Unirradiated Groups Research Articles

Radiomics approach for identifying radiation-induced normal tissue toxicity in the lung

The rapidly evolving field of radiomics has shown that radiomic features are able to capture characteristics of both tumor and normal tissue that can be used to make accurate and clinically relevant predictions. In the present study we sought to determine if radiomic features can characterize the adverse effects caused by normal tissue injury as well as identify if human embryonic stem cell (hESC) derived extracellular vesicle (EV) treatment can resolve certain adverse complications. A cohort of 72 mice (n = 12 per treatment group) were exposed to X-ray radiation to the whole lung (3 × 8 Gy) or to the apex of the right lung (3 × 12 Gy), immediately followed by retro-orbital injection of EVs. Cone-Beam Computed Tomography images were acquired before and 2 weeks after treatment. In total, 851 radiomic features were extracted from the whole lungs and < 20 features were selected to train and validate a series of random forest classification models trained to predict radiation status, EV status and treatment group. It was found that all three classification models achieved significantly high prediction accuracies on a validation subset of the dataset (AUCs of 0.91, 0.86 and 0.80 respectively). In the locally irradiated lung, a significant difference between irradiated and unirradiated groups as well as an EV sparing effect were observed in several radiomic features that were not seen in the unirradiated lung (including wavelet-LLH Kurtosis, wavelet HLL Large Area High Gray Level Emphasis, and Gray Level Non-Uniformity). Additionally, a radiation difference was not observed in a secondary comparison cohort, but there was no impact of imaging machine parameters on the radiomic signature of unirradiated mice. Our data demonstrate that radiomics has the potential to identify radiation-induced lung injury and could be applied to predict therapeutic efficacy at early timepoints.

Rhodamine-B for the mark, release, and recapture experiments in gamma-irradiated male Aedes aegypti (Diptera: Culicidae): Persistence, dispersal, and its effect on survival.

Rhodamine-B (Rh-B) marking shows a great potential for use in mark-release-recapture (MRR) studies for rear-and-release mosquito control strategies, including the radiation-based sterile insect technique. However, its applicability and evaluation in body-stain-irradiated males of Aedes aegypti have received little attention. The present study evaluated the use of Rh-B to mark gamma-irradiated male A. aegypti. Male A. aegypti were irradiated at the pupal stage at a dose of 70 Gy. After emergence, males were fed 0.1, 0.2, 0.3, or 0.4% Rh-B in 10% glucose solution for 4 days. Groups of unirradiated males that received the same feeding treatments were used as control groups. We evaluated the persistence of Rh-B and the longevity of males after Rh-B feeding. Furthermore, the use of Rh-B in irradiated A. aegypti for MRR experiments was evaluated at an urban site. No difference was observed in the Rh-B persistence among all concentrations at the 24-h postmarking period ranging from 91.25 ± 1.61% to 96.25 ± 1.61% and from 90.00 ± 2.28% to 93.13 ± 2.77% for the unirradiated and irradiated groups, respectively. Rh-B persistence significantly decreased over time, and persistence was significantly longer with increased concentrations in both the unirradiated and irradiated groups. Longevity was considerably decreased by Rh-B feeding and irradiation. However, no significant difference in longevity was found among males fed various concentrations of Rh-B. Through MRR experiments, irradiated-Rh-B marked males were mostly detected within a radius of 20 m and 40 m from the center-release point. The mean distance traveled of the released males from the three MRR events was calculated to be 42.6 m. This study confirms that Rh-B body marking through sugar feeding is applicable for irradiated male A. aegypti, with only a slight effect on longevity. Furthermore, considering the significant reduction in persistence over time, further study is needed to assess the impact of this reduction on the calculation of field biological parameters resulting from MRR experiments.

High-Fluence Accelerated PACK-CXL for Bacterial Keratitis Using Riboflavin/UV-A or Rose Bengal/Green in the Ex Vivo Porcine Cornea.

