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N Albright

Publications and source records attributed to N Albright.

13 recordsLinked to original sources
PubMed2001

Description and dosimetric verification of the PEREGRINE Monte Carlo dose calculation system for photon beams incident on a water phantom.

PEREGRINE is a three-dimensional Monte Carlo dose calculation system written specifically for radiotherapy. This paper describes the implementation and overall dosimetric accuracy of PEREGRINE physics algorithms, beam model, and beam commissioning procedure. Particle-interaction data, tracking geometries, scoring, variance reduction, and statistical analysis are described. The BEAM code system is used to model the treatment-independent accelerator head, resulting in the identification of primary and scattered photon sources and an electron contaminant source. The magnitude of the electron source is increased to improve agreement with measurements in the buildup region in the largest fields. Published measurements provide an estimate of backscatter on monitor chamber response. Commissioning consists of selecting the electron beam energy, determining the scale factor that defines dose per monitor unit, and describing treatment-dependent beam modifiers. We compare calculations with measurements in a water phantom for open fields, wedges, blocks, and a multileaf collimator for 6 and 18 MV Varian Clinac 2100C photon beams. All calculations are reported as dose per monitor unit. Aside from backscatter estimates, no additional, field-specific normalization is included in comparisons with measurements. Maximum discrepancies were less than either 2% of the maximum dose or 1.2 mm in isodose position for all field sizes and beam modifiers.

Algorithms↗
PubMed2000

Computerized video time-lapse analysis of apoptosis of REC:Myc cells X-irradiated in different phases of the cell cycle.

Asynchronous rat embryo cells expressing Myc were followed in 50 fields by computerized video time lapse (CVTL) for three to four cycles before irradiation (4 Gy) and then for 6-7 days thereafter. Pedigrees were constructed for single cells that had been irradiated in different parts of the cycle, i.e. at different times after they were born. Over 95% of the cell death occurred by postmitotic apoptosis after the cells and their progeny had divided from one to six times. The duration of the process of apoptosis once it was initiated was independent of the phase in which the cell was irradiated. Cell death was defined as cessation of movement, typically 20-60 min after the cell rounded with membrane blebbing, but membrane rupture did not occur until 5 to 40 h later. The times to apoptosis and the number of divisions after irradiation were less for cells irradiated late in the cycle. Cells irradiated in G(1) phase divided one to six times and survived 40-120 h before undergoing apoptosis compared to only one to two times and 5-40 h for cells irradiated in G(2) phase. The only cells that died without dividing after irradiation were irradiated in mid to late S phase. Essentially the same results were observed for a dose of 9.5 Gy, although the progeny died sooner and after fewer divisions than after 4 Gy. Regardless of the phase in which they were irradiated, the cells underwent apoptosis from 2 to 150 h after their last division. Therefore, the postmitotic apoptosis did not occur in a predictable or programmed manner, although apoptosis was associated with lengthening of both the generation time and the duration of mitosis immediately prior to the death of the daughter cells. After the non-clonogenic cells divided and yielded progeny entering the first generation after irradiation with 4 Gy, 60% of the progeny either had micronuclei or were sisters of cells that had micronuclei, compared to none of the progeny of clonogenic cells having micronuclei in generation 1. However, another 20% of the non-clonogenic cells had progeny with micronuclei appearing first in generation 2 or 3. As a result, 80% of the non-clonogenic cells had progeny with micronuclei. Furthermore, cells with micronuclei were more likely to die during the generation in which the micronuclei were observed than cells not having micronuclei. Also, micronuclei were occasionally observed in the progeny from clonogenic cells in later generations at about the same time that lethal sectoring was observed. Thus cell death was associated with formation of micronuclei. Most importantly, cells irradiated in late S or G(2) phase were more radiosensitive than cells irradiated in G(1) phase for both loss of clonogenic survival and the time of death and number of divisions completed after irradiation. Finally, the cumulative percentage of apoptosis scored in whole populations of asynchronous or synchronous populations, without distinguishing between the progeny of individually irradiated cells, underestimates the true amount of apoptosis that occurs in cells that undergo postmitotic apoptosis after irradiation. Scoring cell death in whole populations of cells gives erroneous results since both clonogenic and non-clonogenic cells are dividing as non-clonogenic cells are undergoing apoptosis over a period of many days.

