Slope Of Survival Curve Research Articles

Survival in Colon, Rectal and Small Intestinal Cancers in the Nordic Countries through a Half Century.

Background: Survival studies in intestinal cancers have generally shown favorable development, but few studies have been able to pinpoint the timing of the changes in survival over an extended period. Here, we compared the relative survival rates for colon, rectal and small intestinal cancers from Denmark (DK), Finland (FI), Norway (NO) and Sweden (SE). Design: Relative 1-, 5- and 5/1-year conditional survival data were obtained from the NORDCAN database for the years 1971-2020. Results: The 50-year survival patterns were country-specific. For colon and rectal cancers, the slopes of survival curves bended upwards for DK, were almost linear for NO and bended downwards for FI and SE; 5-year survival was the highest in DK. Survival in small intestinal cancer was initially below colon and rectal cancers but in FI and NO it caught up toward the end of the follow-up. Conclusions: Relative survival in intestinal cancers has developed well in the Nordic countries, and DK is an example of a country which in 20 years was able to achieve excellent survival rates in colon and rectal cancers. In the other countries, the increase in survival curves for colon and rectal cancer has slowed down, which may be a challenge posed by metastatic cancers.

Accumulation of sublethal radiation damage and its effect on cell survival

Objective. Determine the extent of sublethal radiation damage (SRD) in a cell population that received a given dose of radiation and the impact of this damage on cell survival. Approach. We developed a novel formalism to account for accumulation of SRD with increasing dose. It is based on a very general formula for cell survival that correctly predicts the basic properties of cell survival curves, such as the transition from the linear-quadratic to a linear dependence at high doses. Using this formalism we analyzed extensive experimental data for photons, protons and heavy ions to evaluate model parameters, quantify the extent of SRD and its impact on cell survival. Main results. Significant accumulation of SRD begins at doses below 1 Gy. As dose increases, so does the number of damaged cells and the amount of SRD in individual cells. SRD buildup in a cell increases the likelihood of complex irrepairable damage. For this reason, during a dose fraction delivery, each dose increment makes cells more radiosensitive. This gradual radosensitization is evidenced by the increasing slope of survival curves observed experimentally. It continues until the fraction is delivered, unless radiosensitivity reaches its maximum first. The maximum radiosensitivity is achieved when SRD accumulated in most cells is the maximum damage they can repair. After this maximum is reached, the slope of a survival curve, logarithm of survival versus dose, becomes constant, dose independent. The survival curve becomes a straight line, as experimental data at high doses show. These processes are random. They cause large cell-to-cell variability in the extent of damage and radiosensitivity of individual cells. Significance. SRD is in effect a radiosensitizer and its accumulation is a significant factor affecting cell survival, especially at high doses. We developed a novel formalism to study this phenomena and reported pertinent data for several particle types.

Evaluating 24/7 Sobriety Program participant reoffense risk

Objective: Our study investigated risk factors in survival among a subpopulation of drivers in North Dakota’s 24/7 Sobriety Program. Participants mandated for a second driving-under-the-influence of alcohol (DUI) arrest were studied for a three-year interval that commenced with the start date for a 360-day enrollment. Method: A Stratified Cox regression model was developed to compute the hazard ratios for survival. A subsequent DUI-related offense as event of interest. Relation to the explanatory variable array that could be construed from administrative records were investigated. Results: Older drivers were 6.31 times more likely to reoffend than the younger driver cohort of 18–35-years. The survival curve slope showed the fastest decline in the 361-day to 730-day interval. Neither gender nor residence region was a significant predictor in DUI reoffense over the three-year monitoring interval. Preliminary work suggests reoffense was more likely if an individual had program history prior to this court mandated 360-day term in the 24/7 Sobriety Program for a second DUI. The program experience finding was unexpected but could not be studied in greater detail due to data and resource limitations. Conclusions: Administrative records access created a novel opportunity to explore an evolving impaired driving prevention strategy that has shown early promise. Individual driver survival in and after the 24/7 Sobriety Program was studied for three-years. Findings show age, post-program time interval, and possibly program history as areas to explore to improve survival rates. Driver DUI offense were most common shortly after program completion. Although limited to a single state, findings increase knowledge for refining strategies designed to impact driver subpopulations at higher risk for reoffense.

