<p> Two-pion production reactions in proton-proton collisions have been studied using the PROMICE/WASA detector and an internal cluster gas-jet target at the CELSIUS storage ring in Uppsala. Three out of the four isospin-independent reaction channels have been measured at several energies in the intermediate and near threshold energy region. Important parts of the analysis include the identification of neutral pions from the invariant mass of the decay gammas, the identification of positive pions with the delayed pulse technique and the use of Monte Carlo simulations to understand the detector response. The total cross sections for the pp®ppπ⁺π^-, the pp®ppπ⁰π⁰ and the pp®pnπ⁺π⁰ reactions are presented at beam energies ranging from 650 to 775 MeV. </p><p>The production mechanism for two-pion production near threshold seems to be dominated by resonance production. The contribution from the non-resonant terms alone can not reproduce the total cross sections. In most models, two-pion production is governed by the δ and the <i>N</i>^* resonances in either one or both of the participating nucleons. </p><p>The <i>N</i>^*(1440)®N(πp)^T=0_S−<i>wave</i> transition has been suggested as the dominating production mechanism for two-pion production in proton-proton collisions. However, the total cross sections presented in this thesis show that other production mechanisms also must give large contributions. </p>

The increasing demand for characterization of nuclear fuel, both from an operator and authority point of view, motivates the development of new experimental and, preferable, non-destructive methods. In this thesis, some methods based on nuclear spectroscopic techniques are presented. Various parameters of irradiated fuel are shown to be determined with high accuracy and confidence by utilizing gamma-ray scanning, tomography and passive neutron assay. Specifically, fuel parameters relevant for a secure storage of spent nuclear fuel in a long-term repository, such as e.g. burnup and decay heat, are shown to be determined with adequate accuracy. The techniques developed are expected to be implemented in the planned encapsulation facility in Sweden. Also, a device for tomographic measurements of the spatial distribution of thermal power in nuclear fuel assemblies has been built, tested and evaluated. The device utilizes single photon emission computed tomography (SPECT) in order to reconstruct the gamma-ray source distribution within a fuel assembly. The device is expected to be an important tool for validating reactor core simulators regarding new fuel designs. For safeguards purposes, two experimental methods for verifying the integrity, i.e. the possible loss of fissile material from a nuclear fuel assembly, are presented. Verification of integrity is shown to be possible on an individual fuel rod level.

Two-pion production reactions in proton-proton collisions have been studied using the PROMICE/WASA detector and an internal cluster gas-jet target at the CELSIUS storage ring in Uppsala. Three out of the four isospin-independent reaction channels have been measured at several energies in the intermediate and near threshold energy region. Important parts of the analysis include the identification of neutral pions from the invariant mass of the decay gammas, the identification of positive pions with the delayed pulse technique and the use of Monte Carlo simulations to understand the detector response. The total cross sections for the pp®ppπ+π-, the pp®ppπ0π0 and the pp®pnπ+π0 reactions are presented at beam energies ranging from 650 to 775 MeV. The production mechanism for two-pion production near threshold seems to be dominated by resonance production. The contribution from the non-resonant terms alone can not reproduce the total cross sections. In most models, two-pion production is governed by the δ and the N* resonances in either one or both of the participating nucleons. The N*(1440)®N(πp)T=0S−wave transition has been suggested as the dominating production mechanism for two-pion production in proton-proton collisions. However, the total cross sections presented in this thesis show that other production mechanisms also must give large contributions.

