Academic Interests
My major area of interest is cellular effects of radiation and hypoxia.
This includes:
- Low dose rate effects
- The role of prolonged hypoxia in radiation resistance.
- The role of TGFbeta3 in radiation response
- Proton therapy- new ways to deliver protons and new ways to exploit the physical properties
- Radiation induced immunogenic cell death
- Late effects after radiotherapy, protons vs. X-rays, mechanisms and mitigation
- Relative biological effect of radionuclides
Teaching
FYS2150 Experimental physics
FYS4720/9720 Cellular radiobiology
FYS3820 Arbeidspraksis
Tags:
Life sciences,
Biomedical physics,
biophysics,
medical physics,
Radiation physics,
Radiation biophysics,
Cancer,
Radiation protection,
Hypoxia,
Low dose irradiation,
Cell kinetics,
Cell biology,
Molecular biology,
Proton therapy
Publications
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Kristiansen, Sandra Kvarsvik; Dernjani, Nurtene Berisha; Bruland, Øyvind; Edin, Nina Frederike Jeppesen & Juzeniene, Asta
(2026).
A 3D co-culture model with fibroblast-restricted FAP expression for cancer therapy using [212Pb]Pb-FAPI-46.
EJNMMI Radiopharmacy and Chemistry.
11(1).
doi:
10.1186/s41181-026-00444-0.
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Rykkelid, Anne Marit; Skeie, Hilde Solesvik; Tormodsrud, Vera Helene; Siem, Sunniva; Malinen, Eirik & Edin, Nina Frederike Jeppesen
(2026).
Cell survival and DNA damage along the distal edge of the proton Bragg peak.
International Journal of Radiation Biology.
ISSN 0955-3002.
p. 1–10.
doi:
10.1080/09553002.2026.2666062.
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Arous, Delmon; Lie, Jacob Larsen; Edin, Nina Frederike Jeppesen & Malinen, Eirik
(2025).
Integrating 2D dosimetry and cell survival analysis for predicting local effect in spatially fractionated radiotherapy.
Acta Oncologica.
ISSN 0284-186X.
64,
p. 1465–1472.
doi:
10.2340/1651-226x.2025.44599.
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Background and purpose: Robust methods for analysis and prediction of local cell survival after spatially fractionated radiotherapy (SFRT) in vitro remain limited. We present a methodology integrating spatial dosimetry with colony formation assessment and modelling to improve prediction of SFRT-induced responses.
Patient/material and methods: A549 lung cancer cells were irradiated with 220 kV X-rays in three field patterns: open, striped, and dotted. Colony centroid locations were mapped from scanned images of culture flasks. Dose distributions were measured using radiochromic film dosimetry. Digital images with colony locations and dose maps were divided into 1 mm² quadrats. A Poisson regression model was fitted to colony counts per quadrat, incorporating linear-quadratic (LQ) model parameters α and β. A modified LQ (MLQ) model included an additional interaction between dose and nearest distance to a peak region, with parameter δ.
Results: The methodology was successfully implemented. LQ fitting across all quadrats and patterns yielded α = 0.254 Gy−¹ and β = 0.039 Gy−², while the MLQ model gave α = 0.249 Gy−¹, β = 0.032 Gy−², and δ = −0.040 Gy−¹ cm−¹. Parameter uncertainty was below 0.5%. The MLQ model showed slightly lower fitting errors than the LQ model, indicating improved predictive accuracy.
Interpretation: We introduce a novel analysis pipeline for 2D localization of colonies and SFRT survival modelling in vitro. Findings suggest that distance to peak dose regions significantly influences local SFRT effects. Incorporating this spatial factor via an MLQ model may enhance understanding and prediction of SFRT-induced survival.
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Juvkam, Inga; Zlygosteva, Olga; Schreurs, Olaf Joseph Franciscus; Edin, Nina Frederike Jeppesen; Galtung, Hilde & Malinen, Eirik
[Show all 7 contributors for this article]
(2025).
Regional atrophy, cellular plasticity, and regenerative potential in irradiated murine salivary glands.
Acta Oncologica.
ISSN 0284-186X.
64,
p. 927–938.
doi:
10.2340/1651-226x.2025.44012.
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Background and purpose: Radiotherapy of head and neck cancer may cause detrimental late side effects such as fibrosis and hyposalivation. We investigated mouse salivary glands after fractionated irradiation, with the aim to elucidate cellular plasticity and potential regeneration.
Methods: 12-week-old female C57BL/6JRj mice were irradiated with X-rays to a total dose of 66 Gy, given in 10 fractions over 5 days. The radiation field covered the oral cavity and major salivary glands. The submandibular (SMG), sublingual (SLG), and parotid glands (PG) were dissected at day 100 after finishing irradiation. Using different histological staining techniques, morphological, cellular, and molecular changes were investigated in irradiated and control SMG, SLG, and PG.
Results: Atrophy of acinar cells was observed in irradiated SMG and SLG, but not in PG. Surprisingly, the acinar atrophy was confined to one region of each irradiated gland. These atrophic regions showed distinct cellular and molecular compositions compared to non-atrophic regions and control glands. Increased expression of the ductal cell markers keratin 5 and 19 (K5 and K19), along with increased percentages of proliferating myofibroblasts, fibroblasts, leukocytes, and acinar cells (Nkcc1+) were observed in the atrophic regions compared to controls. In addition, some of the K19+ and K5+ duct-like cells also co-expressed Nkcc1.
Interpretation: Through a detailed histological assessment of the cellular and molecular changes in the major salivary glands of irradiated mice, we observed signs of cellular plasticity where ductal cells adopt an acinar cell phenotype upon irradiation. This suggests a regenerative potential of salivary glands after irradiation.
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Huynh, Bao Ngoc; Kakar, Manish; Zlygosteva, Olga; Juvkam, Inga; Edin, Nina Frederike Jeppesen & Tomic, Oliver
[Show all 8 contributors for this article]
(2025).
CNN-based prediction using early post-radiotherapy MRI as a proxy for toxicity in the murine head and neck.
Acta Oncologica.
