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Biomedical subjects

S L Tucker

Publications and source records attributed to S L Tucker.

At least 19 recordsLinked to original sources
PubMed1995

Damage and morbidity from pneumonitis after irradiation of partial volumes of mouse lung.

PURPOSE: The aims of this study were to: (a) define the relationship of dose and volume irradiated to damage and morbidity in mouse lung, (b) determine the threshold volume for morbidity after partial lung irradiation; and (c) determine whether the response to radiation of mouse lung is independent of the region irradiated. METHODS AND MATERIALS: C3Hf/Kam female mice were used in this study. The fractional volume of the lung to be irradiated was determined by two methods, weights and computed tomography (CT) scanning. Two experiments were performed to define the volume effect and to determine whether the response of the mouse lung to radiation was homogeneous. In the first experiment, single doses of x-rays ranging from 12 to 20 Gy were given to partial volumes of 84%, 70%, and 40% including the base, 50%, 33%, and 17% including the apex, to 43% in the middle, and to the sum of 57% as 17% in the apex and 40% in the base. In the second experiment, the same volumes of 50% and 70-75% in the apex and base of the lung were irradiated with single doses ranging from 12-19.25 Gy. Morbidity from radiation pneumonitis was quantitated by two end points, breathing rate and lethality between 12 and 32 weeks after irradiation. Damage was assessed by histopathological evidence of pneumonitis. RESULTS: Clear well-defined dose-response curves were obtained for both breathing rate and lethality after all volumes irradiated. There was a clear volume-dependent shift of the dose-response curves for breathing rate and lethality at 28 weeks after irradiation, the end of the pneumonitis phase of damage, to higher doses compared with these data after whole-lung irradiation. In addition, the slopes of the dose-response curves for irradiation of partial lung volumes were more shallow compared to those after whole-lung irradiation. Increases in breathing rate correlated with lethality when the volume irradiated was equal to or greater than 50% of the reference volume. However, after irradiation of volumes smaller than 40%, breathing rate increases were not accompanied by death. A heterogeneous response of the mouse lung to radiation was observed in the first experiment and confirmed by the second experiment. For a given volume irradiated, the isoeffect dose was always less for the base than for the apex of the lung. The threshold volume for breathing rate changes was less than 17 and 40% when the irradiated volumes involved the apex and base, respectively. For lethality, the threshold volume was between 40 and 70% for the base and greater than 50% for the apex of the lung. Finally, damage as assessed by histological evidence of pneumonitis was observed in the irradiated area only. CONCLUSIONS: (a) The volume effect was resolvable in mice, (b) the volume effect in mouse lung exhibits a clear threshold for morbidity, (c) the threshold volume for morbidity is dependent on the end point, (d) the response of mouse lung is heterogeneous, dependent on the site irradiated, and is always greater for the same volumes irradiated in the base than the apex, and, (e) histopathological damage does not always produce observable morbidity.

Animals↗
PubMed1995

Fibroblast radiosensitivity versus acute and late normal skin responses in patients treated for breast cancer.

PURPOSE/OBJECTIVE: To determine if the radiosensitivity of normal human skin fibroblasts, measured in early passage cultures, is significantly correlated with the degree of acute or late normal skin damage in patients treated for breast cancer with radiotherapy. METHODS AND MATERIALS: In the 1970s, a series of breast cancer patients was treated at the Department of Oncology in Gothenburg, Sweden with postoperative irradiation to the parasternal region. Patients were treated bilaterally using different fractionation schedules and doses to the right and left fields. Peak acute reactions were scored on a six-point scale, and skin erythema was measured by reflectance spectrophotometry. Telangiectasia was graded over time on a six-point scale. In April 1992, two small skin biopsies were obtained from 22 patients in two treatment groups (i.e., four dose-fractionation schedules) and, using either delayed or immediate plating, fibroblast radiosensitivity was measured in early passage cultures by clonogenic survival, after high and low dose-rate irradiations. Survival at 2.0 Gy (SF2) was calculated from complete survival curves. RESULTS: To test assay reproducibility, SF2 values derived from paired biopsies of the same patient (12 cases) were compared. A reasonably good correlation (p = 0.075) was obtained for SF2s determined by high dose-rate irradiations with immediate plating, but not for delayed plating or low dose-rate treatments. The median coefficient of variation in the replicate SF2s after high dose-rate treatment and immediate plating was 13%, suggesting that the poor correlation in paired SF2 values is due to the magnitude of the uncertainty in SF2 relative to the overall spread in SF2 values between patients (CV = 28%). Individual SF2 values and averaged values from patients with data from two biopsies were compared with the acute and late clinical reactions. A significant negative correlation was found between SF2 and relative clinical response, but only when averaged high dose-rate SF2 values and telangiectasia scores were compared. There was no significant correlation between average SF2 values and acute responses or between individual SF2 measurements and either the acute or late clinical response. CONCLUSION: The results of this study suggest that the degree of late telangiectasia is at least partially dependent upon the intrinsic cellular radiosensitivity of normal fibroblasts, but the relationship is not clear cut. Multiple replicate assays are necessary to obtain reliable estimates of fibroblast SF2 values using current techniques.

