280 research outputs found

    A Monte Carlo Model of Stochastic Alpha Particle Microdosimetry in 3D Multicellular Aggregates

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    Targeted alpha therapy (TAT) is an emerging new approach to radionuclide therapy, and promises to be especially valuable in the treatment of metastatic disease and radioresistant tumors. However, the dosimetry of TAT presents challenges not seen in photon therapy, due to uncertainties in the relative biological effectiveness (RBE) of alpha radiation. One of the most dominant sources of this uncertainty is the stochasticity originating from the discrete nature of alpha particles, resulting in nonuniform cellular uptake patterns at low specific activities. Current approaches to alpha particle internal dosimetry, based on the MIRD formalism, typically assume that activity is uniformly distributed in subcellular compartments, with resulting absorbed dose distributions being unrealistically homogeneous and isotropic. We develop a Monte Carlo generalization of the MIRD-based formalism that explicitly accounts for stochastic nonuniform localization of alpha emitters in a general 3D multicellular aggregate. In the limit of averaging over many replicates, our approach reduces to the MIRD-based one, which we verify by comparing our code’s results with those of MIRDcell, a commonly used software for TAT dosimetry based on the MIRD formalism. At low specific activity, stochasticity manifests itself as an increase in cell survival beyond that expected from MIRD-based calculations, along with corresponding shifts in the generalized equivalent uniform dose. The magnitude of this effect strongly depends on the cellular localization of alpha emission, a parameter that can be experimentally controlled by altering the chemistry of the conjugate delivery vehicle of the radionuclide.M.S

    Application of the Linear-Quadratic model to targeted radionuclide therapy

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    PhDThe principal aim of this work was to test the hypothesis that the Linear-Quadratic (LQ) model of cell survival, developed for external beam radiotherapy (EBRT), could be extended to targeted radionuclide therapy (TRT) in order to predict dose-response relationships. The secondary aim was to establish the relevance of particular radiobiological phenomena to TRT and relate these results to any deviations from the response predicted by the LQ Model. Methods: Cancer cell lines were treated with either EBRT or an in-vitro model of TRT. Dosimetry for the TRT was calculated using radiation transport simulations with the Monte Carlo PENELOPE code. Clonogenic as well as functional biological assays were used to assess cell response. Results: Accurate dosimetry for in-vitro exposures of cell cultures to radioactivity was established. LQ parameters of cell survival were established for cancer cell lines reported to be prone to apoptosis, low dose hypersensitivity (LDH) or the bystander effect. For apoptotic cells and cells exhibiting a bystander effect in response to EBRT, LQ parameters were found to be predictive of cell response to TRT. Apoptosis was not found to be a mode of cell death more specific to TRT than to EBRT. Bystander effects could not be demonstrated in cells exposed to TRT. Exposure to low doses of radiation may even protect against the bystander effect. The LQ model was not predictive of cell response in cells previously shown to exhibit LDH. This led to a development of the LQ model based upon a threshold dose-rate for maximum repair. However, the current explanation of LDH may not explain the inverse dose-rate response. Conclusion: The LQ model of cell survival to radiation has been shown to be largely predictive of response to low dose-rate irradiation. However, in cells displaying LDH, further adaptation of the model was require

    Advances in targeted Alpha therapy for prostate cancer

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    BACKGROUND: Amongst therapeutic radiopharmaceuticals, targeted alpha therapy (TαT) can deliver potent and local radiation selectively to cancer cells as well as the tumor microenvironment and thereby control cancer while minimizing toxicity. DESIGN: In this review, we discuss the history, progress, and future potential of TαT in the treatment of prostate cancer, including dosimetry-individualized treatment planning, combinations with small-molecule therapies, and conjugation to molecules directed against antigens expressed by prostate cancer cells, such as prostate-specific membrane antigen (PSMA) or components of the tumor microenvironment. RESULTS: A clinical proof of concept that TαT is efficacious in treating bone-metastatic castration-resistant prostate cancer has been demonstrated by radium-223 via improved overall survival and long-term safety/tolerability in the phase III ALSYMPCA trial. Dosimetry calculation and pharmacokinetic measurements of TαT provide the potential for optimization and individualized treatment planning for a precision medicine-based cancer management paradigm. The ability to combine TαTs with other agents, including chemotherapy, androgen receptor (AR)-targeting agents, DNA repair inhibitors, and immuno-oncology agents, is under investigation. Currently, TαTs that specifically target prostate cancer cells expressing PSMA represents a promising therapeutic approach. Both PSMA-targeted actinium-225 and thorium-227 conjugates are under investigation. CONCLUSIONS: The described clinical benefit, safety and tolerability of radium-223 and the recent progress in TαT trial development suggest that TαT occupies an important new role in prostate cancer treatment. Ongoing studies with newer dosimetry methods, PSMA targeting, and novel approaches to combination therapies should expand the utility of TαT in prostate cancer treatment

