Proton magnetic resonance spectroscopy of a boron neutron capture therapy 10B-carrier, L-p-boronophenylalanine-fructose complex

Boron neutron capture therapy (BNCT) is a radiotherapy that has mainly been used to treat malignant brain tumours, melanomas, and head and neck cancer. In BNCT, the patient receives an intravenous infusion of a 10B-carrier, which accumulates in the tumour area. The tumour is irradiated with epithermal or thermal neutrons, which result in a boron neutron capture reaction that generates heavy particles to damage tumour cells. In Finland, boronophenylalanine fructose (BPA-F) is used as the 10B-carrier. Currently, the drifting of boron from blood to tumour as well as the spatial and temporal accumulation of boron in the brain, are not precisely known. Proton magnetic resonance spectroscopy (1H MRS) could be used for selective BPA-F detection and quantification as aromatic protons of BPA resonate in the spectrum region, which is clear of brain metabolite signals. This study, which included both phantom and in vivo studies, examined the validity of 1H MRS as a tool for BPA detection. In the phantom study, BPA quantification was studied at 1.5 and 3.0 T with single voxel 1H MRS, and at 1.5 T with magnetic resonance imaging (MRSI). The detection limit of BPA was determined in phantom conditions at 1.5 T and 3.0 T using single voxel 1H MRS, and at 1.5 T using MRSI. In phantom conditions, BPA quantification accuracy of ± 5% and ± 15% were achieved with single voxel MRS using external or internal (internal water signal) concentration references, respectively. For MRSI, a quantification accuracy of <5% was obtained using an internal concentration reference (creatine). The detection limits of BPA in phantom conditions for the PRESS sequence were 0.7 (3.0 T) and 1.4 mM (1.5 T) mM with 20 × 20 × 20 mm3 single voxel MRS, and 1.0 mM with acquisition-weighted MRSI (nominal voxel volume 10(RL) × 10(AP) × 7.5(SI) mm3), respectively. In the in vivo study, an MRSI or single voxel MRS or both was performed for ten patients (patients 1-10) on the day of BNCT. Three patients had glioblastoma multiforme (GBM), and five patients had a recurrent or progressing GBM or anaplastic astrocytoma gradus III, and two patients had head and neck cancer. For nine patients (patients 1-9), MRS/MRSI was performed 70-140 min after the second irradiation field, and for one patient (patient 10), the MRSI study began 11 min before the end of the BPA-F infusion and ended 6 min after the end of the infusion. In comparison, single voxel MRS was performed before BNCT, for two patients (patients 3 and 9), and for one patient (patient 9), MRSI was performed one month after treatment. For one patient (patient 10), MRSI was performed four days before infusion. Signals from the tumour spectrum aromatic region were detected on the day of BNCT in three patients, indicating that in favourable cases, it is possible to detect BPA in vivo in the patient’s brain after BNCT treatment or at the end of BPA-F infusion. However, because the shape and position of the detected signals did not exactly match the BPA spectrum detected in the in vitro conditions, assignment of BPA is difficult. The opportunity to perform MRS immediately after the end of BPA-F infusion for more patients is necessary to evaluate the suitability of 1H MRS for BPA detection or quantification for treatment planning purposes. However, it could be possible to use MRSI as criteria in selecting patients for BNCT.

The virulence of Finnish Pyrenophora teres f. teres isolates and its implications for resistance breeding

