The human thyroid epithelial cell HTori-3 has been transformed with doses of either chronic and acute x-rays or strontium beta particles. Models of the past have relied upon animal cell systems to mimic in vitro carcinogenesis. The HTori-3 system hoped to overcome the limitations associated with these types of models by using a human thyroid cell line immortalised with the SV40 virus. HTori-3 human thyroid epithelial cells were irradiated in vitro, passaged and then transplanted into nude mice. Tumours that grew over a 2-6 month period were excised and re-established in culture. Samples were stored and all tumours were taken for histological examination. Chromosome spreads confirmed the human nature of all tumours. Following exposure to acute x-rays in the range of 0.25-2.0 Gy 13 tumours were observed in 25 recipients. Following 0.25-2.0 Gy of chronic x-rays 10 tumours from 25 recipients were observed. From a single 2 Gy exposure of strontium beta particles 3 primary tumours from 5 recipients were observed. The largest of these was re-transplanted in nude mice resulting in 100% incidence. All tumours were classified as undifferentiated anaplastic carcinomas. A small number of tumours were observed in the control cell lines, these may be the result of a general instability found with the partial transformed parental cell line. All 2Gy tumours and those previously established from this laboratory after alpha or gamma radiation were used to test for the presence of the delayed lethal death phenotype. A number of cell and molecular endpoints were used. These included plating efficiency, cell adherence, micronucleus formation and p53 status. In all incidences, the reproductive viability of irradiated cells was below that of non- irradiated cells at up to 4 weeks post-irradiation. The HTori-3 cell line and the techniques used to study the delayed effects of radiation may be applicable to other cell systems and may be a useful model to study the long-term effects of radiation induced genomic instability.

Ionizing radiation (IR), along with being an important diagnostic and treatment modality, is a potent tumor-causing agent, and the risk of secondary radiation treatment-related cancers is a growing clinical problem. Now some studies propose to link secondary radiation-induced cancers to an enigmatic phenomenon of bystander effects, whereby the exposed cells send signal damage and distress to their naïve neighbors and result in genome destabilization and carcinogenesis. Yet, no data existed on the bystander effects in an organ other than an exposed one. With this in mind, we focused on the analysis of existence and mechanisms of radiation-induced bystander effects in vivo. We have found that bystander effects occur in vivo in distant skin and spleen following half-body or cranial irradiation. These bystander effects resulted in elevated DNA damage, profound dysregulation of epigenetic machinery, and pronounced alterations in apoptosis, proliferation and gene expression. Bystander effects also exhibited persistency and sex specificity. The results obtained while using the animal model systems can potentially be extrapolated to different animals and humans. / xiii, 208 leaves : ill. ; 29 cm.

Approximately 45% of men will develop cancer during their lifetime; some of which will be of reproductive age (Canadian Cancer Society, 2008). Current advances in treatment regimens such as radiotherapy have significantly lowered cancer-related mortality rates; however, one major quality-of-life issue in cancer survivors is the ability to produce healthy offspring. Exposure to ionizing radiation (IR) leads to genomic instability in the germline, and further to transgeneration genome instability in unexposed offspring of preconceptionally exposed parents. The results presented in this thesis define, in part, the molecular consequences of direct and indirect irradiation for the male germline. Direct exposure results in a significant accumulation of DNA damage, altered levels of global DNA methylation and microRNAome dysregulation of testis tissue. Localized cranial irradiation results in a significant accumulation of unrepaired DNA lesions and loss of global DNA methylation in the rodent (rat) germline. Biological consequences of the changes observed are discussed. / xii, 121 leaves : ill. ; 29 cm.