Biopsy↗
PubMed1995

Interphase cytogenetics of renal cortical neoplasms. Correlation with DNA ploidy by flow cytometry.

The genotypic changes in 22 renal cortical neoplasms and 16 of the corresponding normal kidney tissues by fluorescence in situ hybridization (FISH) were studied using directly labelled probes for chromosomes 7, 8, 10, 11, 12, 17, 18, X, and Y, and by flow cytometry (FCM). DNA ploidy analysis revealed 8 DNA aneuploid and 14 DNA diploid neoplasms. The mean single spot hybridization in normal kidney was 5 +/- 0.9% for chromosomes 7, 8, 10, 11, 12, and the X in females. The mean single spot hybridization for chromosomes 17 and 18 was 14.9% and 18.5%, respectively. The mean number of more than two (> 2) hybridization signals in normal kidney cells for all autosomes and the X-chromosome in females was 3 +/- 1.2%. Significant chromosomal loss was restricted to chromosomes 8, 18, X, and Y. The net chromosomal gain and loss correlated with the DIs in aneuploid tumors. All DNA diploid neoplasms showed both chromosomal loss and gain with a tendency to a net loss. No apparent correlation between the chromosomal aberrations and the clinicopathologic factors was found in this cohort. Our study demonstrates that: (1) tissue specific controls may provide better information for definable performance criteria for this technique; (2) monosomy can more reliably be assessed on fresh samples; (3) chromosomal loss is confined to certain chromosomes; (4) DNA diploid tumors manifest heterogeneous gain and loss of various chromosomes with a tendency to a net loss; and (5) integrated FISH and FCM analysis provide more information on the chromosomal abnormalities of these neoplasms.

Adult↗
PubMed1994

Intermediate-grade lymphomas treated with cyclophosphamide-doxorubicin- vincristine-prednisone-bleomycin alternated with cyclophosphamide-methotrexate-etoposide-dexamethasone. Application of prognostic models to data analysis.

BACKGROUND: Numerous treatment strategies have been tried with the aim of improving results for patients with intermediate-grade lymphomas (IGL) over those achieved with cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin (CHOP-Bleo), and numerous prognostic models have been developed to identify and separate risk groups. This study reports on a new protocol for Ann Arbor Stages II-IV IGL that consists of CHOP-Bleo alternated with a new regimen of cyclophosphamide, methotrexate, etoposide, and dexamethasone (CMED) and radiation therapy and demonstrates the usefulness of prognostic models for identifying risk groups and comparing treatment programs. METHODS: One hundred seventy patients with Ann Arbor Stages II-IV IGL were treated with alternating cycles of CHOP-Bleo and CMED for a total of 12 cycles. Involved field radiation therapy was interspersed with courses of chemotherapy for patients with Stage II and Stage III disease. Results were analyzed and compared with those of the authors' previous study of CHOP-Bleo and radiation therapy using the Ann Arbor staging system, their earlier prognostic model, and the recently published International Index. RESULTS: A complete remission occurred in 78% of the patients. The overall 5-year survival rate was 67%. Survival was better for patients with Ann Arbor Stage II disease (80%) than for those with Stage III or Stage IV (67% and 58%, respectively). High tumor burden, above-normal levels of serum lactic dehydrogenase, serum beta 2-microglobulin, and Ann Arbor Stage IV disease were adverse factors. The International Index and the authors' earlier prognostic model separated four prognostic groups. CHOP-Bleo/CMED was generally well tolerated. Neutropenic fever was the major complication that occurred in 25 patients during treatment. Six of these patients died of sepsis. CONCLUSIONS: This study demonstrated that CHOP-Bleo/CMED is a well-tolerated regimen that produced better results than those reported for a former study that used CHOP-Bleo alone. Further, results for CHOP-Bleo/CMED compared favorably with those of other second- and third-generation regimens. The study also validated the usefulness of prognostic models and, in particular, the new International Index for identifying risk groups.

