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Stenerlöw, Bo
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Publications (10 of 49) Show all publications
Hladik, D., Buratovic, S., Von Toerne, C., Azimzadeh, O., Subedi, P., Philipp, J., . . . Tapio, S. (2019). Combined Treatment with Low-Dose Ionizing Radiation and Ketamine Induces Adverse Changes in CA1 Neuronal Structure in Male Murine Hippocampi. International Journal of Molecular Sciences, 20(23), Article ID 6103.
Open this publication in new window or tab >>Combined Treatment with Low-Dose Ionizing Radiation and Ketamine Induces Adverse Changes in CA1 Neuronal Structure in Male Murine Hippocampi
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2019 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 20, no 23, article id 6103Article in journal (Refereed) Published
Abstract [en]

In children, ketamine sedation is often used during radiological procedures. Combined exposure of ketamine and radiation at doses that alone did not affect learning and memory induced permanent cognitive impairment in mice. The aim of this study was to elucidate the mechanism behind this adverse outcome. Neonatal male NMRI mice were administered ketamine (7.5 mg kg(-1)) and irradiated (whole-body, 100 mGy or 200 mGy, Cs-137) one hour after ketamine exposure on postnatal day 10. The control mice were injected with saline and sham-irradiated. The hippocampi were analyzed using label-free proteomics, immunoblotting, and Golgi staining of CA1 neurons six months after treatment. Mice co-exposed to ketamine and low-dose radiation showed alterations in hippocampal proteins related to neuronal shaping and synaptic plasticity. The expression of brain-derived neurotrophic factor, activity-regulated cytoskeleton-associated protein, and postsynaptic density protein 95 were significantly altered only after the combined treatment (100 mGy or 200 mGy combined with ketamine, respectively). Increased numbers of basal dendrites and branching were observed only after the co-exposure, thereby constituting a possible reason for the displayed alterations in behavior. These data suggest that the risk of radiation-induced neurotoxic effects in the pediatric population may be underestimated if based only on the radiation dose.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
hippocampus, proteomics, BDNF, CA1 neurons, dendrite abnormality, Golgi staining, irradiation
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-402388 (URN)10.3390/ijms20236103 (DOI)000504428300285 ()31817026 (PubMedID)
Funder
Swedish Radiation Safety Authority
Available from: 2020-01-24 Created: 2020-01-24 Last updated: 2020-01-24Bibliographically approved
Philippot, G., Stenerlöw, B., Fredriksson, A., Sundell-Bergman, S., Eriksson, P. & Buratovic, S. (2019). Developmental effects of neonatal fractionated co-exposure to low-dose gamma radiation and paraquat on behaviour in adult mice. Journal of Applied Toxicology, 39(4), 582-589
Open this publication in new window or tab >>Developmental effects of neonatal fractionated co-exposure to low-dose gamma radiation and paraquat on behaviour in adult mice
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2019 (English)In: Journal of Applied Toxicology, ISSN 0260-437X, E-ISSN 1099-1263, Vol. 39, no 4, p. 582-589Article in journal (Refereed) Published
Abstract [en]

Radiological methods for screening, diagnostics and therapy are often used in healthcare; however, it has recently been reported that developmental exposure to low-dose ionizing radiation (IR) causes neurotoxicity. Environmental chemicals also have the potential to affect the developing brain and the concomitant effects caused by IR and chemicals are of high interest today. We therefore aim to investigate if low-dose IR can interact with the known neurotoxicant paraquat to induce neurotoxicity in the neonatal mouse model. Using the same model, we also aim to investigate if fractionated low-dose IR can be as neurotoxic as higher acute doses. Male mice were exposed to a single dose of paraquat (0.2 or 0.02 mg/kg) on postnatal day 10 and 11. Two hours following paraquat exposure, mice were whole body irradiated with 100 or 300 mGy gamma radiation (Cs-137). Behavioural observations were performed at 2 and 3 months of age. Following behavioural testing, we evaluated striatal dopaminergic gene transcription. Animals co-exposed to IR and paraquat generally displayed altered spontaneous behaviour compared to controls and single agent exposed mice. Stronger effects by combined exposure were also observed on adult memory and learning. However, dopaminergic gene transcript levels remained unchanged by treatment. Co-exposure to low-dose IR and paraquat can interact to exacerbate neurotoxic effects and to impair cognitive function. Furthermore, fractionation of the radiation dose was observed to be as potent as higher acute exposure for induction of developmental neurotoxicity.

