| 1. |
- Andersson, Björn, 1977, et al.
(författare)
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Development of a machine learning framework for radiation biomarker discovery and absorbed dose prediction.
- 2023
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Ingår i: Frontiers in oncology. - 2234-943X. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Molecular radiation biomarkers are an emerging tool in radiation research with applications for cancer radiotherapy, radiation risk assessment, and even human space travel. However, biomarker screening in genome-wide expression datasets using conventional tools is time-consuming and underlies analyst (human) bias. Machine Learning (ML) methods can improve the sensitivity and specificity of biomarker identification, increase analytical speed, and avoid multicollinearity and human bias.To develop a resource-efficient ML framework for radiation biomarker discovery using gene expression data from irradiated normal tissues. Further, to identify biomarker panels predicting radiation dose with tissue specificity.A strategic search in the Gene Expression Omnibus database identified a transcriptomic dataset (GSE44762) for normal tissues radiation responses (murine kidney cortex and medulla) suited for biomarker discovery using an ML approach. The dataset was pre-processed in R and separated into train and test data subsets. High computational cost of Genetic Algorithm/k-Nearest Neighbor (GA/KNN) mandated optimization and 13 ML models were tested using the caret package in R. Biomarker performance was evaluated and visualized via Principal Component Analysis (PCA) and dose regression. The novelty of ML-identified biomarker panels was evaluated by literature search.Caret-based feature selection and ML methods vastly improved processing time over the GA approach. The KNN method yielded overall best performance values on train and test data and was implemented into the framework. The top-ranking genes were Cdkn1a, Gria3, Mdm2 and Plk2 in cortex, and Brf2, Ccng1, Cdkn1a, Ddit4l, and Gria3 in medulla. These candidates successfully categorized dose groups and tissues in PCA. Regression analysis showed that correlation between predicted and true dose was high with R2 of 0.97 and 0.99 for cortex and medulla, respectively.The caret framework is a powerful tool for radiation biomarker discovery optimizing performance with resource-efficiency for broad implementation in the field. The KNN-based approach identified Brf2, Ddit4l, and Gria3 mRNA as novel candidates that have been uncharacterized as radiation biomarkers to date. The biomarker panel showed good performance in dose and tissue separation and dose regression. Further training with larger cohorts is warranted to improve accuracy, especially for lower doses.
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| 2. |
- 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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| 3. |
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| 4. |
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| 5. |
- Andersson, Charlotte, et al.
(författare)
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Diurnal variations in biodistribution of the radionuclide I-131 in mice
- 2016
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Ingår i: Swedish Cancer Research Meeting, Gothenburg, 2016, November 7-8.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: Radionuclides are routinely used to diagnose and treat many different types of cancer. I-131 is a well-established radioisotope used in e.g. treatment of thyroid cancer and neuroblastoma. Accurate knowledge of I-131 biodistribution is essential to correctly estimate the absorbed dose to normal organs and determine potential risks from I-131 exposure, which is especially important when treating children. Many biological functions in living organisms follow a circadian rhythm. Nevertheless, little is known about diurnal variations in radionuclide biodistribution. This study investigates if circadian rhythm affects I-131 biodistribution in mice and absorbed dose to organs and tissues. Materials & Methods: The radioactivity concentration in mice tissues was studied at different time-points after administration of I-131, and absorbed doses were calculated. The effect of circadian rhythm was studied by varying the time of administration. Results: Difference in activity concentration between the administration time-points was observed at many time-points after administration for most investigated tissues. For some organs differences were also observed in the absorbed dose. The highest activity concentration and absorbed dose were found in the thyroid regardless of time of administration. Conclusion: The results demonstrate that the biodistribution of I-131 in mice is influenced by the time of day of administration. These findings advocate that circadian rhythm should be considered in biodistribution studies and suggests that time-point of administration of radiopharmaceuticals containing I-131 for therapy can be further optimized. An optimized time-point could result in higher absorbed dose to the tumor and/or lower absorbed dose to normal tissues.
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| 6. |
- Andersson, Charlotte, et al.
