| 1. |
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| 2. |
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| 3. |
- Alattar, Abdul Ghani, et al.
(författare)
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Recombinant alpha(1)-Microglobulin (rA1M) Protects against Hematopoietic and Renal Toxicity, Alone and in Combination with Amino Acids, in a Lu-177-DOTATATE Mouse Radiation Model
- 2023
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Ingår i: Biomolecules. - 2218-273X. ; 13:6
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Tidskriftsartikel (refereegranskat)abstract
- Lu-177-DOTATATE peptide receptor radionuclide therapy (PRRT) is used clinically to treat metastasized or unresectable neuroendocrine tumors (NETs). Although Lu-177-DOTATATE is mostly well tolerated in patients, bone marrow suppression and long-term renal toxicity are still side effects that should be considered. Amino acids are often used to minimize renal radiotoxicity, however, they are associated with nausea and vomiting in patients. alpha (1)-microglobulin (A1M) is an antioxidant with heme- and radical-scavenging abilities. A recombinant form (rA1M) has previously been shown to be renoprotective in preclinical models, including in PRRT-induced kidney damage. Here, we further investigated rA1M's renal protective effect in a mouse Lu-177-DOTATATE model in terms of administration route and dosing regimen and as a combined therapy with amino acids (Vamin). Moreover, we investigated the protective effect of rA1M on peripheral blood and bone marrow cells, as well as circulatory biomarkers. Intravenous (i.v.) administration of rA1M reduced albuminuria levels and circulatory levels of the oxidative stress-related protein fibroblast growth factor-21 (FGF-21). Dual injections of rA1M (i.e., at 0 and 24 h post-Lu-177-DOTATATE administration) preserved bone marrow cellularity and peripheral blood reticulocytes. Administration of Vamin, alone or in combination with rA1M, did not show any protection of bone marrow cellularity or peripheral reticulocytes. In conclusion, this study suggests that rA1M, administered i.v. for two consecutive days in conjunction with Lu-177-DOTATATE, may reduce hematopoietic and kidney toxicity during PRRT with Lu-177-DOTATATE.
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| 4. |
- Andersson, Charlotte, et al.
(författare)
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Biodistribution of I-131 in mice is influenced by circadian variations
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Effects of radiation and biodistribution of radionuclides are often studied in animal models. Circadian rhythm affects many biological functions and may influence the biokinetics of radionuclides and observed responses. The aim of this study was to investigate if the time during the day of I-131 injection affects the biodistribution and absorbed dose to tissues in mice. Biodistribution studies were conducted on male C57BL/6 N mice for three diurnal time-series: the animals were i.v. injected with 160 kBq I-131 at 8 am, 12 pm or 4 pm. The activity concentration in organs and tissues was measured at 1 h to 7 days after administration and absorbed dose at day 7 was determined. Comparison between the three time-series showed statistically significant differences in activity concentration in all investigated tissues and organs. Administration performed at 12 pm resulted in general in higher absorbed dose to the organs than injection performed at 8 am and 4 pm. Time of day of administration affects the biodistribution of I-131 in mice and consequently the absorbed dose to individual organs. These findings advocate that subsequent biodistribution studies and dosimetry calculations should consider time-point of administration as a variable that could influence the results.
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| 6. |
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| 7. |
- Andersson, Charlotte, et al.
(författare)
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Diurnal variations in biodistribution of the radionuclide I-131 in mice
- 2016
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Ingår i: Swedish Cancer Research Meeting, Gothenburg, 2016, November 7-8.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: Radionuclides are routinely used to diagnose and treat many different types of cancer. I-131 is a well-established radioisotope used in e.g. treatment of thyroid cancer and neuroblastoma. Accurate knowledge of I-131 biodistribution is essential to correctly estimate the absorbed dose to normal organs and determine potential risks from I-131 exposure, which is especially important when treating children. Many biological functions in living organisms follow a circadian rhythm. Nevertheless, little is known about diurnal variations in radionuclide biodistribution. This study investigates if circadian rhythm affects I-131 biodistribution in mice and absorbed dose to organs and tissues. Materials & Methods: The radioactivity concentration in mice tissues was studied at different time-points after administration of I-131, and absorbed doses were calculated. The effect of circadian rhythm was studied by varying the time of administration. Results: Difference in activity concentration between the administration time-points was observed at many time-points after administration for most investigated tissues. For some organs differences were also observed in the absorbed dose. The highest activity concentration and absorbed dose were found in the thyroid regardless of time of administration. Conclusion: The results demonstrate that the biodistribution of I-131 in mice is influenced by the time of day of administration. These findings advocate that circadian rhythm should be considered in biodistribution studies and suggests that time-point of administration of radiopharmaceuticals containing I-131 for therapy can be further optimized. An optimized time-point could result in higher absorbed dose to the tumor and/or lower absorbed dose to normal tissues.