National Category
Developmental Biology
Identifiers
urn:nbn:se:uu:diva-282374 (URN)10.1002/jat.3748 (DOI)000461835200003 ()30426514 (PubMedID)
Available from: 2016-04-05 Created: 2016-04-05 Last updated: 2019-04-05Bibliographically approved
Lundsten, S., Spiegelberg, D., Stenerlöw, B. & Nestor, M. (2019). The HSP90 inhibitor onalespib potentiates Lu-177-DOTATATE therapy in neuroendocrine tumor cells. International Journal of Oncology, 55(6), 1287-1295
Open this publication in new window or tab >>The HSP90 inhibitor onalespib potentiates Lu-177-DOTATATE therapy in neuroendocrine tumor cells
2019 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 55, no 6, p. 1287-1295Article in journal (Refereed) Published
Abstract [en]

Lu-177-DOTATATE was recently approved for the treatment of somatostatin receptor (SSTR)-positive neuroen-docrine tumors (NETs). However, despite impressive response rates, complete responses are rare. Heat shock protein 90 (HSP90) inhibitors have been suggested as suitable therapeutic agents for NETs, as well as a potential radiosensitizers. Consequently, the aim of this study was to investigate whether the HSP90-inhibitor onalespib could reduce NET cell growth and act as a radiosensitizer when used in combination with Lu-177-DOTATATE. The NET cell lines BON, NCI-H727 and NCI-H460, were first characterized with regards to Lu-177-DOTATATE uptake and sensitivity to onalespib treatment in monolayer cell assays. The growth inhibitory effects of the monotherapies and combination treatments were then examined in three-dimensional multicellular tumor spheroids. Lastly, the molecular effects of the treatments were assessed. Lu-177-DOTATATE uptake was observed in the BON and NCI-H727 cells, while the NCI-H460 cells exhibited no detectable uptake. Accordingly, Lu-177-DOTATATE reduced the growth of BON and NCI-H727 spheroids, while no effect was observed in the NCI-H460 spheroids. Onalespib reduced cell viability and spheroid growth in all three cell lines. Furthermore, the combination of onalespib and Lu-177-DOTATATE exerted synergistic therapeutic effects on the BON and NCI-H727 spheroids. Western blot analysis of BON spheroids revealed the downregulation of epidermal growth factor receptor (EGFR) and the upregulation of gamma H2A histone family member X (gamma H2AX) following combined treatment with onalespib and Lu-177-DOTATATE. Moreover, flow cytometric analyses revealed a two-fold increase in caspase 3/7 activity in the combination group. In conclusion, the findings of this study demonstrate that onalespib exerts antitumorigenic effects on NET cells and may thus be a feasible treatment option for NETs. Furthermore, onalespib was able to synergistically potentiate Lu-177-DOTATATE treatment in a SSTR-specific manner. The radiosensitizing mechanisms of onalespib involved the downregulation of EGFR expression and the induction of apoptosis. Consequently, the combination of onalespib and Lu-177-DOTATATE may prove to be a promising strategy with which to improve therapeutic responses in patients with NETs. Further studies investigating this strategy in vivo regarding the therapeutic effects and potential toxicities are warranted to expand these promising findings.

Place, publisher, year, edition, pages
SPANDIDOS PUBL LTD, 2019
Keywords
neuroendocrine neoplasms, neuroendocrine tumors, peptide receptor radionuclide therapy, Lu-177-DOTATATE, Lutathera, heat shock protein 90, onalespib, AT13387, radiosensitization
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-400409 (URN)10.3892/ijo.2019.4888 (DOI)000500272500009 ()31638190 (PubMedID)
Funder
Swedish Cancer Society, CAN 2018/494Swedish Cancer Society, CAN2016/649Swedish Cancer Society, CAN 2015/1080Swedish Cancer Society, CAN 2015/385Swedish Research Council, 2013-30876-104113-30
Available from: 2020-01-02 Created: 2020-01-02 Last updated: 2020-01-02Bibliographically approved
Buratovic, S., Stenerlöw, B., Sundell-Bergman, S., Fredriksson, A., Viberg, H., Gordh, T. & Eriksson, P. (2018). Effects on adult cognitive function after neonatal exposure to clinically relevant doses of ionising radiation and ketamine in mice. British Journal of Anaesthesia, 120(3), 546-554
Open this publication in new window or tab >>Effects on adult cognitive function after neonatal exposure to clinically relevant doses of ionising radiation and ketamine in mice
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2018 (English)In: British Journal of Anaesthesia, ISSN 0007-0912, E-ISSN 1471-6771, Vol. 120, no 3, p. 546-554Article in journal (Refereed) Published
Abstract [en]

