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PubMed1995

Response of rat spinal cord to very small doses per fraction: lack of enhanced radiosensitivity.

Our previous work with rat spinal cord demonstrated that the linear quadratic (LQ) model based on data for large fraction sizes (alpha/beta of 2.4 Gy) failed to predict isoeffective doses between 1 and 2 Gy per fraction, and under-estimated the sparing effect of small doses per fraction given once daily. In contrast, data from mouse skin and kidney, and recent in vitro results revealed a paradoxical increase in radiosensitivity at below 1 Gy per fraction. To assess whether enhanced radiosensitivity is present in the spinal cord below 1 Gy per fraction, the rat spinal cord (C2-T2) was irradiated initially with three daily doses of 10.25 Gy (top-up doses representing 90% of tolerance), followed by graded single doses or fractionated doses in 1.5, 1.0, 0.8, 0.6 or 0.4 Gy fractions given once daily. To limit the overall treatment time to < or = 8 weeks, a small number of the 0.6- and 0.4-Gy fractions were given twice daily with an interfraction interval of 16 h. The end-point was forelimb paralysis secondary to white matter necrosis, confirmed histologically. The ED50 values, excluding the top-up doses, were 5.8, 10.6, 14.8, 15.2, 15.9 and 19.1 Gy for a single dose and doses in 1.5-, 1.0-, 0.8-, 0.6- and 0.4-Gy fractions, respectively. The data gave an alpha/beta of 2.1 Gy (95% CI, 1.4, 2.7 Gy). Pooling the data separately, the alpha/beta value was 2.3 Gy (95% CI, 0.82, 3.7 Gy) for fraction sizes > or = 1 Gy, and 1.2 Gy (95% CI, 0.16, 2.3 Gy) for the 0.8-, 0.6- and 0.4-Gy experiments.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Low molecular weight pineal and cerebral fractions affecting insulin secretion in vitro.

Studies were performed to examine the effects of various fractions of pineal gland origin upon rates of immunoreactive insulin release during short-term incubations of pancreatic islets from pinealectomized rats. Fractions of cerebral cortex were employed in control incubations. An ultrafiltrate of pineal extracts containing materials of molecular weight less than or equal to 1000 daltons stimulated insulin release while fractions of greater molecular weight were without effect. The stimulation of insulin release observed with the lower molecular weight pineal fraction was seen with both nonstimulatory (2 mM) and stimulatory (10 and 30 mM) medium glucose concentrations, but was abolished in the presence of 2,4-dinitrophenol (200 microM). Upon further fractionation of the low molecular weight pineal extract, fractions I (estimated molecular weight range 700-1000 daltons) and 11 (estimated molecular weight range 180-700 daltons) exhibited comparable stimulatory effects upon islet insulin release: similar effects were observed with cerebral cortical fractions in these molecular weight ranges. However, pineal fraction III (estimated molecular weight range less than 180 daltons) exhibited a striking inhibitory effect upon rates of insulin release compared to cerebral cortical fraction III. Potassium, dopamine, norepinephrine and epinephrine concentrations in both pineal and cortical tissue fractions were similarly low. We conclude that insulinotropic constituent(s) of similar molecular weight occur in pineal gland and cerebral cortex, and that the pineal insulinotropic activity stimulates active insulin secretion by the islets independently of concomitant stimulation by glucose; however, lower molecular weight insulinostatic constituent(s) are notable only in the pineal. It is suggested that mild hyperinsulinemia seen in pinealectomized rats under some circumstances may occur as a result of loss of the pineal insulinostatic factor(s).

2,4-Dinitrophenol↗
PubMed1981

Binding of [35S]saccharin to a protein fraction of rat tongue epithelia.