Adolescent↗
PubMed1994

Radiation-induced injury to the visual pathway.

Radiation-induced injury to the visual pathway was reviewed in a cohort of patients treated for various cancers of the nasal cavity and paranasal sinuses between 1969 and 1985. The study subjects consisted of 219 patients, 137 men and 82 women, in whom detailed records were available on the extent of orbital shielding, treatment plan for estimating doses delivered to various optic structures, and visual acuity follow-up information. There was a wide range in doses administered to various optic structures because patients with different primary lesion types were included and the radiotherapy techniques used varied during this era. The endpoint of the study was visual acuity < 20/100. The Cox proportional hazard model was used to assess the influence of various factors on the latent time to visual impairment and to fit the LQ model to the failure-time data. Actuarial curves showing the proportion of patients with visual impairment as a function of dose and time were generated. Corneal injury occurred in 24 of the 49 patients treated with the 3-field technique without any orbital shielding; variables affecting the incidence of cornea injury were total radiation dose and chemotherapy. Symptomatic retinopathy was diagnosed in 7 of 77 patients who received irradiation to a relatively large retinal surface, but no variables were found to correlate with this complication. Eight patients developed ipsilateral blindness due to optic neuropathy and 11 patients had bilateral visual impairment secondary to chiasm injury. The total radiation dose was identified as the predominant determinant. None of patients receiving a dose of < 50 Gy developed optic neuropathy or chiasm injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Blindness↗
PubMed1992

Mathematical models for the cellular concentrations of cyclin and MPF.

Several mathematical models have been proposed for regulation of the cell cycle in early embryos by cyclin and maturation-promoting factor (MPF). In this paper the previously proposed models for cyclin and MPF activity are analyzed, and the validity of those models based on the mathematical behavior of their solutions and on physical considerations are discussed. In addition, three further models are proposed that exhibit the periodic behavior necessary for modeling the mitotic clock but that do not have certain of the limitations of the other models.

Animals↗
PubMed1992

Can modest escalations of dose be detected as increased tumor control?

Clinically defined groups of tumors are usually characterized by shallow dose-response curves, and this results from heterogeneity among individual dose-response curves, each of which is very likely quite steep. A review of published results for human tumors indicates that a 10% escalation of dose to tumors controlled at the 50% level, where changes in outcome are most likely to be detected, will be detectable in a population of unselected patients only in sizable clinical trials (130-300 patients per dose level). With a few exceptions, a dose escalation of 20% will be detectable in much smaller trials (50-130 patients per dose level). Therefore, clinical trials of improved treatment modalities will be confounded by patient heterogeneity, and modest improvements may go undetected in all but the largest trials. Mathematical modeling was used to study the effect on the steepness of the dose-response curve of selecting patients on the basis of the radiosensitivity measure SF2 (surviving fraction at 2 Gy). If SF2 is a faithful predictor of response in a group of tumors, then heterogeneity could be reduced by excluding the patients with the most sensitive (controlled with near certainty) and most resistant (recurring with near certainty) tumors. The resulting "stochastic fraction" (tumors for which treatment outcome is probabilistic) would be characterized by a steep dose response, and the number of patients required to demonstrate the effect of dose escalation would be substantially reduced (by about 50%).

Dose-Response Relationship, Radiation↗
PubMed1992

Evidence for individual differences in the radiosensitivity of human skin.