Call number: LD2668 .T4 1985 C66 / Master of Science

"Diffusion-weighted nuclear magnetic resonance has gained widespread use in the characterization of various diseases. Developments in the area of porous media theory have been successfully transferred and adapted for the use in biological tissue. Measurement of the displacement of diffusing water molecules can reveal structural information about the environment in which the molecules translate. The return-to-the-origin (RTO) probability and the apparent diffusion coefficient (ADC) are based on the diffusion behavior of water molecules in a restricted environment. Water molecules in restricted space have smaller displacements, for a given diffusion time, than water molecules diffusing in bulk solution. The cell membranes and organelles in healthy biological tissue impart more restrictions on diffusing water molecules as compared to necrotic tumor tissue. In necrotic tissue the degradation of cellular structures by auto- and/or heterolysis allows water molecules to diffuse over larger distances without encountering restrictions. The spectroscopic measurement of the RTO probability and the RTO enhancement in RIF-1 tumors showed that the RTO probability is sensitive to these changes in structure. The study showed that smaller tumors, which are less necrotic, have a larger RTO probability and enhancement than larger RIF-1 tumors with a higher fraction of necrotic tumor tissue. Extension of the methodology to NMR imaging was used to answer the question if the RTO probability can provide spatial information about the necrotic area within RIF-1 tumors. The necrotic area measured by the ADC and histology were compared. While neither ADC or RTO could show its superiority over the other, both methods showed a good correlation between their mean values and the necrotic area fraction as measured by histology. The mean ADC and the mean RTO enhancement had a correlation with the necrotic tumor fraction, as determined by histology, of r = 0.86 and r = -0.82, respectively. Conventional T2-weighted images of the same tumor slice showed a poorer correlation (r = 0.62) with the necrotic fraction and no visual agreement with the histology. The general features of the ADC and RTO enhancement were in agreement with histology, however, more exact comparisons where not possible due to the large differences in slice thickness between the two techniques. Structural changes similar to those caused by tumor tissue necrosis can be induced by chemo- and radiation therapy and ADC and RTO enhancement were used to monitor these changes non-invasively. RIF-1 tumors were grown on the hind leg of C3H mice and monitored daily by diffusion-weighted MRI. ADC and RTO-enhancement maps were created using data acquired from control animals and animals treated with 100 mg/kg 5-Fluorouracil. Both ADC and RTO proved to be useful in the early detection of the efficacy of treatment as well as for monitoring the progress of therapy. Diffusion measurements by pulsed-field-gradient (PFG) MRI have become an important tool for detecting of pathophysiological changes caused by cancer and stroke. The increasing popularity of diffusion measurements has initiated their use on clinical MRI systems that have limited magnetic-field-gradient strength. These limitations make it necessary to lengthen the diffusion-gradient duration to ensure sufficient signal attenuation for calculating the ADC. Unfortunately, increasing of the diffusion-gradient duration to a large extent violates the theoretical model used in the ADC calculation. The diffusion measurements are not performed in the finite pulse width regime, but rather in the constant gradient regime, requiring a different interpretation of the results. Examination of the differences in the measured diffusion coefficient showed that increasing both the diffusion-gradient duration and the echo time have a significant impact on the results of a diffusion measurement. A different way to assess changes in RIF-1 tumors as a function of treatment is the measurement of the tissue oxygen status. Cell hypoxia has long been linked with treatment resistivity and reoccurrence in cancers, where the oxygen status is a determining factor of treatment outcome. Perfluorocarbons (PFC's) have been used successfully to assess the tumor oxygen status in the past, but required a large MRI slice thickness due to compensate for the low PFC concentration. The tissue oxygen status of the tumor is assessed by intravenous injection of a PFC that is subsequently sequestered in the tumor. The measurement of the T1-relaxation time of the PFC allows the calculation of the oxygen content, which is linearly related to the relaxivity and the temperature. Fluorine-19, multiple-slice, inversion-recovery echo-planar imaging (EPI) allowed high spatial resolution assessment of the tissue oxygen status over the entire tumor. The results demonstrated that there is a large variation in tissue oxygenation between adjacent slices. Comparison of the oxygen distribution between various tumors also showed that there is no common pattern in the spatial distribution of oxygen within the tumor. Monitoring of the oxygen status during chemotherapy showed an increase in hypoxic tissue and a reduction in tumor size in response to the toxicity of the chemotherapeutic agent. As the effects of the treatment subsided, rapid cell proliferation caused the tumor to regrow and a subsequent decrease in tissue oxygen tension was observed. The study clearly demonstrated the changes in oxygen tension in response to chemotherapy and the need for multi-slice MRI acquisition at high spatial resolution to detect these changes."

