PubMed Health⌕ Search

Biomedical subjects

C Petersen

Publications and source records attributed to C Petersen.

At least 55 records · Page 3Linked to original sources
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

Characterization of a monoclonal antibody reacting with antigen-4 domain of gp900 in Cryptosporidium parvum invasive stages.

Cryptosporidium parvum (Protozoa, Apicomplexa) infects the apical surface of intestinal epithelial cells, where it grows and divides within a membrane-bound parasitophorous vacuole. gp900, an abundant glycoprotein of C. parvum merozoites and sporozoites, is localized in micronemes and at the surface of invasive stages and participates in the invasion process. Here, we describe a new monoclonal antibody (mAb) against gp900. As shown by immunofluorescence of excysted parasites and immunoelectron microscopy of infected tissues, the mAb reacted with micronemes present in the apical pole of invasive stages. In immunoprecipitation experiments, the mAb was shown to react with a high molecular weight antigen co-migrating with gp900. Finally, three reactive clones were selected upon screening of a C. parvum genomic expression library with the mAb; and sequencing of the insert from one of them showed a 596 bp sequence identical to the DNA region encoding a domain of gp900 identified as antigen 4.

Animals↗
PubMed2001

No evidence for a different magnitude of the time factor for continuously fractionated irradiation and protocols including gaps in two human squamous cell carcinoma in nude mice.

BACKGROUND AND PURPOSE: To study whether the magnitude of the time factor is different for continuously fractionated irradiation and for fractionation protocols including gaps. MATERIALS AND METHODS: Two human head and neck squamous cell carcinomas (SCCs), FaDu and GL, were transplanted subcutaneously into the right hindleg of NMRI (nu/nu) mice and irradiated with 30 fractions under ambient conditions within 2, 6 and 10 weeks. Irradiations within 6 and 10 weeks were given either as a continuous course or with a mid-course gap of 3 weeks. The end-point of the experiments was local tumor control at day 120 (FaDu) or day 180 (GL) after the end of treatment. RESULTS: In FaDu tumors, two experimental cohorts (A, B) yielded significantly different results and were analyzed separately. In cohort A, the tumor control dose 50% (TCD50) increased from 37 to 89 Gy when the treatment time of continuous fractionated irradiation was extended from 2 to 10 weeks. The recovered dose/day (D(r)) was 0.98 Gy (95% confidence interval, 0.72; 1.27). In cohort B, the TCD50 increased from 35 to 63 Gy, and the D(r) was 0.51 Gy (0.24; 0.75). In GL tumors, the TCD50 for continuously fractionated irradiation increased from 41 to 48 Gy. This increase was not significant, and the D(r) was 0.15 Gy (0; 0.30). None of the TCD50 and D(r) values obtained in both tumor models for continuous irradiation vs. irradiation with a gap were significantly different. CONCLUSIONS: Prolongation of the overall treatment time of fractionated irradiation resulted in a pronounced decrease of local control in human FaDu SCC and little decrease of local control in human GL SCC. No evidence was found that the magnitude of the time factor in these tumors is different for continuous fractionation or fractionation protocols including gaps.

Animals↗
PubMed2001

Dose and fractionation concepts in the primary radiotherapy of non-small cell lung cancer.

At present, radiotherapy alone or in combination with chemotherapy offers the only chance of cure of medically inoperable or locally advanced unresectable non-small cell lung cancer. The radiobiological basis and clinical results of current dose and fractionation concepts in the primary radiotherapy of NSCLC are briefly reviewed. Whenever possible, focus is given to the results of randomized phase III trials. With the exception of early disease treated to doses higher than 60 Gy, the prognosis of inoperable localized NSCLC is very poor. Local recurrence is the major cause of failure after radiation therapy calling for intensified local treatment. Dose-escalation using conventional fractionation or moderate hypofractionation is promising but randomized trials are presently not available. Dose-escalated hyperfractionation theoretically offers advantages, however, there appears currently no strong evidence from randomized trials supporting this approach in NSCLC. The highly accelerated CHART regimen significantly improved survival by 9% compared to standard radiotherapy. Nevertheless, even when treated with CHART, about 80% of all patients will eventually develop local recurrence and 60% distant metastases. Many trials on combined radiochemotherapy have used radiotherapy regimens that are not optimal from a current perspective. Because of the high rate of both, local recurrence and distant metastases, future research should be directed to further intensify radiotherapy as well as to integrate such protocols with systemic treatment in carefully selected patients. Since toxicity is expected to increase, state-of-the-art 3D conformal radiation techniques need to be part of clinical trials testing such strategies.

