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PubMed1996

A phase II trial of etoposide, leucovorin and 5-fluorouracil (ELF) in patients with advanced gastric cancer.

Etoposide, leucovorin and 5-fluorouracil (ELF) chemotherapy has been reported to be less toxic yet effective (response rates of 50%) in patients with advanced gastric cancer. A phase II study of ELF in 25 patients (11 males, 14 females, median age 53 years) with advanced adenocarcinoma of the stomach is reported. Patients received outpatient intravenous etoposide 120mg/m2 over 2 hours, folinic acid 300 mg/m2 over 2 hours, 5-fluorouracil 500 mg/m2 boluses daily for 3 days every 21 days. Of 17 measurable patients, there was one complete response (CR), 4 partial responses (PR) for a total response rate of 29.4%. Non-hematologic toxicity was modest (grade 0 vomiting 11/21, stomatitis 16/21, diarrhea 17/21). Grade 3/4 neutropenia was seen in 14/23, thrombocytopenia in 2/23, anemia in 5/23 patients. Median progression-free and overall survival was 4.1 and 7.1 months, respectively. In conclusion, ELF chemotherapy shows only modest activity in patients with advanced gastric cancer and is associated with severe hematologic toxicity.

Adult↗
PubMed1999

Etoposide, l-leucovorin and fluorouracil (ELF) regimen in metastatic gastric cancer: a phase II study.

The role of chemotherapy in metastatic gastric cancer (MGC) is predominantly palliative, therefore regimens with mild toxicity and acceptable activity should be preferred. The combination of etoposide, leucovorin and 5-fluorouracil (ELF) is suitable chemotherapy in this situation. We have enrolled 33 patients with MGC, using the following chemotherapy schedule: l-leucovorin 150 mg/m2 10 minute i.v., followed by etoposide 120 mg/m2 50 minute i.v., followed by 5-fluorouracil 500 mg/m2 10 minute i.v. on days 1-3, every 22 days. All patients are valuable for response, toxicity and survival. Two patients achieved complete response (6%), 10 patients (30%) had a partial response (PR), 9 patients (27%) had stabilization of disease (SD) and 12 patients had disease progression (PD). The median survival for all patients was 6 months (range, 1 to 40+). ELF was well tolerated, the main toxicity being myelosuppression. No toxic deaths occurred. In conclusion, the ELF regimen in our trial demonstrated, in this kind of patient, moderate activity in the absence of relevant toxicity, confirming its suitability in patients in generally poor condition.

Adult↗
PubMed2006

Regulation of the human LAT gene by the Elf-1 transcription factor.

BACKGROUND: The LAT gene encodes an intracellular adaptor protein that links cell-surface receptor engagement to numerous downstream signalling events, and thereby plays an integral role in the function of cell types that express the gene, including T cells, mast cells, natural killer cells, and platelets. To date, the mechanisms responsible for the transcriptional regulation of this gene have not been investigated. RESULTS: In this study we have mapped the transcriptional start sites for the human LAT gene and localized the 5' and 3' boundaries of the proximal promoter. We find that the promoter contains both positive and negative regulatory regions, and that two binding sites for the Ets family of transcription factors have a strong, positive effect on gene expression. Each site binds the Ets family member Elf-1, and overexpression of Elf-1 augments LAT promoter activity. The promoter also contains a Runx binding site adjacent to one of the Ets sites. This site, which is shown to bind Runx-1, has an inhibitory effect on gene expression. Finally, data is also presented indicating that the identified promoter may regulate cell-type specific expression. CONCLUSION: Collectively, these results provide the first insights into the transcriptional regulation of the LAT gene, including the discovery that the Ets transcription factor Elf-1 may play a central role in its expression.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Effect of ELF magnetic fields on protein synthesis in Escherichia coli K12.