To investigate and compare the efficacy of high-fluence accelerated photoactivated chromophore for keratitis-corneal cross-linking (PACK-CXL) using either riboflavin/ultraviolet (UV)-A light or rose bengal/green light to treat Staphylococcus aureus or Pseudomonas aeruginosa infections in an ex vivo porcine cornea model. One hundred and seventeen ex vivo porcine corneas were injected with clinical isolates of S. aureus or P. aeruginosa, divided into eight groups, and cultured for24 hours. Then, either riboflavin with UV-A light irradiation (30 mW/cm2; 8 minutes, 20seconds; 15 J/cm2) or rose bengal with green light irradiation (15 mW/cm2, 16minutes, 40 seconds; 15 J/cm2) was applied; unirradiated infected groups served as controls. All corneas were incubated for another 24 hours. Next, corneal buttons were obtained and vortexed to release the bacterial cells. The irradiated and unirradiated solutions were then plated and incubated on agar plates. The amount of colony-forming units was quantified and the bacterial killing ratios (BKRs) resulting from different PACK-CXL protocols relative to non-treated controls were calculated. Riboflavin/UV-A light PACK-CXL resulted in median BKRs of 52.8% and 45.8% in S. aureus and P. aeruginosa, respectively, whereas rose bengal/green light PACK-CXL resulted in significantly greater BKRs of 76.7% and 81.0%, respectively (both P < 0.01). Both accelerated PACK-CXL protocols significantly decreased S. aureus and P. aeruginosa bacterial loads. Comparing the riboflavin/UV-A light and rose bengal/green light PACK-CXL approaches in the same experimental setup may help develop strain-specific and depth-dependent PACK-CXL approaches that could be used alongside the current standard of care. Our study used an animal model to gain insight into the efficacy of high-fluence accelerated PACK-CXL using either riboflavin/UV-A light or rose bengal/green light to treat Staphylococcus aureus or Pseudomonas aeruginosa infections.

Evaluation of radioprotective efficacy of Drymaria cordata extract on whole-body radiation-induced haematological damage in mice

Introduction: This study aimed to evaluate the radioprotective potential of Drymaria cordata (DC) extract on mice’s haematological parameters following exposure to X-rays radiation.Materials and Methods: Sixty female mice weighing 38-45g, 10-12 weeks old, were used for this study. The mice were divided into six different groups containing ten mice, sub-divided into irradiated and un-irradiated groups. The animals received 250mg/kg extract of DC by oral gavage for thirteen days in addition to feeding and water ad libitum. Mice were irradiated at the Radiotherapy and Oncology Department of Grey’s Hospital using a linear accelerator. Blood samples were collected at different time intervals for the haematology test with post-irradiation monitoring for 30 days. Results: Exposure of mice to 4Gy and 8Gy of X-ray radiation produced significant changes in the mice’s erythrocytes, haematocrit, leukocytes and platelets, in a dose and time-dependent manner compared with the control (CNT) group. The present study revealed a progressive decrease in all the haematological parameters until 30 days among the irradiated groups. However, animals treated with DC extract before irradiation and animals who received extract only exhibited a significant time-dependent increase in the studied haematological parameters compared to the animals in the CNT group. Furthermore, the pre-treatment of mice with the DC delayed the onset of mortality, thereby increasing mice's survival rate compared with the irradiated control. Conclusion: Our findings showed that DC is a potent natural radioprotective agent through its ability to reduce radiation-induced damage in mice’s haematopoietic system and increase the survival rate.

Radioprotective potential of Costus afer against the radiation-induced hematological and histopathological damage in mice.

PurposeThis study investigated the possible radioprotective effect of Costus afer extract (CAE) on hematological and histopathological parameters of mice.Materials and MethodsFifty-four male mice with mass between 37–43 g, 11–13 weeks old were used for this study. We divided the mice into six different groups containing nine animals, which were then further sub-divided into irradiated groups and un-irradiated groups. Animals received 250 mg/kg body weight extract of CAE by oral gavage for 6 days in addition to feeding and water ad libitum. Animals in the irradiated group were exposed to radiation at the Department of Radiotherapy and Oncology, Grey’s Hospital using a linear accelerator. Blood samples were collected at 48-hour post-irradiation for the hematology test followed by histopathology examination of kidney and liver. ResultsOur findings revealed that 3 Gy and 6 Gy dose of X-ray radiation caused a significant reduction in the white blood cell, packed cell volume, hemoglobin, neutrophils, lymphocytes, eosinophils, and platelet counts compared with the control group. However, the administration of CAE before irradiation significantly increased the mentioned parameters. There was no increase in red blood cell and monocyte among treated groups compared with the control. Histopathological changes in the kidney and liver sections revealed that no visible lesion in the pretreated mice. Hepatocytes seem to be within normal histological limits.ConclusionsThis study concludes that CAE offered some protection against radiation-induced hematological alterations, but there was no significant improvement in the histopathological parameters. Thus, further studies are needed to validate its radioprotective effect on histopathological variables.