Animals↗
PubMed1999

Five year results of LINAC radiosurgery for arteriovenous malformations: outcome for large AVMS.

PURPOSE: For radiosurgery of large arteriovenous malformations (AVMs), the optimal relationship of dose and volume to obliteration, complications, and hemorrhage is not well defined. Multivariate analysis was performed to assess the relationship of multiple AVM and treatment factors to the outcome of AVMs significantly larger than previously reported in the literature. METHODS AND MATERIALS: 73 patients with intracranial AVMs underwent LINAC radiosurgery. Over 50% of the AVMs were larger than 3 cm in diameter and the median and mean treatment volumes were 8.4 cc and 15.3 cc, respectively (range 0.4-143.4 cc). Minimum AVM treatment doses varied between 1000-2200 cGy (median: 1600 cGy). RESULTS: The obliteration rates for treatment volumes < 4 cc, 4-13.9 cc, and > or = 14 cc were 67%, 58%, and 23%, respectively. AVM obliteration was significantly associated with higher minimum treatment dose and negatively associated with a history of prior embolization with particulate materials. No AVM receiving < 1400 cGy was obliterated. The incidence of post-radiosurgical imaging abnormalities and clinical complications rose with increasing treatment volume. For treatment volumes > 14 cc receiving > or = 1600 cGy, the incidence of post-radiosurgical MRI T2 abnormalities was 72% and the incidence of radiation necrosis requiring resection was 22%. The rate of post-radiosurgical hemorrhage was 2.7% per person-year for AVMs with treatment volumes < 14 cc and 7.5% per person-year for AVMs > or = 14 cc. CONCLUSION: As AVM size increases, the dose-volume range for the optimal balance between successful obliteration and the risk of complications and post-radiosurgical hemorrhage narrows.

Adolescent↗
PubMed1999

Using computerized video time lapse for quantifying cell death of X-irradiated rat embryo cells transfected with c-myc or c-Ha-ras.

Rat embryo fibroblasts that had been transfected with the c-myc or c-Ha-ras oncogene were X-irradiated, after which individual cells and their progeny were followed in multiple fields for 5-6 days by computerized video time lapse microscopy to quantify the lethal events that resulted in loss of clonogenic survival. The loss of clonogenic survival of X-irradiated (9.5 or 2.5 Gy) REC:myc cells was attributed almost entirely to the cells dying by apoptosis, with almost all of the apoptosis occurring after the progeny had divided from one to four times. In contrast, the loss of clonogenic survival of X-irradiated REC:ras cells was attributed to two processes. After 9.5 Gy, approximately approximately 60% of the nonclonogenic cells died by apoptosis (with a very small amount of necrosis), and the other 40% underwent a senescent-type process in which some of the cells and their progeny stopped dividing but remained as viable cells throughout 140 h of observation. Both processes usually occurred after the cells had divided and continued to occur in the cells' progeny for up to five divisions after irradiation. Furthermore, the duration of the apoptotic process was shorter for REC:myc cells (0.5-1 h) than for REC:ras cells (4-5 h). By using computerized video time lapse to follow individual cells, we were able to determine the mode of cell death. This cannot be determined by conventional clonogenic survival experiments. Also, only by following the individual cells and their progeny can the true amount of apoptosis be determined. The cumulative percentage of apoptosis scored in whole populations, without distinguishing between the progeny of individually irradiated cells, does not reflect the true amount of apoptosis that occurs in cells that undergo postmitotic apoptosis after irradiation. Scoring cell death in whole populations of cells gives erroneous results because both clonogenic and nonclonogenic cells are dividing as nonclonogenic cells are apoptosing or senescing over a period of many days. For example, after 9.5 Gy, which causes reproductive cell death in 99% of both types of cells, the cumulative percentage of the cells scored as dead in the whole population at 60- 80 h after irradiation, when the maximum amount of cumulative apoptosis occurred, was approximately 60% for REC:myc cells, compared with only approximately 40% for REC:ras cells.