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| 8. |
- Andersson, Charlotte, et al.
(författare)
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The influence of circadian rhythm on the biodistribution of I-131
- 2016
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Ingår i: Swedish Radiation Research Association for Young Scientists Workshop, Stockholm, 2016, August 25-26.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: I-131 is well-established in nuclear medicine. The thyroid is a target organ when treating thyroid cancer with unbound I-131, but also a risk organ in I-131-based radionuclide therapy. Exposure to I-131 can also occur from the environment at nuclear accidents. Accurate knowledge of I-131 biodistribution is essential to correctly estimate the absorbed dose to organs and determine potential risks from both medical and hazard exposure. Many biological functions follow a circadian rhythm. Nevertheless, circadian rhythm remains an unknown factor in radionuclide biodistribution. Aim: The purpose of this study was to investigate if circadian rhythm affects I-131 biodistribution in mice and hence absorbed dose to mouse tissues. Methods: The radioactivity concentration in various tissues was studied at different time points after administration of I-131 and absorbed doses were calculated according to the MIRD formalism. The effect of circadian rhythm was studied by varying the time of administration. Male C57BL/6N mice were i.v. injected with I-131 at 8 am, 12 pm or 4 pm and killed after 1h to 7d. Results: Statistically significant difference in activity concentration and absorbed dose between the three injection series was observed for at least one time point after injection for many tissues. Highest activity concentration and absorbed dose were found in the thyroid. Conclusion: The results demonstrated that the biodistribution of I-131 in mice is influenced by the time of day of administration to a certain extent. These findings advocate that circadian rhythm should be considered in biodistribution studies and dose calculations.
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| 9. |
- Dalmo, Johanna, et al.
(författare)
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Biodistribution of 177Lu-octreotate and 111In-minigastrin in female nude mice transplanted with human medullary thyroid carcinoma GOT2.
- 2012
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Ingår i: Oncology reports. - : Spandidos Publications. - 1791-2431 .- 1021-335X. ; 27:1, s. 174-181
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Tidskriftsartikel (refereegranskat)abstract
- To be able to evaluate new radiopharmaceuticals and optimize diagnostic and therapeutic procedures, relevant animal models are required. The aim of this study was to evaluate the medullary thyroid carcinoma GOT2 animal model by analyzing the biodistribution of 177Lu-octreotate and 111In-minigastrin (MG0). BALB/c nude mice, subcutaneously transplanted with GOT2, were intravenously injected with either 177Lu-octreotate or 111In-MG0, with or without excess of unlabeled human minigastrin simultaneously with 111In-MG0. Animals were sacrificed 1-7 days after injection in the 177Lu-octreotate study and 1h after injection of 111In-MG0. The activity concentrations in organs and tissues were determined and mean absorbed doses from 177Lu were calculated. There was a specific tumor uptake of either 177Lu-octreotate or 111In-MG0. 177Lu-octreotate samples showed high activity concentrations in tissues expressing somatostatin receptors (SSTR). For both radiopharmaceuticals the highest activity concentrations were found in the kidneys. Compared to results from similar studies in mice with another MTC cell line (TT) the biodistribution was favorable (higher tumor uptake) for the GOT2 model, while compared to other animal models expressing SSTR, the tumor uptake of 177Lu-octreotate was modest. In conclusion, the GOT2 animal model is a valuable model for evaluation and optimization of diagnostic and therapeutic procedures using radiolabeled somatostatin, CCK2 and gastrin analogues prior to clinical studies.
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| 10. |
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| 11. |
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| 12. |
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| 13. |
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| 14. |
- Dalmo, Johanna, et al.
(författare)
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Priming increases the anti-tumor effect and therapeutic window of 177Lu-octreotate in nude mice bearing human small intestine neuroendocrine tumor GOT1.