Effects of Laser at 810 Nm on Wound Healing in Albino Mice

Many researches focused on laser therapy of wound healing in different animal models due to the lack of a standard protocol in the application of such phototherapy. Objective: To study the effects of 810nm laser at a constant irradiance of 41.63 mw/cm2 and exposure (illumination) time of 5,15 minutes on wounds created on Albino mice (BALB/c).&#x0D; Skin wound with elliptic shape and full thickness was created on the dorsal side of ‘45 mature male albino mice. Irradiated animals were divided into two main groups based on irradiation time, the first was irradiated for 5 min and the second for 15 min, each was subdivided into three subgroups (n=5) according to number of treatment days (3, 5 and 10 days). Both treated and respective control (n=15) subgroups were sacrificed on days 3, 5 and 10 posttreatment. Laser therapy was applied using a 810 nm diode laser with a continuous wave, an output power of 400 mw, and irradiance of 41.63. The 5 min dose was 12 .5 J/cm2, whereas the 15 min dose was 37.4 J/cm2. The shape of the laser beam was fitted with a convex lens as ‘beam expander’ to irradiate a circular area of 3.4 cm diameter. Laser therapy was started after surgery and repeated for 3, 5 and 10 days, while its effects were examined by histological evaluation. Results: At day 3 of treatment with near infrared 810nm laser at doses of 12.5J/cm² and 37.4J/cm², there was no evidence of wounds healing in irradiated groups which showed no differences with the respective control groups. At day 5 of treatment, the results showed an important increase in the scores of the parameters of wound healing (formation of granulation tissue and collagen deposition) in the irradiated groups. Near infrared 810nm laser had photobiostimulation effects on wound healing at irradiance of 41.63mW/cm² and doses of 12.5J/cm² for 5 minutes and 37.4J/cm² for 15 minutes exposure time. A complete picture of wound healing response appeared in all irradiated groups within 10 days of treatment, as expressed by complete ‘re-epithelialization’, moderate granulation tissue formation, and presence of collagen fibers, while incomplete wound healing response was observed in un-irradiated control groups within the same period. The study showed that 810 nm laser therapies had significant effects on wound healing, especially at a dose of 37.4J/cm².

Radiation tolerance and bystander effects in the eutardigrade speciesHypsibius dujardini(Parachaela: Hypsibiidae)

Some tardigrade species can tolerate high radiation doses. Radiation-induced bystander effects – damage in unirradiated cells associated with irradiated cells – have yet to be reported in tardigrades. We investigated radiation tolerance and radiation-induced bystander effects on long-term survival in the eutardigrade species Hypsibius dujardini. To study direct radiation effects, groups were irradiated with gamma radiation at levels of 3 and 5 kGy. To study radiation-induced bystander effects, unirradiated groups were exposed to a single irradiated (3 or 5 kGy) individual. Survivorship was monitored every 2 days until all individuals had died. Direct radiation decreased survivorship in a dose-dependent manner. Survivorship in bystander groups differed significantly from survivorship in groups irradiated directly with 5 kGy but insignificantly from survivorship in groups irradiated directly with 3 kGy, suggesting that radiation-induced bystander effects had saturated. The eutardigrade species H. dujardini can tolerate high radiation doses, with radiation-induced bystander effects that manifest as a threshold response.