Escherichia coli K12 was used as a model system to determine whether ELF magnetic fields (MFs) are a general stress factor. The cells were exposed to ELF MFs (5-100 Hz) at a maximum intensity of 14 mT r. m.s. for circularly polarized MFs and 10 mT r.m.s. for vertically polarized MFs. The response of the cells to the MFs was estimated from the change in protein synthesis by using 2D PAGE. Approximately 1,000 proteins were separated on the 2D gels. The stress-responsive proteins such as CH10, DNAK, CH60, RECA, USPA, K6P1 and SODM were identified from the SWISS-2DPAGE database on the 2D gels. These proteins respond to most stress factors, including temperature change, chemical compounds, heavy metals, and nutrients. When the bacterial cells were exposed to each MF at 5-100 Hz under aerobic conditions (6.5 h) or at 50 Hz under anaerobic conditions (16 h) at the maximum intensity (7.8 to 14 mT r.m.s.), no reproducible changes were observed in the 2D gels. Changes in protein synthesis were detected by 2D PAGE with exposure to heat shock (50 degrees C for 30 min) or under anaerobic conditions (no bubbling for 16 h). Increases in the levels of synthesis of the stress proteins were observed in heat-shocked cells (CH60, CH10, HTPG, DNAK, HSLV, IBPA and some unidentified proteins) and in cells grown under anaerobic conditions (DNAK, PFLB, RECA, USPA and many unidentified proteins). These results suggest that 2D PAGE is sufficient to detect cell responses to environmental stress. The high-intensity ELF MFs (14 mT at power frequency) did not act as a general stress factor.

Aerobiosis↗
PubMed1995

A new fibroblast growth stimulating activity from the human megakaryoblastic leukaemia cell line ELF-153: in vitro and in vivo findings.

Although the exact mechanism for the progression of myelofibrosis in acute megakaryoblastic leukaemia is unclear, certain humoral factors released from the proliferating megakaryoblasts that are unable to store these factors in their defective alpha-granules, including platelet derived growth factor (PDGF), fibroblast growth factors (FGF), platelet factor-4 (PF-4), transforming growth factor-beta (TGF-beta) and beta-thromboglobulin, could result in increased collagen synthesis by bone marrow fibroblasts. Recently, the human megakaryoblastic leukaemia cell line MEG-01 has been shown to produce both TGF-beta and PF-4 which have enhanced the growth of bone marrow fibroblasts. Therefore, we have examined the presence of a fibroblast growth stimulating activity and the humoral factors that might be responsible for it in the supernatant of the human megakaryoblastic leukaemia cell line ELF-153 recently established in our laboratory from a patient with acute myelofibrosis. A new fibroblast growth stimulating activity has been identified in the supernatant of the ELF-153 human megakaryoblastic leukaemia cell line that is independent of the percentage of fetal calf serum in NRK-49F fibroblast agar clonogenic assays and is not due to any of the known fibroblast growth stimulating humoral factors including PDGF, epithelial growth factor, TGF-alpha or beta, tumour necrosis factor-alpha, interleukin-1, 2, 4 or 6, FGF, fibronectin, PF-4 and factor VIII AG. Also, in vivo, subcutaneous injection of ELF-153 megakaryoblastic leukaemia cells into nude mice formed, in three out of the five mice after 6 weeks, subcutaneous tumours with a very rigid texture whose histological examination revealed dense infiltration by blast cells and pronounced reticular fibrosis. Immunohistochemistry demonstrated exclusive deposition of collagen III in the extracellular matrix whereas laminin and collagen IV were absent.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

ELF magnetic field exposure system with feedback-controlled disturbance rejection.

Extremely low-frequency (ELF) magnetic field exposure systems are usually subject to field disturbances induced by external sources. Here, a method for designing a feedback control system for cancelling the effect of external ELF magnetic field disturbances on the magnetic field over the exposure area is presented. This method was used in the design of a feedback-controlled exposure system for an inverted microscope stage. The effectiveness of the proposed feedback control system for disturbance rejection was verified experimentally and by means of computer simulation.

Computer Simulation↗
PubMed1997

Bioelectric potential gradients may initiate cell cycling: ELF and zeta potential gradients may mimic this effect.

When a number of experimental studies in bioelectromagnetics were reviewed, those in which weak, exogenous extremely low frequency (ELF) fields were applied in fixed juxtaposition to their target tissues, were found to initiate mitogenesis or mitogenesis-related signals more successfully than when the target tissue moved freely during the irradiation. It is suggested that ELF fields in fixed juxtaposition to their target tissue and implanted foreign bodies or endogenous tissues with a significant zeta potential, mimic bioelectric fields generated at wounds. When the potential is high enough, they assist healing by moving cells into the wound and stimulating quiescent cells at the wound margin to cycle. Electrophoresis may help the initial migration of cells into the wound to form a clot, and migration of fibroblasts and epithelial cells from the wound margin. When exposed for a long time in a fixed juxtaposition to a potential gradient too weak to show in situ microelectrophoresis along the cell membrane surface, surface particles may coalesce to form microclusters, where like-charged surface particles are in close proximity, and growth factor receptor oligomerization and other cycle-initiating reactions are facilitated.