The binding of [35S]saccharin to ammonium sulfate fractions from homogenates of rat tongue epithelia was measured by equilibrium dialysis. The 40--60% saturated ammonium sulfate fraction from the buffer-soluble fraction had the highest saccharin-binding activity. Binding of [35S]saccharin to the 40--60% ammonium sulfate fraction was inhibited by unlabeled saccharin sodium salt. The inhibition increased with increasing unlabeled saccharin concentration and was nearly complete above 10 mM. [35S]Saccharin binding to the 40--60% ammonium sulfate fraction extracted from the tongue epithelia was inhibited by glucose, lactose and sucrose, while binding to similar fractions from tongue muscle was not affected by these sugars. The inhibition of binding of labeled saccharin to the epithelial fraction increased with increasing glucose concentrations. About 35% of the binding was inhibited by 1 M glucose. No significant difference in the amount of inhibition was seen among the three sugars at 0.1 M. The 40--60% ammonium sulfate fraction from tongue epithelium devoid of taste buds bound much less [35S]saccharin than did a similar fraction from epithelium with taste buds. Binding of [35S]saccharin by the preparation from epithelium devoid of taste buds was not inhibited by glucose. The results provide evidence that the 40--60% ammonium sulfate fraction from tongue epithelia with taste buds contains a protein which binds saccharin and sugars. We hypothesize that it is a sweet taste receptor protein.

Animals↗
PubMed1985

Lack of evidence for increased tolerance of rat spinal cord with decreasing fraction doses below 2 Gy.

The radiation tolerance of the spinal cord, both in man and in rats, has been shown to depend strongly on the size of the dose per fraction. With fraction doses down to about 2 Gy, the spinal cord tolerance can be predicted by a modified Ellis formula: D approximately N0.43. More recently alternative isoeffect formulas were based on the linear-quadratic (LQ) model of cell survival where the effect of dose fractionation is characterized by the ratio alpha/beta which varies from tissue to tissue. For the spinal cord, as well as for other late responding tissues, the ratio alpha/beta is small, in contrast to most acutely responding tissues. Both the Ellis-type formula, and to a lesser extent the LQ-model, predict a continuously increasing tolerance dose with decreasing fraction size. From the LQ model, the concept of "flexure dose" has been derived, which proposes the limit of effective fractionation to be about 0.1 alpha/beta. At this dose per fraction no significant further gain in tolerance would be detected. From previous experiments on the rat cervical spinal cord with doses per fraction down to about 2 Gy, the ratio alpha/beta was determined to be 1.7 Gy, and the LQ-model would predict a rise in tolerance with a reduction in fraction size to far below 2 Gy. Based on these predictions clinical studies have been initiated assuming a significantly increased tolerance by reduction of fraction size to about 1 Gy. However, in the present experiments no evidence was found for such an increase in tolerance with fraction sizes below 2 Gy.

Animals↗
PubMed1990

Fractionation effects and repair kinetics in rat kidney.

Rat kidneys were unilaterally irradiated with up to 40 fractions of X rays. Fractionation regimens were given either with long intervals of 6-24 hr between fractions, resulting in complete recovery from sublethal damage, or with 1-hr intervals, resulting in largely incomplete repair. The non-irradiated kidney was surgically removed 4 weeks after the last fraction. The development of radiation-induced kidney damage was monitored by regular assessment of three different parameters indicative of kidney function: serum urea, the total volume of urine excreted in 24 hr and urine osmolality. At the end of the observation period, 18 months after treatment, the kidney was removed. The hydroxyproline content was determined and a histopathological analysis was performed. Since the 20 and 40-fraction data indicated a higher effectiveness of these regimens than would be expected on the basis of the LQ model, the data were divided in two subsets, 2-10 fractions (high doses per fraction) and 10-40 fractions (low doses per fraction), and analyzed separately. The time course of alpha/beta and T1/2 values was determined for each functional parameter separately, and for the data from the three parameters combined. A complex pattern was found, with the values for alpha/beta as well as T1/2 differing between the two data subsets between about 20 and 40 weeks after treatment. For the lower doses per fraction the alpha/beta values were generally higher and the repair half-times longer. After 40 weeks no significant differences were observed between the two data subsets. If the differences found earlier are ignored, overall alpha/beta and T1/2 values can be calculated. For early endpoints the alpha/beta was 1.69 (1.45, 1.90) Gy (95% confidence limits in parentheses), for late endpoints it was 1.77 (1.56, 2.00) Gy. The corresponding T1/2 values were 1.57 (1.44, 1.73) hr for early endpoints, and 2.10 (1.90, 2.34) hr for late endpoints. Hence, the alpha/beta values do not alter in time, but the T1/2 value for late damage might be higher than that for early damage.