Previously published clinical data have been re-analysed to investigate individual differences in the radiosensitivity of human skin. In the clinical studies, acute and late skin reactions were recorded for 254 breast cancer patients receiving radiotherapy to the internal mammary nodes following simple or modified radical mastectomy. Each patient was treated bilaterally with different fractionation schedules to the right and left fields. Patients were assigned prospectively to 10 different treatment groups of 11-35 patients each, with all patients in a group receiving the same pair of fractionation schedules to the right and left fields. In the present study, correlations between the skin reactions in the two treatment fields per patient were investigated. For each of three different endpoints--peak reflectance measure of erythema, peak acute skin reaction score, and a ranking measure of the progression rate of telangiectasia--significant correlations were found between the levels of skin injury to the right and left treatment fields of the patients in most treatment groups. Although there were correlations between the absorbed doses in the right and left fields, statistical analyses indicated that dose effects were not sufficient to explain fully the patient-to-patient differences in skin response. Thus, these data provide evidence for the existence of individual differences in the radiation response of human skin, both for early and late effects. Whether these differences are dominated by heterogeneity in intrinsic cell radiosensitivity or by other factors has yet to be determined. However, there was no clear evidence of a correlation between the acute and late endpoints, suggesting that the individual differences in radiosensitivity are not dominated by a common genetic component expressed equally in all cells.

Breast Neoplasms↗
PubMed1992

Time course for the hazard of radiation-induced pneumonitis death in mice.

The form of the hazard function for radiation-induced pneumonitis death in mice was investigated. 'Hazard' refers to the instantaneous failure rate at a specified time, conditional upon non-failure to that time. Thus, the hazard function describes the time profile for the risk of pneumonitis death among still-surviving subjects. Single-dose lethality data from nine previously published studies involving irradiation of the lung were combined. Sufficient data were then available to estimate the hazard for eight different dose groups (dose range 12-15 Gy). The results of this study suggest that there are multiple distinct peaks in the hazard function for radiation pneumonitis, corresponding to distinct waves of death separated by an average interval of 33 days. The times of the peak hazards are dose dependent, with the peak hazards occurring earlier after larger doses, and the values of the hazards at the peaks are also dose dependent, with larger doses corresponding to a greater risk of death. The implications of a multiply-peaked hazard function for the possible mechanisms of response to whole-lung irradiation are discussed.

Animals↗
PubMed1991

Predominance of the metastatic phenotype in somatic cell hybrids of the K-1735 murine melanoma.

The purpose of these studies was to determine whether the metastatic phenotype will dominate when metastatic and nonmetastatic clones of the K-1735 mouse melanoma are hybridized by somatic cell fusion. Three nonmetastatic and three metastatic clones were transfected with DNA from plasmids pSV2neo or pSV2hygro, which confer resistance to the drugs neomycin or hygromycin, respectively. The metastatic properties of the six clones were not altered by these transfections. The tumorigenicity and metastatic capacity of cell hybrids formed by somatic cell fusion of nonmetastatic and metastatic clones were examined. To do so, near-tetraploid hybrids containing a nearly complete chromosomal complement from both parental cells were injected i.v. into syngeneic mice, and the number of metastatic nodules in the lung was determined at 45 days or when the mice became moribund. Seven of nine hybrids produced from the fusion of metastatic and nonmetastatic clones exhibited a highly metastatic phenotype, although in most cases the metastatic potential of the hybrids was lower than that of the metastatic parent cells. Very similar results were obtained in athymic nude mice. The metastatic potential of the hybrids was directly correlated with their growth in the subcutis of nude mice. These results indicate that the metastatic capacity of K-1735 cells predominates in somatic cell hybrids between nonmetastatic and metastatic cells. When fusion of nonmetastatic and metastatic cells yields a hybrid with nonmetastatic properties, it may be due to suppression of growth.

Animals↗
PubMed1991

Prognostic value of serum beta-2 microglobulin in low-grade lymphoma.