Animals↗
PubMed2000

Morphologic responses of osteoblast-like cells in monolayer culture to ELF electromagnetic fields.

Osteoblast-like cells (MC 3T3-E1) were exposed for 24 h, immediately after plating, to a 60 Hz, 0.7 mT rms magnetic flux density, sufficient to induce an electric field of 0.5 mV/m rms, in order to investigate the influence of ELF field exposure on cell morphology. Using phase contrast images of the live cells, computerized image-analysis permitted rapid and objective quantification of cell length, width, area, perimeter, circularity and angular orientation. While the field-exposed cells were consistently smaller than sham treated cells, the morphologic alterations were not significantly different in the exposed cell population when cell orientation was not considered. When analyzed with respect to cell orientation, cells oriented parallel to the induced electric field (orthogonal to the applied magnetic field) demonstrated a significant decrease in cell length and an increase in roundness. These results confirm and extend previous studies on the morphologic adaptation of cells to low level ELF electromagnetic fields. The results suggest that the observed responses most likely depend on the induced electric field, with a field intensity threshold well below 1 mV/m. Further, these results provide important clues to the specific mechanism by which such low level fields may be capable of influencing cell behavior, and help to explain some of the difficulties in obtaining robust responses in in vitro EMF experiments.

3T3 Cells↗
PubMed2000

Low stray ELF magnetic field exposure system for in vitro study.

An exposure facility for wide application to cell exposure to an ELF (extremely low frequency) magnetic field was developed. It is suitable for conducting experiments under a high-intensity, variable-frequency magnetic field, on the biological effects of the ELF magnetic field in an in vitro study. The exposure system consists of Merritt's 4-square coil as a basic component to generate the required magnetic field intensity of 10 mT at 50 Hz with spatial field uniformity less than +/-3% in a 400 mm cube. Concentric compensation coils are adopted to eliminate the effects of stray fields on sham (control) samples in the vicinity of the exposure system. The uniformity of the magnetic field in the exposure coil, the increase in the power supply capacity due to the existence of compensation coils, and the stray field estimation were investigated carefully. After fabricating the system, performance tests were carried out and all the characteristics were found to be satisfactory. In addition, the ideal configuration for a concentric coil system was proposed.

Animals↗
PubMed2001

ELF magnetic fields in a city environment.

Some epidemiological studies indicate an association between extremely low frequency electromagnetic field (ELF-EMF) exposure and cancer risks. These studies have mainly taken residential and occupational exposure into consideration. Outdoor environments are often considered as low level areas, but in this paper we show that this is not true in a city environment. We have mapped the ELF magnetic flux densities along certain stretches of sidewalk in central Göteborg City, Sweden. About 50% of the investigated street length shows flux densities of the same order of magnitude (0.2 microT and above) as those associated with increased risks of cancer in epidemiological studies. We conclude that the outdoor exposures in a city environment also should be considered in exposure assessments and risk evaluations. These elevated flux densities are probably due to stray currents. We also found strong magnetic flux densities (> 1.0 microT) close to ordinary distribution pillars, power substations, shoplifting alarms, and other electrical devices.

Electromagnetic Fields↗
PubMed2002

Factors confounding cytosolic calcium measurements in Jurkat E6.1 cells during exposure to ELF magnetic fields.