In Finland, barley, Hordeum vulgare L., covers 50 % of the total acreage devoted to cereal cultivation. The most common disease of barley in Finland is net blotch, a foliar disease caused by the ascomycete Pyrenophora teres Drechsler. Disease resistance based on plant genes is an environmentally friendly and economical way to manage plant diseases caused by biotic stresses. Development of a disease resistance breeding programme is dependent on knowledge of the pathogen. In addition to information on the epidemiology and virulence of a pathogen, knowledge on how the pathogen evolves and the nature of the risks that might arise in the future are essential issues that need to be taken into account to achieve the final breeding aims. The main objectives of this study were to establish reliable and efficient testing methods for Pyrenophora teres f. teres virulence screening, and to understand the role of virulence of P. teres f. teres in Finland from a disease resistance breeding point of view. The virulence of P. teres was studied by testing 239 Finnish P. teres f. teres isolates collected between 1994 2007 originating from 19 locations, and 200 P. teres progeny isolates originating from artificially produced P. teres matings. According to the results of this study, screening for P. teres f. teres isolates on barley seedlings under greenhouse conditions is a feasible and cost efficient method to describe the virulence spectrum of the pathogen. Inoculum concentration and the seedling leaf used to gauge virulence had significant effects. Barley grain size, morphological traits of P. teres isolates, spore production and growth rate on agar did not affect the expression of virulence. A common barley differential set to characterize the P. teres virulence was developed and is recommended to be used globally. The virulence spectrum of Finnish P. teres f. teres isolates collected in 1994-2007 was constant both within and between the years. The results indicated differences in the pathogen s aggressiveness and in barley genotypes resistance. However, differences in virulence were rarely significant. Unlike in laboratory conditions, no indications of changes in virulence caused by the sexual reproduction have been observed in Finnish barley fields. In Finland, durable net blotch resistance has been achieved by introducing resistance from other barley varieties using traditional crossing methods, including wide crossing, and testing the breeding material at early generations at several sites under natural infection pressure. Novel resistance is available, which is recommended to minimize the risk of selection of virulent isolates and breakdown of currently deployed resistance.

Responses of Scots pine to nickel and copper exposure and herbivory

The goal of this thesis was to examine the ecophysiological responses of Scots pine (Pinus sylvestris L.), with an emphasis on the oxidative enzyme peroxidase and plant phenolics to environmental stresses like elevated levels of nickel (Ni) and copper (Cu), and herbivory. The effects of Ni and Cu were studied in a gradient survey at a sulphur dioxide contaminated site in the Kola Peninsula, and with experiments in which seedlings were exposed to Ni mist or to Ni and Cu amended into the soil. In addition, experimental Ni exposure was combined with disturbance of the natural lichen cover of the forest ground layer. Pine sawfly attack was simulated in the early season defoliation experiment, in which mature Scots pine were defoliated (100 %) during two successive years in a dry, nutrient-poor Scots pine stand. In addition, the effect of previous defoliation on the growth of sawfly (Diprion pini L.) larvae was studied. Apoplastic peroxidase activity was elevated in the needles of pine in a Ni- , Cu- and SO2- polluted environment, which indicated an increased oxidative stress. Increased foliar peroxidase activity due to Ni contamination was shown in the experiment, in which Ni was added as mist. No such response was found in peroxidase acitivity of the roots exposed to elevated Ni and/or Cu in the soil. Elevated Ni in the soil increased the concentration of foliar condensed tannins, which are able to bind heavy metals in the cells. Addition of low levels of Ni in the soil appeared to benefit pine seedlings, which was seen as promoted shoot growth and better condition of the roots. Wet Ni deposition of 2000 mg m-2 reduced growth and survival of pine seedlings, whereas deposition levels 200 mg m-2 or 20 mg m-2 caused no effects in a 2-y lasting experiment. The lichen mat on the forest floor did not act as an effective buffer against the adverse impacts of heavy metals on pine seedlings. However, some evidence was found indicating that soil microbes profited from the lichen mat. Artificial defoliation increased peroxidase activity in the Scots pine needles. In addition, defoliation decreased nitrogen, diamine putrescine and glucose concentrations in the needles and increased the concentrations of several phenolic compounds, starch and sucrose. Previous artificial defoliation led to poor growth of sawfly larvae reared on the pines, suggesting delayed induced resistance in Scots pine. However, there was no consistent relationship between inducibility (proportional increase in a compound following defoliation) and adverse effects on the growth of pine sawfly larvae. The observed inducible responses in needle phenolics due to previous defoliation thus appear to represent non-specific responses against sawflies.