- 2017
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Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: 177Lu-[DOTA0, Tyr3]-octreotate (177Lu-octreotate) is used for treatment of patients with somatostatin receptor (SSTR) expressing neuroendocrine tumors. However, complete tumor remission is rarely seen, and optimization of treatment protocols is needed. In vitro studies have shown that irradiation can up-regulate the expression of SSTR1, 2 and 5, and increase 177Lu-octreotate uptake. The aim of the present study was to examine the anti-tumor effect of a 177Lu-octreotate priming dose followed 24 h later by a second injection of 177Lu-octreotate compared to a single administration of 177Lu-octreotate, performed on the human small intestine neuroendocrine tumor cell line, GOT1, transplanted to nude mice. RESULTS: Priming resulted in a 1.9 times higher mean absorbed dose to the tumor tissue per administered activity, together with a reduced mean absorbed dose for kidneys. Priming gave the best overall anti-tumor effects. Magnetic resonance imaging showed no statistically significant difference in tumor response between treatment with and without priming. Gene expression analysis demonstrated effects on cell cycle regulation. Biological processes associated with apoptotic cell death were highly affected in the biodistribution and dosimetry study, via differential regulation of, e.g., APOE, BAX, CDKN1A, and GADD45A. CONCLUSIONS: Priming had the best overall anti-tumor effects and also resulted in an increased therapeutic window. Results indicate that potential biomarkers for tumor regrowth may be found in the p53 or JNK signaling pathways. Priming administration is an interesting optimization strategy for 177Lu-octreotate therapy of neuroendocrine tumors, and further studies should be performed to determine the mechanisms responsible for the reported effects.
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| 15. |
- Druid, Malin, et al.
(författare)
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Late age- and dose-related effects on the proteome of thyroid tissue in rats after 131I exposure.
- 2024
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Ingår i: Radiation. - 2673-592X. ; 4:2, s. 149-166
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Tidskriftsartikel (refereegranskat)abstract
- The physiological process of iodine uptake in the thyroid is used for 131I treatment of thyroid diseases. Children are more sensitive to radiation compared to adults and may react differently to 131I exposure. The aims of this study were to evaluate the effects on thyroid protein expression in young and adult rats one year after 131I injection and identify potential biomarkers related to 131I exposure, absorbed dose, and age. Twelve Sprague Dawley rats (young and adults) were i.v. injected with 50 kBq or 500 kBq 131I and killed twelve months later. Twelve untreated rats were used as age-matched controls. Quantitative proteomics, statistical analysis, and evaluation of biological effects were performed. The effects of irradiation were most prominent in young rats. Protein biomarker candidates were proposed related to age, absorbed dose, thyroid function, and cancer, and a panel was proposed for 131I exposure. In conclusion, the proteome of rat thyroid was differentially regulated twelve months after low-intermediate dose exposure to 131I in both young and adult rats. Several biomarker candidates are proposed for 131I exposure, age, and many of them are known to be related to thyroid function or thyroid cancer. Further research on human samples is needed for validation. Data are avaiable via ProteomeXchange with identifier PXD024786.
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| 16. |
- Elvborn, Mikael, et al.
(författare)
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Sex-dependence in absorbed dose from I-131 in mice
- 2016
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Ingår i: Höstmöte med Cancerfondens Planeringsgrupp för Onkologisk Radionuklidterapi, Uppsala, 2016, November 24-25.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 17. |
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| 18. |
- Elvborn, Mikael, et al.
(författare)
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The influence of biological sex on the biodistribution of I-131 in mice
- 2016
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Ingår i: SweRays Workshop, Stockholm, Sweden, Aug 25-26.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: The thyroid is both a risk and target organ in radionuclide therapy. The gland takes up iodine to synthesize thyroidal hormones which are important for various cellular mechanisms throughout the body. 131I is used in nuclear medicine, but hazard exposure can also occur from fallout of nuclear accidents. Physiological differences between the sexes constitute intrinsic variables that are thought to impact the biodistribution of 131I. Aim: The purpose of this study was to assess potential difference between the sexes concerning 131I biodistribution in mice. Methods: In total, 70 C57BL/6N mice (35 males and 35 females) were used in the experiments (n=5/group). Mice were injected intravenously (at 8 am) with 165−175 kBq 131I, prepared in physiological saline, and killed after 1h to 7d following injection. Various tissue samples were collected, weighed, and subjected to gamma counter measurement to determine 131I activity concentration. Results: The results demonstrated clear differences in 131I biodistribution between male and female mice, notably in the kidneys and salivary glands. Statistically significant differences were found for the majority of tissues and time points. Although maximum uptake in the thyroid was similar for both sexes, the decrease of activity concentration after 18h was distinctly slower in females showing statistical significance. Conclusion: Experiments demonstrated that 131I biodistribution differs between the sexes, which would translate to differences in absorbed dose. The extent of difference is tissue-dependent, with markedly different biodistribution in certain tissues. The results advocate that sex should be considered as a variable in biodistribution studies and dose calculations.
