| 1. |
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| 2. |
- Forssell-Aronsson, Eva, 1961, et al.
(author)
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Advances in the diagnostic imaging of pheochromocytomas
- 2011
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In: Reports in Medical Imaging. - 1179-1586. ; 4, s. 19-37
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Research review (peer-reviewed)abstract
- Pheochromocytomas (PCs) and paragangliomas (PGLs) are routinely localized by computed tomography (CT), magnetic resonance imaging (MRI), and metaiodobenzylguanidine (MIBG) scintigraphy. CT can identify tumors with high sensitivity but rather low specificity. MRI has higher sensitivity and specificity than CT and is superior to detect extra-adrenal disease. Radioiodinated MIBG scintigraphy has been used for more than 30 years and is based on MIBG uptake via the norepinephrine transporter on the cell membrane. The technique is very useful for whole-body studies in case of multiple primary tumors or metastases. Tumors with sole production of dopamine usually cannot be visualized with MIBG and may require positron emission tomographic (PET) studies with 18F-labeled radiotracers. Somatostatin receptor scintigraphy (SRS) using the radiolabeled somatostatin analog octreotide (based on the expression of the somatostatin receptors 2 and 5 by the tumor) can demonstrate PGL or metastases not visualized by MIBG. In this article, we review the use of MIBG scintigraphy to diagnose PC/PGL and compare the sensitivity and specificity with that of CT and MRI. We also describe the recent SRS and PET techniques and review the latest results of clinical studies by comparing these imaging modalities. Future perspectives of functional imaging modalities for PC/PGL are finally presented.
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| 7. |
- Langen, Britta, et al.
(author)
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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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In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 54:6, s. 990-998
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Journal article (peer-reviewed)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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| 12. |
- Langen, Britta, et al.
(author)
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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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In: Radiation research society. San Juan, Puerto Rico. 2012.
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Conference paper (other academic/artistic)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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| 13. |
- Langen, Britta, et al.
(author)
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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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In: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X .- 2191-219X. ; 5:1, s. 1-12
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Journal article (peer-reviewed)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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| 14. |
- Larsson, Maria, 1972, et al.
(author)
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Kidney toxicity in mice treated with 177Lu-octreotate
- 2012
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In: 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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Conference paper (other academic/artistic)
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| 15. |
- Parris, Toshima Z, 1978, et al.
(author)
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Proteomic analysis of normal mouse thyroids after 131I administration
- 2015
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In: 15th International Congress of Radiation Research, Kyoto, Japan, May 25-29.
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Conference paper (other academic/artistic)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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| 16. |
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| 18. |
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| 19. |
- Romiani, Arman, 1991, et al.
(author)
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The potential of Lu-177-octreotate as a therapeutic alternative for metastatic neuroblastoma
- 2016
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In: 62nd Annual International Meeting Radiation Research Society, Waikoloa, HI, USA, October 16-19, 2016.
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Conference paper (other academic/artistic)abstract
- Radionuclide therapy using 177Lu-octreotate is a promising treatment option for neuroendocrine tumors with overexpression of somatostatin receptors (SSTR). In order to screen and evaluate the usefulness of 177Lu-octreotate for therapy of a specific neuroendocrine tumor type, knowledge of the binding and internalization of the 177Lu-octreotate to tumor cells is needed. The aim of this study was to determine the binding and internalization of 177Lu-octreotate in three neuroblastoma (NB) cell lines and to perform biodistribution studies in animals bearing NB. Binding and internalization of 177Lu-octreotate to the human NB cell lines IMR-32 and CLB-BAR were investigated in vitro. Cell cultures were incubated with various amounts of 177Lu-octreotate with or without excess of octreotide and harvested at 24 h and 48 h after administration. The amount of 177Lu associated to the membrane and internalized into the cells were determined. IMR-32, CLB-BAR and GEMO bearing BALB/c nude mice (n=5-6/group) were i.v. injected with 15 MBq 177Lu-octreotate and killed 1 h, 24 h and 7 days after administration. Tissue samples were collected and radioactivity concentrations were determined. Tumor-to-normal-tissue ratios (T/N) were calculated and compared with previous data. The highest binding and internalization of 177Lu in vitro occurred after 48 h: 78% and 47% of the 177Lu-octreotate in IMR-32 and CLB-BAR cells, respectively. Binding and internalization was successfully blocked with octreotide, indicating a specific uptake. In the mice bearing GEMO, T/Blood and T/Kidney values 1 h after injection were 18 and 0.71, respectively, and 7 days after injection 2300 and 27, respectively. Corresponding values for IMR-32 were 7.5 and 0.40; 1300 and 7.8, 1 h and 7 d after injection, respectively. Corresponding values for CLB-BAR were 18 and 0.24; 113 and 0.94, 1 h and 7 d after injection, respectively. This study clearly shows the potential of 177Lu-octreotate as a therapeutic alternative in the treatment of metastatic NB. The T/N values for all three tumor types investigated showed high values compared with previously investigated neuroendocrine tumor types. The results are very promising, and future studies will characterize anti-tumor effects following 177Lu-octreotate therapy.