Theoretical effectiveness of cell survival in fractionated radiotherapy with hypoxia-targeted dose escalation.

The goal of this article is to compute the cell survival during fractionated radiotherapy with non-uniform hypoxia-targeted dose distribution relative to cell survival for a uniform dose distribution with equal integral tumor dose. The analysis is performed for different parameters of radiotherapy with conventional and hypofractionated dose regimens. Our analysis is done using a parsimonious tumor response model that describes the major components of tumor response to radiotherapy such as radiosensitivity, cell proliferation, and hypoxia using as few variables as possible. Two levels of oxygenated and hypoxic cells with the survival curves described by the linear quadratic (LQ) model are implemented in the model. The model allows for analytical solutions for relative cell survival in a single fraction simulation which can be used for additional validation of our numerical simulations. The relative cell survival was computed for conventional and hypofractionated dose regimens in a model problem with radiobiological parameters for the non-small-cell lung cancer. Sensitivity of cell survival to different parameters of radiotherapy such as the relative volume of hypoxic fraction, boost dose ratio, re-oxygenation rate, and delivery errors was investigated. Our computational and analytical results show that relative cell survival for non-uniform and uniform dose distributions is larger than 1.0 during the first few fractions of radiotherapy with conventional fractionation. This indicates that the uniform dose distribution produces a higher cell killing effect for the equal integral dose. This may stem from domination of linear contribution to the cell killing effect seen in the dose range of 1-2 Gy and a steeper slope of survival curve in the oxygenated tumor region. This effect can only happen if the distribution of clonogens is nearly uniform; therefore, after the first few fractions, the non-uniform dose distributions outperform the uniform dose distribution and relative cell survival becomes less than 1.0. However, re-oxygenation and delivery errors can also reduce the effectiveness of hypoxia-targeted non-uniform dose distributions toward the end of treatment. For hypofractionated radiotherapy with fractional dose >3 Gy, the relative cell survival was always below 1.0, which means the non-uniform dose distributions produced higher cell killing effect than the uniform dose distribution during the entire treatment. The data obtained in this work suggest that non-uniform hypoxia-targeted dose distributions are less effective at cell killing than uniform dose distributions at the beginning of radiotherapy with conventional fractionation. However; non-uniform dose distributions can outperform uniform dose distribution by the end of the treatment if the effects of re-oxygenation and delivery errors are reduced. In hypofractionated radiotherapy, non-uniform hypoxia-targeted dose distributions are more efficient than uniform dose distributions during the entire treatment.

Low-Dose Hypersensitivity and Bystander Effect are Not Mutually Exclusive in A549 Lung Carcinoma Cells after Irradiation with Charged Particles

The purpose of this study was to measure survival fraction of A549 lung carcinoma cells irradiated with charged particles of various LET and to determine mechanisms responsible for enhanced cell killing in the low-dose region. A549 cells were irradiated with a broadbeam of either 10 and 25 keV/μm protons or 100 keV/μm alpha particles and then processed for clonogenic assays and phospho-histone H3 staining. The survival fraction of unirradiated A549 cells co-cultured with irradiated cells was also evaluated. A549 cells were shown to exhibit low-dose hypersensitivity (HRS) for both protons and alpha particles. The dose threshold at which HRS occurs decreased with increasing linear energy transfer (LET), whereas αs, the initial survival curve slope, increased with increasing LET. In addition, the enhanced cell killing observed after irradiation with alpha particles was partly attributed to the bystander effect, due to the low proportion of hit cells at very low doses. Co-culture experiments suggest a gap junction-mediated bystander signal. Our results indicate that HRS is likely to be dependent on LET, and that a bystander effect and low-dose hypersensitivity may co-exist within a given cell line.