Animals↗
PubMed1991

Studies of dose-fractionation on early and late responses in pig skin: a reappraisal of the importance of the overall treatment time and its effects on radiosensitization and incomplete repair.

Studies in pig skin have examined the effects of dose fractionation on the acute radiation response. The variation in ED50 values for moist desquamation for doses given as 1-48 fractions over less than or equal to 16 days were best fitted by a log-log plot of iso-effect dose against the number of fractions; the slope of this plot indicated a fraction number exponent (N) of 0.42 +/- 0.007. Based on the assumptions made in applying the linear-quadratic (LQ) model, the alpha/beta ratio was found to decrease with decreasing per fraction: for doses given as 6-27 Gy per fractions the alpha/beta ratio was 8.74 +/- 0.48 Gy, whereas for doses of 2.55-6 Gy per fraction it was only 0.85 +/- 0.29 Gy. A simple approach to a time factor could not be used to calculate iso-effect doses for acute reactions in pig skin when treatment time was increased from less than or equal to 16 days to 28-39 days. This was due to the opposing effects of radiosensitization and repopulation when the cell cycle time of epidermal basal cells was shortened. For late dermal necrosis in pig skin, repair of sublethal damage was not completed in 24 hr. This finding has a significant effect on the interpretation of the results of fractionation studies using this late endpoint. Expressed in terms of a simple power-law function, there was a significant change in the fraction number exponent "N" from 0.43 +/- 0.007 to 0.37 +/- 0.006 for the complete and incomplete repair data, respectively. Many of the fractionation effects reported for acute and late damage to pig skin would appear to be in excellent agreement with those for human skin.

Animals↗
PubMed1993

Effects of fractionated radiation therapy on human brain tumor multicellular spheroids.

We investigated the cytotoxic effects of fractionated radiation therapy on multicellular spheroids of human malignant glioma cell lines U-87 MG, U-251 MG, and U-373 MG. Graded doses of x-rays were administered in 1, 3, 8, 15, and 30 fractions over 15 days. The isoeffect dose for a 1 log cell kill ranged from 4-4.5 Gy for a single fraction to 7-8 Gy for an 8-fraction protocol; no additional dose-sparing was achieved with more fractions. Therefore, the effects of individual doses (1.56 Gy) of the 8-fraction protocol were studied in U-251 MG spheroids. A cell survival assay showed that the first dose of radiation killed 30-50% of the cells; subsequent doses usually killed fewer cells. The cell kill after all 8 doses was about 1.0 log. No consistent relationship between the intracellular glutathione level and fraction number was observed. The 24-hour labeling index of the spheroids did not decrease until after the second fraction. Thus, the higher cell kill of the first dose does not seem to be related to cell cycle synchrony. Multinuclear and mononuclear giant cells were limited almost entirely to the periphery of the spheroids and increased with the number of radiation fractions. We conclude that multicellular spheroids can be used to study the biological effects of fractionated radiation therapy on human brain tumor cells. Although this model cannot be used to evaluate the effect of radiation on normal tissue, it may be useful in developing more effective radiation therapy protocols for human brain tumors.

Brain Neoplasms↗
PubMed1995

Should direct measurements of tumor oxygenation relate to the radiobiological hypoxic fraction of a tumor?

