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Biomedical subjects

D J Brenner

Publications and source records attributed to D J Brenner.

At least 127 records · Page 7Linked to original sources
PubMed1994

Postoperative irradiation for pterygium: guidelines for optimal treatment.

PURPOSE: Postoperative adjuvant strontium-90 beta-ray therapy is a proven technique for reducing the recurrence rate of pterygium. A wide variety of doses and fractionation schemes have been used in the application of the radiation. There have been recent reports of significant rates of late-occurring complications after single-fractioned treatment. Compared with a single-dose application, fractionation would only offer a therapeutic benefit if recurrence prevention were an early-responding tissue phenomenon, in contrast to late-responding sequellae. We investigate this point with a view to elucidating better treatment protocols for postoperative beta-ray therapy for pterygium. METHODS AND MATERIALS: We use the linear-quadratic formalism to analyze published nonrecurrence rates, as a function of dose and fraction number, to obtain a value for the parameter alpha/beta, which is an indicator of whether nonrecurrence is an early or late-responding phenomenon. RESULTS: The estimated value of the linear-quadratic parameter, alpha/beta, is 25 Gy, with 90% confidence limits of +/- 9 Gy. This large value unequivocally suggests that nonrecurrence is an early responding phenomenon, implying that fractionation should give an increased therapeutic ratio between nonrecurrence and late sequellae. CONCLUSIONS: Compared with a single-fractioned treatment, an improved therapeutic ratio (nonrecurrence vs. complications) would be expected from fractionated application of the beta-ray therapy. Given the parameters obtained from fitting literature data, we calculate guidelines for the dose/fraction schemes that should give equivalent disease control to different single-fraction applications, but should reduce the incidence of late-occurring sequellae.

Combined Modality Therapy↗
PubMed1994

Optimizing the time course of brachytherapy and other accelerated radiotherapeutic protocols.

PURPOSE: It is likely that early-responding tissues, such as tumors, repair sublethal damage more rapidly than do late-responding tissues. This difference can be exploited to design protocols with a significantly improved therapeutic advantage for accelerated radiotherapeutic regimens, including brachytherapy. METHODS AND MATERIALS: The time course of potential protocols is computer optimized, maximizing the therapeutic difference between tumor-control probability (TCP), and normal-tissue complication probability (NTCP). These quantities are evaluated with the linear-quadratic model, using clinically derived parameters. The optimization is performed by individually adjusting doses in different parts of the treatment, maximizing the therapeutic advantage. In the main calculations, half times for damage repair were T1/2(late) = 4 h, T1/2(early) = 0.5 h. Two component (fast/slow) repair processes were also investigated. RESULTS: Protocols determined by optimization have significantly greater therapeutic advantage than continuous low-dose rate (CLDR) protocols of the same overall dose and time. The optimized protocols are either (a) acute-dose/gap/CLDR/gap/acute-dose; or (b) a series of acute doses separated by 3-4 h. As a typical example, results are given for 60 Gy/120 h CLDR brachytherapy, which is assumed to give NTCP = 0.2 and TCP = 0.8. Under our assumptions, optimized regimes, with the same overall time and dose, produce an NTCP of approximately 0.11 and TCP of approximately 0.83, a significant therapeutic gain over CLDR. CONCLUSION: Difference in repair rates between early- and late-responding tissues can be exploited to produce clinically practical protocols that are significantly superior to current regimens. Such optimized protocols produce slightly better tumor control than CLDR with the same overall dose and time, significantly less late damage, and similar early normal-tissue sequellae. Temporal optimization, thus, promises to be a powerful tool in designing better treatment protocols.

Animals↗
PubMed1994

Track structure, chromosome geometry and chromosome aberrations.