Formulation of the Multi-Hit Model With a Non-Poisson Distribution of Hits

We proposed a formulation of the multi-hit single-target model in which the Poisson distribution of hits was replaced by a combination of two distributions: one for the number of particles entering the target and one for the number of hits a particle entering the target produces. Such an approach reflects the fact that radiation damage is a result of two different random processes: particle emission by a radiation source and interaction of particles with matter inside the target. Poisson distribution is well justified for the first of the two processes. The second distribution depends on how a hit is defined. To test our approach, we assumed that the second distribution was also a Poisson distribution. The two distributions combined resulted in a non-Poisson distribution. We tested the proposed model by comparing it with previously reported data for DNA single- and double-strand breaks induced by protons and electrons, for survival of a range of cell lines, and variation of the initial slopes of survival curves with radiation quality for heavy-ion beams. Analysis of cell survival equations for this new model showed that they had realistic properties overall, such as the initial and high-dose slopes of survival curves, the shoulder, and relative biological effectiveness (RBE) In most cases tested, a better fit of survival curves was achieved with the new model than with the linear-quadratic model. The results also suggested that the proposed approach may extend the multi-hit model beyond its traditional role in analysis of survival curves to predicting effects of radiation quality and analysis of DNA strand breaks. Our model, although conceptually simple, performed well in all tests. The model was able to consistently fit data for both cell survival and DNA single- and double-strand breaks. It correctly predicted the dependence of radiation effects on parameters of radiation quality.

Physical Parameters that Influence the Effectiveness of Ionizing Radiation at Low Doses

Relative biological effectiveness (RBE) for the inactivation of V79 cells were determined using the initial slopes of survival curves (published in literature), the physical quality parameters are interpolated utilizing the standard values relevant to charged particles such as protons and heliums. The issues of utilizing physical parameters as quantifier of radiation effects that influence the effectiveness have been investigated. The results show that the effectiveness may represent in terms of other physical parameters rather than linear energy transfer (LET). Meanwhile, mean free path for linear primary ionization (λ) is expressed the generalized specifier physical quality parameter to quantify ionizing radiation effects at lower doses. Therefore, plot of mean free path as a function of RBE has been made to identify the physical features of this parameter as an alternative physical quality for LET.

Randomised controlled trials in cystic fibrosis: what, when and how?

The major morbidity and mortality from cystic fibrosis (CF) comes from progressive lung disease with bronchiectasis leading to respiratory failure. There is no doubt that survival of CF patients has increased progressively through the latter part of the 20th and the early part of the 21st centuries, and that the quality of life for patients with CF has increased substantially. However, CF still remains a serious life-shortening disease. Indeed, the most recent data from national CF registries show that the slope of survival curves 1 and the rate of loss of lung function have not changed at all, at least beyond childhood. Potential reasons for this are that CF lung disease begins in early life and that while current treatments may increase the health of children, they do little, if anything, to prevent the onset or progression of destructive lung disease, nor the inevitable onset of chronic respiratory failure. Data from a number of sources have demonstrated that CF lung disease begins very early in life 2–6. Arguably, the best data come from the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF), where essentially all children diagnosed with CF in a geographically defined region of Victoria and in Western Australia following detection by newborn screening are assessed soon after diagnosis and annually until 6–7 yrs of age 7. These data show that a substantial proportion of infants have evidence of pulmonary inflammation and infection at 3 months of age, even in the absence of clinically apparent lung disease 8. Structural lung disease, including bronchiectasis, is prevalent in infants and young children with CF 8–10; the major risk factors being neutrophilic inflammation, the presence of free neutrophil elastase activity in the lungs and pulmonary infection, especially with Pseudomonas aeruginosa 8, …

Prognostic relevance of number and bilaterality of positive surgical margins after radical prostatectomy

PurposePositive surgical margin (PSM) status following radical prostatectomy (RP) is a well-established prognostic factor. The aim of the present study is to evaluate whether number of PSMs or bilaterality of PSMs might have prognostic significance for biochemical recurrence (BCR) in the population with a PSM status following RP.MethodsWe evaluated 1,395 RP pathology reports from our center between 1980 and 2006. All patients who underwent (neo)-adjuvant therapy were excluded, leaving a cohort of 1,009 patients, with 249 (24.7%) subjects having a PSM at RP of whom 29.4% had multiple PSMs (≥ 2 sites), while 13.6% had bilateral PSMs. Median follow-up was 40 months (range 0–258 months). We used BCR-free survival as the primary study outcome. BCR was defined as any rise in PSA above or equal to 0.2 ng/ml.ResultsOf patients with a PSM status, 41% (95% CI: 33–49%) developed BCR within 5 years, compared to 12% (95% CI: 9–15%) in the population without a PSM. Multivariable analysis identified PSA at diagnosis and RP Gleason score as independent predictive factors for BCR. Increasing number and/or bilaterality of PSM did not lead to significant higher rates of BCR.ConclusionIn patients with a PSM, the number of positive sites or bilaterality of PSM status does not add prognostic information for risk of BCR. Survival curve slopes were different for patients with bilateral PSM, showing a significant tendency to progress to BCR earlier during follow-up than patients with unilateral PSM.