PURPOSE: Numerous previous studies have attempted to relate the radiobiological hypoxic fraction (HF) to direct measures of tumor oxygenation such as HbO2 saturations, tumor pO2 levels, or hypoxic cell labeling. Although correlations have been found within tumor lines, no overall relationships were seen across tumor lines. The current objective was to examine the effect on HF of changes in the fractions of the oxygenated and anoxic tumor cells that remain clonogenic. METHODS AND MATERIALS: A mathematical model was developed that relates the HF to direct measures of tumor oxygenation. The primary assumptions were that: (a) the tumor is divided into distinct compartments of either fully oxygenated or fully anoxic cells, and (b) the survival of the oxygenated cells is negligible compared to that of the anoxic cells. Based on these assumptions, the HF is plotted as a function of the fractions of clonogenic or nonclonogenic, and oxygenated or anoxic cells. RESULTS: If all cells are clonogenic, then the HF equals the fraction of anoxic cells. If a higher fraction of anoxic than oxygenated cells are nonclonogenic, then the HF will be overestimated by the fraction of the tumor measured to be anoxic using direct measuring techniques. If a higher fraction of the oxygenated than anoxic cells are nonclonogenic, the HF will be underestimated by the fraction of anoxic cells. CONCLUSION: Correlations between the HF and direct measures of tumor oxygenation have been described within tumor lines evaluated under different physiological condition. However, such relationships can be totally unpredictable between different tumors if the fraction of the anoxic cells that is clonogenic varies substantially. Clearly, if tumor anoxia cannot be detected using direct measures, this is an accurate indication that the tumor is well oxygenated. When tumor anoxia is present, however, the conclusions are ambiguous. Even when a small fraction of the tumor is measured as anoxic, direct measures of tumor oxygenation may not be representative of the HF if a substantial proportion of nonclonogenic cells is present.

Cell Hypoxia↗
PubMed1981

The chemical form of cadmium in microsomal and mitochondrial fractions from rat liver and kidney after long term administration of cadmium chloride.

Wistar rats were given drinking water containing 250 ppm cadmium (Cd) for 12 months. After excising the kidney and liver, the organs were subfractionated into nuclear, mitochondrial, microsomal and cytosol fractions, and the chemical forms of Cd in the subcellular fractions were examined. Although approx. 90% of the total Cd was present in the cytosol, in the form of metallothionein, 3-5% was also present in the mitochondrial fraction and 5-7% in the microsomal fraction from both organs. Each membrane fraction was washed 3 times and there was no contamination of metallothionein from the cytosol according to Cd/protein ratios. By Sephadex G-75 gel filtration, after solubilizing the particulate fractions with sodium deoxycholate, approx. 89% of Cd in the microsomal fraction and 94% in the mitochondrial fraction eluted with the same retention time as that of metallothionein in both liver and kidney, while the remainder was found in a high molecular weight protein fraction. The Cd eluted with the high molecular protein fraction might be involved in dysfunctions in subcellular organelles.

Animals↗
PubMed1992

Quantitative gated blood pool tomographic assessment of regional ejection fraction: definition of normal limits.