    NEPTUNE (Nuclear process-driven Enhancement of Proton Therapy UNravEled)

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    Protontherapy is an important radiation modality that has been used to treat cancer for over 60 years. In the last 10 years, clinical proton therapy has been rapidly growing with more than 80 facilities worldwide [1]. The interest in proton therapy stems from the physical properties of protons allowing for a much improved dose shaping around the target and greater healthy tissue sparing. One shortcoming of protontherapy is its inability to treat radioresistant cancers, being protons radiobiologically almost as effective as photons. Heavier particles, such as 12C ions, can overcome radioresistance but they present radiobiological and economic issues that hamper their widespread adoption. Therefore, many strategies have been designed to increase the biological effectiveness of proton beams. Examples are chemical radiosensitizing agents or, more recently, metallic nanoparticles. The goal of this project is to investigate the use of nuclear reactions triggered by protons generating short-range high- LET alpha particles inside the tumours, thereby allowing a highly localized DNA-damaging action. Specifically, we intend to consolidate and explain the promising results recently published in [2], where a significant enhancement of biological effectiveness was achieved by the p-11B reaction. Clinically relevant binary approaches were first proposed with Boron Neutron Capture Therapy (BNCT), which exploits thermal neutron capture in 10B, suitably accumulated into tumour before irradiation. The radiosensitising effects due to the presence of 10B will be compared to those elicited by p-11B, using the same carrier and relating the observed effects with intracellular 11B and 10B distribution as well as modelled particle action and measured dose deposition at the micro/nanometer scale. Moreover, the p-19F reaction, which also generates secondary particles potentially leading to local enhancement of proton effectiveness, will be investigated. The in-vivo imaging of 11B and 19F carriers will be studied, in particular by optimizing 19F-based magnetic resonance

    Investigation of timepix radiation detector for autoradiography and microdosimetry in targeted alpha therapy