Reported changes in the cytosolic calcium concentration ([Ca2+](c)) as a result of exposure to extremely low frequency (ELF) magnetic fields (MF) have been equivocal. In this study, we examine the possibility that some of these differences are attributable to variability associated with the cell cycle, pH of the suspension medium, and response to a calcium agonist. We used a custom designed spectrofluorimeter to measure [Ca2+](c) in Indo 1-AM loaded Jurkat E6.1 cells suspended in conditioned RPMI 1640 medium containing 10% fetal bovine serum. Four exposures were examined: zero static MF (Null), 60 Hz 100 microT(peak) sinusoidal MF (AC), 78 microT static MF (DC), and the combination of the 60 Hz and the 78 microT static MF (AD + DC). A significant decrease in normalized [Ca2+](c) values between 375-495 s for the DC and AC + DC groups was found in comparison to the Null group. However, statistical analysis indicated that cell cycle and quality of the alpha-CD3 monoclonal antibody response were significant covariates, while pH was not a significant covariate. When the effect of these covariates was taken into account, all exposure groups were significantly different from the control. Our results suggest that ELF MF effects may not be seen unless correction is made for biological variability of each cell preparation with respect to cell cycle and [Ca2+](c) response to antigen stimulation.

Calcium↗
PubMed2003

ELF magnetic fields induce internalization of gap junction protein connexin 43 in Chinese hamster lung cells.

We have previously demonstrated that exposure of Chinese hamster lung (CHL) cells to 50 Hz magnetic fields (MFs) and/or 12-O-tetradecanoylphorbol-3-acetate (TPA)-inhibited gap junctional intercellular communication (GJIC). To explore and compare the mechanisms of GJIC inhibition induced by extremely low frequency (ELF) MF and TPA, the number and localization of connexin 43 (C x 43) were studied. The localization of C x 43 was determined with indirect immunofluorescence histochemical analysis and detected by confocal microscopy after exposing CHL cells to 50 Hz sinusoidal magnetic field at 0.8 mT for 24 h without or with TPA (5 ng/ml) for the last 1 h. The C x 43 levels in nuclei and in cytoplasm were examined by Western blotting analysis. The results showed that the cells exposed to MF and/or TPA displayed individual plaques at regions of intercellular contact, which were fewer than the normal cells in number, while the number of C x 43 in cytoplasm increased and congregated near the nuclei. Western blot analysis further demonstrated the quantity of changes in location of Cx43. These results suggest that reduction of C x 43 at regions of intercellular contact may be one of the mechanisms of GJIC inhibition induced by ELF MF.

Animals↗
PubMed1990

A model to assess personal exposure to ELF magnetic fields from common household sources.

Emission data are inadequate to characterize the contribution of a source to the total personal extremely-low-frequency (ELF) magnetic field exposure. In this paper, a simple model is proposed that takes into consideration the position of the subject with respect to the source and the duration of exposure. The magnetic field is spatially averaged over the whole body of the exposed subject and integrated over time. Exposure is regarded as significant if it approaches or exceeds 400 microT-h/year. By use of this method, the ELF magnetic fields generated by several household sources were compared with the levels of residential external sources, to assess their relative significance. Some common domestic electrical appliances are found to be responsible for an exposure comparable to that from power lines. When the model is used to assess exposure to electric blankets, apparently conflicting findings may be reconciled.

Bedding and Linens↗
PubMed1992

ELF in vitro exposure systems for inducing uniform electric and magnetic fields in cell culture media.

Many in vitro experiments on the biological effects of extremely low frequency (ELF) electromagnetic fields utilize a uniform external magnetic flux density (B) to expose biological materials. A significant number of researchers do not measure or estimate the resulting electric field strength (E) or current density (J) in the sample medium. The magnitude and spatial distribution of the induced E field are highly dependent on the sample geometry and its relative orientation with respect to the magnetic field. We have studied the E fields induced in several of the most frequently used laboratory culture dishes and flasks under various exposure conditions. Measurements and calculations of the E field distributions in the aqueous sample volume in the containers were performed, and a set of simple, quantitative tables was developed. These tables allow a biological researcher to determine, in a straightforward fashion, the magnitudes and distributions of the electric fields that are induced in the aqueous sample when it is subjected to a uniform, sinusoidal magnetic field of known strength and frequency. In addition, we present a novel exposure technique based on a standard organ culture dish containing two circular, concentric annular rings. Exposure of the organ culture dish to a uniform magnetic field induces different average electric fields in the liquid medium in the inner and outer rings. Results of experiments with this system, which were reported in a separate paper, have shown the dominant role of the magnetically induced E field in producing specific biological effects on cells, in vitro. These results emphasize the need to report data about the induced E field in ELF in-vitro studies, involving magnetic field exposures. Our data tables on E and J in standard containers provide simple means to enable determination of these parameters.