OBJECTIVE: To evaluate serum beta-2 microglobulin (beta-2M) and other prognostic indicators in previously untreated low-grade lymphoma. DESIGN: Cohort study of 80 patients with uniformly treated low-grade lymphoma, followed for a median of 21 months. These 80 patients, all of whom had serum beta-2M drawn within 2 weeks before starting therapy, were derived from a cohort of 119 previously untreated patients entered into one of three clinical trials. SETTING: Tertiary referral cancer center. PATIENTS: Eighty previously untreated stage I to IV patients (mean age, 55 years). INTERVENTION: Treatment was given according to Ann Arbor stage: Patients in stage IV were treated with CHOP-bleomycin and maintained on interferon therapy; those in stage III received CHOP-bleomycin and radiotherapy; and those in stages I and II received COP-bleomycin and radiotherapy. MEASUREMENTS: Outcome was determined by assessing complete remission rate and time to treatment failure. Univariate and multivariate analyses were used. RESULTS: The complete remission rate for patients with a beta-2M level of 3.0 mg/L or greater was 36% compared with 71% for those with a level of less than 3.0 mg/L. Using multivariate analysis that tested beta-2M as a continuous variable, it was selected as the most significant factor for complete response. The adjusted odds ratio was 0.285 (95% CI, 0.101 to 0.809). The Ann Arbor stage had marginal significance (adjusted odds ratio, 0.435; CI, 0.150 to 1.263). For time to treatment failure, beta-2M was the only variable retained in the multivariate model. At 42 months, no patient with a beta-2M level of 3.0 mg/L or greater was projected to be in remission as compared with 85% of patients with a beta-2M level of less than 3.0 mg/L. CONCLUSIONS: The serum beta-2M level is a good predictor of complete response and time to treatment failure. A larger number of patients should be studied to clarify the role of other potentially independent variables such as stage and age.

Adult↗
PubMed1991

Stages I and II diffuse large cell lymphomas: prognostic factors and long-term results with CHOP-bleo and radiotherapy.

One hundred forty-seven patients with Ann Arbor stages I and II diffuse large cell lymphoma (DLCL) were treated with combination chemotherapy consisting of cyclophosphamide, doxyrubicin, prednisone, and low-dose bleomycin (CHOP-Bleo) and involved-field radiation (IF XRT) between 1974 and 1984. A complete remission (CR) was attained by 54 of 57 patients with stage I disease and by 78 of 90 patients with stage II disease. Thirty-five patients had relapsing disease that occurred within 3 years in 31. The overall 10-year survival rate, counting all deaths, for patients with stage I was 72% as compared with 43% for patients with stage II (P less than .01). Determinate survival rates, censoring eight unrelated deaths, were similar to the overall survival rates: 77% and 51%, respectively. A multivariate analysis identified three independent prognostic factors: age, tumor extent, and serum lactic dehydrogenase (LDH) level. When the combined effect of tumor extent and LDH level were taken into consideration in the analysis, three risk groups for survival were identified. The best group, which consists of patients with minimum tumor and normal LDH levels, had a 10-year determinate survival of 79%. Patients with extensive tumors and elevated LDH levels had the poorest survival rate of 44%. An intermediate-risk group with a determinant survival of 62% was composed of patients with either extensive tumors or elevated LDH levels. These differences demonstrate the need to develop different treatment strategies based on risk factors for survival for patients with apparently localized Ann Arbor stages I/II DLCL.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Detection of micrometastatic tumor cells in bone marrow of breast carcinoma patients.

To determine the incidence and clinical significance of micrometastases in the bone marrow of breast carcinoma patients, we performed an immunoalkaline phosphatase assay using anticytokeratin (AE1, AE3, MAK-6) and antiepithelial (113F1, 260F9, 317G5) antibodies on the bone marrow aspirates of 71 stage IV disease patients with either recurrent regional or distant metastases. Although we detected tumor cells within the bone marrow of 38% of these patients with this assay, no significant correlation was seen with patient's age, menopausal status, bone scan, bone marrow core histology, response to induction chemotherapy, number of metastatic sites, dominant site of metastasis, or subsequent clinical outcome. The clinical parameters that were associated with improved survival were one dominant site of metastatic disease and regional soft tissue recurrence without distant disease.

Adolescent↗
PubMed1991

Direct analyses of in vivo colony survival after single and fractionated doses of radiation.

Several methods are described for analysing the results of in vivo colony assays using the statistical procedure called maximum-likelihood analysis. The methods differ in the way in which they take into account possible sources of variability in the data. The methods described here for analysing microcolony data are direct methods, in that they use the observed colony counts rather than transformed (e.g. Poisson-corrected) data. Each method can be used to estimate the average number of surviving cells per tissue structure (e.g. per jejunal crypt) in a single dose group, together with 95% confidence intervals, or to fit cell-survival models to data from a range of dose groups (e.g. to obtain estimates of D0 or of the linear-quadratic parameters alpha and beta). Experimental microcolony data from murine jejunum, colon, and hair follicles irradiated in anagen (proliferative) or telogen (resting) phase have been analysed. Estimates of D0 have been derived from single-dose data and estimates of alpha, beta, and the initial number of clonogenic cells per structure have been derived from fractionation data. For hair follicles, the half-time of repair of sublethal radiation injury has also been derived from fractionation data.

