| 1. |
- 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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| 9. |
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| 10. |
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| 11. |
- Langen, Britta, et al.
(författare)
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Circadian rhythm influences genome-wide transcriptional responses to I-131 in a tissue-specific manner in mice
- 2015
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Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Background: Circadian variation of gene expression is often neglected when ionizing radiation-induced effects are studied, whether in animal models or in cell culture. This study characterized diurnal variation of genome-wide transcriptional regulation and responses of potential biomarkers and signature genes in normal mouse tissues at 24 h after i.v. administration of I-131. Methods: Female BALB/c nude mice were i.v. injected with 90 kBq I-131 at 9: 00 a.m., 12: 00 p.m., or 3: 00 p.m. and killed after 24 h (n = 4/group). Paired control groups were mock-treated (n = 3-4/group). The kidneys, liver, lungs, spleen, and thyroid were excised, snap-frozen, and stored at -80 degrees C until extraction of total RNA. RNA microarray technology was used for genome-wide expression analysis. Enriched biological processes were categorized after cellular function. Signature genes for ionizing radiation and thyroid hormone-induced responses were taken from the literature. Absorbed dose was estimated using the Medical Internal Radiation Dose (MIRD) formalism. Results: The thyroid received an absorbed dose of 5.9 Gy and non-thyroid tissues received 0.75-2.2 mGy over 24 h. A distinct peak in the total number of significantly regulated transcripts was observed at 9: 00 a. m. in the thyroid, but 3 h later in the kidney cortex, kidney medulla, and liver. Transcriptional regulation in the lungs and spleen was marginal. Associated cellular functions generally varied in quality and response strength between morning, noon, and afternoon. In the thyroid, 25 genes were significantly regulated at all investigated times of day, and 24 thereof showed a distinct pattern of pronounced down-regulation at 9: 00 a. m. and comparatively weak up-regulation at later times. Eleven of these genes belonged to the species-specific kallikrein subfamily Klk1b. Responses in signature genes for thyroid hormone-induced responses were more frequent than for ionizing radiation, and trends persisted irrespective of time of day. Conclusion: Diurnal variation of genome-wide transcriptional responses to 90 kBq I-131 was demonstrated for the thyroid, kidney cortex and medulla, and liver, whereas variation was only marginal in the lungs and spleen. Overall, significant detection of potential biomarkers and signature genes was validated at each time of day, although direction of regulation and fold-change differed between morning, noon, and afternoon. These findings suggest that circadian rhythm should be considered in radiation research and that biological and analytical endpoints should be validated for circadian robustness.
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| 12. |
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| 13. |
- Langen, Britta, et al.
(författare)
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Comparative Analysis of Transcriptional Gene Regulation Indicates Similar Physiologic Response in Mouse Tissues at Low Absorbed Doses from Intravenously Administered At-211
- 2013
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 54:6, s. 990-998
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Tidskriftsartikel (refereegranskat)abstract
- (211)At is a promising therapeutic radionuclide because of the nearly optimal biological effectiveness of emitted α-particles. Unbound (211)At accumulates in the thyroid gland and in other vital normal tissues. However, few studies have been performed that assess the (211)At-induced normal-tissue damage in vivo. Knowledge about the extent and quality of resulting responses in various organs offers a new venue for reducing risks and side effects and increasing the overall well-being of the patient during and after therapy. METHODS: Female BALB/c nude mice were injected intravenously with 0.064-42 kBq of (211)At or mock-treated, and the kidneys, liver, lungs, and spleen were excised 24 h after injection. A transcriptional gene expression analysis was performed in triplicate using RNA microarray technology. Biological processes associated with regulated transcripts were grouped into 8 main categories with 31 subcategories according to gene ontology terms for comparison of regulatory profiles. RESULTS: A substantial decrease in the total number of regulated transcripts was observed between 0.64 and 1.8 kBq of (211)At for all investigated tissues. Few genes were differentially regulated in each tissue at all absorbed doses. In all tissues, most of these genes showed a nonmonotonous dependence on absorbed dose. However, the direction of regulation generally remained uniform for a given gene. Few known radiation-associated genes were regulated on the transcriptional level, and their expression profile generally appeared to be dose-independent and tissue-specific. The regulatory profiles of categorized biological processes were tissue-specific and reflected the shift in regulatory intensity between 0.64 and 1.8 kBq of (211)At. The profiles revealed strongly regulated and nonregulated subcategories. CONCLUSION: The strong regulatory change observed between 0.64 and 1.8 kBq is hypothesized to result not only from low-dose effects in each tissue but also from physiologic responses to ionizing radiation-induced damage to, for example, the (211)At-accumulating thyroid gland. The presented results demonstrate the complexity of responses to radionuclides in vivo and highlight the need for further research to also consider physiology in ionizing radiation-induced responses.