OBJECTIVE: Our aim was to select a method of analysis for gated blood pool tomography that reduced variability in a group of normal subjects, allowed comparison with normal limit files and displayed results in the bull's-eye format. BACKGROUND: Abnormalities in left ventricular function may not be accurately detected by measures of global function because hyperkinesia in normal regions may compensate for abnormal regional function. Gated blood pool tomography acquires three-dimensional data and offers advantages over other noninvasive modalities for quantitative assessment of global and regional function. METHODS: Alternative methods for selecting the ventricular axis, calculating regional ejection fraction and choosing the number of ventricular divisions were studied in 15 normal volunteers to select the combination of parameters that produced the lowest variability in quantitative regional ejection fraction. Methods for quantitative comparison of regional ejection fraction with normal limit files and for display in the bull's-eye format were also examined. RESULTS: A fixed axis (the geometric center of the ventricle defined for end-diastole and used for end-systole) gave ejection fractions that were significantly higher in the lateral wall versus in the septum, 82 +/- 8 (mean +/- 1 SD) versus 39 +/- 17 (p less than 0.001) at the midcavity and 66 +/- 11 versus 21 +/- 20 (p less than 0.001) at the base. A floating axis system (axis defined individually for end-diastole and end-systole and realigned at the center) gave more uniform regional ejection fraction: 63 +/- 6 versus 64 +/- 8 (p = NS) at the midcavity and 44 +/- 16 versus 45 +/- 15 (p = NS) at the base. The coefficient of variability for regional ejection fraction was consistently lower using a floating axis. Calculating regional ejection fraction by dividing the regional stroke volume by the end-diastolic volume of the region gave a lower coefficient of variability and a more easily understood value than dividing the regional stroke volume by the total end-diastolic volume of the ventricle. Although the variability was lower using five versus nine ventricular divisions, nine regions offer greater spatial resolution. Comparison of regional ejection fraction with normal data identified regions greater than 2.5 SD below the mean as abnormal. We described the two-dimensional bull's-eye format as a method for displaying the regional three-dimensional data and illustrated abnormalities in patients with prior myocardial infarction. CONCLUSIONS: Gated blood pool tomography performed using a floating axis system, regional stroke volume calculation of ejection fraction and nine regions uses all the three-dimensional blood pool data to calculate regional ejection fraction, allow quantitative comparison with normal limit files, display the functional data in the two-dimensional bull's-eye format and demonstrate abnormalities in patients with myocardial infarction.

Adult↗
PubMed2005

Using micellar mole fractions to assess membrane protein stability in mixed micelles.

The increased focus on the structural and physical properties of membrane proteins has made it critical to develop methods that provide a reliable estimate of membrane protein stability. A simple approach is to monitor the protein's conformational changes in mixed detergent systems, typically consisting of an anionic (denaturing) and non-ionic (non-denaturing) component. Linear correlations between, e.g., the melting temperature and the bulk mole fraction of the anionic component have been observed. However, a potential complication is that the bulk mole fraction is not identical to the mole fraction in the mixed micelle, which is the local environment experienced by the membrane protein. Here, we present an extensive analysis of the thermal stability of the membrane-integrated domain of the outer membrane protein AIDA in the presence of different mixed micelles. In the micelle system SDS-octyl-polyoxyethylene, the melting temperature in the absence of SDS extrapolates to 113 degrees C using bulk mole fractions. However, for mixed micelles involving short-chain detergents or phospholipids, the melting temperature calculated using bulk mole fractions reaches values up to several hundred degrees higher than 113 degrees C and can only be obtained by extrapolation over a narrow mole fraction interval. Furthermore, there is a non-linear relationship between the melting temperature and bulk mole fractions for mixed micelle systems involving cationic detergents (also denaturing). We show that if we instead use the micellar mole fraction as a parameter for denaturing detergent strength, we obtain linear correlations which extrapolate to more or less the same value of the melting temperature. There remains some scatter in the extrapolated values of the melting temperature in different binary systems, which suggest that additional micellar interactions may play a role. Nevertheless, in general terms, the mixed micellar composition is a good parameter to describe the membrane protein's microenvironment. Note, however, that for the mixed micelle system involving SDS and dodecyl maltoside, which has been used by several research groups to determine membrane protein stability, the estimate provided by bulk mole fraction leads to similar values as that of micellar mole fractions.

Adhesins, Escherichia coli↗
PubMed2004

The effects of wind speed on the relative relationships between different sized-fractions of airborne particles.