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| 19. |
- Elvborn, Mikael, et al.
(författare)
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The influence of biological sex on thyroid cancer treatment risk assessment
- 2016
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Ingår i: Swedish Cancer Research Meeting, Gothenburg, 2016, November 7-8.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: Researchers are often reluctant towards using females in studies, especially when radiopharmaceuticals and hormonally dependent diseases are concerned. Simultaneously, women are more prone to thyroid-related diseases such as Grave’s disease and Hashimoto’s thyroiditis, with a 7-10 times higher incidence than in men. The thyroid gland synthesizes iodine-containing hormones, which are needed for several cellular processes in the body. I-131 is routinely used in thyroid cancer treatment, and I-131-containing pharmaceuticals are used for treatment of patients with some neuroendocrine tumor types. This study was performed to evaluate possible differences between sexes in tissue uptake of I-131 in mice. Methods: 35 male and 35 female mice (C57BL/6N, n=5/group) were intravenously injected with I-131 at 8 am, and animals were killed 1 h to 7 d after injection. Tissue samples were collected, weighed, and measured to determine I-131 activity concentration. Results: The results indicate differences in I-131 uptake between males and females, especially in the salivary glands and kidneys. In the majority of the tissues and observed time points, statistical significant differences were found. The decrease of activity concentration in thyroid after 18 h was slower for females (statistical significant), though the obtained maximum uptake was similar. Conclusion: The I-131 uptake differs between males and females, which would result in different absorbed doses from exposure to the same amount of I-131. The difference in magnitude is tissue-dependent. The results suggest biological sex to be treated as a variable in dose calculations and risk assessments when treating cancer patients with radiopharmaceuticals containing I-131.
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| 20. |
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| 21. |
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| 22. |
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| 23. |
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| 24. |
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| 25. |
- Forssell-Aronsson, Eva, 1961, et al.
(författare)
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Radionuclide therapy via SSTR - future aspects from experimental animal studies.
- 2013
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 97:1, s. 86-98
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Forskningsöversikt (refereegranskat)abstract
- There is need for better therapeutic options for neuroendocrine tumours. The aim of this review was to summarize results of experimental animal studies and raise ideas for future radionuclide therapy based on high expression of somatostatin (SS) receptors by many neuroendocrine tumours. In summary, one of the major options is individualized treatment for each patient, including choice of SS analogues, radionuclides and treatment schedules. Other options are methods to increase the treatment effect on tumour tissue (increasing tumour uptake and retention by upregulation of receptor expression and avoiding saturation of receptor binding), methods to increase the tumour tissue response (by choice of radionuclides, SS analogues or combined therapies), and methods to reduce side effects (diminished uptake and retention in critical organs and reduced normal tissue response). Furthermore, combination therapy with other radiopharmaceuticals, cytotoxic drugs or radiosensitizers can be considered to enhance the effects of radiolabelled SS analogues.
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| 26. |
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| 27. |
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| 28. |
- Gustafsson, Fredrik, et al.