Culture Media↗
PubMed1992

Magnetite in human tissues: a mechanism for the biological effects of weak ELF magnetic fields.

Due to the apparent lack of a biophysical mechanism, the question of whether weak, low-frequency magnetic fields are able to influence living organisms has long been one of the most controversial subjects in any field of science. However, two developments during the past decade have changed this perception dramatically, the first being the discovery that many organisms, including humans, biochemically precipitate the ferrimagnetic mineral magnetite (Fe3O4). In the magnetotactic bacteria, the geomagnetic response is based on either biogenic magnetite or greigite (Fe3S4), and reasonably good evidence exists that this is also the case in higher animals such as the honey bee. Second, the development of simple behavioral conditioning experiments for training honey bees to discriminate magnetic fields demonstrates conclusively that at least one terrestrial animal is capable of detecting earth-strength magnetic fields through a sensory process. In turn, the existence of this ability implies the presence of specialized receptors which interact at the cellular level with weak magnetic fields in a fashion exceeding thermal noise. A simple calculation shows that magnetosomes moving in response to earth-strength ELF fields are capable of opening trans-membrane ion channels, in a fashion similar to those predicted by ionic resonance models. Hence, the presence of trace levels of biogenic magnetite in virtually all human tissues examined suggests that similar biophysical processes may explain a variety of weak field ELF bioeffects.

Animals↗
PubMed1992

Bioelectric background fields and their implications for ELF dosimetry.

Electrically active cells, such as those comprising nerve, muscle, or bone, produce ELF currents not only across themselves but also in the surrounding tissue including the tight extracellular spaces between cells. An analysis based on "cable models" of neurons or muscle cells is herein used to estimate those extracellular (or "pericellular") current densities. In order to explore frequency bands the neural or muscle action potentials are represented by a Fourier series of sine wave components. The results of this analysis suggest that endogenous currents in, or near, nerve and muscle are far stronger (higher density) than currents likely induced by exogenous ELF fields--such as 1 microT, 60 Hz magnetic fields. This holds true even for "higher harmonics" including those at or near 60 Hz.

Action Potentials↗
PubMed2001

Effects of high ELF magnetic fields on enzyme-catalyzed DNA and RNA synthesis in vitro and on a cell-free DNA mismatch repair.

Environmental electromagnetic fields have been implicated in human cancers. We examined whether high extremely low frequency (ELF) AC magnetic fields could affect DNA synthesis, transcription or repair, using in vitro model systems with defined sequences. The rate and fidelity of DNA polymerase catalyzed DNA synthesis, as well as of RNA polymerase catalyzed RNA synthesis, were not statistically significantly affected by 60 Hz 0.25-0.5 Tesla magnetic fields. The efficiency of mutS dependent mismatch repair with human cell extracts was also not affected by the magnetic field exposure. The results suggest that the core processes related to the transmission of genetic information are stable under high ELF magnetic fields.

Animals↗
PubMed2001

Static and ELF magnetic fields induce tumor growth inhibition and apoptosis.

The ability of static and extremely low frequency (ELF) Magnetic Fields (MF) to interfere with neoplastic cell function has been evaluated. In vitro experiments were carried out to study the role of MF characteristics (intensity, frequency, and modulation) on two transformed cell lines (WiDr human colon adenocarcinoma and MCF-7 human breast adenocarcinoma) and one nontransformed cell line (MRC-5 embryonal lung fibroblast). Increase in cell death morphologically consistent with apoptosis was reported exclusively in the two transformed cell lines. Cell-death induction was observed with MF of more than 1 mT. It was independent of the MF frequency and increased when modulated MF (static with a superimposition of ELF at 50 Hz) were used. Based on the in vitro results, four different MF exposure characteristics were selected and used to treat nude mice xenografted with WiDr cells. The treatment of nude mice bearing WiDr tumors subcutaneously. with daily exposure for 70 min to MF for 4 weeks caused significant tumor growth inhibition (up to 50%) by the end of the treatment when modulated MF were used for at least 60% of the whole treatment period and the time-averaged total MF intensity was higher than 3.59 mT. No toxic morphological changes induced by exposure were observed in renewing, slowly proliferating, or static normal cells. A discussion on the possible biophysical mechanism at the base of the observed biological results is also offered.

Adenocarcinoma↗