The joint role of radiation track structure and chromosome geometry in determining yields of chromosome aberrations is discussed. Ideally, the geometric models of chromosomes used for analyzing aberration yields should have the same degree of realism as track structure models. However, observed chromosome aberrations are produced by processes on comparatively large scales, e.g., misrepair involving two DSB located on different chromosomes or two DSB separated by millions of base pairs on one chromosome, and quantitative models for chromatin on such large scales have to date almost never been attempted. We survey some recent data on large-scale chromosome geometry, mainly results obtained with fluorescence in situ hybridization ("chromosome painting") techniques. Using two chromosome models suggested by the data, we interpret the relative yields, at low and high LET, of inter-chromosomal aberrations compared to intra-chromosomal, inter-arm aberrations. The models consider each chromosome confined within its own "chromosome localization sphere," either as a random cloud of points in one model or as a confined Gaussian polymer in the other. In agreement with other approaches, our results indicate that at any given time during the G0/G1 part of the cell cycle a chromosome is largely confined to a sub-volume comprising less than 10% of the volume of the cell nucleus. The possible significance of the ratio of inter-chromosomal aberrations to intra-chromosomal, inter-arm aberrations as an indicator of previous exposure to high LET radiation is outlined.

Cell Cycle↗
PubMed1994

The influence of dose, dose-rate and particle fragmentation on cataract induction by energetic iron ions.

Because activities in space necessarily involve chronic exposure to a heterogeneous charged particle radiation field it is important to assess the influence of dose-rate and the possible modulating role of heavy particle fragmentation on biological systems. Using the well-studied cataract model, mice were exposed to plateau 600 MeV/amu 56Fe ions either as acute or fractionated exposures at total doses of 5 - 504 cGy. Additional groups of mice received 20, 360 and 504 cGy behind 50 mm of polyethylene, which simulates body shielding. The reference radiation consisted of 60Co gamma radiation. The animals were examined by slit lamp biomicroscopy over their three year life spans. In accordance with our previous observations with heavy particles, the cataractogenic potential of the 600 MeV/amu 56Fe ions was greater than for low-LET radiation and increased with decreasing dose relative to gamma-rays. Fractionation of a given dose of 56Fe ions did not reduce the cataractogenicity of the radiation compared to the acute regimen. Fragmentation of the beam in the polyethylene did not alter the cataractotoxicity of the ions, either when administered singly or in fractions.

Animals↗
PubMed1994

The significance of dose rate in assessing the hazards of domestic radon exposure.

Both miner-based epidemiological data and animal studies suggest that lung cancer induction from radon-progeny alpha-particle exposure depends on the exposure rate, and increases as the exposure rate decreases. This phenomenon has been interpreted to imply that radon risks per unit dose from domestic exposure (which occur at low exposure rates) will be underestimated by risk estimates derived from miner studies (which are at higher exposure rates). There is, however, another variable affecting this phenomenon, namely the absolute cumulative exposure to radon progeny. On basic biophysical grounds, it is argued that when the cumulative exposure is sufficiently low that multiple traversals of target cells are rare, the exposure rate effect disappears. This is the case for typical domestic radon exposures but not for most miner exposures; thus, although risk estimates from miner data refer to higher dose rates, based on dose rate consideration alone they may well overestimate, rather than underestimate, domestic radon risks. Although the data are limited, both miner-based epidemiological data and animal studies appear to follow the trend described here.

Air Pollution, Indoor↗
PubMed1994

"Erwinia nulandii" is a subjective synonym of Erwinia persicinus.

The organism named "Erwinia nulandii" was isolated in 1979 from bean seeds and was described in 1981, but the name was never validated. The results of biochemical tests and membrane protein profile and DNA relatedness studies indicated that this name is synonymous with Erwinia persicinus, a validly published name for a species previously isolated from, but not shown to be pathogenic for, tomatoes, bananas, and cucumbers. Pathogenicity tests revealed that all E. persicinus strains, including an "E. nulandii" strain, were pathogenic for bean pods and seeds.

DNA, Bacterial↗
PubMed1994

Human infections caused by Brevibacterium casei, formerly CDC groups B-1 and B-3.