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| 14. |
- 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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| 15. |
- 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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| 16. |
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| 17. |
- Langen, Britta, et al.
(författare)
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Microarray Studies on 211At Administration in BALB/c Nude Mice Indicate Systemic Effects on Transcriptional Regulation in Non-Thyroid Tissues
- 2017
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 58:2, s. 346-353
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Targeted α-therapy is a promising treatment option for various types of malignant tumors. Radiolabeled cancer-seeking agents, however, undergo degradation resulting in a certain percentage of free radionuclide in the body. The radiohalogen 211At accumulates in various tissues with specifically high uptake in the thyroid. When normal thyroid function is disturbed due to ionizing radiation (IR) exposure, deleterious effects can occur in tissues that depend on thyroid hormone (TH) regulation for normal physiological function. However, knowledge of systemic effects is still rudimentary. We previously reported similarities in transcriptomic regulation between the thyroid and other tissues despite large differences in absorbed dose from 211At (Langen et al. JNM, 2013). Here, we present supportive evidence on systemic effects after 211At administration. Methods: Expression microarray data from kidney cortex and medulla, liver, lungs, and spleen were used from previous studies where mice were i.v. injected with 0.064–42 kBq 211At and killed after 24 h, or injected with 1.7 kBq 211At and killed after 1, 6, or 168 h. Controls were mock-treated and killed after 24 h. Literature-based gene signatures were used to evaluate the relative impact from IR- or TH-induced regulation. Thyroid- and TH-associated upstream regulators as well as thyroid-related diseases and functions were generated using functional analysis software. Results: Responses in IR- or TH-associated gene signatures were tissue-specific, varied over time, and the relative impact of each gene signature differed between the investigated tissues. The liver showed a clear dominance of TH-responding genes. In the kidney cortex, kidney medulla, and lungs, the TH-associated signature was detected to at least similar extent as the IR-associated signature. The spleen was the single tissue showing regulation of only IR-associated signature genes. Various thyroid-associated diseases and functions were inferred from the data: L-triiodothyronine, TH, TH receptor, and triiodothyronine (reverse) were inferred as upstream-regulators with differences in incidence and strength of regulation depending on tissue type. Conclusion: These findings indicate that transcriptional regulation in various non-thyroid tissues was–in part–induced by thyroid (hormone)-dependent signaling. Consideration of the systemic context between tissues could contribute to normal tissue risk assessment and planning of remedial measures.
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| 18. |
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| 19. |
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| 20. |
- 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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| 21. |
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| 22. |
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| 23. |
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| 24. |
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| 25. |
- 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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| 26. |
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| 27. |
- Langen, Britta, et al.