(författare)
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The influence of circadian rhythm on the biodistribution of I-131
- 2016
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Ingår i: Swedish Radiation Research Association for Young Scientists Workshop, Stockholm, 2016, August 25-26.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: I-131 is well-established in nuclear medicine. The thyroid is a target organ when treating thyroid cancer with unbound I-131, but also a risk organ in I-131-based radionuclide therapy. Exposure to I-131 can also occur from the environment at nuclear accidents. Accurate knowledge of I-131 biodistribution is essential to correctly estimate the absorbed dose to organs and determine potential risks from both medical and hazard exposure. Many biological functions follow a circadian rhythm. Nevertheless, circadian rhythm remains an unknown factor in radionuclide biodistribution. Aim: The purpose of this study was to investigate if circadian rhythm affects I-131 biodistribution in mice and hence absorbed dose to mouse tissues. Methods: The radioactivity concentration in various tissues was studied at different time points after administration of I-131 and absorbed doses were calculated according to the MIRD formalism. The effect of circadian rhythm was studied by varying the time of administration. Male C57BL/6N mice were i.v. injected with I-131 at 8 am, 12 pm or 4 pm and killed after 1h to 7d. Results: Statistically significant difference in activity concentration and absorbed dose between the three injection series was observed for at least one time point after injection for many tissues. Highest activity concentration and absorbed dose were found in the thyroid. Conclusion: The results demonstrated that the biodistribution of I-131 in mice is influenced by the time of day of administration to a certain extent. These findings advocate that circadian rhythm should be considered in biodistribution studies and dose calculations.
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| 7. |
- Biermann, Jana, et al.
(författare)
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Radiation-induced genomic instability in breast carcinomas of the Swedish haemangioma cohort.
- 2019
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Ingår i: Genes, chromosomes & cancer. - : Wiley. - 1098-2264 .- 1045-2257. ; 58:9, s. 627-35
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Tidskriftsartikel (refereegranskat)abstract
- Radiation-induced genomic instability (GI) is hypothesized to persist after exposure and ultimately promote carcinogenesis. Based on the absorbed dose to the breast, an increased risk of developing breast cancer was shown in the Swedish haemangioma cohort that was treated with radium-226 for skin haemangioma as infants. Here, we screened 31 primary breast carcinomas for genetic alterations using the OncoScan CNV Plus Assay to assess GI and chromothripsis-like patterns associated with the absorbed dose to the breast. Higher absorbed doses were associated with increased numbers of copy number alterations (CNAs) in the tumour genome and thus a more unstable genome. Hence, the observed dose-dependent GI in the tumour genome is a measurable manifestation of the long-term effects of irradiation. We developed a highly predictive Cox regression model for overall survival based on the interaction between absorbed dose and GI. The Swedish haemangioma cohort is a valuable cohort to investigate the biological relationship between absorbed dose and GI in irradiated humans. This work gives a biological basis for improved risk assessment to minimize carcinogenesis as a secondary disease after radiation therapy. This article is protected by copyright. All rights reserved.
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| 9. |
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| 10. |
- 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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| 11. |
- Druid, Malin, et al.
(författare)
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Late age- and dose-related effects on the proteome of thyroid tissue in rats after 131I exposure.
- 2024
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Ingår i: Radiation. - 2673-592X. ; 4:2, s. 149-166
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Tidskriftsartikel (refereegranskat)abstract
- The physiological process of iodine uptake in the thyroid is used for 131I treatment of thyroid diseases. Children are more sensitive to radiation compared to adults and may react differently to 131I exposure. The aims of this study were to evaluate the effects on thyroid protein expression in young and adult rats one year after 131I injection and identify potential biomarkers related to 131I exposure, absorbed dose, and age. Twelve Sprague Dawley rats (young and adults) were i.v. injected with 50 kBq or 500 kBq 131I and killed twelve months later. Twelve untreated rats were used as age-matched controls. Quantitative proteomics, statistical analysis, and evaluation of biological effects were performed. The effects of irradiation were most prominent in young rats. Protein biomarker candidates were proposed related to age, absorbed dose, thyroid function, and cancer, and a panel was proposed for 131I exposure. In conclusion, the proteome of rat thyroid was differentially regulated twelve months after low-intermediate dose exposure to 131I in both young and adult rats. Several biomarker candidates are proposed for 131I exposure, age, and many of them are known to be related to thyroid function or thyroid cancer. Further research on human samples is needed for validation. Data are avaiable via ProteomeXchange with identifier PXD024786.
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| 12. |
- Elvborn, Mikael, et al.
(författare)
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Sex-dependence in absorbed dose from I-131 in mice
- 2016
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Ingår i: Höstmöte med Cancerfondens Planeringsgrupp för Onkologisk Radionuklidterapi, Uppsala, 2016, November 24-25.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 13. |
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| 14. |
- Elvborn, Mikael, et al.
