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- 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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| 2. |
- Schüler, Emil, et al.
(författare)
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Biological effects of 177Lu-octreotate therapy in mouse: in vivo normal kidney tissue response evaluated with gene expression microarray
- 2012
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Ingår i: 58th Annual Meeting of the Radiation Research Society. San Juan, Puerto Rico. 2012.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The kidneys are the dose limiting organ when patients undergo 177Lu-octreotate therapy. The purpose of the present study was to investigate alterations in gene expression levels in the kidney following exposure to various absorbed doses of 177Lu. Female Balb/c mice were i.v. injected with 1.3-140 MBq 177Lu-octreotate, corresponding to an absorbed dose to the kidneys of 0.13-13 Gy. Control animals did not receive any 177Lu-octreotate. The animals were killed 24 hours after injection and the kidneys were removed, followed by dissection of the kidney medulla and cortex. Total RNA was extracted and processed using the Illumina Mouse-Ref-8 Whole-Genome Expression Beadchips to identify differentially expressed transcripts between irradiated and non-irradiated kidney tissues. The total number of differentially regulated transcripts was 480 and 281 in the kidney medulla and cortex, respectively. Of these, 39 and 32 transcripts were regulated at all absorbed doses in the two renal tissues. Of the affected biological processes, three and five processes were affected at all absorbed dose levels in the medulla and cortex, respectively; glycerol metabolism, immune response, and defense response in the medulla, and immune response, amino acid transport, circadian rhythm, rhythmic processes, and regulation of lipoprotein lipase activity in the cortex. In general, metabolic processes were strongly expressed at all absorbed dose levels studied, however, inversely related to increasing absorbed dose. Furthermore, cellular and developmental processes were strongly associated with kidney medulla, while a strong association with transport and immune response was seen in kidney cortex. The results demonstrate distinct differences in the response seen after 177Lu exposure to different absorbed doses. Effects on metabolism and stress responses were frequently seen, while no processes associated with maintaining DNA integrity were found, which indicates a very diverse response following 177Lu exposure.
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| 5. |
- 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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| 7. |
- 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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| 10. |
- 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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