Tumour targeted radiotherapy is an appealing approach for treatment of disseminated tumour cells. A targeting agent that specifically binds to a structure on tumour cells is then used to transport therapeutically relevant radionuclides. The epidermal growth factor receptor, EGFR, is overexpressed on tumour cells in several malignancies, e.g. highly malignant gliomas. In this thesis, three types of radiolabelled EGF-conjugates, aimed for targeting to EGFR-expressing tumour cells, were developed and studied: EGF-dextran labelled with 125I, EGF labelled with 211At, and two EGF-chelates, DTPA-EGF and Bz-DTPA-EGF, labelled with the radioactive metals 111In and 177Lu. The targeting properties of radioiodinated EGF-dextran were first studied in cultured glioma cells. Radioiodine coupled to the dextran part of EGF-dextran was retained in cells appreciably longer than radioiodine coupled to EGF. This can give about 100 times increased radiation dose to tumour cells. Targeting with 211At-EGF was investigated in combination with the tyrosine kinase inhibitor gefitinib (Iressa™, ZD1839). The uptake of 211At-EGF in EGFR-expressing tumour cells increased with increasing gefitinib concentrations. This was the case for both gefitinib-resistant and gefitinib-sensitive cell lines. The effect of the combined treatment on cell survival, however, differed between the cell lines in an unexpected way. In gefitinib resistant cells, combined treatment decreased cell survival approximately 3.5 times relative to 211At-EGF treatment alone. In gefitinib sensitive cells, however, combined treatment increased the cell survival (i.e. a protective effect). The EGF-chelates studied ([111In]DTPA-EGF, [111In]Bz-DTPA-EGF and [177Lu]Bz-DTPA-EGF) all bound specifically with high affinity (Kd≈2 nM) to EGFR on cultured glioma cells. They were internalised after binding, and the cellular retention of radionuclides was high (60% remained after 45 h). A biodistribution study in mice showed that liver and kidneys accumulated a majority of the radioactivity. The EGF-chelates bound EGFR specifically also in vivo. A tumour-to-blood ratio of 25 was achieved in a preliminary study.

One of the main problems in curing cancer resides in the different microenvironment existing in tumours compared to the normal tissues. The mechanisms of failure are different for radiotherapy and chemotherapy, but they all relate to the poor blood supply known to exist in tumours. It is therefore very important to know the tumour microenvironmental conditions in order to devise techniques that will overcome the problems and will therefore improve the result of the treatment. The aims of the thesis were the modelling of tumour oxygenation and the simulation of polarographic oxygen measurements in order to assess and possibly to improve the accuracy of the electrode in measuring tumour oxygenation. It also aimed to evaluate the implications of tumour microenvironment for the radiotherapy outcome. The project used theoretical modelling as the main tool. The processes of oxygen diffusion and consumption were described mathematically for different conditions, the result being very accurate distributions of oxygen in tissues. A first simple model of tissue oxygenation was based on the oxygen diffusion around a single blood vessel. A more complex model built from the basic physical processes and measurable parameters allowed the simulation of realistical tissues with heterogeneous vasculature. This model also allowed the modelling of the two types of hypoxia known to appear in tumours and their influence on the tumour microenvironment. The computer simulation of tissues was also used for assessing the accuracy of the polarographic technique for measuring tumour oxygenation. The results of this study have shown that it is possible to model theoretically the tissue oxygenation starting from the basic physical processes. The particular application of our theoretical simulation to the polarographic oxygen electrode has shown that this experimental method does not give the oxygen values in individual cells. Because the electrode measures the average oxygenation in a relatively large tissue volume, the resulting oxygen distributions are different from the real ones and the extreme high and low values are not detected. It has further been found that the polarographic electrode cannot make distinction between various types of hypoxia existing in tumours, the geometrical distribution of the hypoxic cells influencing mostly the accuracy of the measurement. It was also shown that because of the averaging implied by the measurement process, electrode results should not be used directly to predict the response to radiation. Thus, the differences between the predictions in clinical tumour control obtained from the real or the measured oxygenations are of the order of tens of percents in absolute value. A method to improve the accuracy of the electrode, i.e. to improve the correlation between the results of the measurements and the actual tissue oxygenation, was proposed. In conclusion, theoretical modelling has been shown to be a very powerful tool for predicting the outcome of radiotherapy and it has the advantage of describing the tumour oxygenation in the least invasive manner. Furthermore it allows the investigation of the invasiveness and the accuracy of various experimental methods.