Outcomes following a limited approach to radiotherapy in rectal cancer

Variation in the use of neoadjuvant and adjuvant radiotherapy for rectal cancer suggests an opportunity to avoid it in all but patients at highest risk of local recurrence. Between 1 July 1999 and 1 February 2006, patients with primary rectal cancer were treated by a single surgeon operating at McMaster University, Hamilton, Ontario, Canada. Digital rectal examination and pelvic computed tomography were used to determine whether the mesorectal margin was threatened by tumour and thus whether preoperative radiotherapy would be needed. The study outcome was local tumour recurrence. Forty-six (48 per cent) of 96 patients received preoperative radiation therapy. The median follow-up was 4·2 years. Tumours were fixed or tethered in 31 (67 per cent) of the 46 irradiated patients. In contrast, no tumour was fixed in unirradiated patients and only ten (20 per cent) of the 50 tumours were tethered. The proportion of patients with stage I or II tumours based on final pathology was similar: 61 per cent (28 of 46) and 56 per cent (28 of 50) in irradiated and unirradiated groups respectively (P = 0·287). There were four (9 per cent) and two (4 per cent) local recurrences among irradiated and unirradiated patients respectively (P = 0·422). Limiting preoperative radiotherapy in rectal cancer to patients with a threatened circumferential margin does not compromise patient outcome.

Restoration of radiation therapy-induced salivary gland dysfunction in mice by post therapy IGF-1 administration

BackgroundRadiotherapy for head and neck cancer results in severe and chronic salivary gland dysfunction in most individuals. This results in significant side effects including xerostomia, dysphagia, and malnutrition which are linked to significant reductions in patients' quality of life. Currently there are few xerostomia treatment approaches that provide long-term results without significant side effects. To address this problem we investigated the potential for post-therapeutic IGF-1 to reverse radiation-induced salivary gland dysfunction.MethodsFVB mice were treated with targeted head and neck radiation and significant reductions in salivary function were confirmed 3 days after treatment. On days 4-8 after radiation, one group of mice was injected intravenously with IGF-1 while a second group served as a vehicle control. Stimulated salivary flow rates were evaluated on days 30, 60, and 90 and histological analysis was performed on days 9, 30, 60, and 90.ResultsIrradiated animals receiving vehicle injections have 40-50% reductions in stimulated salivary flow rates throughout the entire time course. Mice receiving injections of IGF-1 have improved stimulated salivary flow rates 30 days after treatment. By days 60-90, IGF-1 injected mice have restored salivary flow rates to unirradiated control mice levels. Parotid tissue sections were stained for amylase as an indicator of functioning acinar cells and significant reductions in total amylase area are detected in irradiated animals compared to unirradiated groups on all days. Post-therapeutic injections of IGF-1 results in increased amylase-positive acinar cell area and improved amylase secretion. Irradiated mice receiving IGF-1 show similar proliferation indices as untreated mice suggesting a return to tissue homeostasis.ConclusionsPost-therapeutic IGF-1 treatment restores salivary gland function potentially through normalization of cell proliferation and improved expression of amylase. These findings could aid in the rational design of therapy protocols or drugs for the treatment of radiation-induced salivary gland dysfunction in patients who have completed their anti-cancer therapies.

MO‐D‐204B‐09: Characterization of ADC and T2 Responses of Tumor Tissue to Radiation with Histological Interpretation

Purpose: To characterize the temporal, dose, and oxygenation dependence of apparent diffusion coefficient (ADC) and transverse relaxation time (T2) responses of tumor tissue after treatment with ionizing radiation, in the context of histology and observed volume changes. Methods: Human glioblastoma multiforme (GBM) tumors were grown subcutaneously in mice. Multiple groups treated with 200 kVp x‐rays and two unirradiated control groups were formed (n=6 per group). Single fraction groups received doses ranging from 50 cGy to 800 cGy. Fractionated deliveries were 800 cGy in 1, 2 or 3 fractions and fractions were separated by 24 or 72 hours. Oxygenation dependence was investigated with 800 cGy in a single fraction with a ligature in place to deplete the tumor's oxygen supply. Images were acquired on a 9.4 T MR system at multiple time points before and after treatment. Quantitative ADC and T2 maps were produced from each image set. Results: A dose dependent ADC increase was observed in irradiated tumor tissue. Maximum response was observed 7 days post‐treatment. Tumor T2 was maximum 3 days after treatment and had fallen below baseline by 14 days after treatment. Fractionation did not affect amplitude of ADC response, but delayed the time at which maximum ADC occurred and the time for T2 to fall below baseline. Hypoxic tissues showed reduced ADC response after treatment. Preliminary pathology results show ADC response correlated with reduced tumor growth rate and reduced mitotic cell count. Early increases in ADC and T2 were associated with early‐stage necrosis and edema. Later responses were associated with evolving necrosis and extracellular macromolecule accumulation. Conclusion: These results further the understanding of ADC and T2 responses and their development as biomarkers of treatment response.

