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S Petersen

Publications and source records attributed to S Petersen.

At least 55 records · Page 3Linked to original sources
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↗
PubMed2000

[Iatrogenic colon perforation from the viewpoint of the surgeon. Experiences with 11 patients].

Iatrogenic colonic perforation is a rare but very dangerous complication of colonoscopy. We report on eleven prospectively recorded patients treated between 1994 and 1998. In seven cases the colonoscopy had been done for diagnostic and in four cases for therapeutic reason. Nine women and two men (age range 56 to 92 years) were affected. In 77% the perforation was found in the sigmoid colon. All patients were operated on and five sutures, five resections and one colostomy were performed. No significant differences could be shown in six patients with classical perforation compared with five patients presenting with prolonged abdominal pain. Only duration of symptoms was significantly different in the two groups. Three patients (85, 90 and 92 years) died from late complications.

Aged↗
PubMed2000

Photosynthesis tests as an alternative to growth tests for hazard assessment of toxicant.

Acute (3- and 6-h) toxic responses toward Cu, linear alkylbenzene sulfonate (LAS), and tributyltin (TBT) of light-saturated and unsaturated photosynthesis were investigated for Rhodomonas salina and Skeletonema costatum obtained from exponentially growing batch cultures and from chemostat cultures limited by either nitrogen or phosphorus. The sensitivity of the photosynthesis tests were compared to standardized growth tests applied to the same species and toxicants. For Cu and S. costatum the photosynthesis test was up to 300 times more sensitive at light saturation than at light limitation. For the remaining photosynthesis tests no dependence on light condition were found. The photosynthesis tests with Cu and S. costatum were up to 10 times as sensitive as the growth test and most sensitive when the algae were obtained from a phosphate-limited chemostate. For the other photosynthesis tests no dependence on the growth condition were found, and the photosynthesis tests were as sensitive as the growth test. Photosynthesis tests offer an alternative to growth tests for hazard assessment of toxicants.

Alkanesulfonic Acids↗
PubMed2000

[Associated anomalies in lip-maxillopalatal clefts].

BACKGROUND: Retrospective studies of cleft lip and palate patients suggest a multifactorial aetiology for this condition. Many patients exhibit multiple defects, often removed from the orofacial region. The frequency and location of such coexistent abnormalities vary between studies. PATIENTS: A retrospective case-note study of 1,737 individuals with orofacial cleft, treated between 1974 and 1998 at our centre, was undertaken to assess the frequency of associated malformations and syndromes. RESULTS: Associated malformations were found to be present in 33% of all cases investigated. In nearly one half of these individuals (48%), defects could be attributed to recognisable syndromes. Patients with isolated palatal clefts (45.6%) and those with bilateral clefts of the lip and palate (35.3%) were particularly well-represented. The following problems were observed relatively frequently: Cerebral anomalies (16%), facial anomalies (14%), heart malformations (15%), anomalies of the extremities (9%) and urogenital tract abnormalities (8%). In contrast, endocrine aberrations were identified sporadically (0.5%). A partial situs inversus was found only in one case. CONCLUSION: As clefts of the lip and palate are frequently associated with additional malformations, the importance of thorough interdisciplinary neonatal screening cannot be over emphasised.

Abnormalities, Multiple↗
PubMed2000

Genetic imbalances with impact on survival in head and neck cancer patients.

Chromosomal imbalances in 113 primary head and neck squamous cell carcinomas (HNSCCs) determined by comparative genomic hybridization were correlated with patients survival using custom-made computer software which enabled the assessment of individual chromosomal loci. The Kaplan-Meier analysis revealed that overrepresentations of 2q12, 3q21-29, 6p21.1, 11q13, 14q23, 14q24, 14q31, 14q32, 15q24, 16q22, and deletions of 8p21-22 and 18q11.2 were significantly associated with both shorter disease-free interval and disease-specific survival in this tumor collective. Multivariate Cox proportional hazards regression models consistently identified the gains of 3q21-29, 11q13, and the loss of 8p21-22 as independent prognostic markers carrying a higher significance than the nodal status as the only clinicopathological parameter with statistical importance. In addition, these three markers allowed a molecular dissection of the patients with low clinical risk (pN0 and pT2 tumors). Thus, the genomic data being derived from the evaluation of primary HNSCC enabled a stratification of the patients into subgroups with different survival highlighting the necessity of a genetically based tumor classification for refining diagnosis and treatment of HNSCC patients.

Chromosome Aberrations↗
PubMed2000

Serial measurements of serum human placental lactogen (hPL) and serial ultrasound examinations in the evaluation of fetal growth.