Type I Antifreeze Proteins Enhance Ice Nucleation above Certain Concentrations

In this study, we examined the effects that antifreeze proteins have on the supercooling and ice-nucleating abilities of aqueous solutions. Very little information on such nucleation currently exists. Using an automated lag time apparatus and a new analysis, we show several dilution series of Type I antifreeze proteins. Our results indicate that, above a concentration of ∼8 mg/ml, ice nucleation is enhanced rather than hindered. We discuss this unexpected result and present a new hypothesis outlining three components of polar fish blood that we believe affect its solution properties in certain situations.

The Post-Transfusion Recovery and Survival of Red Blood Cells in Mice Is Affected by the Expression of Cellular Prion Protein.

Three documented transfusion cases of vCJD underline the need of better insight in blood prion protein biology. Cellular prion protein (PrPc) plays key role in the pathophysiology of prion diseases. Its expression by cells is necessary for amplification of infectious prions and the disease process itself. Physiological function of PrPc remains obscure. Its clarification may provide important clues for the development of urgently needed blood test and effective disease treatment. PrPc is expressed on CD34+ hematopoietic stem cells and its expression is regulated during blood cell differentiation. Recently the importance of PrPc for self-renewal of long-term repopulating hematopoietic stem cells was suggested and other studies reported the protective function of PrPc against oxidative stress and apoptosis in various cell cultures. We previously demonstrated that human as well as mouse red blood cells (RBC) express approximately 200 PrPc molecules / cell (Holada et al., BJH 2000, 110, 472–80). To test if the PrPc expression plays a role in the post-transfusion recovery and survival of RBC we carried out transfusion study in mice. RBC isolated from blood of wild type (WT) and PrP knockout (KO) FVB mice were labeled “in vitro” by different levels of NHS-biotin. The labeling was optimized to allow simultaneous detection of both populations of RBC in mouse blood using flow cytometry. To exclude the influence of different level of cell biotinylation on the experiment outcome two mixtures of RBC were prepared. The first contained KO RBC labeled with high and WT RBC with low level of biotin and the second mixture contained cells labeled “vice versa”. Each mixture was injected via tail vein in a group of WT mice (n=5) and the survival of RBCs was followed. Samples were analyzed on day 1, 2, 3, 6, 9, 15, 21 and 29. The count of biotinylated RBC was measured in comparison to 100 000 nonlabeled recipient RBC. Simultaneously the expression of PrPc on RBC was monitored using flow cytometry with MAb 6H4. KO RBC displayed significantly higher first day post-transfusion recovery compared to WT RBC in both groups of mice (81 ± 3 % vs. 74 ± 3 %, P<0.005 and 90 ± 4 % vs. 80 ± 4 %, P<0.005). The slope of the RBC survival curve in all individual mice during the initial 15 days was steeper for KO RBC (mavg = − 3.44) than for WT RBC (mavg = − 2.37) suggesting the protective role of PrPc in circulating RBC. The difference in the slope diminished during the 15 to 29 day period which was accompanied by a 50% decrease of PrPc surface expression on transfused WT RBC. To confirm our data the identical experiment was carried out in a group of KO mice (n=5) transfused with a mixture containing KO RBC labeled with low and WT RBC with high level of biotin. Again the first day post-transfusion recovery was higher for KO RBC (80 ± 6 % vs. 75 ± 6 %, P<0.05) and the initial slope of the KO RBC survival curve was steeper in all mice in the group. Our data suggest that PrPc expression plays role in the post-transfusion recovery and survival of RBC. The observation that WT RBC disappear from the circulation at lower rate than KO RBC until their level of surface PrPc reaches 50% is compatible with the protective role of PrPc expression on cells. Taken together our study demonstrates that physiological role of PrPc expression on RBC may lay in facilitating their longer survival in circulation. (GACR 310/04/0419, MSMT 0021620806).