(författare)
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Particle Filters for Positioning, Navigation and Tracking
- 2001
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- A framework for positioning, navigation and tracking problems using particle filters (sequential Monte Carlo methods) is developed. It consists of a class of motion models and a general non-linear measurement equation in position. A general algorithm is presented, which is parsimonious with the particle dimension. It is based on marginalization, enabling a Kalman filter to estimate all position derivatives, and the particle filter becomes low-dimensional. This is of utmost importance for high-performance real-time applications. Automotive and airborne applications illustrate numerically the advantage over classical Kalman filter based algorithms. Here the use of non-linear models and non-Gaussian noise is the main explanation for the improvement in accuracy. More specifically, we describe how the technique of map matching is used to match an aircraft's elevation profile to a digital elevation map, and a car's horizontal driven path to a street map. In both cases, real-time implementations are available, and tests have shown that the accuracy in both cases is comparable to satellite navigation (as GPS), but with higher integrity. Based on simulations, we also argue how the particle filter can be used for positioning based on cellular phone measurements, for integrated navigation in aircraft, and for target tracking in aircraft and cars. Finally, the particle filter enables a promising solution to the combined task of navigation and tracking, with possible application to airborne hunting and collision avoidance systems in cars.
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| 29. |
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| 30. |
- Koppal, Sandeep, et al.
(författare)
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Quantitative fat and R2* mapping in vivo to measure lipid-rich necrotic core and intraplaque hemorrhage in carotid atherosclerosis
- 2017
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Ingår i: Magnetic Resonance in Medicine. - : John Wiley & Sons. - 0740-3194 .- 1522-2594. ; 78:1, s. 285-296
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The aim of this work was to quantify the extent of lipid-rich necrotic core (LRNC) and intraplaque hemorrhage (IPH) in atherosclerotic plaques. Methods: Patients scheduled for carotid endarterectomy underwent four-point Dixon and T1-weighted magnetic resonance imaging (MRI) at 3 Tesla. Fat and R2* maps were generated from the Dixon sequence at the acquired spatial resolution of 0.60×0.60×0.70mm voxel size. MRI and three-dimensional (3D) histology volumes of plaques were registered. The registration matrix was applied to segmentations denoting LRNC and IPH in 3D histology to split plaque volumes in regions with and without LRNC and IPH. Results: Five patients were included. Regarding volumes of LRNC identified by 3D histology, the average fat fraction by MRI was significantly higher inside LRNC than outside: 12.64±0.2737% versus 9.294±0.1762% (mean±standard error of the mean [SEM]; P<0.001). The same was true for IPH identified by 3D histology, R2* inside versus outside IPH was: 71.81±1.276 s-1 versus 56.94±0.9095 s-1 (mean±SEM; P<0.001). There was a strong correlation between the cumulative fat and the volume of LRNC from 3D histology (R2=0.92) as well as between cumulative R2* and IPH (R2=0.94). Conclusion: Quantitative mapping of fat and R2* from Dixon MRI reliably quantifies the extent of LRNC and IPH.
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| 31. |
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| 32. |
- Langen, Britta, et al.
(författare)
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Age and sex effects across the blood proteome after ionizing radiation exposure can bias biomarker screening and risk assessment
- 2022
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Molecular biomarkers of ionizing radiation (IR) exposure are a promising new tool in various disciplines: they can give necessary information for adaptive treatment planning in cancer radiotherapy, enable risk projection for radiation-induced survivorship diseases, or facilitate triage and intervention in radiation hazard events. However, radiation biomarker discovery has not yet resolved the most basic features of personalized medicine: age and sex. To overcome this critical bias in biomarker identification, we quantitated age and sex effects and assessed their relevance in the radiation response across the blood proteome. We used high-throughput mass spectrometry on blood plasma collected 24 h after 0.5 Gy total body irradiation (15 MV nominal photon energy) from male and female C57BL/6 N mice at juvenile (7-weeks-old) or adult (18-weeks-old) age. We also assessed sex and strain effects using juvenile male and female BALB/c nude mice. We showed that age and sex created significant effects in the proteomic response regarding both extent and functional quality of IR-induced responses. Furthermore, we found that age and sex effects appeared non-linear and were often end-point specific. Overall, age contributed more to differences in the proteomic response than sex, most notably in immune responses, oxidative stress, and apoptotic cell death. Interestingly, sex effects were pronounced for DNA damage and repair pathways and associated cellular outcome (pro-survival vs. pro-apoptotic). Only one protein (AHSP) was identified as a potential general biomarker candidate across age and sex, while GMNN, REG3B, and SNCA indicated some response similarity across age. This low yield advocated that unisex or uniage biomarker screening approaches are not feasible. In conclusion, age- and sex-specific screening approaches should be implemented as standard protocol to ensure robustness and diagnostic power of biomarker candidates. Bias-free molecular biomarkers are a necessary progression towards personalized medicine and integral for advanced adaptive cancer radiotherapy and risk assessment.
