| 41. |
- 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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| 42. |
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| 43. |
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| 44. |
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| 45. |
- 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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| 46. |
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| 47. |
- Montelius, Mikael, 1979, et al.
(författare)
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Identification of Potential MR-Derived Biomarkers for Tumor Tissue Response to 177Lu-Octreotate Therapy in an Animal Model of Small Intestine Neuroendocrine Tumor.
- 2018
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Ingår i: Translational oncology. - : Elsevier BV. - 1936-5233. ; 11:2, s. 193-204
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Tidskriftsartikel (refereegranskat)abstract
- Magnetic resonance (MR) methods enable noninvasive, regional tumor therapy response assessment, but associations between MR parameters, underlying biology, and therapeutic effects must be investigated. The aim of this study was to investigate response assessment efficacy and biological associations of MR parameters in a neuroendocrine tumor (NET) model subjected to radionuclide treatment. Twenty-one mice with NETs received 177Lu-octreotate at day 0. MR experiments (day -1, 1, 3, 8, and 13) included T2-weighted, dynamic contrast-enhanced (DCE) and diffusion-weighted imaging (DWI) and relaxation measurements (T1/T2*). Tumor tissue was analyzed using proteomics. MR-derived parameters were evaluated for each examination day and for different radial distances from the tumor center. Response assessment efficacy and biological associations were evaluated using feature selection and protein expression correlations, respectively. Reduced tumor growth rate or shrinkage was observed until day 8, followed by reestablished growth in most tumors. The most important MR parameter for response prediction was DCE-MRI-derived pretreatment signal enhancement ratio (SER) at 40% to 60% radial distance, where it correlated significantly also with centrally sampled protein CCD89 (association: DNA damage and repair, proliferation, cell cycle arrest). The second most important was changed diffusion (D) between day -1 and day 3, at 60% to 80% radial distance, where it correlated significantly also with peripherally sampled protein CATA (association: oxidative stress, proliferation, cell cycle arrest, apoptotic cell death). Important information regarding tumor biology in response to radionuclide therapy is reflected in several MR parameters, SER and D in particular. The spatial and temporal information provided by MR methods increases the sensitivity for tumor therapy response.
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| 48. |
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| 49. |
- Montelius, Mikael, 1979, et al.
(författare)
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Multiparametric MR for non-invasive evaluation of tumour tissue histological characteristics after radionuclide therapy.
- 2019
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Ingår i: NMR in biomedicine. - : Wiley. - 1099-1492 .- 0952-3480. ; 31:3
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Tidskriftsartikel (refereegranskat)abstract
- Early non-invasive tumour therapy response assessment requires methods sensitive to biological and physiological tumour characteristics. The aim of this study was to find and evaluate magnetic resonance imaging (MRI) derived tumour tissue parameters that correlate with histological parameters and that reflect effects of radionuclide therapy. Mice bearing a subcutaneous human small-intestine neuroendocrine tumour were i.v. injected with 177 Lu-octreotate. MRI was performed (7 T Bruker Biospec) on different post-therapy intervals (1 and 13 days) using T2-weighted imaging, mapping of T2* and T1 relaxation time constants, as well as diffusion and dynamic contrast enhancement (DCE-MRI) techniques. After MRI, animals were killed and tumours excised. Four differently stained histological sections of the most central imaged tumour plane were digitized, and segmentation techniques were used to produce maps reflecting fibrotic and vascular density, apoptosis, and proliferation. Histological maps were aligned with MRI-derived parametric maps using landmark-based registration. Correlations and predictive power were evaluated using linear mixed-effects models and cross-validation, respectively. Several MR parameters showed statistically significant correlations with histological parameters. In particular, three DCE-MRI-derived parameters reflecting capillary function additionally showed high predictive power regarding apoptosis (2/3) and proliferation (1/3). T1 could be used to predict vascular density, and perfusion fraction derived from diffusion MRI could predict fibrotic density, although with lower predictive power. This work demonstrates the potential to use multiparametric MRI to retrieve important information on the tumour microenvironment after radiotherapy. The non-invasiveness of the method also allows longitudinal tumour tissue characterization. Further investigation is warranted to evaluate the parameters highlighted in this study longitudinally, in larger studies, and with additional histological methods.
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| 50. |
- Montelius, Mikael, 1979, et al.
(författare)
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Multiparametric MRI (mpMRI) for spatiotemporal characterization of tumor tissue response to radionuclide treatment
- 2016
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Ingår i: 62nd Annual International Meeting Radiation Research Society, Waikoloa, HI, USA, October 16-19, 2016.
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Konferensbidrag (refereegranskat)abstract
- Background: Development and optimization of efficient tumor treatment methods are needed. Increased understanding of the complex and heterogeneous tumor microenvironment in response to treatment is thus required, necessitating multiple, non-invasive biomarker acquisition with spatiotemporal resolution. mpMRI potentially offers methods with the required capabilities. Aim: To assess the possibility to non-invasively retrieve multiple, complementary information on radionuclide treatment effects on tumor microenvironment, using spatiotemporally resolved mpMRI. Methods: 19 mice with neuroendocrine tumors (~1 cm) received 15 MBq 177Lu-octreotate i.v. on day 0 (tumor dose ~4 Gy) and were imaged on day -1, 1, 3, 8 and 13. Imaging included IVIM (reflecting apoptosis/necrosis (AN) and capillary activity (CA)) [1], T1/T2* mapping (microstructural alterations (MA) and hypoxia/hemorrhage (HH)), DCE (microvessel integrity/perfusion tracer kinetics (IK)) and T2w MRI (morphology/size). Matlab based post-processing included voxelwise model fitting and tumor delineation to define a binary mask for volumetry and parameter extraction. An automatic separation of the mask into annular disks of preserved tumor shape but stepwise decreased size was performed, allowing separate regional analyses of central to peripheral parts of the tumor. Results: Groups with high/low response (HRG n = 8/LRG n = 4), based on post-treatment tumor volume (monotonically decreasing/increasing days 1-13) were identified. Post-treatment changes with significant separation of HRG from LRG (p < 0.05) were found in parameters related to AN: 1‡ parameter, CA: 1‡, HH: 1, IK: 10 (3†, 7‡) and MA: 1. Pre-treatment HRG/LRG prediction was possible in all 15 (8†) parameters; AN: 1, CA: 1, HH: 1, IK: 11 (8†) and MA: 1. (†Only after spatial separation. ‡Only transiently). Conclusions: Multiple, complementary biomarker information related to radionuclide tumor treatment could be extracted using spatiotemporally resolved mpMRI. Several parameters required separate analysis of sub-tumoural regions in order to separate high from low responding tumors, and some were only transiently affected, highlighting the importance of repeated measurements with spatially resolved techniques. References: 1. Le Bihan et al. Radiology, 1988
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