Effect of temperature on growth, germination, germ-tube extension and survival of Paecilomyces lilacinus strain 251

Paecilomyces lilacinus and in particular the commercial strain 251 has been intensively tested for biological control of plant parasitic nematodes. Since this species has been mentioned in a number of reports concerning infection of humans, the human health risk for Paecilomyces lilacinus strain 251 was investigated. The effects of time, temperature and growth medium on radial colony growth and germination were determined. Additionally, exposure to 36°C and its effect on germ-tube extension and on survival of conidia was evaluated. Radial growth was significantly affected by temperature, growth medium and their interaction. Optimum temperatures were between 24 and 30°C, but no growth was found at 36°C. Germination rate was significantly influenced by time, medium, temperature and their interactions. The optimum temperature range for germination was between 28 and 30°C. Formulated conidia were capable of germinating at 36°C. However, studies on germ-tube extension conducted at 36°C showed a delay in development for 28–49 h and no further germ-tube extension was found after exposure for 80–95 h. Slopes of survival curves were significantly influenced by the type of conidia tested. In general, conidia did not survive exposure to 36°C for 168 h. These experiments indicate the temperature conditions where the strain is likely to be active and provide supporting data for full environmental and health risk assessments of biocontrol fungi.

Selection bias impacts outcome reports of uremia therapy

Selection bias impacts outcome reports of uremia therapy

Survival of colorectal cancer cell lines treated with paclitaxel, radiation, and 5-FU: Effect of TP53 or hMLH1 deficiency

Clonogenic survival and early cell death during treatment of human colon carcinoma cells were investigated following X-irradiation (IR) alone, IR followed by 5-FU for 24 h, and Taxol administered 24 h before IR and 5F-U. The investigated cell lines were: HCT116, 40-16 clonally derived from HCT116, and two HCT116 variants: N6CHR3 expressing hMLH1, and TP53 null cells denoted HCT116 p53-/-. The objective was to determine efficacy of the combined treatment and to correlate response with constitutive levels of TP53, WAF1, and hMLH1 proteins, as well as with mRNA levels of the apoptosis-related genes survivin, BNIP3, and MYC. At the end of treatment with 5-FU, the proportion of viable cells was between 0.65 and 0.70 for all cell lines. Additional cell loss occurred in 40-16 and HCT116 p53-/- cells following administration of Taxol before IR and 5-FU. Radiation sensitivity was unaffected by combined treatments, except for Taxol, irradiation, and 5-FU sequence in the HCT116 p53-/- and 40-16 cell lines, where radiation sensitivity determined by clonogenic survival curve slopes was doubled or quadrupled, respectively. Under our present experimental conditions, treatment response did not correlate with TP53 or hMLH1 status, but was associated with apoptosis-related genes, most notably BNIP3. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 175-185 (2000).

Fluctuating Temperature and the Longevity of Conidia of Metarhizium flavoviride in Storage

Conidia of Metarhizium flavoviride were hermetically stored at 13.7% moisture content with four constant (20, 30, 40 and 50 C) and six fluctuating temperature regimes (20:30, 20:40, 20:50, 30:40, 30:50 and 40 C:50 C, all 24 h:24 h) for up to 119 days. Survival of conidia stored at both constant and fluctuating temperatures conformed to cumulative negative normal distributions and all 10 survival curves could be constrained to a common origin. The effect of constant storage temperature on conidia longevity was quantified satisfactorily by a negative curvilinear semi-logarithmic relation developed previously, in which the estimates of the constants CH and CQ were 0.0176 (SE 0.0013) and 0.000703 (SE 0.000019), respectively. The fitted relation at constant temperatures showed that Q10 for loss in conidia viability increased the warmer the temperature regime. The effect of the cooler temperature of each fluctuating temperature regime on conidia longevity was small, since the effective temperature of each regime for loss in conidia viability was always much warmer than the mean. Conidia were also stored in two further regimes: at 30 C for 21 or 35 days before transfer to 50 C. The standard deviations of the conidia survival curves at 50 C were unaffected by the duration of previous storage at 30 C. Thus change in temperature per se had no effect on conidia survival: conidia survival curve slopes were solely dependent upon the contemporary storage environment. Approaches are developed in order to predict loss of conidia viability in fluctuating temperature storage environments, and the predictions compared against independent observations.