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| 33. |
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| 34. |
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| 35. |
- Langen, Britta, et al.
(författare)
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Data convolution and circadian rhythm impact identification of biomarker genes for ionizing radiation exposure in vivo: concept study on 131I exposure in mouse thyroid
- 2015
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Ingår i: 15th International Congress of Radiation Research, Kyoto, Japan, May 25-29.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: Expression microarrays have been used increasingly for biomarker discovery of genes related to ionizing radiation (IR) exposure, particularly in vivo. However, diurnal variation of gene expression and data convolution from mixed cell populations can hinder biomarker discovery. For one, candidate biomarker genes may underlie circadian rhythmicity and their expression may oscillate affecting their robustness or indicative potential. For the other, significant responses from a specific cell type can be hidden in expression data from mixed cell populations creating bias in results or even precluding biomarker discovery. Aim: To identify biomarkers of IR exposure in thyroid tissue and asses their robustness with regard to circadian rhythm and data convolution. Methods: Female BALB/c nude mice (n=3–4/group) were i.v. injected with 90 kBq 131I, or mock-treated, at 9am, 12pm, or 3pm and killed after 24h. Total RNA was extracted from excised thyroids and subjected to microarray analysis (Illumina platform). Data were processed with Nexus Expression v3.0 (cut-off adjusted P <0.01; log2 ratio ≥0.58). Enriched biological processes (P value <0.05) were categorized after cellular function according to Gene Ontology terms. Data was deconvoluted by cell frequency of follicular cells and C-cells with csSAM using R/Bioconductor. Thyroid mean absorbed dose was calculated as 5.9 Gy using the MIRD formalism. Results: Twenty-five genes responded to 131I in thyroid irrespective of time of day, notably members of the kallikrein (KLK1) gene family, but direction of regulation and fold-change differed distinctly. All KLK1 transcripts were detected in at least one deconvoluted data set, while five additional KLK1 transcripts were detected upon deconvolution. Deconvolution also increased the detection rate of significant transcript regulation and regulated biological processes: DNA integrity, gene expression integrity, and cellular stress were negative in convoluted data, but showed distinct responses in both follicular cells and C-cells. Conclusions: The KLK1 gene family is a promising biomarker candidate that shows robustness of detection. Circadian rhythm and convolution affected the quality and quantity of detected transcriptional responses and we advocate their consideration in the in vivo setting.
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| 36. |
- Langen, Britta, et al.
(författare)
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Deconvolution of expression microarray data reveals I-131-induced responses otherwise undetected in thyroid tissue
- 2018
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 13:7
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Tidskriftsartikel (refereegranskat)abstract
- High-throughput gene expression analysis is increasingly used in radiation research for discovery of damage-related or absorbed dose-dependent biomarkers. In tissue samples, cell type-specific responses can be masked in expression data due to mixed cell populations which can preclude biomarker discovery. In this study, we deconvolved microarray data from thyroid tissue in order to assess possible bias from mixed cell type data. Transcript expression data [GSE66303] from mouse thyroid that received 5.9 Gy from I-131 over 24 h (or 0 Gy from mock treatment) were deconvolved by cell frequency of follicular cells and C-cells using csSAM and R and processed with Nexus Expression. Literature-based signature genes were used to assess the relative impact from ionizing radiation (IR) or thyroid hormones (TH). Regulation of cellular functions was inferred by enriched biological processes according to Gene Ontology terms. We found that deconvolution increased the detection rate of significantly regulated transcripts including the biomarker candidate family of kallikrein transcripts. Detection of IR-associated and TH-responding signature genes was also increased in deconvolved data, while the dominating trend of TH-responding genes was reproduced. Importantly, responses in biological processes for DNA integrity, gene expression integrity, and cellular stress were not detected in convoluted data-which was in disagreement with expected dose-response relationships-but upon deconvolution in follicular cells and C-cells. In conclusion, previously reported trends of I-131-induced transcriptional responses in thyroid were reproduced with deconvolved data and usually with a higher detection rate. Deconvolution also resolved an issue with detecting damage and stress responses in enriched data, and may reduce false negatives in other contexts as well. These findings indicate that deconvolution can optimize microarray data analysis of heterogeneous sample material for biomarker screening or other clinical applications.