ISSN 0284-186X.
64,
p. 1312–1320.
doi:
10.2340/1651-226X.2025.44020.
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Background and purpose: Radiotherapy (RT) of head and neck cancer can cause severe toxicities. Early identification of individuals at risk could enable personalized treatment. This study evaluated whether convolutional neural networks (CNNs) applied to Magnetic Resonance (MR) images acquired early after irradiation can predict radiation-induced tissue changes associated with toxicity in mice.
Patient/material and methods: Twenty-nine C57BL/6JRj mice were included (irradiated: n = 14; control: n = 15). Irradiated mice received 65 Gy of fractionated RT to the oral cavity, swallowing muscles and salivary glands. T2-weighted MR images were acquired 3–5 days post-irradiation. CNN models (VGG, MobileNet, ResNet, EfficientNet) were trained to classify sagittal slices as irradiated or control (n = 586 slices). Predicted class probabilities were correlated with five toxicity endpoints assessed 8–105 days post-irradiation. Model explainability was assessed with VarGrad heatmaps, to verify that predictions relied on clinically relevant image regions.
Results: The best-performing model (EfficientNet B3) achieved 83% slice-level accuracy (ACC) and correctly classified 28 of 29 mice. Higher predicted probabilities of the irradiated class were strongly associated with oral mucositis, dermatitis, reduced saliva production, late submandibular gland fibrosis and atrophy of salivary gland acinar cells. Explainability heatmaps confirmed that CNNs focused on irradiated regions.
Interpretation: The high CNN classification ACC, the regions highlighted by the explainability analysis and the strong correlations between model predictions and toxicity suggest that CNNs, together with post-irradiation magnetic resonance imaging, may identify individuals at risk of developing toxicity.
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Rødland, Gro Elise; Temelie, Mihaela; Mariampillai, Adrian Eek; Serban, Ana Maria; Edin, Nina Frederike Jeppesen & Malinen, Eirik
[Show all 11 contributors for this article]
(2024).
Interferon signaling is enhanced by ATR inhibition in glioblastoma cells irradiated with X-rays, protons or carbon ions.
Radiotherapy and Oncology.
ISSN 0167-8140.
203.
doi:
10.1016/j.radonc.2024.110669.
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Background and purpose Interferon (IFN) signaling plays an important role in antitumor immune responses. Inhibitors of the DNA damage response, such as ATR inhibitors, can increase IFN signaling upon conventional radiotherapy with X-rays. However, it is not known whether such inhibitors also enhance IFN signaling after irradiation with high linear energy transfer (LET) particles. Materials and methods Human glioblastoma U-251 and T98G cells were irradiated with X-rays, protons (LET: 4.8 and 41.9 keV/µm) and carbon ions (LET: 28 and 73 keV/µm), with and without ATR inhibitor (VE-822) or ATM inhibitor (AZD1390). DNA damage signaling and cell cycle distribution were analyzed by immunoblotting and flow cytometry, and radiosensitivity was assessed by clonogenic survival assay. IFN-β secretion was measured by ELISA, and STAT1 activation was examined by immunoblotting. Results High-LET protons and carbon ions caused stronger activation of the DNA damage response compared to low-LET protons and X-rays at similar radiation doses. G2 checkpoint arrest was abrogated by the ATR inhibitor and prolonged by the ATM inhibitor after all radiation types. The inhibitors increased radiosensitivity, as measured after X- and carbon ion irradiation. ATR inhibition increased IFN signaling following both low-LET and high-LET irradiation. ATM inhibition also increased IFN signaling, but to a lesser extent. Notably, both cell lines secreted significantly more IFN-β when the inhibitors were combined with high-LET compared to low-LET irradiation. Conclusion These findings indicate that DNA damage response inhibitors can enhance IFN signaling following X-, proton and carbon ion irradiation, with a strong positive dependency on LET.
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Hanson, Ingunn; Juvkam, Inga; Zlygosteva, Olga; Søland, Tine Merete; Galtung, Hilde & Malinen, Eirik
[Show all 7 contributors for this article]
(2024).
TGF-β3 increases the severity of radiation-induced oral mucositis and salivary gland fibrosis in a mouse model.
International Journal of Radiation Biology.
ISSN 0955-3002.
100(5),
p. 767–776.
doi:
10.1080/09553002.2024.2324476.
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Purpose Toxicities from head and neck (H&N) radiotherapy (RT) may affect patient quality of life and can be dose-limiting. Proteins from the transforming growth factor beta (TGF-β) family are key players in the fibrotic response. While TGF-β1 is known to be pro-fibrotic, TGF-β3 has mainly been considered anti-fibrotic. Moreover, TGF-β3 has been shown to act protective against acute toxicities after radio- and chemotherapy. In the present study, we investigated the effect of TGF-β3 treatment during fractionated H&N RT in a mouse model. Materials and methods 30 C57BL/6J mice were assigned to three treatment groups. The RT + TGF-β3 group received local fractionated H&N RT with 66 Gy over five days, combined with TGF-β3-injections at 24-hour intervals. Animals in the RT reference group received identical RT without TGF-β3 treatment. The non-irradiated control group was sham-irradiated according to the same RT schedule. In the follow-up period, body weight and symptoms of oral mucositis and lip dermatitis were monitored. Saliva was sampled at five time points. The experiment was terminated 105 d after the first RT fraction. Submandibular and sublingual glands were preserved, sectioned, and stained with Masson’s trichrome to visualize collagen. Results A subset of mice in the RT + TGF-β3 group displayed increased severity of oral mucositis and increased weight loss, resulting in a significant increase in mortality. Collagen content was significantly increased in the submandibular and sublingual glands for the surviving RT + TGF-β3 mice, compared with non-irradiated controls. In the RT reference group, collagen content was significantly increased in the submandibular gland only. Both RT groups displayed lower saliva production after treatment compared to controls. TGF-β3 treatment did not impact saliva production. Conclusions When repeatedly administered during fractionated RT at the current dose, TGF-β3 treatment increased acute H&N radiation toxicities and increased mortality. Furthermore, TGF-β3 treatment may increase the severity of radiation-induced salivary gland fibrosis.