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    The Timepix detector developed by CERN is a novel and sophisticated particle detector. It consists of a semiconductor layer divided into an array of pixels. This array of pixels is bumpbonded to an electronics integrated layer (i.e. the readout chip). Timepix can be used for a wide range of measurements of electromagnetic radiation and particles and their applications in different fields such as space physics, nuclear physics, radiotherapy physics, imaging and radiation protection. The Timepix detector used in this work was purchased from Amsterdam Scientific Instruments, the Netherlands, in order to investigate its use for microdosimetry purposes, in particular in targeted alpha therapy. The device has the following properties: 256 x 256 pixels of 55 x 55 ÎŒm2 area each, the chip is effective for positive or negative charge and can be used to detect electrons, X-rays, neutrons and heavy charge particles. It can work as an energy spectrometer, has good spatial resolution and reason1ble detection efficiency. The device can operate in three common modes: Timepix mode, Medipix mode, and Time-Over-Threshold (TOT) mode. Targeted alpha therapy (TAT) is a novel type of radionuclide therapy in which an alpha emitting radioisotope is attached to a cancer cell seeking vector (so called radioimmunoconjugate (RIC)). Once attached to a cancer cell, it causes localized damage due to traversal and energy deposition high LET a-particles. There is, however, a lack of data related to a-particle distribution in TAT. These data are required to more accurately estimate the absorbed dose on a cellular level. As a result, this work aims to develop a microdosimetry technique, using Timepix detector that will estimate, or better yet determine the absorbed dose deposited by a-particles in cells as well as will measure the biodistribution of the radioisotope in a tumour. Initially, extensive Timepix characterization and testing has been done to evaluate the detector's response, including linearity, reproducibility, and sensitivity to low doses of radiations (ÎŒGy-mGy dose region) and energy dependence. 1-125 seeds and superficial X-rays (below 70 kVp), produced by the Gulmay superficial X-ray unit, were used. The measured Timepix pixel value was correlated with the known dose (based on the irradiation time used and TLD-100 measurements) and a pixel-value-to- dose calibration curve was obtained. It was confinned that Timepix value increased linearly with the dose delivered. The dose calibration curves using the superficial X-ray beams showed that the pixel value, however, depended on the energy of the X-ray beam. The application of Timepix to measure radioisotope biodistribution (i.e. autoradiography) was investigated. Mice with Lewis lung (LL2) tumours were treated with about 18 kBq oP27Thlabelled DAB4 murine monoclonal antibody that bounds to necrotic tumour cells. The rationale is to develop a-particle-mediated bystander kill of nearby viable tumour cells. To generate more necrotic tumour cells for 227Th-DAB4 binding, some mice also received chemotherapy before being injected with Th-227-DAB4. Finally, 5 mm tumour sections were cut from treated mice for autoradiography with Timepix. Each tumour section was mounted onto a slide with front face uncovered to allow emission of a-particles from the tumour section. Simple steel collimator (I cm radius, 2 cm length) was manufactured in-house and positioned around the tumour section. The slide was placed 2 cm away from the Timepix detector. Bias voltage of 7 V was applied, and a-particle filter was selected for acquisition. Detector cover was removed, exposing the Si layer, to allow the emitted a-particles ( - 6 Me V) to reach the detector. Image acquisition took -14 h. Good resolution autoradiographs of radiolabelled tumour sections were acquired, showing a-particle, electron and X-ray tracks. Timepix measurements also showed an increased Th-227-DAB4 uptake following chemotherapy due to increase in necrotic tissue volume. Timepix was also used to measure the uptake of Cr-51 by A549 cells (lung carcinoma cell line) for different pH levels and the dependence of uptake on pH was investigated. Timepix was observed to be sensitive to detect small changes in the activity/uptake of radioactive sources depending on the environmental condition and the number of cells. The last part of this thesis deals with the development of a transmitted a-particle microdosimetry technique. First, A549 cells were grown in vitro using standard protocols and were irradiated using a 6 MY photon beam with different doses varying between 2-8 Gy and Ra-226 source was used for a-particle irradiation to evaluate A549 radiation sensitivity using clonogenic assay and MTT assay. The cell line was found radiosensitive, with 050 of~ 2 Gy for X-ray irradiation. For transmitted dosimetry, A549 cells were either unirradiated (control) or irradiated for ~2, 1, 2 or 3 hours with a-particles emitted from a Ra-223 source positioned below a monolayer of A549 cells. The HTS Transwell" 96 well system (Corning, USA), consisting of 2 compartments, was used to develop a method for tracking a-particles through a cell mono layer. This system comprises of two compartments, with liquid Ra-223 evaporated in the lower compartment to avoid a-particle self-absorption inside the liquid. The measured activity of 5 kBq was unifonnly distributed, as confirmed by Timepix detector. The second compartment consists of a flat bottom polycarbonate membrane (I 0 ÎŒm thick) where cells are plated. It is sufficiently thin to allow a-particles to penetrate through and hit the cells. Fifteen thousand A549 cells were seeded in the upper compartment that was then inserted into the lower compartment containing the evaporated Ra-223. The transwell system was positioned under the Timepix detector. Transmitted a-particles were detected for 1;2, I, 2 or 3 hour irradiation times. Additionally, DNA double strand breaks (DSBs) in the form of y-H2AX foci, were examined by fluorescence microscopy. The number of transmitted a-particles was correlated with the observed DNA DSBs and the delivered radiation dose was estimated. Additionally, the dose deposited was calculated using Monte Carlo code SRIM. Approximately 20% of a-particles were transmitted and detected by Timepix. The frequency and number of y-H2AX foci increased significantly following a-particle irradiation as compared to unirradiated controls. The RBE equivalent dose delivered to A549 cells was estimated to be approximately 0.66 Gy, 1.32 Gy, 2.53 Gy and 3. 96 Gy after Y2, I, 2 and 3 h irradiation, respectively, considering a relative biological effectiveness of a-particles of 5.5. In summary, the Timepix detector can be used effectively for autoradiography in TAT, providing high resolution images and excellent spatial resolution of detected a-particles, as well as a transmitted a-particle microdosimetry detector. If cross-calibrated using biological dosimetry, this method will give a good indication of the biological effects of a-particles without the need for repeated biological dosimetry which is costly, time consuming and not readily available.Thesis (Ph.D.) (Research by Publication) -- University of Adelaide, School of Physical Sciences, 2017