Background: Radiological methods for screening, diagnostics and therapy are frequently used in healthcare. In infants and children, anaesthesia/sedation is often used in these situations to relieve the patients' perception of stress or pain. Both ionising radiation (IR) and ketamine have been shown to induce developmental neurotoxic effects and this study aimed to identify the combined effects of these in a murine model. Methods: Male mice were exposed to a single dose of ketamine (7.5 mg kg(-1) body weight) s.c. on postnatal day 10. One hour after ketamine exposure, mice were whole body irradiated with 50-200 mGy gamma radiation (Cs-137). Behavioural observations were performed at 2, 4 and 5 months of age. At 6 months of age, cerebral cortex and hippocampus tissue were analysed for neuroprotein levels. Results: Animals co-exposed to IR and ketamine displayed significant (P <= 0.01) lack of habituation in the spontaneous behaviour test, when compared with controls and single agent exposed mice. In the Morris Water Maze test, co-exposed animals showed significant (P <= 0.05) impaired learning and memory capacity in both the spatial acquisition task and the relearning test compared with controls and single agent exposed mice. Furthermore, in co-exposed mice a significantly (P <= 0.05) elevated level of tau protein in cerebral cortex was observed. Single agent exposure did not cause any significant effects on the investigated endpoints. Conclusion: Co-exposure to IR and ketamine can aggravate developmental neurotoxic effects at doses where the single agent exposure does not impact on the measured variables. These findings show that estimation of risk after paediatric low-dose IR exposure, based upon radiation dose alone, may underestimate the consequences for this vulnerable population.

Place, publisher, year, edition, pages
ELSEVIER SCI LTD, 2018
Keywords
cognition, gamma rays, ketamine, mice, tau proteins
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-360552 (URN)10.1016/j.bja.2017.11.099 (DOI)000438191300019 ()29452811 (PubMedID)
Funder
Swedish Radiation Safety Authority
Available from: 2018-09-14 Created: 2018-09-14 Last updated: 2018-09-14Bibliographically approved
Lundsten, S., Spiegelberg, D., Raval, N., Stenerlöw, B. & Nestor, M. (2018). Potentiating Lu-177-DOTATATE Therapy By HSP90 Inhibition - First In Vivo Study. Paper presented at 31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY. European Journal of Nuclear Medicine and Molecular Imaging, 45, S12-S13
Open this publication in new window or tab >>Potentiating Lu-177-DOTATATE Therapy By HSP90 Inhibition - First In Vivo Study
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2018 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, p. S12-S13Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Springer, 2018
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-372968 (URN)000449266200003 ()
Conference
31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY
Available from: 2019-01-11 Created: 2019-01-11 Last updated: 2019-01-11Bibliographically approved
Abramenkovs, A., Spiegelberg, D. & Stenerlöw, B. (2018). Ra223 induced clustered DNA damage reduces cell survival independently of androgen receptor variant 7 expression. Paper presented at 31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY. European Journal of Nuclear Medicine and Molecular Imaging, 45, S634-S635
Open this publication in new window or tab >>Ra223 induced clustered DNA damage reduces cell survival independently of androgen receptor variant 7 expression
2018 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, p. S634-S635Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Springer, 2018
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-372955 (URN)000449266206036 ()
Conference
31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY
Available from: 2019-01-24 Created: 2019-01-24 Last updated: 2019-01-24Bibliographically approved
Abramenkovs, A. & Stenerlöw, B. (2018). Removal of heat-sensitive clustered damaged DNA sites is independent of double-strand break repair. PLoS ONE, 13(12), Article ID e0209594.
Open this publication in new window or tab >>Removal of heat-sensitive clustered damaged DNA sites is independent of double-strand break repair
2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 12, article id e0209594Article in journal (Refereed) Published
Abstract [en]