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Hanson, Ingunn; Vatne, Jenny Tovseth & Edin, Nina Frederike Jeppesen
(2024).
Effects of Bone Marrow Sparing and TGF-β3 Treatment in Total Body Irradiation of C57BL/6J Mice.
Applied Biosciences.
3(2),
p. 165–185.
doi:
10.3390/applbiosci3020011.
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Introduction: Mortality from acute radiation syndrome is frequently caused by hematopoietic or gastrointestinal radiotoxicity, the latter of which currently has no effective treatment. Transforming growth factor-beta 3 (TGF-β3) may decrease the severity of radiation-induced gastrointestinal damage in mice. In addition, treatment with TGF-β3 may alleviate radiation-induced fibrosis. Objectives: The current study aimed to investigate the effect of TGF-β3 treatment on acute and late radiotoxicity in whole body irradiated mice. Methods: C57BL/6J mice were total body irradiated with 8.5 Gy X-rays with or without shielding of one hind leg to alleviate hematopoietic radiotoxicity. The effects of intravenous TGF-β3 treatment were investigated. Body weight and pain expression were monitored. Intestine, lung, and liver tissues were preserved and analyzed. Alpha smooth muscle actin (α-SMA) expression in MRC-5 cells after 3.5 Gy X-irradiation combined with TGF-β3 treatment was analyzed using flow cytometry. Results: All total body irradiated animals died within ten days after irradiation. Ninety-three percent of femur-shielded mice survived until sampling or termination. No effect of TGF-β3 treatment was observed in either group. No increase in collagen content was detected in the lungs or liver from irradiated mice regardless of TGF-β3 treatment. In vitro, α-SMA expression increased synergistically after irradiation and TGF-β3 treatment. Conclusions: Shielding of the femur during total body irradiation decreased acute gastrointestinal radiation toxicity and increased survival. TGF-β3 treatment did not impact symptoms or survival. TGF-β3 treatment and irradiation increased α-SMA expression in MRC-5 cells synergistically.
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Rykkelid, Anne Marit; Sinha, Priyanshu Manojkumar; Folefac, Charlemagne Asonganyi; Horsman, Michael R.; Sørensen, Brita Singers & Søland, Tine Merete
[Show all 9 contributors for this article]
(2024).
Combination of proton- or X-irradiation with anti-PDL1 immunotherapy in two murine oral cancers.
Scientific Reports.
14(1).
doi:
10.1038/s41598-024-62272-z.
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Combining radiation therapy with immunotherapy is a strategy to improve both treatments. The purpose of this study was to compare responses for two syngeneic head and neck cancer (HNC) tumor models in mice following X-ray or proton irradiation with or without immune checkpoint inhibition (ICI). MOC1 (immunogenic) and MOC2 (less immunogenic) tumors were inoculated in the right hind leg of each mouse (C57BL/6J, n = 398). Mice were injected with anti-PDL1 (10 mg/kg, twice weekly for 2 weeks), and tumors were treated with single-dose irradiation (5–30 Gy) with X-rays or protons. MOC2 tumors grew faster and were more radioresistant than MOC1 tumors, and all mice with MOC2 tumors developed metastases. Irradiation reduced the tumor volume in a dose-dependent manner. ICI alone reduced the tumor volume for MOC1 with 20% compared to controls, while no reduction was seen for MOC2. For MOC1, there was a clear treatment synergy when combining irradiation with ICI for radiation doses above 5 Gy and there was a tendency for X-rays being slightly more biologically effective compared to protons. For MOC2, there was a tendency of protons being more effective than X-rays, but both radiation types showed a small synergy when combined with ICI. Although the responses and magnitudes of the therapeutic effect varied, the optimal radiation dose for maximal synergy appeared to be in the order of 10–15 Gy, regardless of tumor model.
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Juvkam, Inga; Zlygosteva, Olga; Sitarz, Mateusz; Sørensen, Brita Singers; Aass, Hans Christian & Edin, Nina Frederike Jeppesen
[Show all 9 contributors for this article]
(2024).
Proton- compared to X-irradiation leads to more acinar atrophy and greater hyposalivation accompanied by a differential cytokine response.
Scientific Reports.
14:22311(1),
p. 1–12.
doi:
10.1038/s41598-024-73110-7.
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Proton therapy gives less dose to healthy tissue compared to conventional X-ray therapy, but systematic comparisons of normal tissue responses are lacking. The aim of this study was to investigate late tissue responses in the salivary glands following proton- or X-irradiation of the head and neck in mice. Moreover, we aimed at investigating molecular responses by monitoring the cytokine levels in serum and saliva. Female C57BL/6J mice underwent local fractionated irradiation with protons or X-rays to the maximally tolerated acute level. Saliva and serum were collected before and at different time points after irradiation to assess salivary gland function and cytokine expression. To study late responses in the major salivary glands, histological analyses were performed on tissues collected at day 105 after onset of irradiation. Saliva volume after proton and X-irradiation was significantly lower than for controls and remained reduced at all time points after irradiation. Protons caused reduced saliva production and fewer acinar cells in the submandibular glands compared to X-rays at day 105. X-rays induced a stronger inflammatory cytokine response in saliva compared to protons. This work supports previous preclinical findings and indicate that the relative biological effectiveness of protons in normal tissue might be higher than the commonly used value of 1.1.
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Printzell, Lisa; Reseland, Janne Elin; Edin, Nina Frederike Jeppesen; Ellingsen, Jan Eirik & Tiainen, Hanna
(2023).
Backscatter from therapeutic doses of ionizing irradiation does not impair cell migration on titanium implants in vitro.
Clinical Oral Investigations.
ISSN 1432-6981.
doi:
10.1007/s00784-023-05128-6.
