Investigating variance in radiosensitivity amongst cell populations contributes to the overall improvement in our understanding of the effects of low dose ionizing radiation. The aim of this thesis was to investigate factors influencing radiosensitivity through analysis of survival curves. The radiation-induced bystander effect and low dose hyperradiosensitivty were observed to help elucidate relationships between these phenomena. First heterogeneity of a cell population was investigated and seven clonal lines of an HCT 116 p53 wild type cell line were derived. Survival curves with a wide range of dose points (0.5 to 15 Gy) were developed and curves were fitted with the linear- quadratic and multi-target models. The McMaster Taylor Radiobiology Cesium-137 source was used for all irradiations in this thesis. Here it was evident that the multi- target model provided a better fit and further analysis revealed a relationship between the curve shoulder and toxicity of bystander effect signals. Clonal lines with a large shoulder size did not show evidence of the radiation induced bystander effect. Since the lowest dose point in curves was 0.5 Gy, a more focused look was taken in the low dose range. iii Survival curves were again produced for all clonal lines adding data to now include six dose points in the low dose region (below 0.5 Gy). Survival curves were re-analyzed with this extensive data set including doses from 0.01 to 15 Gy and now instances of hyperradiosensitivty were evident in all cell lines. The linear-quadratic model did not provide a meaningful fit to the data and so the induced-repair model was used and found to be appropriate in low doses. It was concluded that whether the radiation-induced bystander effect was produced or not, low dose effects such as hyperradiosensitivity may contribute to the overall radiosensitivity of a cell line. Finally, sex of the cell line was investigated using four cell lines. Of the four cell lines, two were included as controls for radiosensitivity. These two cell lines were null for the protein Artemis which assists in the repair of double strand DNA breaks. Thus, when this protein is not functioning as normal, radiosensitivity is induced in the cell line. Through medium transfer bystander effect assays a greater reduction in cell survival was observed in the normal female cell line compared to the normal male cell line. In conclusion, this thesis contributes to the understanding of low dose effects and non-targeted effects of ionizing radiation. Understanding these mechanisms both separately and in combination may contribute to the betterment of radiation therapies and radiation protection. / Thesis / Doctor of Philosophy (PhD)

No description available.

<p>Several extensions to the Standard Model predict the existence of charged Higgs bosons. This thesis describes the search for such a particle using the data collected by the DELPHI detector at the Large Electron Positron (LEP) collider at the European laboratory for particle physics (CERN) in Geneva, Switzerland. </p><p>In <i>e</i>⁺<i>e </i>^-collisions charged Higgs bosons are predicted to be produced in pairs via an intermediate photon or Z⁰ boson. In the two Higgs doublet model (2HDM) the production cross section for a pair of charged Higgs bosons depends only on the centre of mass energy of the collision and the mass of the charged Higgs boson. </p><p>Higgs bosons decay to the heaviest particles kinematically allowed. For a charged Higgs boson with a mass that can be produced at the LEP collider this means either a <i>cs</i> quark pair or a <i>τυ</i>_t lepton pair. The branching ratio between these decay channels depends on the parameters of the model. </p><p>No statistically significant signal compatible with a charged Higgs boson was found. Using the predicted production cross sections from the 2HDM the existence of a charged Higgs boson with a mass lower than 73.8 GeV/<i>c</i>² has been excluded at 95% confidence level independently of the decay branching ratios of the charged Higgs boson. </p>