(författare)
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Transcriptional gene regulation in abdominal organs and the lung after i.v. injection of 211At in mouse
- 2012
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Ingår i: Radiation research society. San Juan, Puerto Rico. 2012.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Astatine-211 (211At) is a promising radionuclide for radiation therapy with a nearly optimal biological effectiveness of emitted α-particles. Despite its potential, few studies have analysed 211At-induced normal tissue responses in vivo. In order to determine the quality and extent of 211At-induced cellular responses in vivo, the transcriptional gene regulation was analysed in the kidney cortex and medulla, liver, lung, and spleen. Female BALB/c nude mice were i.v. injected with 0.064, 0.64, 1.8, 14, and 42 kBq 211At and killed after 24h. Respective organs were excised and stored at -80°C until further analysis. Extracted total RNA was analysed with the Illumina MouseRef-8 Whole Genome Beadchip platform and data processing was performed with Nexus Expression 2.0. A common strong decrease in the total number of regulated transcripts was seen between 0.64 and 1.8 kBq 211At corresponding to absorbed doses between 2 and 50 mGy for all investigated tissues. Only minor responses in previously identified radiation-associated transcripts could be observed at any exposure. Among tissues at similar absorbed dose levels, the similarity in transcript up- and down-regulation decreased with increased absorbed dose. This phenomenon was more pronounced when the increase in absorbed dose corresponded also to an increase between 0.64 and 1.8 kBq 211At. Biological processes associated with regulated transcripts were categorised to assess the regulatory profiles in each tissue at a given exposure. These profiles showed distinct patterns which mirrored the threshold behaviour on the categorical and sub-categorical level of biological processes. The strong regulatory change demonstrated at the low absorbed doses in the tissues studied might be due to both radiation-induced effects of each tissue and physiological response from radiation-induced effects on the 211At-accumulating thyroid gland. These findings demonstrate the complexity of responses in vivo and highlight the need for a better understanding of the physiology when studying effects of ionizing radiation exposure.
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| 28. |
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| 29. |
- 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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| 30. |
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| 31. |
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| 32. |
- 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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| 33. |
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| 34. |
- Larsson, Maria, 1972, et al.
(författare)
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Kidney toxicity in mice treated with 177Lu-octreotate
- 2012
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Ingår i: 25th Annual Congress on European Association of Nuclear Medicine, Milano, Italy, October 27-31, 2012 . (European Journal of Nuclear Medicine and Molecular Imaging). - 1619-7070.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 35. |
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| 36. |
- 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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| 37. |
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| 38. |
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| 39. |
- Larsson, Malin, et al.
(författare)
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Transcriptome and proteome analysis for potential biomarker discovery of long-term effects in rat thyroid and blood tissue after I-131 exposure
- 2016
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Ingår i: SweRays Workshop, Stockholm, Sweden, Aug 25-26.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- After the Chernobyl accident, an increased incidence of thyroid cancer was seen in children due to exposure from 131I fallout. The aim of this study was to identify biomarkers for long-term effects in vivo related to carcinogenesis and thyroid function. Young male Sprague Dawley rats (5w) were i.v. injected with 0, 0.50, 5, 50, or 500 kBq 131I (Dthyroid = 0 ̶ 10 Gy), and adult rats (17w) were i.v. injected with 0 and 50 kBq 131I (Dthyroid = 0 ̶ 1 Gy). Thyroid and blood samples were collected after termination at three, six, or nine months after injection. Gene expression analysis was performed on total RNA extracted from thyroids using the Agilent microarray platform. Differentially regulated transcripts were identified using Nexus Expression 3.0. LC-MS/MS was performed to analyze protein expression in thyroid and blood. Gene and protein expression in response to 131I differed with time and age-at-exposure. Interesting dosedependent transcripts were identified, for instance, after nine months (young rats). The number of proteins with altered level was 3111 in thyroid and 1213 in blood. For example, the CLIP2 (biomarker candidate for thyroid cancer) level in blood differed between young and old rats. At six months the level was increased for young and decreased for old rats, but opposite pattern was seen after nine months. For the threemonth- groups, the level was increased for young and old rats. In conclusion, potential biomarker candidates for 131I exposure were found in rat thyroid and blood and will be further studied.
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| 40. |
- Parris, Toshima Z, 1978, et al.