The concentrations of three different size fractions of particulate matter (PM) including PM2.5, PM10, and TSP were determined continuously at hourly intervals from four different sites in Seoul, Korea during the spring of 2001. To learn the effects of wind speed change on PM fractionation, the entire data sets were initially sorted into three particle fractions such as: fine (F: PM2.5), coarse (C: PM10-PM2.5), and giant (G: TSP-PM10). The inter-fraction relationships of PM were then explored by linear regression analysis of the data divided into four wind speed regimes. The results of this analysis, when examined in terms of either relative dominance between different PM fractions (i.e., in terms of their slope values) or strength of correlations, indicate the existence of diverse inter-fraction patterns. Most importantly, the physical influence of wind speed is seen to be reflected most efficiently between fine and coarse particle fractions, as the relative contribution of coarse fraction to the mass concentration of total particles (e.g., PM10) changes proportionally with changes in wind speed. However, such systematic patterns decrease noticeably between fine and giant fractions, as they can be affected more sensitively by such factors as the nature of their sources or the surrounding environmental conditions. The results of our comparative analysis thus confirm that wind speed is a useful barometer to distinguish and predict the behavior of different particle fractions in relation to each other.

Air Pollutants↗
PubMed1999

Accuracy of cancellous bone volume fraction measured by micro-CT scanning.

Volume fraction, the single most important parameter in describing trabecular microstructure, can easily be calculated from three-dimensional reconstructions of micro-CT images. This study sought to quantify the accuracy of this measurement. One hundred and sixty human cancellous bone specimens which covered a large range of volume fraction (9.8-39.8%) were produced. The specimens were micro-CT scanned, and the volume fraction based on Archimedes' principle was determined as a reference. After scanning, all micro-CT data were segmented using individual thresholds determined by the scanner supplied algorithm (method I). A significant deviation of volume fraction from method I was found: both the y-intercept and the slope of the regression line were significantly different from those of the Archimedes-based volume fraction (p < 0.001). New individual thresholds were determined based on a calibration of volume fraction to the Archimedes-based volume fractions (method II). The mean thresholds of the two methods were applied to segment 20 randomly selected specimens. The results showed that volume fraction using the mean threshold of method I was underestimated by 4% (p = 0.001), whereas the mean threshold of method II yielded accurate values. The precision of the measurement was excellent. Our data show that care must be taken when applying thresholds in generating 3-D data, and that a fixed threshold may be used to obtain reliable volume fraction data. This fixed threshold may be determined from the Archimedes-based volume fraction of a subgroup of specimens. The threshold may vary between different materials, and so it should be determined whenever a study series is performed.

Adolescent↗
PubMed1984

Use of TSK-SW columns for the high-performance liquid chromatographic analysis of proteins, isolated from sympathetic nerves and fractionated by fractogel TSK-HW chromatography. Purification of L-DOPA decarboxylase.

The soluble proteins isolated from sympathetic nerves were separated on Fractogel TSK-HW columns. With a mobile phase of 0.1 M phosphate + 0.1 M K2SO4, pH 6.8, the main fractions I-VI were obtained. These fractions were analysed by high-performance (HPLC) on TSK-SW columns. Fractogel fractions I-III showed peaks of molecular weights, Mr670,000, as estimated by HPLC. With sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) these fractions show no bands stainable with Coomassie Blue. The protein of fraction IV was L-DOPA decarboxylase (AADC E.C. 4.1.1.28) with Mr 150,000 existing of subunits with Mr 55,000, 45,000, 27,000 and purified according to Christenson et al. (Arch. Biochem. Biophys., 141 (1970) 356). The dopamine-beta-hydroxylase (E.C. 1.14.2.1) subunits with Mr 75,000 proteins were detected in Fractogel fraction V. Fraction VI was Mr 27,000 protein. Proteins with molecular weights Mr less than 5,000 were also detected. With Phenothiazine-Affigel the proteins of fraction V (mr 75,000) showed no affinity to the phenothiazine column equilibrated with application buffer containing Ca2+ X 50-70% fraction IV (Mr 150,000), eluted with Tris-EGTA buffer, and 100% fraction VI (Mr 27,000) showed affinity to the Phenothiazine-Affigel column.