Radiopotentiation by the oral platinum agent, JM216: role of repair inhibition

Purpose: To test for in vitro radiopotentiation by the orally-administered platinum (IV) complex, JM216; to compare these results to cisplatin and carboplatin; and to investigate whether the mechanism of radiopotentiation involves repair inhibition of radiation-induced DNA damage. Methods and Materials: H460 human lung carcinoma cells were incubated with the drugs for 1 h at 37°C, irradiated at room temperature, and returned to 37°C for 20 min. Cells were then rinsed and colony forming ability was assessed. Wild-type V79 Chinese hamster cells and radiosensitive, DNA repair-deficient mutant cells (XR-V15B) were also studied along with H460 cells. Ku86 cDNA, which encodes part of a protein involved in DNA repair, was transfected into XR-V15B cells as previously described. The effect of JM216 on sublethal damage repair (SLDR) was also assessed using split-dose recovery. Results: Using equally cytotoxic doses of JM216, cisplatin, and carboplatin, the radiation dose enhancement ratios (DER) were 1.39, 1.31, and 1.20, respectively; the DER with 20 μM JM216 was 1.57. JM216 (20 μM) did not significantly change the final slope of radiation survival curves, but greatly reduced the survival curve shoulder. V79 cells also showed radioenhancement using 20 μM JM216, but no enhancement occurred using XR-V15B cells. Transfection of Ku86 cDNA into XR-V15B cells restored radiopotentiation by JM216 to wild-type V79 levels. In addition, 20 μM JM216 completely inhibited sublethal damage repair in H460 cells. Conclusion: Our results show that JM216 can potentiate the effects of radiation in human lung cancer cells, and that the mechanism of this effect is probably inhibition of DNA repair by JM216.

Enhancement of tumor cell killing in vitro by pre- and post-irradiation exposure to aclacinomycin A

Aclacinomycin A (ACM), a potent inducer of leukemic cell differentiation, significantly enhances the radiosensitivity of a human colon tumor cell line (Clone A) when cultures are exposed to 15-nM concentrations for 3 days before irradiation. We now demonstrate that incubation with ACM after irradiation can also enhance Clone A cell killing. The maximum increase in cell killing, based on colony-forming ability, occurred when Clone A cells were exposed for 1 h to 5 μM ACM added 1 or 2 h after irradiation. The post-irradiation ACM protocol reduced the terminal slope (as reflected by D 0) of the radiation cell survival curve with no change in the low-dose, shoulder region of the curve ( D q value). In contrast, for pre-irradiation treatment with ACM (15 nM, 3 days), the shoulder region of the curve was reduced with no change in the terminal slope. For pre- and post-irradiation ACM treatment the dose enhancement factors at 0.10 survival were 1.22 and 1.28, respectively. When ACM was given both before and after irradiation both the shoulder and terminal slope values decreased to produce a dose enhancement factor at a surviving fraction of 0.10 of 1.50. These data suggest that the enhanced cell killing produced by pre- and post-irradiation treatment with ACM is achieved through different mechanisms.

Intrinsic radiation resistance of primary clonogenic blasts from children with newly diagnosed B-cell precursor acute lymphoblastic leukemia.