(författare)
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Proteomic analysis of normal mouse thyroids after 131I administration
- 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
- Iodine is essential for the normal function of the thyroid gland, which in turn is susceptible to cellular damage after treatment with the β-emitter radioiodine (131I). Individuals exposed to 131I at a young age via contaminated food or nuclear crises such as the Chernobyl nuclear accident are at greater risk of developing e.g. thyroid cancer and other thyroid disorders later on in life. These factors may therefore have clinical implications for patients receiving 131I-based radionuclide therapy. The aim of this study was to identify potential biomarkers in normal thyroid tissue that are induced by 131I administration. Non-tumor-bearing female Balb/c nude mice were i.v. injected with 490 kBq 131I or physiological saline and killed 24 h after injection. The mean absorbed dose to the thyroid was calculated to 32 Gy. Protein lysates were extracted from surgically excised thyroids and analyzed using liquid chromatography tandem-mass spectrometry (LC-MS/MS), followed by database-dependent protein identification and relative quantification. The LC-MS/MS analysis identified 17 differentially expressed proteins (p<0.05), of which 13 showed down-regulation in the 131I-treated group compared to the controls. There was an enrichment of proteins associated with hypoxia/ischemia, oxygen transport/erythrocyte development, regulation of cell cycle, and metabolism. Interestingly, Hypoxia up-regulated protein 1 (HYOU1), known to be up-regulated during hypoxic conditions, was up-regulated in treated samples. In addition, five proteins associated with oxygen transport/erythrocyte development were identified, all of which were down-regulated, i.e. Bisphosphoglycerate mutase (PMGE), Ankyrin-1 (ANK1), and Hemoglobin subunits beta-1 (HBB1), beta-2 (HBB2), alpha (HBA). Taken together, these findings suggest the presence of hypoxic conditions and reduced oxygen transport in normal mouse thyroids 24 h after 131I administration. However, further studies are needed to determine whether these effects are time- and/or dose-dependent.
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| 41. |
- Rudqvist, Nils, et al.
(författare)
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Astatine-211 exposure of Balb/c mice in vivo resulted in distinct effets on thyroid at 1, 6 hours and 7 days after injection
- 2012
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Ingår i: 58th Annual Meeting of the Radiation Research Society, San Juan, Puerto Rico, September 30 - October 3, 2012.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Astatine-211 (211At) is a promising therapeutic radionuclide due to a nearly optimal linear energy transfer for generating double stand breaks in DNA. However, free 211At targets the thyroid gland due to chemical similarities with iodine. There are gaps in our knowledge about the general radiation-induced changes in basal cellular functions in thyroid tissue. The specific aim of this study was to investigate how global gene expression levels in thyroids change with time after 211At injection in mice. Female BALB/c nude mice were i.v. injected with 1.7 kBq 211At in the tail vein. The animals were killed at 1 hour, 6 hours, and 7 days post injection and the thyroids were removed and snap-frozen. The thyroids in each group were pooled and total RNA was extracted and processed using Illumina MouseRef-8 Whole-Genome Expression Beadchips. The gene expression in irradiated thyroids was compared with mock treated controls and regulated transcripts were associated with biological functions using Nexus Expression 2.0. Analysis revealed a distinct impact on global gene expression at all time points in thyroids exposed to 211At. The number of regulated transcripts decreased with time after injection (358, 260, and 193 at 1 h, 6 h, and 7 d, respectively). Generally, transcripts were more often down- than up-regulated. A total of 48 transcripts were detected at all time points (8 up- and 40 down-regulated). The regulated transcripts at the three separate times were associated with 66, 60, and 65 Gene Ontology terms (p < 0.05). At 1 and 6 h, DNA and gene expression integrity were affected and at 7 d after injection, an impact on cellular integrity was seen. A significant impact on transcripts involved in the immune system was also seen at all time points, but this was more pronounced at 1 h and 7 d. An inflammatory response was detected at 1 h but was even more distinct at 7 d. Conclusively, exposure to 211At caused a significant impact on normal cellular functions in thyroid tissue. Processes related to gene expression were affected early while at a later time point, radiation had an impact on processes related to cellular integrity. Interestingly, there was a decrease in the immune and inflammatory response at 6 h compared to either 1 hour or 7 d. Also, 48 transcripts were detected at all time points, which may be of interest for retrospective biodosimetry.
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- Rudqvist, Nils, et al.
(författare)
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Dose-specific transcriptional responses in thyroid tissue in mice after (131)I administration.
- 2015
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Ingår i: Nuclear medicine and biology. - : Elsevier BV. - 1872-9614 .- 0969-8051. ; 42:3, s. 263-8
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Tidskriftsartikel (refereegranskat)abstract
- In the present investigation, microarray analysis was used to monitor transcriptional activity in thyroids in mice 24 h after (131)I exposure. The aims of this study were to 1) assess the transcriptional patterns associated with (131)I exposure in normal mouse thyroid tissue and 2) propose biomarkers for (131)I exposure of the thyroid.