Forty-one clinical strains of CDC coryneform groups B-1 and B-3 were compared biochemically, by analysis of cell wall sugars, amino acids, and cellular fatty acids, and by DNA relatedness to the type strains of Brevibacterium casei, Brevibacterium epidermidis, and Brevibacterium linens. Twenty-two strains were shown to be B. casei, while five other strains formed a phenotypically inseparable genomospecies in the same genus. The remaining isolates were genetically heterogeneous, and most are probably members of the genus Brevibacterium. They were not further identified, but they were biochemically distinguishable from B. casei. Eleven of the clinical strains of B. casei were isolated from blood, and two each were isolated from cerebrospinal fluid and from pleural fluid. At least five isolates were from multiple blood or cerebrospinal fluid cultures. To our knowledge, these strains are the first described clinical isolates identified as B. casei, which was previously considered to be a nonpathogenic species.

Actinomycetales Infections↗
PubMed1994

Recognition of Dermabacter hominis, formerly CDC fermentative coryneform group 3 and group 5, as a potential human pathogen.

Thirty strains of fermentative coryneform-like bacteria designated CDC fermentative coryneform group 3 and coryneform group 5 were compared biochemically by cellular fatty acid analysis and by DNA relatedness with the type strain of Dermabacter hominis, ATCC 49369. DNA from 22 strains of both CDC groups showed 69 to 96% relatedness (hydroxyapatite method) to labeled DNA from ATCC 49369 and to DNA from CDC group 3 strain G4964, and the strains are considered to belong to D. hominis. The remaining eight strains were genetically but not phenotypically differentiable from D. hominis. They were genetically heterogeneous, but hybridization results indicated that they probably belong to the genus Dermabacter. Thirteen of the 22 D. hominis strains and all 8 of the other Dermabacter strains had been isolated from blood, which indicates the pathogenic potential of this species and genus.

Actinomycetales↗
PubMed1994

Oncogenic transformation through the cell cycle and the LET dependent inverse dose rate effect.

Synchronised populations of mouse C3H/10T-1/2 cells were obtained by a stringent mitotic dislodgment procedure. Mitotic cells rapidly attach and progress sequentially through the cell cycle. Irradiation (3 Gy of X rays) was carried out at intervals from 0 to 18 h after initiating cell cycle progression of the mitotic cells. Oncogenic transformation was enhanced 10-fold over cells irradiated soon after replating (G1 and S phases) for cells in a near 2 h period corresponding to cells in G2 phase but not in mitosis. The cell surviving fraction had a 2-1/2-fold variation with resistant peaks corresponding to the late G1 and late S phases. These findings provide experimental support for the hypothesis initiated by Rossi and Kellerer and developed by Brenner and Hall to explain the LET dependent inverse dose rate effect for oncogenic transformation.

Animals↗
PubMed1994

Chromosomal "fingerprints" of prior exposure to densely ionizing radiation.

A biomarker that would distinguish radiation-induced biological damage from damage produced by other agents has long been a goal in radiation biology. We suggest that densely ionizing radiations such as alpha particles from radon daughters, or fission neutrons, leave a distinctive chromosomal marker that may be detected and measured long after radiation exposure. Specifically, they produce an anomalously low ratio (F) of interchromosomal to intrachromosomal, interarm exchange-type chromosome aberrations, in comparison with either X rays or chemical carcinogens. For densely ionizing radiations and for other agents, experimental values of this F ratio, determined both in vitro and in vivo, are quantitatively consistent with theoretical expectations based on considerations of chromosomal geometry and radiation track structure. The use of fluorescence in situ hybridization to measure F values in stable chromosomal aberrations, together with recent developments in techniques for harvesting viable human cells, makes the application of this biological marker quite feasible. For example, the use of this marker could greatly facilitate epidemiological studies of radon-exposed cohorts.

Biomarkers↗
PubMed1993

Polymer models for interphase chromosomes.