Animals↗
PubMed1991

The geographic relationships between physicians' residency sites and the locations of their first practices.

The uneven geographic distribution of physicians has been identified as a significant problem for the delivery of health care services. The present study examined one of the factors that contribute to the distribution of physicians; how far they move from their residency sites to establish their first practices. In 1989, the authors selected a random sample of 701 U.S. residency programs in the ten specialties with the most practitioners, and measured the distance each of these physicians moved to his or her first practice location. Of the 701 programs, 58.5% provided usable information about 2,612 physicians. Of these physicians, over 40% had moved less than 10 miles from their residencies, and over 50% had moved less than 75 miles. Comparisons among the physicians from the various specialties showed that the primary care physicians moved significantly shorter distances than did those from the other specialties. In the last two decades, many efforts have been made to increase the geographic distribution of physicians. The evidence from this study suggests that so far as the distances that physicians move from their practice sites are concerned, little has changed. Recent graduates of residency programs show no more tendency to move far from their residency sites than did their counterparts 30 years ago, as reported in the literature.

Internship and Residency↗
PubMed1990

The selection of patients for accelerated radiotherapy on the basis of tumor growth kinetics and intrinsic radiosensitivity.

Mathematical modeling was used to reach qualitative conclusions concerning the relative rate of local tumor control that might be achieved by using accelerated fractionation to treat only the patients with the most rapidly growing tumors, compared with the control rates that could be expected from either conventional or accelerated radiotherapy alone. The results suggest that concomitant boost therapy is equally or more effective than conventional dose fractionation for all tumors, regardless of their growth kinetics. For tumors with very short clonogen doubling times, CHART (continuous hyperfractionated accelerated radiotherapy) may be even more effective than concomitant boost treatment, but CHART is less effective than conventional or concomitant boost therapy for tumors with longer clonogen doubling times. Thus, there is a rationale for using a predictive assay of tumor clonogen doubling times to identify the patients who should be treated with CHART. However, improvements in local tumor control resulting from concomitant boost treatment or the selective use of CHART are not likely to be apparent in the population as a whole, because the overall control rates are largely determined by refractory tumors having little chance of control with any of the treatments and by highly responsive tumors that are likely to be controlled regardless of the treatment choice. Differences in control rates with different treatment strategies are most apparent in the stochastic fraction of the population, which excludes those patients for whom there is either very little chance (e.g. less than 1%) or a very high chance (e.g. greater than 99%) of achieving local control with both treatments. The stochastic fraction can be approximated by excluding those patients with the most radioresistant and the most radiosensitive tumors, since intrinsic tumor radiosensitivity appears to be the single most important factor determining treatment outcome.

Dose-Response Relationship, Radiation↗
PubMed1990

Comments on a time-dependent version of the linear-quadratic model.

The accuracy and interpretation of the "LQ + time" model (E = D(alpha + beta d) - gamma T) are discussed. Evidence is presented, based on data in the literature, that this model does not accurately describe the changes in isoeffect dose occurring with protraction of the overall treatment time during fractionated irradiation of the lung. This lack of fit of the model explains, in part, the surprisingly large values of gamma/alpha that have been derived from experimental lung data. The large apparent time factors for lung suggested by the model are also partly explained by the fact that gamma T/alpha, despite having units of dose, actually measures the influence of treatment time on the effect scale, not the dose scale, and is shown to consistently overestimate the change in total dose. The unusually high values of alpha/beta that have been derived for lung using the model (approximately 5 Gy) are shown to be influenced by the method by which the model was fitted to data. Reanalyses of the data using a more statistically valid regression procedure produce estimates of alpha/beta more typical of those usually cited for lung (approximately 3 Gy). Most importantly, published isoeffect data from lung indicate that the true deviation from the linear-quadratic (LQ) model is nonlinear in time, instead of linear, and also depends on other factors such as the effect level and the size of dose per fraction. Thus, we do not advocate the use of the "LQ + time" expression as a general isoeffect model.

Animals↗