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| 37. |
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| 38. |
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| 39. |
- Langen, Britta, et al.
(författare)
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Non-targeted transcriptomic effects upon thyroid irradiation: similarity between in-field and out-of-field responses varies with tissue type
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Non-targeted effects can induce responses in tissues that have not been exposed to ionizing radiation. Despite their relevance for risk assessment, few studies have investigated these effects in vivo. In particular, these effects have not been studied in context with thyroid exposure, which can occur e.g. during irradiation of head and neck tumors. To determine the similarity between in-field and out-offield responses in normal tissue, we used a partial body irradiation setup with female mice where the thyroid region, the thorax and abdomen, or all three regions were irradiated. After 24h, transcriptional regulation in the kidney cortex, kidney medulla, liver, lungs, spleen, and thyroid was analyzed using microarray technology. Thyroid irradiation resulted in transcriptional regulation in the kidney medulla and liver that resembled regulation upon direct exposure of these tissues regarding both strength of response and associated biological function. The kidney cortex showed fewer similarities between the setups, while the lungs and spleen showed little similarity between in-field and out-of-field responses. Interestingly, effects were generally not found to be additive. Future studies are needed to identify the molecular mechanisms that mediate these systemic effects, so that they may be used as targets to minimize detrimental side effects in radiotherapy.
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| 40. |
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| 41. |
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| 42. |
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| 43. |
- Langen, Britta, et al.
(författare)
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Thyroid irradiation and non-targeted effects: in-field and out-of-field responses on the transcriptomic level show tissue-specific similarity
- 2016
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Ingår i: SweRays Workshop, Stockholm, Sweden, Aug 25-26.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: Radiation exposure can result in non-targeted effects that strongly influence cellular responses in non-irradiated tissues. However, radiotherapy planning does not consider out-of-field effects in current risk assessment, because knowledge of these effects is still scarce. Non-targeted effects from the thyroid are of particular concern, since it is a major regulatory gland and often subject to exposure during irradiation of e.g. head and neck, lung and breast tumors. The aim of this study was to characterize in-field and out-of-field responses on the transcriptomic level in vivo after thyroid irradiation. Methods: Anaesthetized female BALB/c nude mice were irradiated with 2 Gy from 4 MV photon beams in a partial body irradiation setup: the thyroid region, the thorax and abdomen, or all three regions combined (n=3/group). Control mice (n=5) were anaesthetized but not irradiated. Mice were killed after 24h and the kidneys, liver, lungs, spleen, and thyroid were sampled. Expression microarray analysis was performed on total RNA extracted from tissue samples. Results: Thyroid irradiation induced complex gene regulation responses in kidney medulla and liver that were highly similar to direct exposure of these tissues. In contrast, kidney cortex showed a lesser degree of similarity between setups, while lungs and spleen exhibited only marginal out-of-field responses. Interestingly, non-targeted effects and in-field responses did not appear to show simple additive behavior. Conclusions: Thyroid exposure can induce significant responses in other tissues similar to direct irradiation, but these non-targeted effects show tissue-specificity. The underlying mechanisms may yield molecular targets for minimizing systemic side-effects in radiotherapy.
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| 44. |
- Langen, Britta, et al.
(författare)
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Transcriptional response in normal mouse tissues after i.v. 211At administration - response related to absorbed dose, dose rate, and time
- 2015
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Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X .- 2191-219X. ; 5:1, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- Background In cancer radiotherapy, knowledge of normal tissue responses and toxicity risks is essential in order to deliver the highest possible absorbed dose to the tumor while maintaining normal tissue exposure at non-critical levels. However, few studies have investigated normal tissue responses in vivo after 211At administration. In order to identify molecular biomarkers of ionizing radiation exposure, we investigated genome-wide transcriptional responses to (very) low mean absorbed doses from 211At in normal mouse tissues. Methods Female BALB/c nude mice were intravenously injected with 1.7 kBq 211At and killed after 1 h, 6 h, or 7 days or injected with 105 or 7.5 kBq and killed after 1 and 6 h, respectively. Controls were mock-treated. Total RNA was extracted from tissue samples of kidney cortex and medulla, liver, lungs, and spleen and subjected to microarray analysis. Enriched biological processes were categorized after cellular function based on Gene Ontology terms. Results Responses were tissue-specific with regard to the number of significantly regulated transcripts and associated cellular function. Dose rate effects on transcript regulation were observed with both direct and inverse trends. In several tissues, Angptl4, Per1 and Per2, and Tsc22d3 showed consistent transcript regulation at all exposure conditions. Conclusions This study demonstrated tissue-specific transcriptional responses and distinct dose rate effects after 211At administration. Transcript regulation of individual genes, as well as cellular responses inferred from enriched transcript data, may serve as biomarkers in vivo. These findings expand the knowledge base on normal tissue responses and may help to evaluate and limit side effects of radionuclide therapy. Keywords: Astatine-211; Ionizing radiation; Normal tissue response; Radionuclide therapy; Biomarke
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- Larsson, Malin, et al.