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Objective The influence of radiation backscatter from titanium on DNA damage and migration capacity of human osteoblasts (OBs) and mesenchymal stem cells (MSCs) may be critical for the osseointegration of dental implants placed prior to radiotherapy. In order to evaluate effects of radiation backscatter, the immediate DNA damage and migration capacity of OBs and MSCs cultured on titanium or plastic were compared after exposure to ionizing irradiation. Materials and methods Human OBs and MSCs were seeded on machined titanium, moderately rough fluoride-modified titanium, or tissue culture polystyrene, and irradiated with nominal doses of 2, 6, 10, or 14 Gy. Comet assay was performed immediately after irradiation, while a scratch wound healing assay was initiated 24 h post-irradiation. Fluorescent live cell imaging documented the migration. Results DNA damage increased with higher dose and with backscatter from titanium, and MSCs were significantly more affected than OBs. All doses of radiation accelerated the cell migration on plastic, while only the highest dose of 10 Gy inhibited the migration of both cell types on titanium. Conclusions High doses (10 Gy) of radiation inhibited the migration capacity of both cell types on titanium, whereas lower doses (2 and 6 Gy) did not affect the migration of either OBs or MSCs. Clinical relevance Fractionated doses of 2 Gy/day, as distributed in conventional radiotherapy, appear not to cause severe DNA damage or disturb the migration of OBs or MSCs during osseointegration of dental implants.
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Arous, Delmon; Lie, Jacob Larsen; Håland, Bjørg Vårli; Børsting, Magnus; Edin, Nina Frederike Jeppesen & Malinen, Eirik
(2023).
2D mapping of radiation dose and clonogenic survival for accurate assessment of in vitro X-ray GRID irradiation effects.
Physics in Medicine and Biology.
ISSN 0031-9155.
68:025024(2).
doi:
10.1088/1361-6560/acaf20.
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Nattudurai, Ravikumar; Arous, Delmon; Edin, Nina Frederike Jeppesen; Pandey, Anant & Malinen, Eirik
(2023).
New characterization and evaluation of BaSO<inf>4</inf>: Eu as a thermoluminescent radiation dosimeter.
Nuclear Instruments and Methods in Physics Reseach B.
ISSN 0168-583X.
541,
p. 19–25.
doi:
10.1016/j.nimb.2023.05.025.
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Juvkam, Inga Solgård; Zlygosteva, Olga; Sitarz, Mateusz; Thiede, Bernd; Sørensen, Brita Singers & Malinen, Eirik
[Show all 9 contributors for this article]
(2023).
Proton Compared to X-Irradiation Induces Different Protein Profiles in Oral Cancer Cells and Their Derived Extracellular Vesicles.
International Journal of Molecular Sciences.
ISSN 1661-6596.
24(23),
p. 1–17.
doi:
10.3390/ijms242316983.
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Extracellular vesicles (EVs) are membrane-bound particles released from cells, and their cargo can alter the function of recipient cells. EVs from X-irradiated cells have been shown to play a likely role in non-targeted effects. However, EVs derived from proton irradiated cells have not yet been studied. We aimed to investigate the proteome of EVs and their cell of origin after proton or X-irradiation. The EVs were derived from a human oral squamous cell carcinoma (OSCC) cell line exposed to 0, 4, or 8 Gy from either protons or X-rays. The EVs and irradiated OSCC cells underwent liquid chromatography–mass spectrometry for protein identification. Interestingly, we found different protein profiles both in the EVs and in the OSCC cells after proton irradiation compared to X-irradiation. In the EVs, we found that protons cause a downregulation of proteins involved in cell growth and DNA damage response compared to X-rays. In the OSCC cells, proton and X-irradiation induced dissimilar cell death pathways and distinct DNA damage repair systems. These results are of potential importance for understanding how non-targeted effects in normal tissue can be limited and for future implementation of proton therapy in the clinic.
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Hanson, Ingunn; Pitman, Kathinka Elinor & Edin, Nina Frederike Jeppesen
(2023).
The Role of TGF-β3 in Radiation Response.
International Journal of Molecular Sciences.
ISSN 1661-6596.
24(8).
doi:
10.3390/ijms24087614.
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Transforming growth factor-beta 3 (TGF-β3) is a ubiquitously expressed multifunctional cytokine involved in a range of physiological and pathological conditions, including embryogenesis, cell cycle regulation, immunoregulation, and fibrogenesis. The cytotoxic effects of ionizing radiation are employed in cancer radiotherapy, but its actions also influence cellular signaling pathways, including that of TGF-β3. Furthermore, the cell cycle regulating and anti-fibrotic effects of TGF-β3 have identified it as a potential mitigator of radiation- and chemotherapy-induced toxicity in healthy tissue. This review discusses the radiobiology of TGF-β3, its induction in tissue by ionizing radiation, and its potential radioprotective and anti-fibrotic effects.
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Huynh, Thuy-Tien Maria; Dale, Einar; Falk, Ragnhild Sørum; Hellebust, Taran Annette Paulsen; Astrup, Guro Lindviksmoen & Malinen, Eirik
[Show all 12 contributors for this article]
(2023).
Radiation-induced long-term dysphagia in survivors of head and neck cancer and association with dose-volume parameters.
Radiotherapy and Oncology.
ISSN 0167-8140.
190.
doi:
10.1016/j.radonc.2023.110044.
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Background Although dysphagia is a common side effect after radiotherapy (RT) of head and neck cancer (HNC), data on long-term dysphagia is scarce. We aimed to 1) compare radiation dose parameters in HNC survivors with and without dysphagia, 2) investigate factors associated with long-term dysphagia and its possible impact on health-related quality of life (HRQoL), and 3) investigate how our data agree with existing NTCP models. Methods This cross-sectional study conducted in 2018–2020, included HNC survivors treated in 2007–2013. Participants attended a one-day examination in hospital and filled in patient questionnaires. Dysphagia was measured with the EORTC QLQ-H&N35 swallowing scale. Toxicity was scored with CTCAE v.4. We contoured swallowing organs at risk (SWOAR) on RT plans, calculated dose-volume histograms (DVHs), performed logistic regression analyses and tested our data in established NTCP models. Results Of the 239 participants, 75 (31%) reported dysphagia. Compared to survivors without dysphagia, this group had reduced HRQoL and the DVHs for infrahyoid SWOAR were significantly shifted to the right. Long-term dysphagia was associated with age (OR 1.07, 95% CI 1.03–1.10), female sex (OR 2.75, 95% CI 1.45–5.21), and mean dose to middle pharyngeal constrictor muscle (MD-MPCM) (OR 1.06, 95% CI 1.03–1.09). NTCP models overall underestimated the risk of long-term dysphagia. Conclusions Long-term dysphagia was associated with higher age, being female, and high MD-MPCM. Doses to distally located SWOAR seemed to be risk factors. Existing NTCP models do not sufficiently predict long-term dysphagia. Further efforts are needed to reduce the prevalence and consequences of this late effect.