Carcinoma, Non-Small-Cell Lung↗
PubMed2001

[Testing and validation of the German version of the Stroke Impact Scale].

Suitable and psychometrically tested instruments to assess health-related quality of life in stroke patients are still lacking in German speaking countries. The current paper describes the translation and psychometric testing of the German version of the Stroke Impact Scale, which was developed as a self- and proxy- report measure in the United States to assess the consequences of a stroke. The instrument contains 64 Likert-scaled items and assesses eight dimensions of health-related quality of life ("strength", "memory and thinking", "emotion", "communication", "ADL/IADL", "mobility", "hand function", and "participation"). The questionnaire was used in a cross-sectional study of 137 persons with stroke and was psychometrically tested. The results of this psychometric testing show a good acceptance on part of the interviewees. Convergent validity of the SIS dimensions was assessed with correlation of the SIS subscales and subscales of the short form SF-36 and Nottingham Health Profile and criteria-related validity was examined by comparison of mean scores across groups defined by Rankin scores. The reliability of the questionnaire was determined through internal consistency (Cronbach's). The German version of the SIS is a reliable and valid instrument to assess health-related quality of life, but more studies are needed to make statements about sensitivity of the instrument, psychometric quality of the proxy version and suitability of the questionnaire for specific stroke subgroups.

Adult↗
PubMed2001

Radiobiological hypoxia, oxygen tension, interstitial fluid pressure and relative viable tumour area in two human squamous cell carcinomas in nude mice during fractionated radiotherapy.

Very little is known about the correlation between the radiobiological hypoxic fraction (rHF) and other measures of tumour oxygenation during fractionated irradiation. In the present study the rHF is determined in untreated human FaDu and GL squamous cell carcinoma in nude mice and in tumours irradiated with 10 fractions in 2 weeks and 20 fractions in 4 weeks, using tumour control as the experimental endpoint. The results were compared with measurements of the pO2, the interstitial fluid pressure (IFP) and the relative viable tumour area. In FaDu tumours the radiobiological hypoxic fractions (rHFs) before and during irradiation were not statistically different from 100%. Depending on the assumptions made for D0, the rHFs of GL tumours were between 0.2 and 4% or 30 and 53%. The median pO2 values were 2.8 mmHg for untreated FaDu tumours and 0.2 mmHg for GL tumours (p < 0.001). The median IFP values were 2.6 mmHg in FaDu and 5.3 mmHg in GL tumours (p = 0.01). No important changes in the pO2 and IFP values were observed during fractionated irradiation. The relative viable tumour area during irradiation decreased by 83% in FaDu tumours (p = 0.002) and by 54% in GL tumours (p = 0.003). It is concluded that differences in rHF exist between FaDu and GL tumours before and during fractionated irradiation and that these differences are not reflected by pO2 and IFP values and the relative viable tumour area.

Animals↗
PubMed2001

Impact of the tumour bed effect on microenvironment, radiobiological hypoxia and the outcome of fractionated radiotherapy of human FaDu squamous-cell carcinoma growing in the nude mouse.