Thesis (Ph.D.)--Ohio University, March, 2009. / Release of full electronic text on OhioLINK has been delayed until April 1, 2010. Includes bibliographical references (leaves 70-91)

Thesis (Ph.D.)--Ohio University, March, 2009. / Title from PDF t.p. Release of full electronic text on OhioLINK has been delayed until April 1, 2010. Includes bibliographical references (leaves 70-91)

Purpose: In the contemporary management of early-stage lung cancer with RadiationTherapy (RT), there is increased imaging utilization for the diagnosis and treatment and follow-up after completion of treatment. We evaluated whether this increased radiation exposure to patients with early-stage lung cancer that receive stereotactic body radiotherapy (SBRT) significantly increases the risk of radiation-induced carcinogenesis (RIC). Methods: Following IRB approval, one hundred and ninety-six consecutively treated lung cancer patients treated with SBRT were selected for analysis. Information collected included demographics and all ionizing imaging scans one year before SBRT treatment and one year following treatment. These included chest X-rays (CXR), computerized tomography scan (CT scan), positron emission tomography scan (PET-CT scan), bone scan, ventilation-perfusion scan (VQ scan), cone-beam CT scans. In addition to the lung cancer patients, comparative data on ten prostate and breast cancer patients each was collected to get an estimate of the radiation-induced risk (RIC) in other common malignancies. For each patient, the total effective dose (mSv) was calculated by the sum of all effective doses for all scans (1 year before SBRT to 1-year post-SBRT). After calculating the total effective dose, the summed dose was used to calculate the RIC using the RadRat tool. For the study, we decided that a 1% increase in the baseline risk of radiation-induced lung cancer will be considered a significant increase. Results: Among lung cancer patients, there were 87 males (44.4%) and 109 females (55.6%). The median number of Pre-SBRT CXRs (PA/lateral) was 2 (Range: 1-22), the median number of pre-SBRT CT scans was 2 (Range: 1-6), the median number of pre-SBRT PET-CT scans was 1 (Range: 1-4), the median number of Bone Scans or VQ scans pre-SBRT was 1. The median effective exposure dose from all scans was 72mSv (Range: 24-140.36mSv). The median excess lifetime risk (ELR) of developing lung cancer (a chance in 100,000) with a 90% uncertainty range was 57.15. The Excess Future risk (EFR), the risk from 2019 to the end of the expected lifetime of developing cancer (a chance in 100,000), showed a median of EFR mean of 73.75 (Range: 8.45- 416). The total future risk (TFR, a sum of baseline and excess risk) of developing cancer, from 2019 to end of an expected lifetime was 2732.5 (Range: 808-8290), the median of TFR upper bound was 2785.5 (Range: 856-8400) and median of TFR lower bound was 2679.5 (Range: 761- 8183). At 6 months, survival was 94.7% (144/152), at 1 year, 79% (94/119), at 3 years 32.5% (27/83). At five years, with survival data on 77 patients available, 9 (11.6%) were alive. Regarding the comparison of RIC from imaging before RT for patients with prostate cancer, the median total effective radiation dose from all pre-SBRT and post-SBRT scans was 20mSv (Range: 20-30mSv), and the median of mean ELR for development of RIC prostate cancer was 4.24 (per 100,000). Regarding early-stage breast cancer, the median total effective radiation dose from all pre-RT and post-RT scans was 16.56mSv (Range: 10.52-31.48mSv), and the median of mean ELR for development of RIC was 35.95 (per 100,000). Conclusion: The median excess cancer lifetime radiation-induced cancer risk for the lung cancer cohort was 0.05%, which is significantly less than the 1% risk that was determined to be clinically significant as per our study objective. The survival in this cohort of patients was poor. Enhanced imaging to enhance staging accuracy, safety during SBRT treatment, and adequate follow-up outweigh the RIC risk.