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| 20. |
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| 21. |
- Rudqvist, Nils, et al.
(author)
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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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In: 58th Annual Meeting of the Radiation Research Society, San Juan, Puerto Rico, September 30 - October 3, 2012.
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Conference paper (other academic/artistic)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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| 22. |
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| 23. |
- Rudqvist, Nils, et al.
(author)
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Dose-specific transcriptional responses in thyroid tissue in mice after (131)I administration.
- 2015
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In: Nuclear medicine and biology. - : Elsevier BV. - 1872-9614 .- 0969-8051. ; 42:3, s. 263-8
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Journal article (peer-reviewed)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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| 24. |
- Rudqvist, Nils, et al.
(author)
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Gene expression signature in mouse thyroid tissue after 131I and 211At exposure
- 2015
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In: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X .- 2191-219X. ; 5
-
Journal article (peer-reviewed)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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| 25. |
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| 26. |
- Rudqvist, Nils, et al.
(author)
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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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In: 15th International Congress of Radiation Research, Kyoto, Japan, May 25-29.
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Conference paper (other academic/artistic)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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| 35. |
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| 36. |
- Rudqvist, Nils, et al.
(author)
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Transcriptional Response in Mouse Thyroid Tissue after 211At Administration: Effects of Absorbed Dose, Initial Dose-Rate and Time after Administration
- 2015
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:7
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Journal article (peer-reviewed)abstract
- Background 211At-labeled radiopharmaceuticals are potentially useful for tumor therapy. However, a limitation has been the preferential accumulation of released 211At in the thyroid gland, which is a critical organ for such therapy. The aim of this study was to determine the effect of absorbed dose, dose-rate, and time after 211At exposure on genome-wide transcriptional expression in mouse thyroid gland. Methods BALB/c mice were i.v. injected with 1.7, 7.5 or 100 kBq 211At. Animals injected with 1.7 kBq were killed after 1, 6, or 168 h with mean thyroid absorbed doses of 0.023, 0.32, and 1.8 Gy, respectively. Animals injected with 7.5 and 100 kBq were killed after 6 and 1 h, respectively; mean thyroid absorbed dose was 1.4 Gy. Total RNA was extracted from pooled thyroids and the Illumina RNA microarray platform was used to determine mRNA levels. Differentially expressed transcripts and enriched GO terms were determined with adjusted p-value <0.01 and fold change >1.5, and p-value <0.05, respectively. Results In total, 1232 differentially expressed transcripts were detected after 211At administration, demonstrating a profound effect on gene regulation. The number of regulated transcripts increased with higher initial dose-rate/absorbed dose at 1 or 6 h. However, the number of regulated transcripts decreased with mean absorbed dose/time after 1.7 kBq 211At administration. Furthermore, similar regulation profiles were seen for groups administered 1.7 kBq. Interestingly, few previously proposed radiation responsive genes were detected in the present study. Regulation of immunological processes were prevalent at 1, 6, and 168 h after 1.7 kBq administration (0.023, 0.32, 1.8 Gy).
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| 37. |
- Rudqvist, Nils, et al.
(author)
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Transcriptional response of BALB/c mouse thyroids following in vivo astatine-211 exposure reveals distinct gene expression profiles.
- 2012
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In: EJNMMI research. - 2191-219X. ; 2:1
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Journal article (peer-reviewed)abstract
- ABSTRACT: BACKGROUND: Astatine-211 (211At) is an alpha particle emitting halogen with almost optimal linear energytransfer for creating DNA double-strand breaks and is thus proposed for adionuclide therapy when bound to tumor-seeking agents. Unbound 211At accumulates in the thyroid gland, and the concept of basal radiation-induced biological effects in the thyroid tissue is, to a high degree, unknown and is most valuable. METHODS: Female BALB/c nude mice were intravenously injected with 0.064 to 42 kBq of 211 At, resulting in absorbed doses of 0.05 to 32 Gy in the thyroid gland. Thyroids were removed 24h after injection; total RNA was extracted from pooled thyroids and processed in triplicate using Illumina MouseRef-8 Whole-Genome Expression Beadchips. RESULTS: Thyroids exposed to 211 At revealed distinctive gene expression profiles compared to nonirradiated controls. A larger number of genes were affected at low absorbed doses (0.05 and 0.5 Gy) compared to intermediate (1.4 Gy) and higher absorbed doses (11 and 32 Gy). The proportion of dose-specific genes increased with decreased absorbed dose. Additionally, 1.4 Gy often exerted opposite regulation on gene expression compared to the other absorbed doses. Using Gene Ontology data, an immunological effect was detected at 0.05 and 11 Gy. Effects on cellular response to external stress and cell cycle regulation and proliferation were detected at 1.4 and 11 Gy. CONCLUSIONS: Conclusively, the cellular response to ionizing radiation is complex and differs with absorbed dose. The response acquired at high absorbed doses cannot be extrapolated down to low absorbed doses or vice versa. We also demonstrated that the thyroid - already at absorbed doses similar to those obtained in radionuclide therapy - responds with expression of a high number of genes. Due to the increased heterogeneous irradiation at low absorbed doses, we suggest that this response partly originates from non-irradiated cells in the tissue, i.e., bystander cells.