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Zlygosteva, Olga; Juvkam, Inga; Arous, Delmon; Sitarz, Mateusz; Sørensen, Brita Singers & Ankjærgaard, Christina
[Show all 11 contributors for this article]
(2023).
Acute normal tissue responses in a murine model following fractionated irradiation of the head and neck with protons or X-rays.
Acta Oncologica.
ISSN 0284-186X.
doi:
10.1080/0284186X.2023.2254481.
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Background The purpose of this study was to investigate acute normal tissue responses in the head and neck region following proton- or X-irradiation of a murine model. Materials and methods Female C57BL/6J mice were irradiated with protons (25 or 60 MeV) or X-rays (100 kV). The radiation field covered the oral cavity and the major salivary glands. For protons, two different treatment plans were used, either with the Bragg Peak in the middle of the mouse (BP) or outside the mouse (transmission mode; TM). Delivered physical doses were 41, 45, and 65 Gy given in 6, 7, and 10 fractions for BP, TM, and X-rays, respectively. Alanine dosimetry was used to assess delivered doses. Oral mucositis and dermatitis were scored using CTC v.2.0-based tables. Saliva was collected at baseline, right after end of irradiation, and at day 35. Results The measured dose distribution for protons (TM) and X-rays was very similar. Oral mucositis appeared earlier, had a higher score and was found in a higher percentage of mice after proton irradiation compared to X-irradiation. Dermatitis, on the other hand, had a similar appearance after protons and X-rays. Compared to controls, saliva production was lower right after termination of proton- and X-irradiation. The BP group demonstrated saliva recovery compared to the TM and X-ray group at day 35. Conclusion With lower delivered doses, proton irradiation resulted in similar skin reactions and increased oral mucositis compared to X-irradiation. This indicates that the relative biological effectiveness of protons for acute tissue responses in the mouse head and neck is greater than the clinical standard of 1.1. Thus, there is a need for further investigations of the biological effect of protons in normal tissues.
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Nattudurai, Ravikumar; Arous, Delmon; Edin, Nina Frederike Jeppesen; Pandey, Anant & Malinen, Eirik
(2023).
The energy dependence of BaSO<inf>4</inf>: Eu nanophosphors for thermoluminescence dosimetry of orthovoltage X-rays and low energy protons.
Radiation Physics and Chemistry.
ISSN 0969-806X.
208.
doi:
10.1016/j.radphyschem.2023.110928.
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Zlygosteva, Olga; Juvkam, Inga; Aass, Hans Christian; Galtung, Hilde; Søland, Tine Merete & Malinen, Eirik
[Show all 7 contributors for this article]
(2023).
Cytokine Levels in Saliva Are Associated with Salivary Gland Fibrosis and Hyposalivation in Mice after Fractionated Radiotherapy of the Head and Neck.
International Journal of Molecular Sciences.
ISSN 1661-6596.
24(20).
doi:
10.3390/ijms242015218.
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Cytokines are mediators of inflammation that could lead to fibrosis. The aim was to monitor cytokine levels in saliva and serum after locally fractionated radiotherapy of the head and neck in mice and investigate associations with salivary gland fibrosis and hyposalivation. C57BL/6 mice were randomized to sham or X-ray irradiation of 66 Gy in 10 fractions over 5 days. Blood and saliva were collected on days −7, 5, 35, 80, and 105 following cytokine analysis. The harvested submandibular salivary gland was assessed for the presence of fibrosis. Decision tree regression analysis was used to investigate whether cytokine levels could predict late endpoints in terms of hyposalivation or fibrosis. Significant formation of fibrosis in gland tissue and reduced saliva production was found after irradiation. The pro-inflammatory cytokines IL-1α, TNF, TIMP1, G-CSF, KC, and MIP-1α showed increased levels in saliva in irradiated mice and a strong correlation with late endpoints. The decision tree analysis largely separated controls from irradiated animals, with IL-1α being the strongest predictor. Pro-inflammatory cytokines in saliva, but not in serum, were associated with late endpoints. This indicates that cytokine expression in saliva is a good biomarker for local salivary gland damage with IL-1α as the strongest single predictor.
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Printzell, Lisa; Reseland, Janne Elin; Edin, Nina Frederike Jeppesen; Tiainen, Hanna & Ellingsen, Jan Eirik
(2023).
The dose-dependent impact of γ-radiation reinforced with backscatter from titanium on primary human osteoblasts.
Biomaterial Investigations in Dentistry.
10(1).
doi:
10.1080/26415275.2023.2209116.
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In head and neck cancer patients receiving dental implants prior to radiotherapy, backscatter from titanium increases the radiation dose close to the surface, and may affect the osseointegration. The dose-dependent effects of ionizing radiation on human osteoblasts (hOBs) were investigated. The hOBs were seeded on machined titanium, moderately rough fluoride-modified titanium, and tissue culture polystyrene, and cultured in growth- or osteoblastic differentiation medium (DM). The hOBs were exposed to ionizing γ-irradiation in single doses of 2, 6 or 10 Gy. Twenty-one days post-irradiation, cell nuclei and collagen production were quantified. Cytotoxicity and indicators of differentiation were measured and compared to unirradiated controls. Radiation with backscatter from titanium significantly reduced the number of hOBs but increased the alkaline phosphatase activity in both types of medium when adjusted to the relative cell number on day 21. Irradiated hOBs on the TiF-surface produced similar amounts of collagen as unirradiated controls when cultured in DM. The majority of osteogenic biomarkers significantly increased on day 21 when the hOBs had been exposed to 10 Gy, while the opposite or no effect was observed after lower doses. High doses reinforced with backscatter from titanium resulted in smaller but seemingly more differentiated subpopulations of osteoblasts.