PURPOSE: To investigate the impact of the tumour bed effect (TBE) on histological parameters of the micromilieu, radiobiological hypoxic fraction and local control after fractionated irradiation in FaDu squamous-cell carcinoma in the nude mouse. This tumour has previously shown a clear-cut TBE caused by increased necrotic cell loss at a constant cell production rate in the viable tumour compartment. MATERIALS AND METHODS: Human FaDu tumours were studied in the NMRI nude mouse. Tumours were transplanted either into unirradiated subcutaneous (s.c.) tissues (controls) or s.c. tissues pre-irradiated with 12.5 Gy (TBE group). In both groups we measured the volume doubling time (VDT), potential doubling time (T(pot)), relative necrotic area, and in the viable tumour compartment the relative vascular area (9F1 mAb), relative hypoxic area (NITP or pimonidazole), relative perfused area (Hoechst 33342), and the perfused fraction of vasculature. The tumour control dose 50% (TCD 50), radiobiological hypoxic fraction (rHF) and dose-modifying factors (DMF) for the comparison of tumours in the TBE and control groups were determined from local tumour control data after treatment with single doses under ambient conditions or under clamp hypoxia, and after irradiation with 30 fractions under ambient conditions within 6 weeks using maximum-likelihood analysis. RESULTS: A clear-cut TBE (VDT = 4.0 days (95%CI 2.9;4.4) for the control group versus 7.2 days (6.4;8.9) for the TBE group; p <0.0001) caused by increased necrosis (mean relative necrotic area of 12% (5;20)) versus 33% (10;41); p = 0.07) at a constant cell production rate (T(pot) = 2.2 days (1.4;2.3) versus 2.2 days (1.7;2.6); p = 0.30) was confirmed. Histological analysis of the micromilieu within the vital subarea revealed no systematic differences between the TBE and control groups. The rHF of 2% (0.1;27) for control tumours was lower than the 15% (95% CI 2;91) for the TBE group, but this difference was nonsignificant (p = 0.12). Compared with control tumours, the TCD50 for irradiation under clamped hypoxia was in a statistical trend lower for tumours in the TBE group (DMF 1.11 (0.98;1.28), p = 0.09). After fractionated irradiation, tumours of the TBE group were significantly more radiosensitive (TCD50 56.6 Gy (46;70) versus 78.7 Gy (63;100); p = 0.003). CONCLUSIONS: The results on FaDu tumours growing in pre-irradiated tissues indicate that increased necrosis caused by impairment of the vascular supply may increase the radiosensitivity of tumours treated by fractioned irradiation.

Animals↗
PubMed2000

Control of copper homeostasis in Escherichia coli by a P-type ATPase, CopA, and a MerR-like transcriptional activator, CopR.

We have isolated and characterized a copper sensitive Escherichia coli mutant that is deficient in the copper transporting P-type ATPase encoded by the copA gene (previously ybaR). Measurements of uptake and efflux of 64Cu by wild-type and mutant cells implicated the CopA protein in copper efflux from the cytoplasm, and further demonstrated that cell-associated copper in intact E. coli cells is distributed between two kinetically distinguishable pools, the ratio of which was dramatically disturbed by the copA mutation. Using a copA-lacZ gene fusion the copA promoter was found to be specifically induced by copper, and this induction was shown to be dependent on a MerR-like transcriptional activator encoded by a previously uncharacterized gene, copR (previously ybbI). In the copA deficient background the copA-lacZ fusion was super induced to very high levels even in the absence of copper addition to the medium, and this induction was dependent on CopR. These results indicated that the cytoplasmic copper concentration was dramatically increased in the copA mutant, in agreement with the 64Cu uptake experiments. Moreover, they implied, that the copper concentration in wild type cells is determined primarily by the CopA efflux pump, while copper is taken up by an essentially constitutive mechanism.

Adenosine Triphosphatases↗
PubMed2000

Characterization of the hCTR1 gene: genomic organization, functional expression, and identification of a highly homologous processed gene.

The human hCTR1 gene was originally identified by its ability to complement a yeast mutant deficient in high-affinity copper uptake (Zhou, B., Gitschier, J., 1997. A human gene for copper uptake identified by complementation in yeast. Proc. Natl. Acad. Sci. USA 94, 7481-7486). Here, we have determined the DNA sequence of the exon-intron borders of the hCTR1 structural gene and report that the coding sequence is disrupted by three introns, all of which comply with the GT/AG rule. Furthermore, human fibroblasts, transfected with hCTR1 cDNA, were shown to have a dramatically increased capacity for (64)Cu uptake, indicating that the hCtr1 protein is functional in copper uptake in human cells. In contrast, no evidence was found for involvement of the hCTR2 gene product in copper uptake. Finally, we have identified a highly homologous processed pseudogene, hCTR1psi, which was localized to chromosome 3q25/26. The processed gene was found to be transcribed, but due to a frame shift mutation, it only had the potential to encode a truncated protein of 95 amino acid residues, and cells transfected with hCTR1psi DNA showed no increase of (64)Cu uptake.