The development of digital detectors for X-ray imaging in medical diagnostics receives an increasing amount of attention. The detector under development at the Department of Radiation Sciences at Uppsala University is a hybrid pixel detector, which consists of a semiconductor sensor mounted onto a readout chip. The readout chip is capable of performing photon counting and has an externally adjustable threshold. A simulation tool for the detector and a model applying the linear-systems transfer theory to X-ray hybrid pixel detectors have been developed. Also a characterization of the readout chip has been done. In order to estimate the potential of the detector for diagnostic radiology, we investigate the image quality using the spatial frequency dependent detective quantum efficiency (DQE). By means of the detector simulations, the influence of threshold setting, noise sources, level of exposure and charge sharing on the DQE have been studied. By means of the linear-systems theory, a single analytical expression is provided to obtain the DQE of a hybrid pixel detector. The method developed in this thesis will make it possible to optimize a detector design according to a particular medical application. It will also permit modifications and new features to be included without having to construct a full detector system.

Biological treatment optimization aim at improving radiation therapy by accounting for the radiobiological tumour and normal tissues response properties when optimizing the dose delivery. Generally traditional methods, using only dosimetrical measures, disregard the nonlinear radiation response of different tumours and normal tissues. The accumulated knowledge on tissue response to radiation, in the form of more accurate dose response relations, cell survival models and their associated biological parameters, alongside with the tools for biological treatment plan optimization, has allowed the present investigation on the potential merits of biologically based treatment optimization in radiation therapy. With a more widespread implementation of intensity modulated radiation therapy in the clinic, there is an increasing demand for faster and safer treatment delivery techniques. In this thesis biological treatment plan optimization, using the probability to achieve complication free tumour control as the quantifier for treatment outcome, was applied to radiation therapy of early breast cancer and advanced cervix cancer. It is shown that very conformal dose distributions can generally be produced with 3 or 4 optimally orientated coplanar intensity modulated beams, without having clinically significant losses in treatment outcome from the optimal dose distribution. By using exhaustive search methods, the optimal coplanar beam directions for intensity modulated photon beams for early breast cancer and the optimal non-coplanar directions for an advanced cervix cancer were investigated. Although time consuming, exhaustive search methods have the advantage of revealing most features involving interactions between a small number of beams and how this may influence the treatment outcome. Thus phase spaces may serve as a general database for selecting an almost optimal treatment configuration for similar patients. Previous knowledge acquired with physically optimized uniform beam radiation therapy may not apply when intensity modulated biological optimization is used. Thus unconventional treatment directions were sometimes found.

Medical X-ray imaging is an important tool in diagnostic radiology. The ionising-radiation dose to the patient is justified by the clinical benefit of the examination. Nonetheless, detectors that operate at even lower doses and provide more information to the radiologist are desired. A hybrid pixel detector has the potential to provide a leap in detector technology as it incorporates a more advanced signal-processing capability than currently used detectors. The DIXI digital detector is a hybrid pixel detector developed for X-ray imaging. It consists of a readout chip and a semiconductor sensor. The division in two parts makes it possible to optimise each part individually. The detector is divided into square pixels with a size of 270 x 270 μm2. DIXI has the ability to count single photons and every readout pixel has two embedded counters to allow the acquisition of two images close in time. A discriminator enables the selection of photons with energies above a preset threshold level. The readout chip Angie has been developed and its performance has been evaluated in terms of noise, threshold variation and capability to perform energy weighted counting. Silicon sensors have been fabricated, and a control system for DIXI has been designed and built. An electroless process for deposition of Ni/Au bumps on the chip and sensor has been optimised as a preparation for the assembly of a complete detector, which is being assembled by flip-chip bonding using anisotropic conductive film. A simulation library for the DIXI detector has been set up and results on the image quality are reported for different exposures and working conditions. A theoretical model for hybrid pixel detectors based on the cascaded linear system theory has been developed. The model can be used to investigate and optimise the detector for different detector configurations and operating conditions.