Aerosol size distribution and its connection to cloud droplet number concentration

In order to predict the current state and future development of Earth s climate, detailed information on atmospheric aerosols and aerosol-cloud-interactions is required. Furthermore, these interactions need to be expressed in such a way that they can be represented in large-scale climate models. The largest uncertainties in the estimate of radiative forcing on the present day climate are related to the direct and indirect effects of aerosol. In this work aerosol properties were studied at Pallas and Utö in Finland, and at Mount Waliguan in Western China. Approximately two years of data from each site were analyzed. In addition to this, data from two intensive measurement campaigns at Pallas were used. The measurements at Mount Waliguan were the first long term aerosol particle number concentration and size distribution measurements conducted in this region. They revealed that the number concentration of aerosol particles at Mount Waliguan were much higher than those measured at similar altitudes in other parts of the world. The particles were concentrated in the Aitken size range indicating that they were produced within a couple of days prior to reaching the site, rather than being transported over thousands of kilometers. Aerosol partitioning between cloud droplets and cloud interstitial particles was studied at Pallas during the two measurement campaigns, First Pallas Cloud Experiment (First PaCE) and Second Pallas Cloud Experiment (Second PaCE). The method of using two differential mobility particle sizers (DMPS) to calculate the number concentration of activated particles was found to agree well with direct measurements of cloud droplet. Several parameters important in cloud droplet activation were found to depend strongly on the air mass history. The effects of these parameters partially cancelled out each other. Aerosol number-to-volume concentration ratio was studied at all three sites using data sets with long time-series. The ratio was found to vary more than in earlier studies, but less than either aerosol particle number concentration or volume concentration alone. Both air mass dependency and seasonal pattern were found at Pallas and Utö, but only seasonal pattern at Mount Waliguan. The number-to-volume concentration ratio was found to follow the seasonal temperature pattern well at all three sites. A new parameterization for partitioning between cloud droplets and cloud interstitial particles was developed. The parameterization uses aerosol particle number-to-volume concentration ratio and aerosol particle volume concentration as the only information on the aerosol number and size distribution. The new parameterization is computationally more efficient than the more detailed parameterizations currently in use, but the accuracy of the new parameterization was slightly lower. The new parameterization was also compared to directly observed cloud droplet number concentration data, and a good agreement was found.

Finnish Dosimetric Practice for Epithermal Neutron Beam Dosimetry in Boron Neutron Capture Therapy

Boron neutron capture therapy (BNCT) is a form of chemically targeted radiotherapy that utilises the high neutron capture cross-section of boron-10 isotope to achieve a preferential dose increase in the tumour. The BNCT dosimetry poses a special challenge as the radiation dose absorbed by the irradiated tissues consists of several dose different components. Dosimetry is important as the effect of the radiation on the tissue is correlated with the radiation dose. Consistent and reliable radiation dose delivery and dosimetry are thus basic requirements for radiotherapy. The international recommendations for are not directly applicable to BNCT dosimetry. The existing dosimetry guidance for BNCT provides recommendations but also calls for investigating for complementary methods for comparison and improved accuracy. In this thesis the quality assurance and stability measurements of the neutron beam monitors used in dose delivery are presented. The beam monitors were found not to be affected by the presence of a phantom in the beam and that the effect of the reactor core power distribution was less than 1%. The weekly stability test with activation detectors has been generally reproducible within the recommended tolerance value of 2%. An established toolkit for epithermal neutron beams for determination of the dose components is presented and applied in an international dosimetric intercomparison. The measured quantities (neutron flux, fast neutron and photon dose) by the groups in the intercomparison were generally in agreement within the stated uncertainties. However, the uncertainties were large, ranging from 3-30% (1 standard deviation), emphasising the importance of dosimetric intercomparisons if clinical data is to be compared between different centers. Measurements with the Exradin type 2M ionisation chamber have been repeated in the epithermal neutron beam in the same measurement configuration over the course of 10 years. The presented results exclude severe sensitivity changes to thermal neutrons that have been reported for this type of chamber. Microdosimetry and polymer gel dosimetry as complementary methods for epithermal neutron beam dosimetry are studied. For microdosimetry the comparison of results with ionisation chambers and computer simulation showed that the photon dose measured with microdosimetry was lower than with the two other methods. The disagreement was within the uncertainties. For neutron dose the simulation and microdosimetry results agreed within 10% while the ionisation chamber technique gave 10-30% lower neutron dose rates than the two other methods. The response of the BANG-3 gel was found to be linear for both photon and epithermal neutron beam irradiation. The dose distribution normalised to dose maximum measured by MAGIC polymer gel was found to agree well with the simulated result near the dose maximum while the spatial difference between measured and simulated 30% isodose line was more than 1 cm. In both the BANG-3 and MAGIC gel studies, the interpretation of the results was complicated by the presence of high-LET radiation.