The aim of the present thesis was to evaluate sonographic methods for investigation of the chronic painful Achilles tendon. In a prospective study on patients with chronic painful mid-portion Achilles tendinosis, grey-scale ultrasound (US) showed a decreased tendon thickness and a “normalized” structure in the majority of patients successfully treated with eccentric calf-muscle training. By combining US with colour Doppler examination (CDV), a neovascularisation was shown in the region with structural tendon changes in all painful tendons, but not in any of the pain-free normal tendons. In a small pilot study, the sclerosing agent Polidocanol was injected towards the neovessels under US and CDV guidance. The majority of the patients became painfree and had no remaining neovessels, while the patients with remaining pain had remaining neovessels. The combined findings from US, immuno-histochemical analyses of biopsies, and diagnostic injections, showed that the patients were temporarily pain-free after US and CDV guided injections of local anaesthesia towards the region with neovessels, and biopsies from the region with tendon changes and neovascularisation showed nerve structures in close relation to blood vessels. The presence of neovessels was shown also in patients with chronic pain in the Achilles tendon insertion, and it was found that treatment with sclerosing injections cured the pain in the majority of patients. A good result of treatment was associated with no remaining neovessels. In a prospective study on patients with chronic mid-portion Achilles tendinosis treated with eccentric training, CDV after treatment showed no remaining neovessels in the majority of the pain-free patients. In the patients with remaining tendon pain there were remaining neovessels. In conclusion, the findings in this thesis indicate that neovessels and accompanying nerves might be the source of chronic Achilles tendon pain. Sclerosing injections towards the neovessels, and eccentric training, seem to have a potential to cure the pain.

No description available.

Several extensions to the Standard Model predict the existence of charged Higgs bosons. This thesis describes the search for such a particle using the data collected by the DELPHI detector at the Large Electron Positron (LEP) collider at the European laboratory for particle physics (CERN) in Geneva, Switzerland. In e+e - collisions charged Higgs bosons are predicted to be produced in pairs via an intermediate photon or Z0 boson. In the two Higgs doublet model (2HDM) the production cross section for a pair of charged Higgs bosons depends only on the centre of mass energy of the collision and the mass of the charged Higgs boson. Higgs bosons decay to the heaviest particles kinematically allowed. For a charged Higgs boson with a mass that can be produced at the LEP collider this means either a cs quark pair or a τυt lepton pair. The branching ratio between these decay channels depends on the parameters of the model. No statistically significant signal compatible with a charged Higgs boson was found. Using the predicted production cross sections from the 2HDM the existence of a charged Higgs boson with a mass lower than 73.8 GeV/c2 has been excluded at 95% confidence level independently of the decay branching ratios of the charged Higgs boson.

<p>It has been observed that the radiation response of a cell line may positively correlate with baseline levels of reactive oxygen species (ROS) generation, which is facilitated, in part, by the function ofNADPH oxidase membrane proteins. Apocynin has been successfully used to inhibit ROS generation via NADPH oxidase for other uses. Here, the effectiveness of apocynin to improve sensitivity to radiation in the MATLyLu cell line was examined. MATLyLu-implanted Cop/Hsd rats undergoing lOGy/SfX radiation treatment demonstrated improved tumour control, as measured by survival time (to predetennined endpoints), when given apocynin orally throughout their radiation treatment, but not when given apocynin only before radiation. Rats given apocynin without radiation did not demonstrate improved survival over controls. MA TLyLu cells given apocynin in vitro, however, did not demonstrate improved response to radiation or a reduction in baseline ROS production on a per cell basis, and apocynin was found to inhibit growth when given alone. These contradictory in vivo and in vitro findings may be explained by certain proposed mechanisms of action for apocynin which requires it to be first synthesized into its dimer, diapocynin, before it will inhibit NADPH oxidase, and this synthesis may occur during ingestion. Further investigations with diapocynin and the MATLyLu cell line are required. Therefore the mechanism is uncertain, but it was concluded that apocynin and radiation administered together in vivo improves radiation response as compared to either treatment alone.</p> / Master of Science (MS)