Theoretical modeling of biological response to radiation describes qualitatively and quantitatively the results of radiobiological effects at the molecular, chromosomal, and cellular level. The repair-misrepair (RMR) model is the radiobiological model chosen for our study. It models deoxyribonucleic acid (DNA) damage formation and lesion repair through linear and quadratic processes. Double strand breaks (DSB) are a critical lesion in DNA. With increasing LET, the number of DSB per track traversing the cell nucleus increases. Using a compound Poisson process (CPP), we describe DNA damage formation. Three models were considered: a simple CPP using constant LET, a CPP using a chord length distribution, and a CPP using specific energy distribution. In the two first cases, and for low LET radiation the initial distribution of DSB was well approximated by a Poisson distribution, while for high LET radiation the initial distribution of DSB deviated slightly from a Poisson distribution. In the last case, DSB distribution was much broader than a pure Poisson distribution. Datasets from the literature for seven human cell lines, exhibiting various sensitivities to radiation were analyzed. We compared stochastic, CPP, and CPP using chord length distribution, with deterministic RMR models. For low LET radiation and at high dose rates the stochastic survival results agree well with the deterministic survival results. Also the stochastic model allows for non-linearity at low doses due to the accumulation of sub-lethal damage. At low dose rates deterministic results overestimate the surviving fraction compared to stochastic results. For high LET radiation stochastic and deterministic survival results agree. Stochastic survival results using specific energy distribution diverged from deterministic results by underestimating the surviving fraction at low and high LET radiation. The dose rate sparing curve, representing surviving fraction at a dose of 10Gy vs. dose rate shows that deterministic survival results are consistent with stochastic survival results, using CPP, or CPP with chord length distribution, for low and high dose rate values. Compared to deterministic aspects of DNA damage formation we concluded that stochastic aspects of DNA damage formation and repair using CPP or CPP with chord length distribution are not as prominent as reported in the earlier studies.

<p>At the present time, here is no approved medical countermeasure (MCM) for mitigating or treating pneumonitis/fibrosis following acute radiation exposure. Since it is neither ethical nor feasible to evaluate potential MCMs against radiation injury in the clinical setting, the FDA permits MCM licensure under an alternative drug development pathway ("Animal Efficacy Rule") that relies on the predictive validity of animal models. The purpose of the current project was to design a research platform that addresses many of the critical knowledge gaps associated with successful adherence to the FDA Animal Rule. </p><p>In these studies, we evaluated the dose-response relationship for survival and function injury among CBA/J, C57L/J, and C57BL/6J mouse strains. These strains were previously identified to represent the full spectrum of pulmonary pathology associated with acute radiation exposure to the thorax. We next evaluated ultrastructural pathology to identify differences in tissue response among strains as early as twenty-four hours after radiation. Global differential gene expression analysis was utilized to identify the major signaling pathways and genes associated with development of radiation pneumonitis and/or fibrosis by exploiting the phenotypic differences in radiation-injury among strains. Genes with significant differences were validated by quantitative real-time PCR and their protein products validated by western blot. Finally, we performed longitudinal analysis of hypoxia-associated gene expression to elucidate the natural history of disease progression in "fibrosis prone" C57BL/6J mice. </p><p>In these studies, we identified significant differences in the dose-response, temporal onset, disease progression, and pathologic manifestations of radiation lung injury among murine strains. The severity of ultrastructural damage at twenty-four hours also differed among strains indicating the early tissue response to the radiation insult was dissimilar. A significant difference was found in gene expression among strains. The most interesting differences were associated with the acute-phase response, iron homeostasis, cell cycle/proliferation, and cell death. Lastly, hypoxia-associated gene expression, including HIF-1alpha; and HIF-2alpha; mRNA and protein stabilization, was dynamically altered during the temporal course of radiation pathogenesis in the "fibrosis-prone" C57BL/6J mice. As the C57BL/6J strain is more "resistant" to radiation-induced lung injury, a better understanding of the pathways involved in tissue response to radiation in this strain might elucidate the mechanisms that make the lungs of this strain significantly more radiotolerant than their counterparts. </p><p>The research platform developed in this project provides essential information to interpret and define the complex interrelationships in clinically relevant models of the human response to potentially lethal irradiation and treatment. The overall goal is to provide a rigorous scientific platform for MCM development under the Animal Efficacy Rule with reasonable expectation that MCMs acquired for the Strategic National Stockpile will effectively prevent, treat, or mitigate radiation-induced lung injury and improve survival among the exposed population.</p> / Dissertation