Amino Acid Sequence↗
PubMed2000

The antioxidant drug dipyridamole spares the vitamin E and thiols in red blood cells after oxidative stress.

OBJECTIVE: To test the antioxidant effect of therapeutic doses of dipyridamole on cellular membranes, human erythrocytes were chosen as an appropriate model to study oxidative stress induced by cumene hydroperoxide because of their high content in heme-Fe(2+). METHODS: The oxidative stress was induced by incubation with 160 micromoll(-1) cumene hydroperoxide and expressed by three main factors: lipid peroxidation by means of kinetics of decrease in fluorescence emission of the probe incorporated in the cell membranes, vitamin E oxidation and intracellular thiol content. The concentrations of dipyridamole tested (2-20 micromoll(-1)) did not exceed pharmacological doses. RESULTS: After 7 min of incubation at 25 degrees C with the oxidant and 20 micromoll(-1) dipyridamole thiol content was 50.1%+/-2.6 compared with 31.5%+/-2.4 in the absence of the drug. After 12 min vitamin E content was 88.3%+/-2.3 compared with 64.7%+/-3.4 of untreated cells in the absence of dipyridamole. Dipyridamole added 5 min after the oxidation reaction suppressed the fluorescence decrease for a time proportional to the drug concentration. CONCLUSIONS: Thus, at clinically realistic doses dipyridamole shows a concentration-dependent antioxidant effect. It protects membranes from oxidation and spares the antioxidant power of erythrocytes.

Antioxidants↗
PubMed2000

Similar splice-site mutations of the ATP7A gene lead to different phenotypes: classical Menkes disease or occipital horn syndrome.

More than 150 point mutations have now been identified in the ATP7A gene. Most of these mutations lead to the classic form of Menkes disease (MD), and a few lead to the milder occipital horn syndrome (OHS). To get a better understanding of molecular changes leading to classic MD and OHS, we took advantage of the unique finding of three patients with similar mutations but different phenotypes. Although all three patients had mutations located in the splice-donor site of intron 6, only two of the patients had the MD phenotype; the third had the OHS phenotype. Fibroblast cultures from the three patients were analyzed by reverse transcriptase (RT)-PCR to try to find an explanation of the different phenotypes. In all three patients, exon 6 was deleted in the majority of the ATP7A transcripts. However, by RT-PCR amplification with an exon 6-specific primer, we were able to amplify exon 6-containing mRNA products from all three patients, even though they were in low abundance. Sequencing of these products indicated that only the patient with OHS had correctly spliced exon 6-containing transcripts. We used two different methods of quantitative RT-PCR analysis and found that the level of correctly spliced mRNA in this patient was 2%-5% of the level found in unaffected individuals. These findings indicate that the presence of barely detectable amounts of correctly spliced ATP7A transcript is sufficient to permit the development of the milder OHS phenotype, as opposed to classic MD.

Adenosine Triphosphatases↗
PubMed2000

Increase in plasma adenosine during brain ischemia in man: a study during transient ischemic attacks, and stroke.

Adenosine is a "retaliatory metabolite" which accumulates during experimental brain ischemia and has vasodilatory and putative neuroprotective effects. The aim of this study was to assess whether human cerebral ischemia and necrosis-evaluated in the clinical models of transient ischemic attack (TIA) and stroke, respectively-acutely raise plasma adenosine levels. We studied 20 patients: 10 with TIA and 10 with stroke. In all, blood was serially sampled for assessment of plasma adenosine by an high-performance liquid chromatography method. Sampling occurred on peripheral blood during TIA and stroke upon admission, and serially thereafter every day up to 7 days and every other day up to 20 days. We found that in TIA and stroke patients, peripheral adenosine levels were increased to a similar extent upon admission (TIA = 264 +/- 53 vs. stroke = 257 +/- 60 nM, p = ns), peaked on the day 2 for TIA (300 +/- 60) and on day 3 for stroke (289 +/- 43) patients, and steadily decreased towards the normal range, reached by all TIA patients by day 5 and by stroke patients by day 15. Stroke and TIA are associated with a rapid increase in circulating plasma adenosine concentration in man, detectable in peripheral vein. The adenosine surge likely mirrors an increased production from the ischemic brain, and it lasts days (for TIA) and weeks (for stroke) after the acute event.