The Influence of Intraarterial High-Dose Cisplatin With Concomitant Irradiation on Arterial Microanastomosis

In this experimental study with rabbits, the influence of intraarterial high-dose cisplatin with concomitant irradiation on arterial microanastomoses was evaluated to determine their impact on free-tissue transfers. The right and left iliac arteries of 10 rabbits were injected with 150 mg/m of cisplatin (group 1). To serve as physiological controls, the iliac arteries of 10 other rabbits were injected with the same volume of saline (group 2). Hypofractionated radiotherapy was given to the right inguinal area of all rabbits using a Co unit, 1.25 MeV, and an SSD of 80 cm for 25 Gy at 5 fractions a day for 5 days (groups 1A and 2A) and the left inguinal areas remained unirradiated (groups 1B and 2B). Both femoral arteries of all 20 rabbits were transected and anastomosed using microsurgical techniques on day 7 after the treatment. All femoral artery anastomoses were examined under anesthesia for pulsatile blood flow 14 days after the surgery. Arteries, including the anastomotic site, were harvested and fixed for histologic evaluation by light microscopy and transmission electron microscopy. Microscopic evaluation showed that all femoral artery anastomoses had good, pulsatile blood flow. Histologic examination of the femoral artery anastomotic site revealed changes of the arterial walls that varied between the groups. Evidence of intimal changes included detachment of endothelial cells in the intimal layer, edema of the endothelial cells in the intima, intimal thickening, separation of the intima from the tunica media, and collagen deposition. Evidence of damage to the tunica media included vacuolation and disarray of the smooth muscle cells, fibrinoid necrosis, and hemorrhage. The damage was most pronounced in the arteries that received both intraarterial cisplatin and radiotherapy (group 1A). The degree of damage diminished in the arteries of the radiotherapy-alone group (group 2A) and the intraarterial cisplatin-alone arteries (group 1B) compared with the control arteries (group 2B). Despite the arterial damage after irradiation and/or cisplatin, the patency rates after vascular anastomosis were 100% for every group. Although damage to the arterial walls in the group that received intraarterial high-dose cisplatin with concomitant irradiation was most obvious, there were no differences in the patency rates after vascular anastomosis between any of the groups. Thus, after intraarterial high-dose cisplatin with concomitant irradiation, the femoral arteries can be used with caution as recipient vessels for free-tissue transfer.

Ultraviolet B Suppresses Immunity by Inhibiting Effector and Memory T Cells

Contact hypersensitivity is a T-cell-mediated response to a hapten. Exposing C57BL/6 mice to UV B radiation systemically suppresses both primary and secondary contact hypersensitivity responses. The effects of UVB on in vivo T-cell responses during UVB-induced immunosuppression are unknown. We show here that UVB exposure, before contact sensitization, inhibits the expansion of effector CD4+ and CD8+ T cells in skin-draining lymph nodes and reduces the number of CD4+ and IFN-gamma+ CD8+ T cells infiltrating challenged ear skin. In the absence of UVB, at 10 weeks after initial hapten exposure, the ear skin of sensitized mice was infiltrated by dermal effector memory CD8+ T cells at the site of challenge. However, if mice were previously exposed to UVB, this cell population was absent, suggesting an impaired development of peripheral memory T cells. This finding occurred in the absence of UVB-induced regulatory CD4+ T cells and did not involve prostaglandin E2, suggesting that the importance of these two factors in mediating or initiating UVB-induced immunosuppression is dependent on UVB dose. Together these data indicate that in vivo T-cell responses are prone to immunoregulation by UVB, including a novel effect on both the activated T-cell pool size and the development of memory T cells in peripheral compartments.