Basic in vitro cell experiments were conducted on the P388 mouse leukaemia cell line to determine whether a supra-additive cell killing effect from combining hyperthermia with ionising radiation exists in the case of leukaemia. Methods were established to measure the cell kill, using a Coulter counter, from hyperthermia alone, radiation alone and several combined regimes. The cell kill from hyperthermia, in the range of 38-50 degrees for 30 minutes, 1 hour, 2 hours and 3 hours, and radiation, for 1, 3, 5, 9, 11 and 15 Gy was investigated. The approach used had various limitations, such as the underestimation of cell kill. Consistent trends, however, were found for the hyperthermia and radiation data, in accordance with the literature, which killed cells in a predictable manner. Subsequently, after other preliminary combined experiments were completed, the cell kill from both 5 and 11 Gy combined with hyperthermia at 43, 45 and 47 degrees for 2 hours were investigated. 5 Gy in combination with all levels of hyperthermia resulted in a direct additive cell killing effect. This, however, was not observed for 11 Gy in which a diminished effect was found. The overall level of cell kill from 5 Gy combined with hyperthermia was found to be equal, in the case of 43 degrees, or higher, as for 45 and 47 degrees, to that of those combined with 11 Gy. A supra-additive effect was not observed.

The focus of this thesis is the development of two molecularly targeted imaging methods, in both cases based on contrast agents encompassing micron-sized microparticles of iron oxide (MPIO). MPIO are obligate intravascular agents and as presented in this thesis the half-life in the blood circulation is < 1min. In the first approach described in the thesis, the overall goal was to detect metastasis in mouse lungs, very early in metastatic development, by targeting vascular cell adhesion molecule 1 (VCAM-1) using conjugates of an anti-VCAM-1 antibody and 1 μm MPIO (VCAM-MPIO). In Chapter 3, I demonstrate specific retention of VCAM-MPIO in the vasculature of a lung metastasis model, and also the very short blood half-life of the contrast agent; both of which suggest the potential for in vivo detection. In Chapter 4, I show that whilst the bound VCAM-MPIO do not sufficiently dephase the signal obtained with the bright lung MRI approaches used (hyperpolarized ³He/¹²⁹Xe or ¹⁹F MRI), it is possible to sensitively detect the presence of lung metastases in vivo using radiolabelled VCAM-MPIO (⁸⁹Zr-DFO-VCAM-MPIO) in combination with PET imaging. The overall goal of the second approach described, was to detect and characterize tumour angiogenesis by targeting &alpha;_v&beta;₃-expressing endothelium in vivo, using a conjugate of cyclic penta-peptides c(RGDyK) and 2.8 &mu;m MPIO [c(RGDyK)-MPIO]. To this end, I demonstrate in Chapter 5 that c(RGDyK)-MPIO specifically binds to &alpha;_v&beta;₃-expressing endothelium in subcutaneous tumours and yields quantifiable contrast effects on T₂&ast;-weighted MRI. Furthermore, I have implemented in this approach gadolinium DCE imaging, providing dynamic vascular information. To date there is no reported detection method for pulmonary metastasis at the micrometastastic stage, as presented in this thesis. Translation of this method into clinic could allow for earlier therapeutic intervention and, thus, more effective treatment. The angiogenesis characterization imaging method presented here may provide a sensitive approach for the characterization of heterogeneity in tumour angiogenesis/vascularity and monitoring of anti-angiogenic therapies.

As radiation specialists, one of our primary objectives in the Navy is protecting people and the environment from the effects of ionizing and non-ionizing radiation. Focusing on radiological dispersal devices (RDD) will provide increased personnel protection as well as optimize emergency response assets for the general public. An attack involving an RDD has been of particular concern because it is intended to spread contamination over a wide area and cause massive panic within the general population. A rapid method of triage will be necessary to segregate the unexposed and slightly exposed from those needing immediate medical treatment. Because of the aerosol dispersal of the radioactive material, inhalation of the radioactive material may be the primary exposure route. The primary radionuclides likely to be used in a RDD attack are Co-60, Cs-137, Ir-192, Sr-90 and Am-241. Through the use of a MAX phantom along with a few Simulink MATLAB programs, a good anthropomorphic phantom was created for use in MCNPX simulations that would provide organ doses from internally deposited radionuclides. Ludlum model 44-9 and 44-2 detectors were used to verify the simulated dose from the MCNPX code. Based on the results, acute dose rate limits were developed for emergency response personnel that would assist in patient triage.