Adenosine↗
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

Invariance of the nucleoside triphosphate pools of Escherichia coli with growth rate.

The ATP and GTP pools of Escherichia coli have recently been reported to increase approximately 10-fold with increasing growth rates in the range from 0.4 to 1.4 generations/hour (Gaal, T., Bartlett, M. S., Ross, W., Turnbough, C. L., and Gourse, R. L. (1997) Science 278, 2092-2097). Moreover, it was proposed that this variation of the nucleotide pools, particularly the ATP pool, might be responsible for the well known growth rate-dependent regulation of rRNA synthesis in E. coli. To test this hypothesis we have measured the nucleoside triphosphate pools as a function of growth rate for several E. coli strains. We found that the size of all four RNA precursor pools are essentially invariant with growth rate, in the range from 0.5 to 2.3 generations/hour. Nevertheless we observed the expected growth rate-dependent increase of RNA accumulation in these strains. In light of these results, it seems unlikely that nucleotide pool variations should be responsible for the growth rate-dependent regulation of rRNA synthesis.

Escherichia coli↗
PubMed2000

Random mutagenesis and functional analysis of the Ran-binding protein, RanBP1.

Ran GTPase is required for nucleocytoplasmic transport of many types of cargo. Several proteins that recognize Ran in its GTP-bound state (Ran x GTP) possess a conserved Ran-binding domain (RanBD). Ran-binding protein-1 (RanBP1) has a single RanBD and is required for RanGAP-mediated GTP hydrolysis and release of Ran from nuclear transport receptors (karyopherins). In budding yeast (Saccharomyces cerevisiae), RanBP1 is encoded by the essential YRB1 gene; expression of mouse RanBP1 cDNA rescues the lethality of Yrb1-deficient cells. We generated libraries of mouse RanBP1 mutants and examined 11 mutants in vitro and for their ability to complement a temperature-sensitive yrb1 mutant (yrb1-51(ts)) in vivo. In 9 of the mutants, the alteration was a change in a residue (or 2 residues) that is conserved in all known RanBDs. However, 4 of these 9 mutants displayed biochemical properties indistinguishable from that of wild-type RanBP1. These mutants bound to Ran x GTP, stimulated RanGAP, inhibited the exchange activity of RCC1, and rescued growth of the yrb1-51(ts) yeast cells. Two of the 9 mutants altered in residues thought to be essential for interaction with Ran were unable to rescue growth of the yrb1(ts) mutant and did not bind detectably to Ran in vitro. However, one of these 2 mutants (and 2 others that were crippled in other RanBP1 functions) retained some ability to co-activate RanGAP. A truncated form of RanBP1 (lacking its nuclear export signal) was able to complement the yrb1(ts) mutation. When driven from the YRB1 promoter, 4 of the 5 mutants most impaired for Ran binding were unable to rescue growth of the yrb1(ts) cells; remarkably, these mutants could nevertheless form ternary complexes with importin-5 or importin-beta and Ran-GTP. The same mutants stimulated only inefficiently RanGAP-mediated GTP hydrolysis of the Ran x GTP x importin-5 complex. Thus, the essential biological activity of RanBP1 in budding yeast correlates not with Ran x GTP binding per se or with the ability to form ternary complexes with karyopherins, but with the capacity to potentiate RanGAP activity toward GTP-bound Ran in these complexes.

Animals↗
PubMed2000

[What do we know about the mechanisms of the time factor in oncological therapy?].

BACKGROUND: Experimental studies and prospective randomized clinical trials have demonstrated a detrimental effect of prolongation of overall treatment time on local tumor control. METHODS: In a brief review of the literature, possible mechanisms of the time factor are discussed. RESULTS AND CONCLUSIONS: The mechanisms of the time factor in cancer treatment are complex and, at present, not fully understood. In experimental tumors, rapid proliferation of clonogenic cells during fractionated irradiation and treatment gaps has been determined as a major cause of the time factor in radiotherapy. Also, chemotherapy can stimulate repopulation of experimental tumors by clonogenic cells. Besides repopulation of clonogenic tumor cells, other factors such as the deterioration of the tumor vasculature with increasing tumor hypoxia might contribute to the time factor.

Animals↗