Animals↗
PubMed1997

Pulsed-field gel electrophoretic migration of DNA broken by X irradiation during DNA synthesis: experimental results compared with Monte Carlo calculations.

Synchronous CHO cells were X-irradiated in G1 or mid-S phase with 30-750 Gy, and then the size distribution of DNA molecules resulting from DNA double-strand breaks (DSBs) was studied by pulsed-field gel electrophoresis (PFGE). Cells irradiated in S phase also were pulse-labeled with [3H]dThd for 15 min to compare the migration patterns of replicating DNA with those of DNA mass, measured by imaging with a CCD camera. When cells were irradiated immediately after pulse labeling, a large amount of the 3H-labeled replicating DNA was trapped in the plug, i.e. > 90% for doses < 100 Gy. As the dose increased, the percentage trapped decreased, i.e. to approximately 50% for 750 Gy. The same results were observed for DNA mass when cells were irradiated in S phase, except that much less of the DNA was trapped, i.e. approximately 60% for 70-100 Gy, which produced approximately 2-Mbp molecules, compared to approximately 10% for 750 Gy, which produced approximately 0.3-Mbp molecules. These results and the migration patterns of DNA released into the lane indicated that large molecules are trapped more readily than small molecules because they contain more replicating regions (bands with bubbles) of DNA than small molecules. Our interpretation is that as the dose increases, a greater fraction of the breaks occur between the replicating bands, thus releasing linear molecules that are not replicating. The relatively small amount of 3H-labeled replicating DNA that is released from the PFGE plug migrates aberrantly, with a small amount migrating like linear G1-phase molecules and a large amount, depending on dose, migrating much more slowly than the DNA mass from cells irradiated in G1 or S phase. To explain these results, a Monte Carlo computer program was written to introduce DSBs randomly into DNA that is configured according to a model of DNA replication that is developed in a related study (Dewey and Albright, Radiat. Res. 148, 421-434, 1997). In relating the experimental observations to the results of the Monte Carlo calculations, we assumed that (a) molecules containing replication bubbles with and without forks are trapped in the PFGE plug, (b) linear molecules and molecules with replication forks only that are < or = 8 Mbp are released into the lane, and (c) molecules having replication forks migrate more slowly than linear molecules.

Animals↗
PubMed1997

Developing a model of DNA replication to be used for Monte Carlo calculations that predict the sizes and shapes of molecules resulting from DNA double-strand breaks induced by X irradiation during DNA synthesis.

A Monte Carlo computer program was written to introduce double-strand breaks (DSBs) randomly into cellular DNA that is configured according to different models of DNA replication. Then, from a review of the literature using DNA fiber autoradiography and other studies relating to rates of replication of DNA that is organized in approximately 3-Mbp regions or bands, a particular model for DNA replication was developed. Using this model, Monte Carlo calculations were made to predict the types and sizes of molecules that would result from introducing DSBs into DNA when synchronous cells are irradiated in the middle of S phase. Then results of the Monte Carlo calculations were compared with migration profiles obtained by pulsed-field gel electrophoresis (PFGE) for molecular size distributions of linear DNA molecules. For these comparisons, CHO cells irradiated in S phase also were pulse-labeled at the time of irradiation with [3H]dThd for 15 min to compare the migration patterns of 3H-labeled replicating DNA with those of the mass of S-phase DNA, measured by imaging with a CCD camera. For the Monte Carlo calculations, we assumed from the reports in the literature that molecules containing replication bubbles with and without forks would be trapped in the PFGE plug. We also assumed that those molecules that are < or = 8 Mbp, both linear and with replication forks, would be released into the lane. However, approximately 75% of the 3H-labeled DNA that is released from the plug migrated much more slowly than linear molecules, which we attributed to the slow migration of 3H-labeled molecules having replication forks not attached to bubbles. The percentages of both mass of S-phase DNA and 3H-labeled replicating DNA released from the plug, as determined by PFGE, were compared with comparable values determined from Monte Carlo calculations. A DNA replication model that provides good agreement between the PFGE results and Monte Carlo calculations is described. Furthermore, Monte Carlo methodology is presented that can be used for comparing data obtained with PFGE with results of Monte Carlo calculations that are based on different models of DNA replication and different assumptions for the migration of various types of replicating molecules.