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| 38. |
- Rudqvist, Nils, et al.
(author)
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Transcriptional response to 131I exposure of rat thyroid gland
- 2017
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:2
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Journal article (peer-reviewed)abstract
- Humans are exposed to 131I in medical diagnostics and treatment but also from nuclear accidents, and better knowledge of the molecular response in thyroid is needed. The aim of the study was to examine the transcriptional response in thyroid tissue 24 h after 131I administration in rats. The exposure levels were chosen to simulate both the clinical situation and the case of nuclear fallout. Thirty-six male rats were i.v. injected with 0–4700 kBq 131I, and killed at 24 h after injection (Dthyroid = 0.0058–3.0 Gy). Total RNA was extracted from individual thyroid tissue samples and mRNA levels were determined using oligonucleotide microarray technique. Differentially expressed transcripts were determined using Nexus Expression 3.0. Hierarchical clustering was performed in the R statistical computing environment. Pathway analysis was performed using the Ingenuity Pathway Analysis tool and the Gene Ontology database. T4 and TSH plasma concentrations were measured using ELISA. Totally, 429 differentially regulated transcripts were identified. Downregulation of thyroid hormone biosynthesis associated genes (e.g. thyroglobulin, thyroid peroxidase, the sodium-iodine symporter) was identified in some groups, and an impact on thyroid function was supported by the pathway analysis. Recurring downregulation of Dbp and Slc47a2 was found. Dbp exhibited a pattern with monotonous reduction of downregulation with absorbed dose at 0.0058–0.22 Gy. T4 plasma levels were increased and decreased in rats whose thyroids were exposed to 0.057 and 0.22 Gy, respectively. Different amounts of injected 131I gave distinct transcriptional responses in the rat thyroid. Transcriptional response related to thyroid function and changes in T4 plasma levels were found already at very low absorbed doses to thyroid.
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| 39. |
- Saadati, Sofia, 1992, et al.
(author)
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Binding and internalization of 177Lu-octreotate in human tumor cell lines of different origin
- 2017
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In: 63rd Annual Meeting of the Radiation Research Society, Cancun, Mexico.
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Conference paper (other academic/artistic)abstract
- Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-octreotate is used for systemic treatment of patients with somatostatin receptor (SSTR)-expressing neuroendocrine tumors (NETs), mainly for small-intestine NETs and endocrine pancreatic tumors. Further research is needed to evaluate the possibility of using this type of treatment in patients with other SSTR-expressing tumors. Tumor binding and uptake of the radiopharmaceutical is highly dependent on SSTR expression. In order to determine the potential of using 177Lu-octreotate for treatment of other tumor cell lines, in vitro studies of binding and internalization are needed. The aim of this study was to asses binding and internalization of 177Lu-octreotate in various cancer cell lines and compare with our previous results. In vitro studies were performed on neuroblastoma (CLB-BAR, IMR-32), lung adenocarcinoma (h1975, h2228) and invasive breast carcinoma (BT474, MCF-7, MDA-MB-231, MDA-MB-361, T47D, ZR-75-1) cell lines. Cell cultures were incubated with low or high amounts of 177Lu-octreotate. To block SSTR and thereby determine the specific uptake, control groups were incubated with 177Lu-octreotate and excess octreotide. The amount of unbound, membrane-bound, and internalized 177Lu in each sample was determined after 24 h. Several of the studied tumor cell lines showed specific binding of 177Lu-octreotate. The highest binding and internalization after 24 h was seen for the neuroblastoma cell lines IMR-32 (58% internalized, 9.4% membrane-bound) and CLB-BAR (26% internalized, 3.4% membrane-bound). Specific binding was also found in some breast cancer cell lines (e.g. 3.1% internalized, 0.5% membrane-bound in MDA-MB-361). No specific binding was found in lung adenocarcinoma. In comparison with our previous findings in NET and NET-like cell lines, these results indicate that SSTR-based PRRT may be a potential treatment option for patients with neuroblastoma and certain types of breast cancer. Promising results showing specific tumor uptake of 177Lu-octreotate were obtained for SSTR-expressing tumor cell lines in vitro, indicating the possibility of using SSTR-based diagnostic and therapeutic regimes on more tumor types than those in current clinical practice.
