| 1. |
- 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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| 3. |
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| 4. |
- 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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| 5. |
- 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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| 6. |
- Andersson, Charlotte, et al.
(författare)
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Biodistribution of I-131 in mice is influenced by circadian variations
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Effects of radiation and biodistribution of radionuclides are often studied in animal models. Circadian rhythm affects many biological functions and may influence the biokinetics of radionuclides and observed responses. The aim of this study was to investigate if the time during the day of I-131 injection affects the biodistribution and absorbed dose to tissues in mice. Biodistribution studies were conducted on male C57BL/6 N mice for three diurnal time-series: the animals were i.v. injected with 160 kBq I-131 at 8 am, 12 pm or 4 pm. The activity concentration in organs and tissues was measured at 1 h to 7 days after administration and absorbed dose at day 7 was determined. Comparison between the three time-series showed statistically significant differences in activity concentration in all investigated tissues and organs. Administration performed at 12 pm resulted in general in higher absorbed dose to the organs than injection performed at 8 am and 4 pm. Time of day of administration affects the biodistribution of I-131 in mice and consequently the absorbed dose to individual organs. These findings advocate that subsequent biodistribution studies and dosimetry calculations should consider time-point of administration as a variable that could influence the results.
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| 7. |
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| 8. |
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| 9. |
- Dalmo, Johanna, et al.
(författare)
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Priming increases the anti-tumor effect and therapeutic window of 177Lu-octreotate in nude mice bearing human small intestine neuroendocrine tumor GOT1.
- 2017
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Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: 177Lu-[DOTA0, Tyr3]-octreotate (177Lu-octreotate) is used for treatment of patients with somatostatin receptor (SSTR) expressing neuroendocrine tumors. However, complete tumor remission is rarely seen, and optimization of treatment protocols is needed. In vitro studies have shown that irradiation can up-regulate the expression of SSTR1, 2 and 5, and increase 177Lu-octreotate uptake. The aim of the present study was to examine the anti-tumor effect of a 177Lu-octreotate priming dose followed 24 h later by a second injection of 177Lu-octreotate compared to a single administration of 177Lu-octreotate, performed on the human small intestine neuroendocrine tumor cell line, GOT1, transplanted to nude mice. RESULTS: Priming resulted in a 1.9 times higher mean absorbed dose to the tumor tissue per administered activity, together with a reduced mean absorbed dose for kidneys. Priming gave the best overall anti-tumor effects. Magnetic resonance imaging showed no statistically significant difference in tumor response between treatment with and without priming. Gene expression analysis demonstrated effects on cell cycle regulation. Biological processes associated with apoptotic cell death were highly affected in the biodistribution and dosimetry study, via differential regulation of, e.g., APOE, BAX, CDKN1A, and GADD45A. CONCLUSIONS: Priming had the best overall anti-tumor effects and also resulted in an increased therapeutic window. Results indicate that potential biomarkers for tumor regrowth may be found in the p53 or JNK signaling pathways. Priming administration is an interesting optimization strategy for 177Lu-octreotate therapy of neuroendocrine tumors, and further studies should be performed to determine the mechanisms responsible for the reported effects.
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