Animals↗
PubMed1995

Methods for the quantification of DNA double-strand breaks determined from the distribution of DNA fragment sizes measured by pulsed-field gel electrophoresis.

Different methods were used for evaluating data for DNA double-strand breaks (DSBs), as obtained by pulsed-field gel electrophoresis (PFGE) after X irradiation of Chinese hamster ovary cells. A total of 60 data points in the dose range of 0 to 116 Gy, along with repair data for 30 and 60 Gy, were analyzed by four methods: (1) percentage of DNA released from the plug, (2) specific size markers (percentage of DNA less than specific sizes, (3) fragment size distributions and (4) shape of the molecular weight (M) distributions. With the last method, both the slope and the intercept of the logarithm of the amount of radioactive DNA/delta M/M plotted as a function of M were used for calculating DSBs/100 Mbp. The slope and the intercept analyses differ in that the former is relatively independent of DNA trapped in the agarose plugs, i.e. cannot be released by doses of 100-150 Gy, whereas the intercept is dependent on the percentage of DNA trapped. Also, calculations of DSBs/100 Mbp for methods 1, 2 and 3 depend on the amount of DNA trapped in the plug. However, the slope method is unreliable for doses below about 20 Gy, and the scatter of data points is much greater than that obtained by the intercept method and by methods 1, 2 and 3. Therefore, the fragment size distribution and the specific size marker methods give the most consistent results, with 0.49 +/- 0.03 (95% CI) (DSBs/100 Mbp)/Gy. With the specific size marker method, however, care must be taken in selection of size markers in relation to the levels of DSBs of interest. Assuming randomly distributed DSBs, all four methods gave essentially the same results; i.e., the dose response was linear with a calculated level of 0.5-0.6 (DSBs/100 Mbp)/Gy, which is the same as 0.47-0.62 determined previously by calibrating with 125IdU.

Animals↗
PubMed1994

Hyperthermia can reduce cytotoxicity from etoposide without a corresponding reduction in the number of topoisomerase II-DNA cleavable complexes.

The chemotherapeutic drug etoposide (VP-16) causes the equilibrium reaction between noncleavable and cleavable topoisomerase II-DNA complexes to shift in favor of the cleavabel complex [H. Zang, P. D'Arpa, and L.F. Liu, Cancer Cells (Cold Spring Harbor), 2:23-27, 1990]. Pulsed-field gel electrophoresis was used to study induction and removal of cleavable complexes in cells heated before, during, or after VP-16 treatment. Pulsed-field gel electrophoresis results were evaluated both as the fraction of activity (DNA) released from the plug and as the number of double-strand breaks (DSBs) calculated from molecular weight distributions; both end points led to the same conclusions. When cells were heated at 42 degrees C during treatment with VP-16 (12 micrograms/ml up to 60 min), a slight decrease in cleavable complexes (from 30 to 20 DSBs/100 megabase pairs) was detected immediately after treatment when compared with cells treated with the drug at 37 degree C. Furthermore, heating at 42 degrees C caused a slight decrease in drug cytotoxicity as measured by less than a 2-fold increase in clonogenic survival. When cells were heated for 10 min at 45.5 degrees C prior to or after treatment with the drug, there was a reduction (approximately 50%) immediately after treatment in the number of DSBs/100 megabase pairs compared with unheated cells. The rate of removal of cleavable complexes was decreased slightly by heat. After 120 min at 37 degrees C, the number of DSB/100 megabase pairs decreased to approximately 6 for both unheated cells and those heated prior to drug treatment and to approximately 8 for cells heated after drug treatment. In agreement with a low effect of heat on the number of cleavable complexes after drug treatment, there was no significant effect of this heating protocol on drug cytotoxicity. However, heating at 45.5 degrees C prior to drug treatment at 37 degrees C protected cells from drug cytotoxicity (e.g., increased survival after 12 micrograms/ml for 60 min by approximately 100-fold) despite the similarity in the induction and rate of removal of cleavable complexes when compared with nonheated cells. Thus, when cells are heated prior to administration of VP-16, drug cytotoxicity does not correlate with the number of cleavable complexes measured either immediately after treatment or 180 min later when approximately 75% of the initial number have been removed. Finally, since hyperthermia can actually decrease drug cytotoxicity, the use of hyperthermia as an adjuvant to chemotherapy involving topoisomerase II poisons, such as VP-16, should be approached with caution.