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| 40. |
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| 41. |
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| 42. |
- Schüler, Emil, et al.
(author)
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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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In: 58th Annual Meeting of the Radiation Research Society. San Juan, Puerto Rico. 2012.
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Conference paper (other academic/artistic)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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| 43. |
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| 44. |
- Schüler, Emil
(author)
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Biomarker discovery and assessment for prediction of kidney response after 177Lu-octreotate therapy
- 2014
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Doctoral thesis (other academic/artistic)abstract
- Patients suffering from neuroendocrine tumors are oftentimes presented with spread disease at the time of diagnosis. Therapy using somatostatin analogs is today the only potentially curative treatment option for these patients. However, the kidneys are the dose-limiting organs in this type of therapy and the biological impact from radiopharmaceutical treatment is not fully understood. Furthermore, considering the large inter-individual variations in renal absorbed dose and toxicity, biomarkers for radiation damage would be of great significance in this type of therapy. The aims of this project were to study the normal kidney tissue response in vivo in mice following 177Lu and 177Lu-octreotate administration, to identify potential biomarkers following 177Lu exposure and evaluate their dependencies of absorbed dose, dose-rate, and time after injection, and to correlate these results with functional and morphological effects. The injected activity ranged between 0.3 and 150 MBq following 177Lu/177Lu-octreotate administration and the biological effect was investigated between 15 minutes and one year after administration. Transcriptional and miRNA variations were studied using microarray analysis and protein expression was investigated using mass spectrometry. Correlations between the transcriptional and protein variations were performed with functional parameters, as determined by 99mTc-DTPA/99mTc-DMSA scintigraphy, and with the morphological effects following 177Lu-octreotate administration. The number of differentially regulated transcripts following 177Lu/177Lu-octreoate administration was dependent on absorbed dose, dose-rate, time after injection, and tissue (kidney cortex or medulla) investigated. No transcript was found to be differentially regulated at all exposure conditions. The most recurrently regulated genes were the Serpina10 gene in kidney cortex, and the Egr1, Pck1, and Hmgcs2 genes in kidney medulla. Substantial differences in response were found between 177Lu-octreotate and 177LuCl3. Concerning the miRNA and protein data, a high absorbed dose-specificity was found, with few miRNAs/proteins found recurrently regulated at most exposure conditions. The transcriptional analyses showed a strong and diverse transcriptional response and the functional analyses revealed clear negative effects on renal function, with enhanced negative effects with absorbed dose and time after administration. Several potentially useful biomarkers were detected at the transcriptional level, markers with potential applicability in early prediction of late renal injury after 177Lu/177Lu-octreotate exposure.
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- Schüler, Emil, et al.
(author)
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Effects of internal low-dose irradiation from 131I on gene expression in normal tissues in Balb/c mice.
- 2011
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In: EJNMMI research. - 2191-219X. ; 1:1
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Journal article (peer-reviewed)abstract
- Background The aim of this study was to investigate the global gene expression response of normal tissues following internal low absorbed dose irradiation of 131I. Methods Balb/c mice were intravenously injected with 13 to 260 kBq of 131I and euthanized 24 h after injection. Kidneys, liver, lungs, and spleen were surgically removed. The absorbed dose to the tissues was 0.1 to 9.7 mGy. Total RNA was extracted, and Illumina MouseRef-8 Whole-Genome Expression BeadChips (Illumina, Inc., San Diego, California, USA) were used to compare the gene expression of the irradiated tissues to that of non-irradiated controls. The Benjamini-Hochberg method was used to determine differentially expressed transcripts and control for false discovery rate. Only transcripts with a modulation of 1.5-fold or higher, either positively or negatively regulated, were included in the analysis. Results The number of transcripts affected ranged from 260 in the kidney cortex to 857 in the lungs. The majority of the affected transcripts were specific for the different absorbed doses delivered, and few transcripts were shared between the different tissues investigated. The response of the transcripts affected at all dose levels was generally found to be independent of dose, and only a few transcripts showed increasing or decreasing regulation with increasing absorbed dose. Few biological processes were affected at all absorbed dose levels studied or in all tissues studied. The types of biological processes affected were clearly tissue-dependent. Immune response was the only biological process affected in all tissues, and processes affected in more than three tissues were primarily associated with the response to stimuli and metabolism. Conclusion Despite the low absorbed doses delivered to the tissues investigated, a surprisingly strong response was observed. Affected biological processes were primarily associated with the normal function of the tissues, and only small deviations from the normal metabolic activity in the tissues were induced.
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