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- Sun, Aijun, 1973-
(författare)
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Radiolabeled acetate PET in oncology imaging : studies on head and neck cancer, prostate cancer and normal distribution
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The use of positron emission tomography (PET) for imaging in oncology has grown rapidly in recent years. 2-[18F]-fluorodeoxyglucose (FDG) is the most common tracer of PET, although drawbacks exist. Radiolabeled 1-[11C]-acetate (C-AC) is a simple probe for evaluation of perfusion, anabolism (lipogenesis) and catabolism (oxidative metabolism) in all living tissues. This study explored the potential of AC PET in head and neck cancer, benign and malignant lymph nodes in prostate cancer and normal distribution. In head and neck cancer, C-AC PET detected more primaries and lymph node metastases than FDG PET. The mean primary tumor volumes delineated by C-AC was 51% larger than that of FDG before radiotherapy (RT). Both FDG and C-AC PET tumor volumes must be carefully validated before used in clinical routine. Baseline tumor clearance rate (kmono) was higher in complete responders (CR) than that in partial responders (PR). kmono tended to correlate inversely with FDG SUV at baseline. Radiosensitive tumors might rely predominantly on oxidative metabolism for their biogenetic needs. kmono increased in PR during RT. The potential reversibility of impaired kmono in radioresistant tumors imply that treatment targeting the intermediary metabolism might improve the outcome. Tumor relative perfusion index (rF) and kmono were coupled in CR throughout the RT, but not in PR. Dynamic C-AC PET provides a new non-invasive method to simultaneously evaluate the tumor oxidative metabolism and perfusion which link the RT response in patients by a single tracer injection. In prostate cancer, elevated C-AC accumulation is common in benign inguinal lymph nodes, probably due to increased lipogenesis rather than lymphatic drainage. CT Hounsfield unit of benign nodes was lower than that of metastases, suggesting that density measurement using CT might improve the specificity of nodal staging of prostate cancer. A novel tracer 2-[18F]-fluoroacetate (F-AC) was synthesized and used for dynamic PET-CT imaging in animals. Compared with C-AC PET-CT, F-AC showed prolonged blood retention, no detectable trapping in myocardium and salivary glands, rapid excretion from liver to bile and urine and de-fluorination resulting in intensive skeletal activity. F-AC does not mimic the normal physiologic path of C-AC and appears to be of little use for assessment of perfusion, intermediary metabolism or lipogenesis.
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| 2. |
- Fessé, Per, 1973-
(författare)
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Epidermal Melanocyte Response to Radiotherapy
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cutaneous interfollicular melanocytes protect the skin from UV-radiation (UVR), and their response to UVR is well established. To date, the response activated in melanocytes by repeated genotoxic insults from radiotherapy (RT) has not been explored. Assuming that the molecular pathways involved in the melanocyte response to UVR are similar upon ionizing radiation, the aim of this work was to examine the effects of RT concerning UVR-response proteins and resistance to DNA damage to reveal mechanisms behind hyperpigmentation and depigmentation caused by RT. The results are based on immunostained tissue sections of 530 not sun-exposed skin punch biopsies. These are collected before, during, and after the end of adjuvant RT from the thoracic wall of breast cancer patients and the hip region of prostate cancer patients receiving curative RT. Fractionated RT with daily doses between 0.05 and 2.0 Gy, as well as hypofractionation and accelerated fractionation were investigated. Based on this clinical assay sterilizing the hair follicles, excluding migration of immature melanocytes from the bulge, it was ensured that interfollicular melanocytes are an autonomous self-renewing cell population with cells presenting different degrees of differentiation of which one fourth is immature; the melanocytes divide rarely and are absolute radioresistant to any dose schedule of RT applied, keeping the number of melanocytes intact. Hyperradiosensitivity to dose fractions of 0.05 to 0.3 Gy is observed for DNA double strand breaks (DSBs), differentiation and anti-apoptotic signaling. Proliferation is not stimulated and apoptosis is negligible upon exposure to RT, and also post-treatment. Melanocyte differentiation is maintained during RT, but dedifferentiation occurs after RT ends. The expected activation of the p53/p21 signaling upon RT appears in keratinocytes but is attenuated in melanocytes. A new observation is that melanocytes constitutively express BMI1, further upregulated upon irradiation, indicating that melanocytes have stem cell properties, which suggest that BMI1 prevents apoptosis, terminal differentiation and premature senescence and likely allows dedifferentiation by suppressing the p53/p21-mediated response to genotoxic damage, in addition to the repression of p16 and ARF. Melanocytes exhibit and accumulate a higher amount of DSBs during the RT period compared to keratinocytes, indicating reduced repair capacity of DSBs in melanocytes. Thus, only efficient pro-survival mechanisms can explain the melanocyte radioresistance regarding cell death. The findings in this thesis suggest that melanocytes are protected by activation of the BMI1-NF-kappa/β-CXCL8/CXCR2 pathway, in addition to upregulation of Bcl-2 by melanocyte-specific MITF (microphthalmia-associated transcription factor).