Animals↗
PubMed1994

Applicability of standard irregular field calculations for high-energy photon beams.

Irregular-field calculations are usually based on a sector-summation technique. This technique typically involves separating the dose into primary and scatter components. While the conceptual basis for this procedure is valid at lower energies, it becomes suspect at higher energies. However, despite this limitation, a straightforward application of the technique yields good accuracy for 18 MV X-rays if certain limitations are observed. This work describes the calculational formalism used and the approximations made. Computed results are compared with measurements. The levels of uncertainty in both are discussed.

Humans↗
PubMed1989

Modification of SR 2508 sensitization in hypoxic V79 cells by manipulation of glutathione levels.

This series of experiments employed the hypoxic cell sensitizer SR 2508 in concentrations ranging from 0.1 to 10 mM and V-79 cells irradiated in air or made hypoxic in glass syringes, then irradiated with 15 MV X rays. Using a series of survival curves measured at the various concentrations, K curves relating sensitizer enhancement ratio (SER) to SR 2508 concentration were calculated with normal GSH levels or with depletion of GSH to 0% using 1 mM buthionine sulfoximine (BSO) or elevation to 200% of normal using 1 mM oxothiazolidine carboxylate (OTZ). Survival curves were fitted by computer, allowing calculation of standard errors for the SER values. The depletion of GSH by BSO sensitized hypoxic and aerated cells significantly and caused more than additive enhancement of SR 2508 sensitization in hypoxic cells. Elevation of GSH with OTZ protects cells irradiated in air or hypoxia and reduces the SER obtained with SR 2508. The results further support the importance of GSH levels in influencing sensitization by nitroimidazoles.

Animals↗
PubMed1989

A Markov formulation of the repair-misrepair model of cell survival.

Tobias' repair-misrepair (RMR) model of cell survival is formulated as a Markov process, a sequence of discrete repair steps occurring at random times, and the probability of a sequence of viable repairs is calculated. The Markov formulation describes the time evolution of the probability distribution for the number of lesions in a cell. The probability of cell survival is calculated from the distribution of the initial number of lesions and the probabilities of the repair events. The production of lesions is formulated in accordance with the principles of microdosimetry, and the distribution of the initial number of lesions is obtained as an approximation for high and low linear energy transfer cases. The Markov formulation of the RMR model uses the same biological hypotheses as the original version with two statistical approximations deleted. These approximations are the neglect of the effect of statistical fluctuations in calculating the average rate of repair of lesions and the assumption that the final number of unrepaired and lethally misrepaired lesions has a Poisson distribution. The quantitative effect of these approximations is calculated, and a basis is provided for an alternative approach to calculating survival probabilities.

Cell Survival↗
PubMed1987

Computer programs for the analysis of cellular survival data.

Four programs have been written to enable radiobiologists to build a computer data base of cellular dose-survival data, calculate cell survival with a correction for cell multiplicity at the time of irradiation, fit various survival models to the data by iteratively weighted least squares, and calculate the ratio of survival levels corresponding to specified doses or the ratio of doses that produce specified survival levels (e.g., oxygen enhancement ratio or relative biological effectiveness). The programs make plots of survival curves and data, and they calculate standard errors and confidence intervals of the fitted survival curve parameters and ratios. The programs calculate survival curves for the linear-quadratic, repair-saturation, single-hit multitarget, linear-multitarget, and repair-misrepair models of cell survival and have been designed to accommodate the addition of other survival models in the future. The programs can be used to compare the accuracy with which different models fit the data, determine if a difference in fit is statistically significant, and show how the estimated value of a survival curve parameter, such as the extrapolation number or the final slope, varies with the survival model. The repair of radiation-induced damage is analyzed in a novel way using these programs.

Cell Survival↗