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Hanson, Ingunn; Pitman, Kathinka Elinor; Altanerova, Ursula; Altaner, Čestmír; Malinen, Eirik & Edin, Nina Frederike Jeppesen
(2022).
Low-Dose-Rate Radiation-Induced Secretion of TGF-β3 Together with an Activator in Small Extracellular Vesicles Modifies Low-Dose Hyper-Radiosensitivity through ALK1 Binding.
International Journal of Molecular Sciences.
ISSN 1661-6596.
23(15).
doi:
10.3390/ijms23158147.
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Arous, Delmon; Schrunner, Stefan; Hanson, Ingunn; Edin, Nina Frederike Jeppesen & Malinen, Eirik
(2022).
Principal component-based image segmentation: a
new approach to outline in vitro cell colonies.
Computer Methods in Biomechanics and Biomedical Engineering: Imaging and Visualization.
ISSN 2168-1163.
doi:
10.1080/21681163.2022.2035822.
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Identification, segmentation and counting of stained in vitro cell colonies play a vital part in biological assays. Automating these tasks by optical scanning of cell dishes and subsequent image processing is not trivial due to challenges with, e.g. background noise and contaminations. Here, we present a machine learning procedure to amend these issues by characterising, extracting and segmenting inquired cell colonies using principal component analysis, k-means clustering and a modified watershed segmentation algorithm to automatically identify visible colonies. The proposed segmentation algorithm was tested on two data sets: a T-47D (proprietary) cell colony and a bacteria (open source) data set. High F1 scores (∼0.90 for T-47D and >0.95 for bacterial images), along with low absolute percentage errors (∼11% for T-47D and <5% for bacterial images), underlined good agreement with ground truth data. Our approach outperformed a recent state-of-the-art method on both data sets, demonstrating the usefulness of the presented algorithm.
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Reaz, Fardous; Sjobak, Kyrre Ness; Malinen, Eirik; Edin, Nina Frederike Jeppesen & Adli, Erik
(2022).
Sharp dose profiles for high precision proton therapy using strongly focused proton beams.
Scientific Reports.
12(1).
doi:
10.1038/s41598-022-22677-0.
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The main objective of radiotherapy is to exploit the curative potential of ionizing radiation while inflicting minimal radiation-induced damage to healthy tissue and sensitive organs. Proton beam therapy has been developed to irradiate the tumor with higher precision and dose conformity compared to conventional X-ray irradiation. The dose conformity of this treatment modality may be further improved if narrower proton beams are used. Still, this is limited by multiple Coulomb scattering of protons through tissue. The primary aim of this work was to develop techniques to produce narrow proton beams and investigate the resulting dose profiles. We introduced and assessed three different proton beam shaping techniques: (1) metal collimators (100/150 MeV), (2) focusing of conventional- (100/150 MeV), and (3) focusing of high-energy (350 MeV, shoot-through) proton beams. Focusing was governed by the initial value of the Twiss parameter 𝛼 (𝛼0), and can be implemented with magnetic particle accelerator optics. The dose distributions in water were calculated by Monte Carlo simulations using Geant4, and evaluated by target to surface dose ratio (TSDR) in addition to the transverse beam size (σ𝑇) at the target. The target was defined as the location of the Bragg peak or the focal point. The different techniques showed greatly differing dose profiles, where focusing gave pronouncedly higher relative target dose and efficient use of primary protons. Metal collimators with radii <2 mm gave low TSDRs (< 0.7) and large σ𝑇(> 3.6 mm). In contrast, a focused beam of conventional (150 MeV) energy produced a very high TSDR (> 80) with similar σ𝑇 as a collimated beam. High-energy focused beams were able to produce TSDRs > 100 and σ𝑇 around 1.5 mm. From this study, it appears very attractive to implement magnetically focused proton beams in radiotherapy of small lesions or tumors in close vicinity to healthy organs at risk. This can also lead to a paradigm change in spatially fractionated radiotherapy. Magnetic focusing would facilitate FLASH irradiation due to low losses of primary protons.
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Juvkam, Inga; Zlygosteva, Olga; Arous, Delmon; Galtung, Hilde; Malinen, Eirik & Søland, Tine Merete
[Show all 7 contributors for this article]
(2022).
A preclinical model to investigate normal tissue damage following fractionated radiotherapy to the head and neck.
Journal of radiation research.
ISSN 0449-3060.
p. 1–9.
doi:
10.1093/jrr/rrac066.
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Abstract Radiotherapy (RT) of head and neck (H&N) cancer is known to cause both early- and late-occurring toxicities. To better appraise normal tissue responses and their dependence on treatment parameters such as radiation field and type, as well as dose and fractionation scheme, a preclinical model with relevant endpoints is required. 12-week old female C57BL/6 J mice were irradiated with 100 or 180 kV X-rays to total doses ranging from 30 to 85 Gy, given in 10 fractions over 5 days. The radiation field covered the oral cavity, swallowing structures and salivary glands. Monte Carlo simulations were employed to estimate tissue dose distribution. The follow-up period was 35 days, in order to study the early radiation-induced effects. Baseline and post irradiation investigations included macroscopic and microscopic examinations of the skin, lips, salivary glands and oral mucosa. Saliva sampling was performed to assess the salivary gland function following radiation exposure. A dose dependent radiation dermatitis in the skin was observed for doses above 30 Gy. Oral mucositis in the tongue appeared as ulcerations on the ventral surface of the tongue for doses of 75–85 Gy. The irradiated mice showed significantly reduced saliva production compared to controls. In summary, a preclinical model to investigate a broad panel of normal tissue responses following fractionated irradiation of the H&N region was established. The optimal dose to study early radiation-induced effects was found to be around 75 Gy, as this was the highest tolerated dose that gave acute effects similar to that observed in cancer patients.
