the absence of PEP carboxykinase activity and the inability to grow on acetate or lactate indicating that the enzyme is essential for growth on these carbon sources and thus, for gluconeogenesis. The growth on glucose was not affected. Examination of glutamate production by the recombinant C. glutamicum strains revealed that the PEP carboxykinase-deficient mutant showed about fourfold higher, the pck-overexpressing strain two- to threefold lower glutamate production than the parental strain. Inactivation and overexpression of pck in a lysine-producer of C. glutamicum led to an only 20% higher and lower lysine accumulation, respectively. The results show that PEP carboxykinase activity in C. glutamicum is counteractive to the production of glutamate and lysine and indicate that the enzyme is an important target in the development of strains producing amino acids derived from citric acid cycle intermediates.

Amino Acid Sequence↗
PubMed2000

In vivo quantification of parallel and bidirectional fluxes in the anaplerosis of Corynebacterium glutamicum.

The C(3)-C(4) metabolite interconversion at the anaplerotic node in many microorganisms involves a complex set of reactions. C(3) carboxylation to oxaloacetate can originate from phosphoenolpyruvate and pyruvate, and at the same time multiple C(4)-decarboxylating enzymes may be present. The functions of such parallel reactions are not yet fully understood. Using a (13)C NMR-based strategy, we here quantify the individual fluxes at the anaplerotic node of Corynebacterium glutamicum, which is an example of a bacterium possessing multiple carboxylation and decarboxylation reactions. C. glutamicum was grown with a (13)C-labeled glucose isotopomer mixture as the main carbon source and (13)C-labeled lactate as a cosubstrate. 58 isotopomers as well as 15 positional labels of biomass compounds were quantified. Applying a generally applicable mathematical model to include metabolite mass and carbon labeling balances, it is shown that pyruvate carboxylase contributed 91 +/- 7% to C(3) carboxylation. The total in vivo carboxylation rate of 1.28 +/- 0.14 mmol/g dry weight/h exceeds the demand of carboxylated metabolites for biosyntheses 3-fold. Excess oxaloacetate was recycled to phosphoenolpyruvate by phosphoenolpyruvate carboxykinase. This shows that the reactions at the anaplerotic node might serve additional purposes other than only providing C(4) metabolites for biosynthesis.

Amino Acids↗
PubMed2000

A novel approach in drug discovery: synthesis of estrone--talaromycin natural product hybrids.

Hetero-Diels-Alder reaction of the steroidal exocyclic enol ethers 14 and 15, obtained from the secoestrones 8 and 9 by reduction, iodoetherification, and elimination, with ethyl O-benzoyldiformylacetate (16) leads to the spiroacetals 17 and 18 as a mixture of four diastereomers. Reduction of the major diastereomers 17a and 18a with DIBAH and subsequent hydrogenation yields the novel natural product hybrids 21, 23, 24, and 25, which possess the structural features of the steroid estrone (7) and the mycotoxin talaromycin 6.

Acetals↗
PubMed2000

Analysis of the DMBT1 gene in carcinomas of the respiratory tract.

Loss of chromosome 10q is a critical step during the progression and metastasis formation of lung cancer. We recently defined 3 distinct regions of allelic imbalances and considered the DMBT1 gene at 10q25-q26 an interesting candidate for the most telomeric region. Therefore, we investigated DMBT1 in 25 cancer cell lines and 39 primary tumors of the respiratory tract. The analysis by RT-PCR and Northern blot hybridization revealed that the gene is expressed in all tumors and cell lines and diminished in the SCLC line H187, indicating that RT-PCR is critical when used as the single method for the evaluation of gene expression. No mutations were found by SSCP analysis of the cDNA and the partially known genomic sequence. Similarly, Southern blot hybridization was unable to detect homozygous deletions. Allelotyping of the markers D10S587, D10S1708 and D10S1723 located near or within the DMBT1 gene did not reach the peak incidence of the 3 minimally deleted regions that we recently defined. In summary, our data do not confirm previous findings reporting frequent loss of DMBT1 expression in lung cancer. However, they strengthen the notion that the responsible gene on chromosome 10q25-q26 mediating tumor progression and metastasis formation in respiratory tract cancer remains enigmatic.

Agglutinins↗
PubMed2000

Gene expression profiling of advanced lung cancer.

Lung cancer is a highly aggressive neoplasm with 85% mortality. To identify new tumor-associated genes, we compared the expression profile of a primary metastasizing adenocarcinoma with normal airway epithelial cells. Two cDNA libraries of up- and downregulated genes were generated, comprising 253 and 299 clones, respectively. The sequence analysis revealed 205 different known genes and 314 cDNA fragments of unknown functions. Northern-blot analysis of 167 clones confirmed differential expression in 58%, and indicated a similar expression pattern in additional lung-cancer cell lines for selected clones, strengthening the value of this model for the identification of new candidate genes in lung carcinogenesis.

Chromosome Mapping↗
PubMed2000

Preferential enhancement of tumor radioresponse by a cyclooxygenase-2 inhibitor.

Cyclooxygenase-2 (COX-2), an inducible isoform of cyclooxygenase, is overexpressed in many types of malignant tumors, where it mediates production of prostaglandins (PGs), which in turn may stimulate tumor growth and protect against damage by cytotoxic agents. This study investigated whether SC-'236, a selective inhibitor of COX-2, potentiates antitumor efficacy of radiation without increasing radiation injury to normal tissue. Mice bearing the sarcoma FSA in the hind legs were treated daily for 10 days with SC-'236 (6 mg/kg given in the drinking water) when tumors were 6 mm in diameter. When tumors reached 8 mm in diameter, the mice were given 11- to 50-Gy single-dose local tumor irradiation with or without SC-'236. SC-'236 inhibited tumor growth on its own, and it greatly enhanced the effect of tumor irradiation. The growth delay was increased from 14.8 days after 25-Gy single dose to 28.4 days after the combined treatment (P = 0.01). SC-'236 reduced TCD50 (radiation dose yielding 50% tumor cure) from 39.2 Gy to 20.9 Gy (enhancement factor = 1.87). SC-'236 did not appreciably alter radiation damage to jejunal crypt cells and tissue involved in the development of radiation-induced leg contractures. The SC-'236-induced enhancement of tumor radioresponse was associated with a decrease in PGE2 levels in FSA tumors. The drug had no effect on radiation-induced apoptosis. Neoangiogenesis was inhibited by SC-'236, which could account for some of the increase in tumor radioresponse. Overall, our findings demonstrated that treatment with a selective inhibitor of COX-2 greatly enhanced tumor radioresponse without markedly affecting normal tissue radioresponse. Thus, COX-2 inhibitors have a high potential for increasing the therapeutic ratio of radiotherapy.

Animals↗