(författare)
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The influence of biological sex on the biodistribution of I-131 in mice
- 2016
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Ingår i: SweRays Workshop, Stockholm, Sweden, Aug 25-26.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: The thyroid is both a risk and target organ in radionuclide therapy. The gland takes up iodine to synthesize thyroidal hormones which are important for various cellular mechanisms throughout the body. 131I is used in nuclear medicine, but hazard exposure can also occur from fallout of nuclear accidents. Physiological differences between the sexes constitute intrinsic variables that are thought to impact the biodistribution of 131I. Aim: The purpose of this study was to assess potential difference between the sexes concerning 131I biodistribution in mice. Methods: In total, 70 C57BL/6N mice (35 males and 35 females) were used in the experiments (n=5/group). Mice were injected intravenously (at 8 am) with 165−175 kBq 131I, prepared in physiological saline, and killed after 1h to 7d following injection. Various tissue samples were collected, weighed, and subjected to gamma counter measurement to determine 131I activity concentration. Results: The results demonstrated clear differences in 131I biodistribution between male and female mice, notably in the kidneys and salivary glands. Statistically significant differences were found for the majority of tissues and time points. Although maximum uptake in the thyroid was similar for both sexes, the decrease of activity concentration after 18h was distinctly slower in females showing statistical significance. Conclusion: Experiments demonstrated that 131I biodistribution differs between the sexes, which would translate to differences in absorbed dose. The extent of difference is tissue-dependent, with markedly different biodistribution in certain tissues. The results advocate that sex should be considered as a variable in biodistribution studies and dose calculations.
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| 15. |
- Elvborn, Mikael, et al.
(författare)
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The influence of biological sex on thyroid cancer treatment risk assessment
- 2016
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Ingår i: Swedish Cancer Research Meeting, Gothenburg, 2016, November 7-8.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: Researchers are often reluctant towards using females in studies, especially when radiopharmaceuticals and hormonally dependent diseases are concerned. Simultaneously, women are more prone to thyroid-related diseases such as Grave’s disease and Hashimoto’s thyroiditis, with a 7-10 times higher incidence than in men. The thyroid gland synthesizes iodine-containing hormones, which are needed for several cellular processes in the body. I-131 is routinely used in thyroid cancer treatment, and I-131-containing pharmaceuticals are used for treatment of patients with some neuroendocrine tumor types. This study was performed to evaluate possible differences between sexes in tissue uptake of I-131 in mice. Methods: 35 male and 35 female mice (C57BL/6N, n=5/group) were intravenously injected with I-131 at 8 am, and animals were killed 1 h to 7 d after injection. Tissue samples were collected, weighed, and measured to determine I-131 activity concentration. Results: The results indicate differences in I-131 uptake between males and females, especially in the salivary glands and kidneys. In the majority of the tissues and observed time points, statistical significant differences were found. The decrease of activity concentration in thyroid after 18 h was slower for females (statistical significant), though the obtained maximum uptake was similar. Conclusion: The I-131 uptake differs between males and females, which would result in different absorbed doses from exposure to the same amount of I-131. The difference in magnitude is tissue-dependent. The results suggest biological sex to be treated as a variable in dose calculations and risk assessments when treating cancer patients with radiopharmaceuticals containing I-131.
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| 16. |
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| 17. |
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| 18. |
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| 19. |
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| 20. |
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| 21. |
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| 22. |
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| 23. |
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| 24. |
- Langen, Britta, et al.
(författare)
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Age and sex effects across the blood proteome after ionizing radiation exposure can bias biomarker screening and risk assessment
- 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
- Molecular biomarkers of ionizing radiation (IR) exposure are a promising new tool in various disciplines: they can give necessary information for adaptive treatment planning in cancer radiotherapy, enable risk projection for radiation-induced survivorship diseases, or facilitate triage and intervention in radiation hazard events. However, radiation biomarker discovery has not yet resolved the most basic features of personalized medicine: age and sex. To overcome this critical bias in biomarker identification, we quantitated age and sex effects and assessed their relevance in the radiation response across the blood proteome. We used high-throughput mass spectrometry on blood plasma collected 24 h after 0.5 Gy total body irradiation (15 MV nominal photon energy) from male and female C57BL/6 N mice at juvenile (7-weeks-old) or adult (18-weeks-old) age. We also assessed sex and strain effects using juvenile male and female BALB/c nude mice. We showed that age and sex created significant effects in the proteomic response regarding both extent and functional quality of IR-induced responses. Furthermore, we found that age and sex effects appeared non-linear and were often end-point specific. Overall, age contributed more to differences in the proteomic response than sex, most notably in immune responses, oxidative stress, and apoptotic cell death. Interestingly, sex effects were pronounced for DNA damage and repair pathways and associated cellular outcome (pro-survival vs. pro-apoptotic). Only one protein (AHSP) was identified as a potential general biomarker candidate across age and sex, while GMNN, REG3B, and SNCA indicated some response similarity across age. This low yield advocated that unisex or uniage biomarker screening approaches are not feasible. In conclusion, age- and sex-specific screening approaches should be implemented as standard protocol to ensure robustness and diagnostic power of biomarker candidates. Bias-free molecular biomarkers are a necessary progression towards personalized medicine and integral for advanced adaptive cancer radiotherapy and risk assessment.