Serial serum hPL measurements and serial ultrasound fetometry were compared in the evaluation of fetal growth by relating these two parameters to size at birth and to clinical factors known to influence size at birth. The data were from a prospective study of 1000 consecutive pregnant women considered to be at risk for fetal growth retardation with retrospective analysis. Serum hPL was measured by radioimmunoassay and fetal weight estimated by ultrasound every 3 weeks during the last trimester. hPL values were expressed as multiples of the median (MoM) and linear regression analysis of the hPL MoM values was carried out for each pregnancy to find the slope of the line (hPL-slope); at least 3 serum hPL values were required. The estimated fetal weight and weight-for-age at birth was expressed in Z-scores. The individual intrauterine growth velocity was calculated by regression analysis and expressed as change in Z-score for 12 weeks. At least two ultrasound measurements over an interval of at least 42 days were used to estimate the fetal growth velocity. In 588 women the file was complete. The main outcome measures were the individual mean hPL, hPL-slope, fetal growth velocity, birth weight deviation, smoking in pregnancy and diagnosis of preeclampsia. A significant correlation was found between the hPL-slope and the intrauterine fetal growth velocity (r=0.34), and between hPL-slope and birth weight deviation (r=0.32). Mean hPL was correlated to birth weight deviation (r=0.27), but only very weakly to intrauterine growth velocity (r=0.08). hPL-slope and intrauterine growth velocity independently predicted birth weight deviation. Heavy smoking which was stopped before the third trimester was not associated with low intrauterine growth velocity, but with a low hPL-slope. Preeclampsia was associated with a trend towards low and decreasing hPL and with an increasing intrauterine growth velocity and birth weight deviation. In conclusion the rate of change of serial hPL measurements correlated well to intrauterine fetal growth velocity in the third trimester as estimated by ultrasound and to the deviation in birth weight, but hPL seems to have a separate physiological significance, since it did not pick up when smoking was stopped and growth velocity was normalised and it did not at all detect the increased growth associated with preeclampsia.

Birth Weight↗
PubMed2000

Human papilloma virus status and chromosomal imbalances in primary cervical carcinomas and tumour cell lines.

Human papilloma virus (HPV) infection is the crucial step in the initiation of cervical carcinomas. In addition, HPV18 has been implicated in tumour progression and adverse clinical outcome. We determined the HPV types in 12 primary cervical carcinomas and 12 cell lines and compared the findings with the comparative genetic hybridisation (CGH) pattern of chromosomal alterations. The most frequent alteration was the deletion at 3p14 followed by the loss of 2q34-q36 along with 3q gain. High risk HPV types were detected in all samples except one primary tumour. In contrast to the normal distribution, HPV18 was present in 75% of cases including all cell lines. The cell lines carried a higher number of genetic alterations and a different CGH pattern for several chromosomes than the primary tumours, despite microdissection. Purely HPV18 positive cases indicated a high incidence of imbalances at specific loci with peaks of the histogram coinciding with known HPV integration sites. The study suggests that HPV infection is associated with a recurrent pattern of chromosomal changes in cervical carcinomas and that the development and progression of these alterations is triggered by integration into the host genome.

Carcinoma, Squamous Cell↗
PubMed2000

Analysis of chromosomal alterations in non-small cell lung cancer by multiplex-FISH, comparative genomic hybridization, and multicolor bar coding.

Lung cancer has a considerable impact on morbidity and mortality throughout the world. Despite extensive effort, no lung cancer-specific cytogenetic changes, such as lineage-specific translocations or inversions, have been described to date. In this study we used multiplex fluorescence in situ hybridization (M-FISH), comparative genomic hybridization, and multicolor bar coding to analyze eight cell lines derived from non-small cell lung cancers. M-FISH did not identify any balanced translocations, which are the dominating feature in leukemias and lymphomas. Instead, M-FISH unraveled an enormous number of numerical and structural aberrations, with each tumor having its own "private" pattern of chromosomal changes. In contrast, comparative genomic hybridization demonstrated similarities between tumors, because each cell line shared some chromosomal segments that were commonly gained or lost. One of these involved chromosome 12. Chromosome 12 specific bar code probe sets were constructed and used to demonstrate that breaks on chromosome 12 occur preferentially within specific bands. With the progressive use of higher resolution approaches, more information can be gained about the chromosomal alterations in cancer.

Carcinoma, Non-Small-Cell Lung↗
PubMed2000

The challenge of p53 as prognostic and predictive factor in gliomas.