Aromatic-L-Amino-Acid Decarboxylases↗
PubMed1979

Uptake and metabolism of female sex steroids by isolated small neurons and other cell fractions from the rat medial basal hypothalamus.

Rat medial basal hypothalami (MBH) and sections of cerebral cortex (CC) were dissociated with trypsin to prepare single cells and subcellular fractions. They were then separated into four fractions on a discontinuous sucrose gradient. The small neurons in Fraction D were highly purified. Fraction A had synaptosomes, myelin and other cell particulates. Fraction B had glial cells, neurons and a few synaptosomes. Fraction C had large neurons and red blood cells. All four fractions contained LHRH, but most (62.5%) of this hormone was present in Fraction A. Dissociated cell suspensions were incubated with [3H]-steroids, with and without a 100-fold excess of unlabeled steroids, then separated on sucrose gradients. In most fractions the total uptake and specific uptake of [3H]-progesterone, [3H]-5 alpha-pregnane-3,20-dione (5 alpha-dihydroprogesterone) and [3H]-17 beta-estradiol were greater for the dissociated cells from the MBH than the CC. The dissociated cells and cell particulates in all four fractions from the MBH and CC metabolized progesterone, 5 alpha-dihydroprogesterone and 17 beta-estradiol. These results indicate that hypothalamic neurons contain small amounts of LHRH and retain the ability to take up and metabolize progesterone, 5 alpha-dihydroprogesterone and 17 beta-estradiol.

20-alpha-Dihydroprogesterone↗
PubMed1997

An antiangiogenic agent (TNP-470) inhibited reoxygenation during fractionated radiotherapy of murine mammary carcinoma.

PURPOSE: TNP-470, a synthetic analogue of fumagillin which is a natural product of Aspergillus fumigatus, has been noted as an angiogenesis inhibitor. Combined effects of TNP-470 with fractionated radiotherapy (RT) were investigated using a mouse tumor. METHODS AND MATERIALS: Tumors were early generations of mammary carcinoma in C3H/He mice. Treatments were initiated when tumors reached an average diameter of 4-5 mm. Tumor response was evaluated by tumor growth (TG) time assay and 50% tumor control dose (TCD50) assay. Tumors were irradiated locally under hypoxic conditions or in air. Five fractionated radiation doses were given in the TG time assay, whereas a single dose or 10 fractionated doses were given in the TCD50 assay. TNP-470 (100 mg/kg) was administered subcutaneously twice a week during and/or after RT. RESULTS: In the TG time assay, significant delay of tumor growth was observed by TNP-470 alone (100 mg/kg x 2) compared with control tumors (p < 0.001), indicating that TNP-470 alone has an antitumor effect in vivo. When TNP-470 was administered during fractionated RT, no additional delay of tumor growth was observed. However, additive effects of TNP-470 was noted when it was given after the end of fractionated RT. In the TCD50 assay, no significant difference in TCD50s was observed between RT alone and RT combined with TNP-470 in single dose experiments. Hypoxic fraction of tumors calculated from the TCD50s was not affected significantly by administrating TNP-470 24 h before RT. On the other hand, in 10-fraction experiments, the TCD50 (RT with TNP-470, in air) was significantly higher than the TCD50 (RT alone, in air) (p < 0.005), indicating that TNP-470 given during fractionated RT decreased radiocurability. This negative effect of TNP-470 was not observed when TNP-470 was combined with fractionated RT given under hypoxic conditions. CONCLUSION: The tumor control probability decreased by administrating TNP-470 during fractionated RT in air. This unexpected result may be attributable to partial inhibition of reoxygenation by TNP-470, because no significant difference was noted between the TCD50 (RT with TNP-470) and the TCD50 (RT alone) under hypoxic conditions.

Animals↗
PubMed1998

Induction of sister chromatid exchanges (SCE) in human tracheal epithelial cells by the fractions PM-10 and PM-2.5 of airborne particulates.