(författare)
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Age-related long-term response in rat thyroid tissue and plasma after internal low dose exposure to I-131
- 2022
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- I-131 is used clinically for therapy, and may be released during nuclear accidents. After the Chernobyl accident papillary thyroid carcinoma incidence increased in children, but not adults. The aims of this study were to compare I-131 irradiation-dependent differences in RNA and protein expression in the thyroid and plasma of young and adult rats, and identify potential age-dependent biomarkers for I-131 exposure. Twelve young (5 weeks) and twelve adult Sprague Dawley rats (17 weeks) were i.v. injected with 50 kBq I-131 (absorbed dose to thyroid = 0.1 Gy), and sixteen unexposed age-matched rats were used as controls. The rats were killed 3-9 months after administration. Microarray analysis was performed using RNA from thyroid samples, while LC-MS/MS analysis was performed on proteins extracted from thyroid tissue and plasma. Canonical pathways, biological functions and upstream regulators were analysed for the identified transcripts and proteins. Distinct age-dependent differences in gene and protein expression were observed. Novel biomarkers for thyroid I-131 exposure were identified: (PTH), age-dependent dose response (CA1, FTL1, PVALB (youngsters) and HSPB6 (adults)), thyroid function (Vegfb (adults)). Further validation using clinical samples are needed to explore the role of the identified biomarkers.
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- Larsson, Malin, et al.
(författare)
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Long-term transcriptomic and proteomic effects in Sprague Dawley rat thyroid and plasma after internal low dose 131I exposure.
- 2020
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 15:12
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Tidskriftsartikel (refereegranskat)abstract
- Radioiodide (131I) is commonly used to treat thyroid cancer and hyperthyroidis.131I released during nuclear accidents, have resulted in increased incidence of thyroid cancer in children. Therefore, a better understanding of underlying cellular mechanisms behind 131I exposure is of great clinical and radiation protection interest. The aim of this work was to study the long-term dose-related effects of 131I exposure in thyroid tissue and plasma in young rats and identify potential biomarkers.Male Sprague Dawley rats (5-week-old) were i.v. injected with 0.5, 5.0, 50 or 500 kBq 131I (Dthyroid ca 1-1000 mGy), and killed after nine months at which time the thyroid and blood samples were collected. Gene expression microarray analysis (thyroid samples) and LC-MS/MS analysis (thyroid and plasma samples) were performed to assess differential gene and protein expression profiles in treated and corresponding untreated control samples. Bioinformatics analyses were performed using the DAVID functional annotation tool and Ingenuity Pathway Analysis (IPA). The gene expression microarray data and LC-MS/MS data were validated using qRT-PCR and ELISA, respectively.Nine 131I exposure-related candidate biomarkers (transcripts: Afp and RT1-Bb, and proteins: ARF3, DLD, IKBKB, NONO, RAB6A, RPN2, and SLC25A5) were identified in thyroid tissue. Two dose-related protein candidate biomarkers were identified in thyroid (APRT and LDHA) and two in plasma (DSG4 and TGM3). Candidate biomarkers for thyroid function included the ACADL and SORBS2 (all activities), TPO and TG proteins (low activities). 131I exposure was shown to have a profound effect on metabolism, immune system, apoptosis and cell death. Furthermore, several signalling pathways essential for normal cellular function (actin cytoskeleton signalling, HGF signalling, NRF2-mediated oxidative stress, integrin signalling, calcium signalling) were also significantly regulated.Exposure-related and dose-related effects on gene and protein expression generated few expression patterns useful as biomarkers for thyroid function and cancer.
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