In recent years, increasing interest in genetic abnormalities and biologic factors such as the tumour suppressor gene p53 as possible predictive and prognostic factor in gliomas has emerged. Inactivation of p53 can result in resistance to apoptosis, one of the mechanisms thought to explain the failure to respond to DNA-damaging agents. Thus, inactivation of p53 might be associated with a worse prognosis. Considering the inconsistent results of several recent studies, it has remained controversial whether p53 actually can be related to response to treatment and patients' prognosis. Therefore, a systematic review of the literature was performed, which included 28 publications. Techniques for assessing the inactivation of p53 varied widely. Overall, approximately 50% or more of astrocytoma specimens evaluated by immunohistochemistry stained positively for p53, regardless of histologic grade. Eight studies were restricted to comparably treated patients within a single histologic group. In most instances, non-restrictive inclusion criteria and use of statistical methods, which were not sufficient to correct the possible bias, make it difficult to reach unequivocal conclusions. However, it appears that the prognostic information of p53 is at best marginal, especially when compared to established parameters such as grading, age, etc. Its predictive value, which most likely is rather limited too, can hardly be judged without prospective studies also evaluating other biological factors as well as end-points other than time to radiological progression.

Astrocytoma↗
PubMed2000

Chromosomal alterations in the clonal evolution to the metastatic stage of squamous cell carcinomas of the lung.

Comparative genomic hybridization (CGH) was applied to squamous cell carcinomas (SCC) of the lung to define chromosomal imbalances that are associated with the metastatic phenotype. In total, 64 lung SCC from 50 patients were investigated, 25 each with or without evidence of metastasis formation. The chromosomal imbalances summarized by a CGH histogram of the 50 cases revealed deletions most frequently on chromosomes 1p21-p31, 2q34-q36, 3p, 4p, 4q, 5q, 6q14-q24, 8p, 9p, 10q, 11p12-p14, 13q13-qter, 18q12-qter and 21q21. DNA over-representations were most pronounced for chromosomes 1q11-q25, 1q32-q41, 3q, 5p, 8q22-qter, 11q13, 12p, 17q21-q22, 17q24-q25, 19, 20q and 22q. In ten cases, paired samples of primaries and at least one metastasis were analysed. The comparison revealed a considerable chromosomal instability and genetic heterogeneity; however, the CGH pattern indicated a clonal relationship in each case. The difference in histograms from the metastatic and non-metastatic tumour groups was most useful in pinpointing chromosomal imbalances associated with the metastatic phenotype, indicating that the deletions at 3p12-p14, 3p21, 4p15-p16, 6q24-qter, 8p22-p23, 10q21-qter and 21q22, as well as the over-representations at 1q21-q25, 8q, 9q34, 14q12 and 15q12-q15, occurred significantly more often in the metastatic tumour group. The comparison of the paired samples confirmed these findings in individual cases and suggested distinct genetic changes, in particular the extension of small interstitial deletions, during tumour progression. Importantly, metastasis-associated lesions were frequently detectable in the primary tumour providing a method of identifying patients at risk for tumour dissemination. Individual profiles and histograms are accessible at our web site http://amba.charite.de/cgh.

Carcinoma, Squamous Cell↗
PubMed2000

[Deletion of chromosome 10q--a marker for metastasis of head-neck carcinomas?].

BACKGROUND: Comparative genomic hybridization (CGH) was applied to squamous cell carcinomas of the head and neck to define genetic alterations that are associated with the metastatic phenotype. METHODS: CGH is a molecular cytogenetic method allowing the comprehensive analysis of a tumor genome for chromosomal imbalances. In total, 23 primary squamous cell carcinomas without evidence of metastasis formation and 20 lymph node metastases were investigated. RESULTS: Prevalent changes observed in more than 50% of the primary tumors included deletions on chromosomes 3p, 4p/q, 5q, 6q, 9p, 11q, 13q, and 18q, and DNA overrepresentations on chromosomes 1p, 3q, 5p, 8q, 9q, 11q13, 16p, 17q, 19p, 20q, and 22q. To evaluate the differences between both groups we used a histogram representation, calculation of a difference histogram, and statistical analysis. The analysis revealed that the lymph node metastases were frequently characterized by deletions on chromosomes 10, 11, and 14. In particular, DNA loss of the chromosomal bands 5p12, 10p11.2-12, 10q21, 10q22-23, 10q24-26, 11p13-14, 11q24-25, and 14q22-24 were significantly associated with metastases formation. The statistical analysis indicated that particularly the deletions on chromosome 10q were highly significant markers for the incidence of lymph node metastases. CONCLUSION: Our data indicate that tumor phenotypes are determined by patterns of chromosomal alterations, and that 10q deletions may predict the metastatic phenotype in head and neck squamous cell carcinomas.

Biomarkers, Tumor↗