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| 3. |
- Pettersson, Anna, 1979-
(författare)
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Diet and Gastrointestinal Symptoms in Patients with Prostate Cancer Treated with Radiotherapy
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Objective The main objective of this thesis was to explore the effects of diet on gastrointestinal symptoms in prostate cancer patients treated with local curative radiotherapy, by evaluating dietary intake prior to treatment (Study I), the psychometric properties of a new questionnaire on patient-reported gastrointestinal side effects (Study II), and the effect of a dietary intervention on acute and long-term gastrointestinal symptoms up to 2 years after radiotherapy completion (Study III-IV).Methods A total of 130 men with localized prostate cancer referred to dose-escalated radiotherapy (ED2 87-102 Gy, α/β=3 Gy) were recruited to a dietary intervention trial. Patients were randomized to receive either standard care plus the dietary intervention of a fibre- and lactose-restricted diet (intervention group, IG; n=64) or standard care alone (standard care group, SCG; n=66). Data on gastrointestinal symptoms and dietary intake were collected pre-treatment and at seven time points during a follow-up period of 26 months.Results Prior to treatment, grain products and milk products were major sources of energy. Unbalanced fatty acid intake and low intake of selenium were observed (Study I). Validation of the Gastrointestinal Side Effects Questionnaire (GISEQ) revealed satisfactory internal consistency, moderate concurrent validity and adequate responsiveness (Study II). There were no significant effects of the intervention on acute or long-term gastrointestinal symptoms, but a tendency towards lower prevalence and severity of bloating and diarrhoea in the IG compared to the SCG during radiotherapy. Gastrointestinal symptoms were predominantly mild, and the frequency of clinically relevant symptoms was merely a few percent. Dietary adherence in the IG was initially good, but tended to decline beyond 12 months post-radiotherapy (Study III-IV).Conclusions A fibre- and lactose-restricted diet was not superior to the habitual diet in reducing gastrointestinal symptoms in patients undergoing high-dose, small-volume radiotherapy for localized prostate cancer. The GISEQ enables assessment of patient-perceived change in symptoms, but further work is needed to strengthen its psychometric qualities. It is suggested that continued research in this area target patient categories referred to irradiation of larger pelvic volumes with a higher risk of gastrointestinal symptoms, and that dietary interventions incorporate established strategies to enhance adherence and effectiveness.
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| 4. |
- Svensson, J. Peter, 1975-
(författare)
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Systematic Modular Approaches to Reveal DNA Damage Responses in Mammalian Cells
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancer therapy operates by inflicting damage in malignant cells. The most lethal target is the genomic DNA. As a single double strand DNA break has the potential to kill the cell, mechanisms have evolved to detect and block propagation of the damage. Genes and their products function in a highly connected network-structure with ample cross-talk between different pathways. This interplay can be studied by genome-wide experiments, such as expression profiling. The aim of this thesis is to study the cellular effects of DNA damaging agents.A theoretical framework is explored to improve understanding of expression profiling results. To analyse large datasets, computational methods were developed to model the data. Further, the response to DNA damage was investigated in different cellular systems. As late radiation toxicity is a severe limitation of radiotherapy of cancer patients, patients were enrolled in a study to search for a molecular signature to identify high-risk patients. Ex vivo irradiation of lymphocytes revealed a signature of functionally related gene sets that were capable to separate patients with regard to toxicity status. The gene set analysis was also applied to a dataset where mouse embryonic stem cells had been exposed to various doses of cisplatin. At several time-points after administration of the drug, expression profiles were determined. In addition to the expected increase of genes related to apoptosis and cell cycle progression, damaged cells also seemed to have embarked upon a p53-dependent differentiation programme. Finally, in a study of cardiac rodent cells, the genotoxic treatment with irradiation was compared to the mechanical stress induced in heart tissue.In conclusion, this thesis presents evidence for the advantage of using functionally related sets of genes in analysis and interpretation of genome-wide experiments. This strategy may improve clinical understanding of the effects of DNA damaging agents used for cancer therapeutics.
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