The overall geometry of chromosomes in mammalian cells during interphase is analyzed. On scales larger than approximately 10(5) bp, a chromosome is modeled as a Gaussian polymer subjected to additional forces that confine it to a subvolume of the cell nucleus. An appropriate partial differential equation for the polymer Green's function leads to predictions for the average geometric length between two points on the chromosome. The model reproduces several of the experimental observations: (i) a square root dependence of average geometric distance between two marked chromosome locations on their genomic separation over genomic length scales from approximately 10(5) to approximately 10(6) bp; (ii) an approach of the geometric distance to a maximum value for still larger genomic separations of the two points; (iii) overall chromosome localization in subdomains of the cell nucleus, as suggested by fluorescent labeling of whole chromosomes and by radiobiological evidence. The model is also consistent with known properties of the 30-nm chromatin fiber. It makes a testable prediction: that for two markers a given number of base pairs apart on a given chromosome, the average geometric separation is larger if the configuration is near one end of the chromosome than if it is near the center of the chromosome.

Animals↗
PubMed1993

Dose, volume, and tumor-control predictions in radiotherapy.

PURPOSE: Tumor volume has a profound influence on the dose required to control a given type of tumor. The most obvious explanation for this is related to the larger number of stem cells which must be sterilized, leading to a more stringent requirement on cell survival. There are, however, other mechanisms by which volume may influence tumor control, such as clonogenic fraction, oxygenation or inter-cellular communication. We investigate the question of whether the effect of volume on tumor control is, in general, predictable on the basis solely of the differing number of stem cells. METHODS AND MATERIALS: We investigate whether the effect of volume on tumor control in four sites can be predicted, using the linear-quadratic formalism, based on the assumption that the number of cells that must be sterilized is directly proportional to the tumor volume. We require that the biological parameters in the model should have plausible values. RESULTS: We find that the results of four clinical data sets, exhibiting a wide range of doses, volumes, and tumor control rates, are consistent with the hypothesis that the number of potential stem cells which must be sterilized is proportional to the tumor volume. CONCLUSIONS: If these considerations are correct, the potential exists that realistic radiobiologically-based dose corrections for tumor size could be routinely made. This applies both to an entire treatment, and also between fractions, as the tumor shrinks. Such an approach may contribute towards optimized radiotherapy.

Breast Neoplasms↗
PubMed1993

The radiobiology of radiosurgery: rationale for different treatment regimes for AVMs and malignancies.

Based on basic radiobiological principles, we suggest that the radiosurgery technique of delivering a radiation dose in a single fraction, whilst appropriate for benign brain lesions such as arteriovenous malformations (AVM), is not optimal for treating malignant tumors. Radiosurgery was originally developed to treat benign lesions in the brain, such as AVMs, and has been successfully used for this purpose for over four decades. Recently, the technique has been adopted for treating small primary malignant brain tumors or single metastases. We argue, and derive radio-biological data to support the view that, treating malignant tumors with a single fraction will result in a suboptimal therapeutic ratio between tumor control and late effects, even for small tumors; and that improved therapeutic ratios would be expected if the treatment were fractionated into a small number of fractions. On the other hand, no therapeutic gain is to be expected from fractionating treatment of AVMs. A new generation of noninvasive relocatable stereotactic head frames makes feasible the use of fractionated stereotactic external-beam radiotherapy, and may allow significant benefits over single, radiosurgical, treatments for malignant brain tumors. As stereotactic fractionation/protraction regimes become more widespread, a uniform approach for determining equivalent fractionation schemes becomes important for intercomparing clinical results, and such calculations can be reliably carried out using the linear-quadratic formalism.

Brain Neoplasms↗
PubMed1993

Effect of LET on chromosomal aberration yields. I. Do long-lived, exchange-prone double strand breaks play a role?