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| 25. |
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| 26. |
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| 27. |
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| 28. |
- 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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| 29. |
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| 30. |
- 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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| 31. |
- 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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| 32. |
- 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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| 33. |
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| 34. |
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| 35. |
- 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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| 36. |
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| 37. |
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| 38. |
- 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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| 39. |
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| 40. |
- Langen, Britta, et al.
(författare)
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Radiobiological effects of I-131 exposure in rodents
- 2018
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Ingår i: Meeting with the Japan Society for the Promotion of Science (JSPS) on Environmental Radioactivity: Experience from Japan and Sweden, Gothenburg, Sweden, Nov 15-16, 2018..
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 41. |
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| 44. |
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| 45. |
- Langen, Britta
(författare)
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Systemic effects after ionizing radiation exposure: Genome-wide transcriptional analysis of mouse normal tissues exposed to (211)At, (131)I, or 4 MV photon beam
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The radionuclides 131I and 211At are used or proposed for a variety of cancer treatments. Both radiohalogens exhibit considerable uptake in the thyroid gland and–to a lower degree–in various other tissues if they are unbound or released from a cancer-targeting agent. The resulting differential exposure throughout the body introduces two paradigms when studying effects in non-thyroid tissues in vivo: 1) low-dose effects of the organ, and 2) systemic effects due to a dominantly exposed regulatory organ. Normal tissue response is an important parameter in risk assessment in order to give the highest possible absorbed dose to malignant tumors while minimizing detrimental side effects in healthy tissue. The aim of this work was to increase fundamental knowledge of normal tissue responses to differential ionizing radiation exposure in vivo and to evaluate key findings regarding circadian rhythm and data convolution. Female BALB/c nude mice were used as a model system and the kidney cortex, kidney medulla, liver, lungs, spleen, and thyroid were studied using RNA microarray technology. Genome-wide transcriptional regulation and basically all analytical endpoints studied were tissue-specific. In various tissues, the Angptl4, Per1 and Per2, and Tsc22d3 genes may be potential biomarkers for 211At exposure (Papers I, II). In the thyroid, the Klk1 gene-family may serve as biomarker candidates for 131I exposure (Paper V). Similarity in the extent of regulation irrespective of absorbed dose level generated a hypothesis on thyroid-dependent systemic effects in non-thyroid tissues, which was supported by gene signature and pathway analysis (Papers I, III). Results from partial body irradiation with 4 MV photon beams confirmed the hypothesis (Paper IV). Circadian rhythm affected the extent and quality of regulation in a tissue-specific manner, but key findings showed certain robustness to diurnal variation (Paper V). Deconvolution of microarray data increased detection rate of significantly differentially expressed transcripts in thyroid data, but also confirmed key results derived from convoluted data (Paper VI). In conclusion, low-dose exposure, systemic effects, and circadian rhythm have a pronounced impact on normal tissue response in vivo and should be considered for more accurate risk assessment in radionuclide therapy.
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| 46. |
- Langen, Britta, et al.
(författare)
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The IRI-DICE hypothesis: ionizing radiation-induced DSBs may have a functional role for non-deterministic responses at low doses
- 2020
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Ingår i: Radiation and Environmental Biophysics. - : Springer Science and Business Media LLC. - 0301-634X .- 1432-2099. ; 59, s. 349-355
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Tidskriftsartikel (refereegranskat)abstract
- Low-dose ionizing radiation (IR) responses remain an unresolved issue in radiation biology and risk assessment. Accurate knowledge of low-dose responses is important for estimation of normal tissue risk in cancer radiotherapy or health risks from occupational or hazard exposure. Cellular responses to low-dose IR appear diverse and stochastic in nature and to date no model has been proposed to explain the underlying mechanisms. Here, we propose a hypothesis on IR-induced double-strand break (DSB)-induced cis effects (IRI-DICE) and introduce DNA sequence functionality as a submicron-scale target site with functional outcome on gene expression: DSB induction in a certain genetic target site such as promotor, regulatory element, or gene core would lead to changes in transcript expression, which may range from suppression to overexpression depending on which functional element was damaged. The DNA damage recognition and repair machinery depicts threshold behavior requiring a certain number of DSBs for induction. Stochastically distributed persistent disruption of gene expression may explain-in part-the diverse nature of low-dose responses until the repair machinery is initiated at increased absorbed dose. Radiation quality and complexity of DSB lesions are also discussed. Currently, there are no technologies available to irradiate specific genetic sites to test the IRI-DICE hypothesis directly. However, supportive evidence may be achieved by developing a computational model that combines radiation transport codes with a genomic DNA model that includes sequence functionality and transcription to simulate expression changes in an irradiated cell population. To the best of our knowledge, IRI-DICE is the first hypothesis that includes sequence functionality of different genetic elements in the radiation response and provides a model for the diversity of radiation responses in the (very) low dose regimen.
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| 47. |
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| 48. |
- 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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| 49. |
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| 50. |
- 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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