Age and gender effects on contact sensitization and photoimmune suppression in young and middle‐aged adults

The contact hypersensitivity (CHS) response has been used to assess ultraviolet radiation (UVR)-induced immunosuppression and to evaluate the photoimmune protection of different sunscreen preparations in vivo. Earlier reports of the effect of age and gender on CHS response have led to variations in inclusion criteria for participants in regards to age and gender in the study of sunscreen immune protection factor (IPF). This study is a retrospective analysis of data from 73 volunteers from prior CHS studies with the goal of determining the effect of age and gender in young and middle-aged adults on CHS response to dinitrochlorobenzene (DNCB) in unirradiated and UV-irradiated skin. In patients aged 18-63 years, the effect of age on CHS response as well as on UV suppression of CHS response was not statistically significant. In the unirradiated (n=45) and UV-irradiated (n=28) groups, the CHS response between men and women was similar when the timing of DNCB application avoided the period within 5 days before or after the first day of the menstrual cycle. Within a certain range, 18-63 years, age does not significantly affect the normal CHS response and the suppression of CHS response by UV. This study also demonstrated that as long as certain days of the menstrual cycle are avoided when sensitizing women of reproductive age, gender does not significantly affect CHS response. Thus, within these parameters, CHS can be appropriately evaluated in healthy individuals without much concern regarding independent effects of age and gender.

Cardiovascular death and second non–breast cancer malignancy after postmastectomy radiation and doxorubicin-based chemotherapy

Purpose To assess the incidence of long-term toxicity after postmastectomy radiation and doxorubicin-based adjuvant chemotherapy. Methods Records of 470 patients treated with mastectomy, doxorubicin-based chemotherapy, and postmastectomy radiation in five institutional prospective trials were retrospectively reviewed. Actuarial toxicity rates were compared with those of 1031 patients treated with mastectomy and doxorubicin-based chemotherapy who did not receive postmastectomy radiation. For those treated with radiation, the chest wall received a median dose of 55 Gy with Co-60 (42%) or electrons (51%). Adjuvant chemotherapy consisted of a doxorubicin-based regimen, often followed by 2 years of cyclophosphamide, methotrexate, and fluorouracil. Results Median follow-up was 10 years. The overall 10-year actuarial rates of RTOG toxicity Grade >1 and ≥3 after radiation were 4% and 2%, respectively. The overall 10- and 15-year actuarial rates of second non–breast cancer malignancy were 3.8% and 7%, respectively. There was no statistical difference between the rates of non–breast cancer second malignancy in the radiated and unirradiated cohorts (3.4% vs. 4.7% 10-year actuarial rates). Increasing age and treatment with >10 cycles of chemotherapy were associated with higher rates of second malignancy ( p = 0.025, p = 0.016). The 10-year actuarial rate of death from myocardial infarction (MI) was 2.4% (eight events) and 0.5% (five events) in the radiated and unirradiated groups, respectively ( p = 0.058). Of the 8 irradiated patients who died of MI, 2 patients had left-sided breast cancer. Conclusions We found very low rates of serious sequelae after postmastectomy radiation, including death from myocardial infarction and non–breast cancer second malignancy. The rate of second non–breast cancer malignancy was increased among patients treated with >10 cycles of cyclophosphamide-containing chemotherapy.

Induction of myeloid leukemias in C3H/He mice with low-dose rate irradiation

C3H/He male mice were exposed to whole body gamma-ray irradiation at 8 weeks of age. Radiation at a high-dose rate of 88.2 cGyears/min with doses of 0.125–5.0 Gyears, a medium dose rate of 9.56 cGyears/min with doses of 1.0–5.0 Gyears, and low-dose rates of 0.0298 cGyear/min with doses of 1.0–10 Gyears, 0.0067 cGyear/min with doses of 1.0–10.0 Gyears or 0.0016 cGyear/min with doses of 1.0–4.0 Gyears were delivered from 137Cs sources. The mice in the low-dose rate groups were irradiated continuously for 22 h daily during a period of 3 to 200 days. All the mice were maintained for their entire life span and were pathologically examined after their death. Myeloid leukemia developed significantly more frequently in the irradiated groups with doses over 1 Gyear than in the unirradiated groups. The maximum values were 23.5% in the high-dose rate group, 11% in the medium dose rate group, 7.3%, 7.2%, 6.3% in the low-dose rate groups, and 0.99% in the unirradiated control group. These dose–effect curves had their highest values on each curve at about 3 Gyears. We obtained the dose and dose rate effectiveness factor (DDREF) values of 2.96 by linear fittings for their dose–response curves of the dose ranges in which leukemia incidences were increasing.