    Tools for the Advancement of Radiopharmaceutical Therapy

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    Radiopharmaceutical therapy is used to treat cancers and other diseases with radiolabeled pharmaceuticals. The treatment targets specific cells, and the emitted ionizing radiation cause cytotoxic damage. Dosimetry is performed to estimate the absorbed dose from the energy deposited in the body. This requires measurement of the activity in vivo and knowledge of the retention time of the activity in tumor and organs. Preclinical trials precede clinical studies and evaluate the potential of new radiopharmaceuticals for treatment. Similarly, in vitro and in vivo experiments with radiopharmaceuticals and sources of ionizing radiation are performed to increase radiobiological knowledge, which is helpful in the optimization of radiopharmaceutical therapy. Dosimetry is also necessary for these studies to correctly quantify the biological response to ionizing radiation.However, standard dosimetry only considers macroscopic volumes such as organs or solid tumors. Due to the short range of the emitted radiation, heterogeneous activity uptake can generate heterogeneous energy depositions. In a tumor, this means a large variation in particle tracks hitting the cell nuclei, where cells inundertreated areas will not receive any particle tracks through the cell nucleus. Since damage to DNA in the cell nucleus is the main cause of radiation-induced cell death, this can reduce the treatment effect. Early insight into these limitations of a new radiopharmaceutical can be achieved in preclinical studies investigatingthe intra-tumoral distribution of the radiopharmaceutical uptake. Paper 4 investigated the tumor control probability from the intra-tumoral distribution of 177Lu-PSMA-617 in LNCaP xenografts. Monte Carlo simulations can be used for small-scale and microscopic dosimetry, where small targets such as cells and cellnuclei are considered. Similarly, in paper 3, simulations of an alpha particle source and cell nuclei irradiated were used to estimate the distribution of induced Îł-H2AX foci in PC3 cells irradiated with an 241Am source in vitro.In preclinical studies of therapeutic radiopharmaceuticals, xenografted animal models are followed postinjection over long periods to evaluate the treatment response. This is usually done by measuring changes in tumor size over time. In addition, molecular imaging with positron emission tomography (PET) offers anopportunity to measure biochemical changes in vivo, such as the radiation damage response. However, as investigated in paper 1, gamma emission from the therapeutic radiopharmaceutical in the animal model can cause perturbations to the image by increasing dead-time losses and causing signal pile-up. However, assuggested in paper 2, preclinical intra-therapeutic PET imaging can still be performed during 177Lu-labeled radiopharmaceutical therapy, with shielding attenuating the excess photons while still allowing coincidence detection of annihilation photons

    In Silico Nanodosimetry: New Insights into Nontargeted Biological Responses to Radiation

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    The long-held view that radiation-induced biological damage must be initiated in the cell nucleus, either on or near DNA itself, is being confronted by mounting evidence to suggest otherwise. While the efficacy of cell death may be determined by radiation damage to nuclear DNA, a plethora of less deterministic biological responses has been observed when DNA is not targeted. These so-called nontargeted responses cannot be understood in the framework of DNA-centric radiobiological models; what is needed are new physically motivated models that address the damage-sensing signalling pathways triggered by the production of reactive free radicals. To this end, we have conducted a series of in silico experiments aimed at elucidating the underlying physical processes responsible for nontargeted biological responses to radiation. Our simulation studies implement new results on very low-energy electromagnetic interactions in liquid water (applicable down to nanoscales) and we also consider a realistic simulation of extranuclear microbeam irradiation of a cell. Our results support the idea that organelles with important functional roles, such as mitochondria and lysosomes, as well as membranes, are viable targets for ionizations and excitations, and their chemical composition and density are critical to determining the free radical yield and ensuing biological responses

    Investigating the mechanisms of α-particle therapy in prostate cancer

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    The use of α-particle radionuclide emitters in the treatment of bone metastasis has been an active area of research within targeted radionuclide therapies. From a radiobiological perspective, α-particles are known to be more effective at killing cells in comparison to low linear energy transfer (LET) radiation particles, such as X-rays, with increased relative biological effectiveness of around a factor of 3 in most models. α-particle irradiated cells also show a reduced dependency on radioresistance mechanisms observed in the absence of oxygen, with an oxygen enhancement ratio (OER) close to 1.0. Such advantageous radiobiological properties of α-particles demonstrate their potential for radiotherapy treatments. In recent years, the bone targeting high LET radionuclide Radium-223 (223Ra) has been shown to not only have a palliative effect but also a survival prolonging effect in castration resistant prostate cancer patients with bone metastases. This has encouraged the use of 233Ra in more extensive clinical trials. Despite the clinical utility of 233Ra, little is known regarding the radionuclide’s mechanisms of action in this treatment setting, where accurate assessments of the dosimetry underpinning its effectiveness are lacking. There is a pressing need to model and quantify α-emitter effects in pre-clinical models so the next generation of trials utilising 223Ra can be optimally designed. The research work presented in this thesis focused on studying the dosimetry involved in α-particle irradiation systems for in vitro and clinical settings, using computational simulation methods. We have also studied the α-particle irradiation effects on cell survival, DNA damage and tumour control, focusing specifically on 223Ra treatment scenarios