Dicentric chromosomal aberrations produced by ionizing radiation probably result from pairwise interaction of DNA double strand breaks (dsbs). It has been suggested that high LET radiation may preferentially produce a subclass of 'severe' dsbs that are long-lived and/or exchange-prone, and that it is the production of these severe dsbs which account for the increased biological effectiveness of high-LET radiation. We present a quantitative formalism to describe the induction of these severe dsbs, and the subsequent production of exchange-type chromosomal aberrations. Using a Markov model and microdosimetric methods, we conclude that dicentric production by such severe dsbs has properties similar to those observed at high LET. Specifically, at high doses, the yield is nearly linear with dose even if dsbs from different tracks interact. The model is applied to published data on dicentric aberrations produced by irradiation of human lymphocytes in vitro. Corrections for the effects of interphase death are estimated. From comparisons with the experiments we conclude that interaction of severe dsbs could make a significant contribution to the observed dicentric production at high LET and also perhaps for low doses (though not high doses) at low LET. Proximity explanations of high-LET effects continue to offer the main prospect for obtaining a unified picture of chromosomal aberration formation by all ionizing radiation types, but a hybrid model in which severe dsbs contribute to the high-LET aberration yield cannot be ruled out. If all or part of high-LET radiation damage is qualitatively different from low-LET radiation damage, as this severe dsb model may suggest, there could be far-reaching implications for the field of radiation protection.

Animals↗
PubMed1993

The influence of cell killing on radiation oncogenesis: possible implications for high-let risk assessment at medium doses.

As the radiation dose increases, the prevalence of radiation-induced cancer in vivo, and transformation frequency per exposed cell in vitro, reach a maximum and often decrease. The most commonly considered mechanism to account for these effects is one in which, as the dose increases, cell killing becomes an important factor and ultimately controls the rate of oncogenesis. However, this model is by no means proven. We investigate the biophysical consequences of such a mechanism and show that it leads to the testable prediction that, at high LET, the maximum incidence of oncogenesis that can be achieved (the maximum oncogenic potential) is independent of LET. Data contradicting this prediction could therefore be taken as arguing against the model; what relevant data are available do not contradict this prediction. If the model is correct (or even if it is not, but the dose-oncogenesis relation follows this trend for other reasons), then it follows that the conventional risk assessment system, in which risk increases linearly with dose, would be inappropriate at medium doses (> 0.5 Gy) of high-LET (> or = 30 ke V/microns) radiation. In this dose-LET region, a risk assessment system based on the maximum oncogenic potential might be a) more credible than a system in which risk increases linearly with dose; b) appropriately conservative; c) independent of dose rate; and d) simple and practical to use.

Animals↗
PubMed1993

Five new Legionella species isolated from water.

Fourteen Legionella-like strains isolated from aquatic sources have been characterized serologically, biochemically, and in terms of DNA relatedness. The strains grew on buffered charcoal-yeast extract agar but not on blood agar and displayed phenotypic characteristics typical of the family Legionellaceae, including a requirement for cysteine, cellular fatty acid compositions in which branched-chain acids predominate, and the possession of isoprenoid quinones of the ubiquinone series with more than 10 isoprene units in their side chains. All were nonfermentative, lacked urease, were incapable of nitrate reduction, and reacted positively with a DNA probe specific for the Legionellaceae. DNA hybridization studies in which the hydroxyapatite method was used demonstrated that the strains represented five new species of the genus Legionella. Nine of the strains were more than 90% interrelated, and the name Legionella londiniensis sp. nov. is proposed for this group. Two strains formed a second hybridization group, for which the name Legionella nautarum sp. nov. is proposed, while the three remaining species, Legionella geestiana sp. nov., Legionella quateirensis sp. nov., and Legionella worsleiensis sp. nov., are each represented by a single strain. The levels of relatedness of the new species to each other are 23% or less, and the levels of relatedness to other members of the genus ranged from 0 to 36%. L. geestiana, L. nautarum, and L. londiniensis are serologically unrelated to all other known Legionella species. L. worsleiensis cannot be separated from Legionella pneumophila serogroup 4 by serological methods and is also serologically indistinguishable from L. quateirensis; distinctions may be made on the basis of fatty acid composition and biochemical reactions.

Bacterial Typing Techniques↗