Ageing tests of radiation damaged lasers and photodiodes for the CMS experiment at CERN

The effects of thermally accelerated ageing in irradiated and unirradiated 1310 nm InGaAsP edge-emitting lasers and InGaAs p-i-n photodiodes are presented. 40 lasers (20 irradiated) and 30 photodiodes (19 irradiated) were aged for 4000 hours at 80/spl deg/C. Periodic measurements were made of laser threshold and efficiency, and p-i-n leakage current and photocurrent. There were no sudden failures and there was very little wearout related degradation in either unirradiated or irradiated sample groups. The results suggest that the tested devices have a sufficiently long lifetime to operate for at least 10 years inside the Compact Muon Solenoid experiment despite being exposed to a harsh radiation environment.

Effects of Radiation on the Longitudinal Trends of Total Serum Cholesterol Levels in the Atomic Bomb Survivors

The effects of radiation on the long-term trends of the total serum cholesterol levels of the Hiroshima and Nagasaki atomic bomb survivors were examined using data collected in the Adult Health Study over a 28-year period (1958-1986). The growth-curve method was used to model the longitudinal age-dependent changes in cholesterol levels. For each sex, temporal trends of cholesterol levels were characterized with respect to age, body mass index, city and birth year. We then examined whether the temporal trends differed by radiation dose. We showed that the mean growth curve of cholesterol levels for the irradiated subjects were significantly higher than that for the unirradiated subjects, and that the increase was greater for women than for men. No difference in dose response was detected between Hiroshima and Nagasaki. An increased mean level of cholesterol was evident for irradiated women in general, but a notable increase was apparent in males only for the youngest birth cohort of 1935-1945. The difference in the mean cholesterol levels between the irradiated and unirradiated subjects diminished past 70 years of age. It is not known whether this is due to natural progression or is an artifact of nonrandom variation in the rate of participation in the examinations. The maximum predicted increase at 1 Gy for women occurred at age 52 years for the 1930 cohort: 2.5 mg/dl (95% CI 1.6-3.3 mg/dl) for Hiroshima and 2.3 mg/dl (95% CI 1.5-3.1 mg/dl) for Nagasaki. The corresponding increase for men occurred at age 29 years for the 1940 cohort: 1.6 mg/dl (95% CI 0.4-2.8) for Hiroshima and 1.4 mg/dl (95% CI 0.3-2.6) for Nagasaki. Controlling for cigarette smoking did not alter the dose-response relationship. Although the difference in the mean growth curves of the irradiated and unirradiated groups was statistically significant, there was a considerable overlap in the individual growth curves of the two groups. The significant sex difference and the greater magnitude of radiation effects in women suggest that hormonal changes resulting from radiation exposure, such as accelerated menopause, is an area worth investigating to delineate the mechanisms underlying the increased cholesterol levels of the irradiated female subjects. This increase may also partially explain the increased rate of coronary heart disease seen in the atomic bomb survivors.