The radiation sensitivity of primary clonogenic blasts from 44 children with newly diagnosed B-cell precursor acute lymphoblastic leukemia (ALL) was analyzed using leukemic progenitor cell (LPC) colony assays. The derived values for SF2 (surviving fraction at 200 cGy) and alpha (initial slope of radiation survival curves constructed according to the linear quadratic model) indicated a marked interpatient heterogeneity in intrinsic radiation sensitivity of LPC populations. The SF2 values ranged from 0.01 to 1.00 (median = 0.430; mean +/- SE = 0.47 +/- 0.04), and the alpha values ranged from 0.000 to 3.272 Gy-1 (median = 0.280 Gy-1; mean +/- SE = 0.430 +/- 0.093 Gy-1). When CD19+ CD34+ versus CD19+ CD34- immunophenotypes were compared, a trend toward higher SF2 and lower alpha values were observed in LPC from CD34+ patients, consistent with greater radiation resistance. When patients were divided into three approximately equal groups based on increasing levels of CD34 expression, a clear ordering effect was observed indicating that increased CD34 expression levels are associated with significantly higher radiation resistance at the level of B-lineage LPC. The highest CD34 expression group (> or = 75% positivity) had 1.4-fold higher SF2 (P = 0.05) and twofold lower alpha values (P = 0.06) than the lowest group (< 30% positivity). Furthermore, the CD34 positivity of radiation resistant (alpha < or = 0.2 and SF2 > or = 0.5) B-cell precursor ALL cases was greater than the CD34 positivity of radiation sensitive (alpha > 0.2 and/or SF2 < 0.5) cases (56 +/- 9% versus 34 +/- 9%, P = 0.09). Whereas only 6 of 16 (38%) of radiation sensitive cases were CD34+, 11 of 15 (73%) of radiation resistant cases expressed CD34 (P = 0.04). Our results offer new insights into the inherent and/or acquired radiation resistance of primary clonogenic blasts from B-cell precursor ALL patients.

On the Question of the Cause of the Initial Slope of Survival Curves

In the double-strand break (DSB) model, the initial slope (alpha) of the survival curve is determined by the number of DSBs remaining unrepaired at a certain time after irradiation. There are three types of calculations which confirm the validity of this approach. First, the model quite reasonably predicts the low-LET alpha values for Chinese hamster V79, mouse L5178Y-R, normal fibroblast, ataxia telangiectasia (AT), and Ehrlich ascites tumor (EAT) cells using the measured values of the cellular DNA content, the radiation yield for DSB induction, the time constant for DSB repair, and the time available for DSB repair. Second, this approach correctly predicts an increase in alpha values for V79 and Chinese hamster ovary (CHO) cells due to postirradiation treatments with hypertonic saline or a high concentration of araA. These calculations are based on the duration of the DSB repair block induced by those treatments. Third, a fair agreement between the predicted and measured initial slopes for 3- to 4-MeV alpha particles was obtained for normal fibroblast, EAT, V79, CHO, Chinese hamster HS-23, C3H 10T1/2, and lung epithelial cells. However, the alpha values for AT and xrs-6 cells were overestimated. The calculation of high-LET alpha values uses the experimental values of the relative increase in the DSB repair time constant and in the radiation yield for DSB induction for alpha particles in comparison with those for X rays.

Modification of radiation-induced damage by hyperthermia--role of repair processes.

The role of repair inhibition in hyperthermic sensitization has been investigated by carrying out interaction studies (non-lethal heat plus radiation) using three radiosensitive mutant strains rad 9-4, rad 51, rad 52 of diploid yeast. The radiosensitization observed in these mutants is compared with that obtained in a wild type strain X2180. Stationary phase cells were heat treated at 51 degrees C for 30 min and log-phase cells at 49 degrees C for 5 min such that the heat treatment per se was non-lethal. Thermal enhancement ratios (TER) were calculated as the ratio of D0 values as well as D10 values, for radiation alone and for combination of heat and radiation. In stationary phase cells TER values ranged from 1.25 to 2 in different strains. There was no significant difference in the degree of sensitization in wild type and mutant strains. However in log-phase cells TER calculated as the ratio of D10 values was 1.84 for wild type strain; whereas the same was 1.2, 1.18 and 1.50 for rad 9-4, rad 51 and rad 52 strains. TER value obtained from ratio of D0 values was also significantly higher for wild type cells in log-phase cultures. These results suggest that the radiosensitization by heat occurs prominently in radioresistant log-phase cells and reflects as a reduction in the shoulder width of survival response curves. Prompt sensitization as seen by the increase in slope of survival curve also contributes to the TER. Inhibition of recovery from sublethal damage by heat appears to be an important mechanism of radiosensitization in log-phase cells.(ABSTRACT TRUNCATED AT 250 WORDS)