DNA double-strand breaks (DSBs) are the most deleterious lesions that can arise in cells after ionizing radiation or radiometric drug treatment. In addition to prompt DSBs, DSBs may also be produced during repair, evolving from a clustered DNA damaged site, which is composed of two or more distinct lesions that are located within two helical turns. A specific type of cluster damage is the heat-sensitive clustered site (HSCS), which transforms into DSBs upon treatment at elevated temperatures. The actual lesions or mechanisms that mediate the HSCS transformation into DSBs are unknown. However, there are two possibilities; either these lesions are transformed into DSBs due to DNA lesion instability, e.g., transfer of HSCS into single-strand breaks (SSBs), or they are formed due to local DNA structure instability, e.g., DNA melting, where two SSBs on opposite strands meet and transform into a DSB. The importance of these processes in living cells is not understood, but they significantly affect estimates of DSB repair capacity. In this study, we show that HSCS removal in human cells is not affected by defects in DSB repair or inhibition of DSB repair. Under conditions where rejoining of prompt DSBs was almost completely inhibited, heat-sensitive DSBs were successfully rejoined, without resulting in increased DSB levels, indicating that HSCS do not transfer into DSB in cells under physiological conditions. Furthermore, analysis by atomic force microscopy suggests that prolonged heating of chromosomal DNA can induce structural changes that facilitate transformation of HSCS into DSB. In conclusion, the HSCS do not generate additional DSBs at physiological temperatures in human cells, and the repair of HSCS is independent of DSB repair.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-374120 (URN)10.1371/journal.pone.0209594 (DOI)000454621900032 ()30592737 (PubMedID)
Funder
Swedish Cancer Society, CAN2014/661Swedish Cancer Society, CAN2016/649Swedish Radiation Safety Authority, SSM2017-2374Swedish Radiation Safety Authority, SSM2018-2181
Available from: 2019-01-23 Created: 2019-01-23 Last updated: 2019-03-08Bibliographically approved
Häggblad Sahlberg, S., Mortensen, A. C., Haglöf, J., Engskog, M. K. R., Arvidsson, T., Pettersson, C., . . . Nestor, M. (2017). Different functions of AKT1 and AKT2 in molecular pathways, cell migration and metabolism in colon cancer cells. International Journal of Oncology, 50(1), 5-14
Open this publication in new window or tab >>Different functions of AKT1 and AKT2 in molecular pathways, cell migration and metabolism in colon cancer cells
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2017 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 50, no 1, p. 5-14Article in journal (Refereed) Published
Abstract [en]

AKT is a central protein in many cellular pathways such as cell survival, proliferation, glucose uptake, metabolism, angiogenesis, as well as radiation and drug response. The three isoforms of AKT (AKT1, AKT2 and AKT3) are proposed to have different physiological functions, properties and expression patterns in a cell type-dependent manner. As of yet, not much is known about the influence of the different AKT isoforms in the genome and their effects in the metabolism of colorectal cancer cells. In the present study, DLD-1 isogenic AKT1, AKT2 and AKT'/2 knockout colon cancer cell lines were used as a model system in conjunction with the parental cell line in order to further elucidate the differences between the AKT isoforms and how they are involved in various cellular pathways. This was done using genome wide expression analyses, metabolic profiling and cell migration assays. In conclusion, downregulation of genes in the cell adhesion, extracellular matrix and Notch-pathways and upregulation of apoptosis and metastasis inhibitory genes in the p53-pathway, confirm that the knockout of both AKT1 and AKT2 will attenuate metastasis and tumor cell growth. This was verified with a reduction in migration rate in the AKT1 KO and AKT2 KO and most explicitly in the AKT1/2 KO. Furthermore, the knockout of AKT1, AKT2 or both, resulted in a reduction in lactate and alanine, suggesting that the metabolism of carbohydrates and glutathione was impaired. This was further verified in gene expression analyses, showing downregulation of genes involved in glucose metabolism. Additionally, both AKT1 KO and AKT2 KO demonstrated an impaired fatty acid metabolism. However, genes were upregulated in the Wnt and cell proliferation pathways, which could oppose this effect. AKT inhibition should therefore be combined with other effectors to attain the best effect.