Adaptive response induced by low dose ionizing radiation in human cervical carcinoma cells

Adaptive response induced by low dose γ-ray irradiation in human cervical carcinoma cells was examined. Cells were exposured to low dose of γ-ray (1 cGy) followed by high doses of γ-ray irradiation (0, 1, 2, 3, 5, 7 and 9 Gy for clonogenic assay or 1.5 Gy for micronucleus assay) with various time intervals. Survival fractions of cells in both low dose-irradiated and unirradiated groups were analyzed by clonogenic assay. Survival fractions of low dose-irradiated cells was higher than that of control group irradiated only with high dose γ-ray. The increase in cell survival was maximum when low and high dose irradiation time interval was 4 hr. Frequencies of micronuclei which is an indicative of chromosome aberration were also enumerated in both low dose-irradiated and unirradiated groups. In consistent with the result obtained from survival fractions analyzed by clonogenic assay, maximum reduction in frequencies of micronuclei was observed when low dose radiation was given 4 hr prior to high dose irradiation. These results demonstrate that low dose γ-ray irradiation induced adaptive response to subsequent high dose γ-ray irradiation in human cervical carcinoma cells. Our data suggest that one of the possible mechanisms of adaptive response induced by low dose radiation is the increase in repair of DNA double strand breaks in low dose radiation-adapted cells.

Quantifying the Frequency of Radiogenic Thyroid Cancer per Clonogenic Cell In Vivo

We used quantitative cell transplantation to evaluate the frequencies of the formation of radiogenic thyroid cancer per clonogenic rat thyroid epithelial cell in vivo. Irradiation of thyroid cells with 5 Gy 137Cs gamma rays before transplantation significantly increased the incidence of thyroid carcinoma formation in such grafts compared to similar grafts of unirradiated thyroid cells. We calculated the frequencies of radiogenic cancer by subtracting cancer incidences in unirradiated groups from incidences in irradiated groups and dividing by the number of clonogens grafted. The highest observed frequencies of radiogenic thyroid cancer so calculated were 0.141 and 0.046 cancers per surviving irradiated clonogenic cell. These cancer frequencies occurred in grafts containing averages of three and ten clonogens per site, respectively, and represent one cancer per approximately 7 and approximately 22 irradiated clonogens. We conclude that the highest observed frequencies of radiogenic cancer are likely to be the best estimates of the "real" frequency per irradiated clonogen in that virtually all the methodological sources of inaccuracy tend to decrease the observed frequency compared to the "real" frequency. Radiogenic initiation of cancer is thus a highly common cellular event among surviving irradiated clonogenic thyroid cells. To examine the role of endocrine-mediated tumor promotion on the expression of radiogenic cancer, we attenuated the intensity of thyrotropin (TSH)-mediated tumor promotion in some groups of recipient animals. We found that the incidence rates for radiation-associated cancer were significantly higher in rats with higher serum TSH levels compared to rats with lower TSH levels. We conclude from these data that (1) radiogenic thyroid cancer occurs with a high frequency and (2) chronic TSH stimulation accelerates progression of radiogenic neoplasms to overt carcinomas and promotes development of later-arising carcinomas in grafts of unirradiated thyroid clonogens.

Histopathologic effects of soluble glucan and WR-2721, independently and combined in C3H/HeN mice.

Soluble glucan, an immunomodulator, and Walter Reed (WR)-2721, a radioprotectant, increase postirradiation survival when administered before and after exposure, respectively. Combined, these agents act synergistically through WR-2721's ability to spare hematopoietic stem/progenitor cells from radiation injury and glucan's ability to subsequently stimulate spared cells to proliferate. In this study, the histopathologic effects of WR-2721 (200 mg/kg, ip) and glucan (250 mg/kg, iv), at doses capable of increasing survival in lethally irradiated mice, were evaluated in unirradiated and irradiated female C3H/HeN mice. After treatment, whole body weights and wet organ weights of liver, spleen, and kidney, as well as gross and histologic changes in these and other tissues, were monitored on Days 1, 4, 7, 11, 15, 21, and 28. Morphometric studies of splenic white and red pulps were also performed. Soluble glucan, with or without WR-2721, in unirradiated groups, was associated with splenomegaly, transient morphometrically determined perturbations of white and red pulp areas, and histologic alterations of white pulp. In irradiated mice, splenic weight loss was initially dampened in glucan groups and accompanied by morphologic and histologic changes similar to those seen in unirradiated counterparts. The subsequent rebound of splenic parameters in irradiated mice was limited to WR-2721-treated mice and was associated with hematopoietic reconstitution. Glucan, with or without WR-2721, in unirradiated groups was associated with transient hepatomegaly and associated histologic changes. Similar changes in irradiated animals were seen only in the combined treatment group.