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

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    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.BoorineutronisÀdehoito (BNCT-hoito) on kemiallisesti kohdennettu sÀdehoito, jossa sÀteilyn vaikutus kohdennetaan kasvaimeen hyödyntÀmÀllÀ boori-10 isotoopin neutronikaappausreaktiota ja kasvainsoluihin hakeutuvaa kantaja-ainetta. BNCT:n sÀteilyannoksen mÀÀritys on haasteellista, koska sÀteilyannos koostuu useista biologisilta vaikutuksiltaan erilaisista annoskomponenteista. SÀteilyannoksen mÀÀritys on tÀrkeÀÀ, koska sÀdehoidon vaikutus riippuu potilaan saamasta sÀteilyannoksesta. SÀdehoidon annosmittauksen kansainvÀliset suositukset eivÀt suoraan sovellu BNCT annosmittauksiin. Olemassa oleva BNCT annosmittausohjeistus antaa menetelmÀsuosituksia, mutta myös kehottaa tutkimaan vaihtoehtoisia annosmittausmenetelmiÀ tulosten vertailtavuuden ja menetelmien tarkkuuden parantamiseksi. TÀssÀ vÀitöskirjassa esitetÀÀn BNCT-hoidoissa kÀytettÀvÀn neutronisÀteilykeilan laadunvarmistusmittauksia ja vertaillaan niitÀ kansainvÀliseen suositukseen. SÀteilykeilassa oleva testikappale ei vaikuttanut annosmonitorikammion herkkyyteen ja reaktorin tehojakauman vaikutus oli alle 1%. Viikoittainen tasaisuusmittaus on ollut yleisesti suositellun 2% vaihteluvÀlin rajoissa. VÀitöskirjassa esitellÀÀn neutronisÀteilykeilan annosmittauksiin kehitetty mittavÀlinekokonaisuus ja sitÀ kÀytetÀÀn kansainvÀlisessÀ annosvertailututkimuksessa. Annosvertailuun osallistuneiden ryhmien mittaustulokset (neutroni vuo, nopeiden neutronien annos ja fotoniannos) olivat yleisesti yhtenevÀt mittauksiin liittyvien epÀvarmuuksien puitteissa. EpÀvarmuusrajat olivat suuret, 3-30% (1 keskihajonta) riippuen mittausmenetelmÀstÀ. Tulokset korostavat osaltaan annosvertailujen tÀrkeyttÀ, jotta kliinisiÀ tuloksia eri BNCT-hoitokeskusten vÀlillÀ voidaan verrata. Otaniemen tutkimusreaktorin neutronikeilassa on tehty 10 vuoden aikana mittauksia samanlaisessa mittausgeometriassa Exradin 2M -mallisella ionisaatiokammiolla. TÀssÀ työssÀ esitetyt tulokset nÀistÀ mittauksista poissulkevat merkittÀvÀt herkkyysmuutokset, jollaisia on raportoitu tÀmÀn malliselle ionisaatiokammiolle. VÀitöskirjassa selvitetÀÀn lisÀksi verrannollisuuskammiolla ja geeliannosmittareilla saavutettavaa hyötyÀ epitermisen neutronikeilan annosmittauksissa. Verrannollisuuskammiolla mitattuna fotoniannos oli alhaisempi kuin ionisaatiokammiolla tai tietokonesimulaatiolla laskettu fotoniannos. Neutroniannoksen osalta verrannollisuuskammiomittaukset ja tietokonesimulaatiotulokset olivat yhteneviÀ 10% tarkkuudella, kun taas ionisaatiokammiomittauksilla saatiin 10-30% alhaisempia neutroniannoksia. BANG-3 -tyyppisen geeliannosmittarin vaste havaittiin lineaariseksi sekÀ fotoni- ettÀ epitermisessÀ neutronikeilassa. MAGIC-tyyppisen geeliannosmittarin annosmaksimiin normitettu annos vastasi tietokonesimulaation perusteella laskettua annosjakaumaa, mutta yhtenevÀisyys oli heikompi pienemmÀn annoksen alueella
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