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| 44. |
- Rudqvist, Nils, et al.
(författare)
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Gene expression signature in mouse thyroid tissue after 131I and 211At exposure
- 2015
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Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X .- 2191-219X. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Background 131 I and 211 At are used in nuclear medicine and accumulate in the thyroid gland and may impact normal thyroid function. The aim of this study was to determine transcriptional profile variations, assess the impact on cellular activity, and identify genes with biomarker properties in thyroid tissue after 131 I and 211 At administration in mice. Methods To further investigate thyroid tissue transcriptional responses to 131 I and 211 At administration, we generated a new transcriptional dataset that includes re-evaluated raw intensity values from our previous 131 I and 211 At studies. Differential transcriptional profiles were identified by comparing treated and mock-treated samples using Nexus Expression 3.0 software. Further data analysis was performed using R/Bioconductor and IPA. Results A total of 1144 genes were regulated. Hierarchical clustering subdivided the groups into two clusters containing the lowest and highest absorbed dose levels, respectively, and revealed similar transcriptional regulation patterns for many kallikrein-related genes. Twenty-seven of the 1144 genes were recurrently regulated after 131 I and 211 At exposure and divided into six clusters. Several signalling pathways were affected, including calcium, integrin-linked kinase, and thyroid cancer signalling, and the peroxisomal proliferator-activated receptor network. Conclusions Substantial changes in transcriptional regulation were shown in 131 I and 211 At-treated samples, and 27 genes were identified as potential biomarkers for 131 I and 211 At exposure. Clustering revealed distinct differences between transcriptional profiles of both similar and different exposures, demonstrating the necessity for better understanding of radiation-induced effects on cellular activity. Additionally, ionizing radiation-induced changes in kallikrein gene expression and identified canonical pathways should be further assessed. Keywords: Radiation biology; Microarray; Radiation biomarkers; Radionuclide therapy; Transcriptomics; Radiogenomics
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| 46. |
- Rudqvist, Nils, et al.
(författare)
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Identification of Dbp as a candidate biomarker gene of low-level 131I exposure that affects thyroid function
- 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
- 131I is frequently used in nuclear medicine. However, unbound or released 131I accumulates in the thyroid gland and may be detrimental to normal thyroid function. The aim of the present study was to identify biomarkers for 131I exposure in rat thyroid tissue and to assess the effect on thyroid function. Thirty-six male Sprague Dawley rats were i.v. injected with 150 µl saline solution containing 9.0, 88, 170, 260, 340, 760, 1300, or 4700 kBq (group A-H) 131I, or mock-treated with 150 µl saline solution, and killed at 24 h after injection. Total RNA was extracted from individual thyroid tissue samples and mRNA levels were determined with the Agilent microarray platform. Nexus Expression 3.0 was used to identify differentially expressed transcripts between irradiated groups and controls. Estimated absorbed dose to thyroid (D) in groups A-H was 0.0058, 0.057, 0.11, 0.17, 0.22, 0.5, 0.8, and 3 Gy, respectively. Totally, 429 transcripts were identified with a fold change ≥ 1.5 and adjusted p-value ≤ 0.01. A trend with downregulation of thyroid hormone biosynthesis associated genes (e.g. thyroglobulin, thyroid peroxidase, the sodium-iodine symporter) was identified, but only statistically significant after 0.0058 and 0.22 Gy. Three transcripts coding for isoform 1 of the DBP protein showed monotonous decrease in downregulation with increasing D up to 0.22 Gy. Change in Dbp expression was not statistically significant for 0.5-3 Gy; however, a trend with downregulation at 0.5 and 0.8 Gy and upregulation at 3 Gy was identified. Previously, 131I (0.85-17 Gy) and 211At (0.023-32 Gy) exposure resulted in upregulation of Dbp in mouse thyroid tissue 24 h after administration. Furthermore, a monotonous decrease in Dbp downregulation was identified in mouse kidney tissue at 8 and 12 months after 177Lu-octreotate administrations (0.13-13 Gy). In conclusion, the Dbp gene is a promising candidate biomarker gene for thyroid exposure to 131I. Further studies should be performed to establish how Dbp expression varies with dose-rate, absorbed dose, and time after administration, and the role of different radiation qualities.
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