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Görgen, Andreas; Guttormsen, Magne Sveen; Larsen, Ann-Cecilie; Siem, Sunniva; Adli, Erik & Edin, Nina Frederike J
[Show all 14 contributors for this article]
(2021).
The Oslo Cyclotron Laboratory.
The European Physical Journal Plus.
136,
p. 1–13.
doi:
10.1140/epjp/s13360-021-01150-3.
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Research at the Oslo Cyclotron Laboratory at the University of Oslo is focused on spectroscopy experiments for nuclear structure and nuclear astrophysics using the Oslo Scintillator Array OSCAR. Light-ion beams from the K=35 cyclotron are furthermore used for studies in radiation biology and medical physics, for research and development related to medical isotope production, and for irradiation of materials and electronics components. Here we present an overview of the laboratory and its research infrastructure, give a brief discussion of the respective research programs and methods, and present recent highlights.
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Asperud, Jonas; Arous, Delmon; Edin, Nina Frederike Jeppesen & Malinen, Eirik
(2021).
Spatially fractionated radiotherapy: Tumor response modelling including immunomodulation.
Physics in Medicine and Biology.
ISSN 0031-9155.
66(17).
doi:
10.1088/1361-6560/ac176b.
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Grigalavicius, Mantas; Mastrangelopoulou, Maria; Berg, Kristian; Arous, Delmon; Ménard, Mathilde & Henriksen-Raabe, Tine Therese
[Show all 12 contributors for this article]
(2019).
Proton-dynamic therapy following photosensitiser activation by accelerated protons demonstrated through fluorescence and singlet oxygen production.
Nature Communications.
10(1).
doi:
10.1038/s41467-019-12042-7.
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We demonstrate excitation of photosensitisers (PSs) by accelerated protons to produce fluorescence and singlet oxygen. Their fluorescence follows a pattern similar to the proton energy loss in matter, while proton-derived fluorescence spectra match the photon-induced spectra. PSs excited in dry gelatin exhibit enhanced phosphorescence, suggesting an efficient PSs triplet state population. Singlet oxygen measurements, both optically at ~1270 nm and through the photoproduct of protoporphyrin IX (PpIX), demonstrate cytotoxic singlet oxygen generation by proton excitation. The singlet oxygen-specific scavenger 1,4-diazabicyclo[2.2.2]octane (DABCO) abrogates the photoproduct formation under proton excitation, but cannot countermand the overall loss of PpIX fluorescence. Furthermore, in two cell lines, M059K and T98G, we observe differential cell death upon the addition of the PS cercosporin, while in U87 cells we see no effect at any proton irradiation dose. Our results pave the way for a novel treatment combining proton therapy and “proton-dynamic therapy” for more efficient tumour eradication.
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Printzell, Lisa; Reseland, Janne Elin; Edin, Nina Frederike J & Ellingsen, Jan Eirik
(2019).
Effects of ionizing irradiation and interface backscatter on human mesenchymal stem cells cultured on titanium surfaces.
European Journal of Oral Sciences.
ISSN 0909-8836.
127(6),
p. 500–507.
doi:
10.1111/eos.12654.
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Radiotherapy to the head and neck region negatively influences the osseointegration and survival of dental implants. The effects of cobalt 60 (60Co) ionizing radiation and the impact of backscatter rays were investigated on human mesenchymal stem cells cultured on titanium surfaces. Bone marrow‐derived human mesenchymal stem cells were seeded on titanium (Ti), fluoride‐modified titanium (TiF), and tissue culture plastic. Cells were exposed to ionizing γ ‐radiation in single doses of 2, 6, or 10 Gy using a 60Co source. Density and distribution of cells were evaluated using confocal laser‐scanning microscopy, 21 d post‐irradiation. Lactate dehydrogenase concentration and the levels of total protein and cytokines/chemokines were measured in the cell‐culture medium on days 1, 3, 7, 14, and 21 post‐irradiation. Unirradiated cells were used as the control. Irradiation had no effect on cell viability, collagen and actin expression, or cell distribution, but induced an initial increase in the secretion of interleukin (IL )‐6, IL ‐8, monocyte chemotactic protein 1 (MCP ‐1), and vascular endothelial growth factor (VEGF ), followed by a decrease in secretion after 3 or 7 d. Irradiation resulted in secretion of a lower amount of all analytes examined compared with controls on day 21, irrespective of radiation dose and growth surface. Backscattering from titanium did not influence the cell response significantly, suggesting a clinical potential for achieving successful osseointegration of dental implants placed before radiotherapy.
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Bousquet, Paula; Sandvik, Joe Alexander; Edin, Nina Frederike J & Krengel, Ute
(2018).
Hypothesis: Hypoxia induces de novo synthesis of NeuGc gangliosides in humans through CMAH domain substitute.
Biochemical and Biophysical Research Communications - BBRC.
ISSN 0006-291X.
495(1),
p. 1562–1566.
doi:
10.1016/j.bbrc.2017.11.183.
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Immunotherapy is a growing field in cancer research. A privileged tumor-associated antigen that has received much attention is N-glycolyl (NeuGc) GM3. This ganglioside is present in several types of cancer, but is almost undetectable in human healthy tissues. However, its non-hydroxylated variant, NeuAc GM3, is abundant in all mammals. Due to a deletion in the human gene encoding the key enzyme for synthesis of NeuGc, humans, in contrast to other mammals, cannot synthesize NeuGc GM3. Therefore the presence of this ganglioside in human cancer cells represents an enigma. It has been shown that hypoxic conditions trigger the expression of NeuGc gangliosides, which not only serve as attractive targets for cancer therapy, but also as diagnostic and prognostic tumor marker. Here, we confirm hypoxia-induced expression of the NeuGc GM3 ganglioside also in HeLa cells and reveal several candidate proteins, in particular GM3 synthase and subunit B of respiratory complex II (SDHB), that may be involved in the generation of NeuGc GM3 by SILAC-based proteome analysis. These findings have the potential to significantly advance our understanding of how this enigmatic tumor-associated antigen is produced in humans, and also suggest a possible mechanism of action of anti-tumor antibodies that recognize hypoxia markers, such as 14F7.