Recent epidemiological studies in the United States and in Europe indicate, that the coarse fraction (PM-10) of airborne particulates, smaller than 10 microm and particularly the fine fraction (PM-2.5) smaller than 2.5 microm are responsible for adverse health effects, causing an increasing morbidity and mortality. Furthermore, an association was reported between air pollution, especially the levels of the fine respirable particles and death from lung cancer. The epithelium of the respiratory tract is the major target of airborne particulates and the location of the most common cancer in man, bronchogenic carcinoma. The genotoxic activity of the coarse (PM-10) and the fine fraction (PM-2.5) of airborne particulates leading to mutation and cancer can be analyzed using in vitro models of human bronchoepithelial cells. In our study collection of the coarse (PM-10) and the fine fraction (PM-2.5) of airborne particulates was conducted in the winter of 1996 in the highly industrialized Rhine-Ruhr region (Germany). For collection we selected an urban area (Düsseldorf), an industrialized area Duisburg and a rural area (Borken). Airborne particulates were collected with a Low Volume M-10 dichotomous sampler (Graseby-Andersen) equipped with glass fiber filters. Chemical substances were extracted from filters with di-chloromethane and quantitatively transferred to dimethylsulfoxide (DMSO). As target cells for testing the genotoxic activity we used cultures of the human bronchioepithelial cell line (BEAS-2B). As a sensitive cytogenetic endpoint for evaluation of the genotoxic activity of extracts of airborne particulates we utilized the induction of 'sister chromatid exchanges' (SCE). The coarse fraction PM-10 and especially the fine fraction PM-2.5 of airborne particulates from all three locations caused a strong dose-related induction of 'sister chromatid exchanges'. The fine fractions PM-2.5 from the three locations exerted a stronger genotoxic activity than the corresponding coarse fractions PM-10. While airborne particulates from Düsseldorf and Duisburg revealed a comparable genotoxic activity, the samples from Borken disclosed a lower genotoxicity. It is important that especially the fine fraction PM-2.5, exerted a strong genotoxicity equivalent to substances of airborne particulates from less than 0.5 m3 of air. Results of this study and earlier reports demonstrate that the human tracheobronchial epithelial cell line (BEAS-2B) in vitro offer a reliable and sensitive in vitro model for genotoxicity testing of airborne particulates, especially of the coarse (PM-10) and fine fraction (PM-2.5).

Air Pollutants↗
PubMed2003

Antioxidant supplementation in vitro improves boar sperm motility and mitochondrial membrane potential after cryopreservation of different fractions of the ejaculate.

Antioxidant supplementation during cooling was assayed to improve the motility of frozen-thawed (FT) boar spermatozoa from two different fractions of the ejaculate, the first component of the sperm-rich fraction (Fraction I) and the rest of the bulk ejaculate (Fraction II). Using a split-sample design, addition of two different concentrations (100 and 200 microMl(-1)) of the water-soluble Vitamin E analogue Trolox (6-hydroxy -2,5,7,8-tetramethylchroman -2-carboxylic acid) was evaluated for an effect on sperm motility (measured both subjectively and by means of a computer assisted motility assessment (CASA)), and on mitochondrial membrane potential using flow cytometry after cell-loading with JC-1. The effect of the Vitamin E analogue was clearly dose-dependent and varied with the fraction of the ejaculate considered. Motility was significantly higher in Trolox-treated spermatozoa (200 microm), from either ejaculate fraction, albeit the effect was more evident in spermatozoa from Fraction II (P<0.05) for any Trolox-concentration. Antioxidant supplementation resulted, also dose-dependent, in a higher number of spermatozoa showing high mitochondrial activity as assessed by the JC-1 staining, in both ejaculate fractions. In the present trial, exogenous Trolox positively affected post-thaw sperm viability (as motility and mitochondrial membrane potential) in both fractions of the ejaculate. The magnitude of the effect appeared, however, to be dependent of the fraction of the ejaculate considered.

Animals↗