Keywords
Microarray, metabolism, cell migration AKT1, AKT2, AKT, PKB, gene expression, colon-cancer, DLD-1, metabolomics, CD44, CD133
National Category
Biochemistry and Molecular Biology
Research subject
Biomedical Radiation Science; Biology with specialization in Molecular Cell Biology; Biology with specialization in Molecular Biology
Identifiers
urn:nbn:se:uu:diva-222834 (URN)10.3892/ijo.2016.3771 (DOI)000391419200001 ()
Available from: 2014-04-14 Created: 2014-04-14 Last updated: 2017-12-05Bibliographically approved
Spiegelberg, D., Lundsten, S., Mortensen, A. C., Abramenkovs, A., Stenerlöw, B. & Nestor, M. (2017). In Vitro and In Vivo Growth Inhibitory and Radiosensitizing Effects of the Anti-HSP90 agent Onalespib. European Journal of Nuclear Medicine and Molecular Imaging, 44, S182-S182
Open this publication in new window or tab >>In Vitro and In Vivo Growth Inhibitory and Radiosensitizing Effects of the Anti-HSP90 agent Onalespib
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2017 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 44, p. S182-S182Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Springer, 2017
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-377089 (URN)000455019400106 ()
Available from: 2019-02-19 Created: 2019-02-19 Last updated: 2019-02-19Bibliographically approved
Abramenkovs, A. & Stenerlöw, B. (2017). Measurement of DNA-Dependent Protein Kinase Phosphorylation Using Flow Cytometry Provides a Reliable Estimate of DNA Repair Capacity. Radiation Research, 188(6), 597-604
Open this publication in new window or tab >>Measurement of DNA-Dependent Protein Kinase Phosphorylation Using Flow Cytometry Provides a Reliable Estimate of DNA Repair Capacity
2017 (English)In: Radiation Research, ISSN 0033-7587, E-ISSN 1938-5404, Vol. 188, no 6, p. 597-604Article in journal (Refereed) Published
Abstract [en]

Uncontrolled generation of DNA double-strand breaks (DSBs) in cells is regarded as a highly toxic event that threatens cell survival. Radiation-induced DNA DSBs are commonly measured by pulsed-field gel electrophoresis, microscopic evaluation of accumulating DNA damage response proteins (e.g., 53BP1 or gamma-H2AX) or flow cytometric analysis of gamma-H2AX. The advantage of flow cytometric analysis is that DSB formation and repair can be studied in relationship to cell cycle phase or expression of other proteins. However, gamma-H2AX is not able to monitor repair kinetics within the first 60 min postirradiation, a period when most DSBs undergo repair. A key protein in non-homologous end joining repair is the catalytic subunit of DNA-dependent protein kinase. Among several phosphorylation sites of DNA-dependent protein kinase, the threonine at position 2609 (T2609), which is phosphorylated by ataxia telangiectasia mutated (ATM) or DNA-dependent protein kinase catalytic subunit itself, activates the end processing of DSB. Using flow cytometry, we show here that phosphorylation at T2609 is faster in response to DSBs than gamma-H2AX. Furthermore, flow cytometric analysis of T2609 resulted in a better representation of fast repair kinetics than analysis of gamma-H2AX. In cells with reduced ligase IV activity, and wild-type cells where DNA-dependent protein kinase activity was inhibited, the reduced DSB repair capacity was observed by T2609 evaluation using flow cytometry. In conclusion, flow cytometric evaluation of DNA-dependent protein kinase T2609 can be used as a marker for early DSB repair and gives a better representation of early repair events than analysis of gamma-H2AX.

Place, publisher, year, edition, pages
RADIATION RESEARCH SOC, 2017
National Category
Biophysics
Identifiers
urn:nbn:se:uu:diva-343567 (URN)10.1667/RR14693.1 (DOI)000416744600001 ()
Funder
Swedish Cancer SocietySwedish Radiation Safety Authority
Available from: 2018-03-02 Created: 2018-03-02 Last updated: 2019-03-08Bibliographically approved
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