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Mikalsen, Stine Gyland; Edin, Nina Frederike J; Sandvik, Joe Alexander & Pettersen, Erik O
(2018).
Separation of two sub-groups
with different DNA content after
treatment of T-47D breast cancer
cells with low dose-rate irradiation
and intermittent hypoxia.
Acta Radiologica.
ISSN 0284-1851.
59(1),
p. 26–33.
doi:
10.1177/0284185117699999.
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Edin, Nina Frederike J; Altaner, Čestmír; Altanerova, Veronica; Ebbesen, Peter & Pettersen, Erik O
(2016).
Low-Dose-Rate Irradiation for 1 Hour Induces Protection Against Lethal Radiation Doses but Does Not Affect Life Span of DBA/2 Mice.
Dose-Response.
14(4).
doi:
10.1177/1559325816673901.
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Edin, Nina Frederike J; Christoffersen, Stine; Fenne, Siri; Sandvik, Joe Alexander & Pettersen, Erik O
(2015).
Cell inactivation by combined low dose-rate irradiation and intermittent hypoxia.
International Journal of Radiation Biology.
ISSN 0955-3002.
91(4),
p. 336–345.
doi:
10.3109/09553002.2014.996262.
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Edin, Nina Frederike J; Sandvik, Joe Alexander; Chang, Cheng; Bergersen, Linda Hildegard & Pettersen, Erik O
(2014).
The roles of TGF-β3 and peroxynitrite in removal of hyper-radiosensitivity by priming irradiation.
International Journal of Radiation Biology.
ISSN 0955-3002.
90(7),
p. 527–537.
doi:
10.3109/09553002.2014.906767.
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Edin, Nina Frederike J
(2014).
The role of interleukin-13 in the removal of hyper-radiosensitivity by priming irradiation.
Journal of radiation research.
ISSN 0449-3060.
55(6),
p. 1066–1074.
doi:
10.1093/jrr/rru053.
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It has previously been demonstrated that the presence of fetal bovine serum is necessary for TGF-β3 (transforming growth factor beta 3)-dependent elimination of low-dose hyper-radiosensitivity (HRS) in cells by 1 h of low-dose-rate γ-irradiation (0.2–0.3 Gy/h). The purpose of the present study was to identify the serum constituent involved. Two human HRS-positive (T-47D, T98G) cell lines were used. The effects of different pretreatments on HRS were investigated using the colony assay. Total inducible nitric oxide synthase (iNOS) levels were measured using a cell-based ELISA assay. The serum factor was identified as interleukin-13 (IL-13). In order for low dose-rate irradiation to eliminate HRS through the TGF-β3-dependent mechanism, the cells must be exposed to IL-13 first. Inhibiting receptor IL-13Rα2 showed that this receptor is involved in the response. Adding IL-13 to serum-free medium restored the properties of full medium but not when an inhibitor of proprotein convertase activity was added together with IL-13. The presence of IL-13 resulted in upregulation of total iNOS protein levels. Thus, this study indicates that IL-13 interacts with the cells though receptor IL-13Rα2 and induces upregulation of iNOS and activation of one or more furin-like proprotein convertases.
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Edin, Nina Frederike J; Sandvik, Joe Alexander; Vollan, Hilde Synnøve; Reger, Katharina; Görlach, Agnes & Pettersen, Erik O
(2013).
The role of nitric oxide radicals in removal of hyper-radiosensitivity by priming irradiation.
Journal of radiation research.
ISSN 0449-3060.
54(6),
p. 1015–1028.
doi:
10.1093/jrr/rrt061.
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Edin, Nina Frederike J; Olsen, Dag Rune; Sandvik, Joe Alexander; Malinen, Eirik & Pettersen, Erik O
(2012).
Low dose hyper-radiosensitivity is eliminated during exposure to cycling hypoxia but returns after reoxygenation.
International Journal of Radiation Biology.
ISSN 0955-3002.
88(4),
p. 311–319.
doi:
10.3109/09553002.2012.646046.
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View all works in NVA
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Edin, Nina Frederike Jeppesen
(2025).
DIFFERENTIAL INFLAMMATORY RESPONSE AND TISSUE DAMAGE IN MOUSE HEAD AND NECK FOLLOWING PROTON VERSUS X-RAY RADIOTHERAPY.
Full text in Research Archive
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Edin, Nina Frederike Jeppesen
(2025).
In vitro measurements of relative biological effectiveness of proton radiation with different LETd values for survival and double strand breaks.
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Rykkelid, Anne Marit; Sinha, Priyanshu Manojkumar; Folefac, Charlemagne Asonganyi; Horsman, Michael R.; Sørensen, Brita Singers & Søland, Tine Merete
[Show all 9 contributors for this article]
(2024).
Correction to: Combination of proton- or X-irradiation with anti-PDL1 immunotherapy in two murine oral cancers (Scientific Reports, (2024), 14, 1, (11569), 10.1038/s41598-024-62272-z).
Scientific Reports.
14(1).
doi:
10.1038/s41598-024-66148-0.
Full text in Research Archive
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Edin, Nina Frederike Jeppesen
(2024).
Proton irradiation of the head and neck induced more severe
side effects than X-rays, but only X-rays induced an inflammatory cytokine response in saliva.
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Hanson, Ingunn; Pitman, Kathinka Elinor & Edin, Nina Frederike Jeppesen
(2024).
Mechanisms of TGF- β3 induced modulation of low dose hyperradiosensitivity.
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Pitman, Kathinka Elinor; Hanson, Ingunn & Edin, Nina Frederike Jeppesen
(2024).
Mechanisms of TGFb3 induced modulation of low dose hyper-radiosensitivity.
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Edin, Nina Frederike Jeppesen
(2023).
Normal tissue responses in a murine model following fractionated irradiation of the head and neck with protons or X-rays.
Full text in Research Archive
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Edin, Nina Frederike Jeppesen
(2023).
The role of the immune system in radiation responses - are protons better than photons in inducing immunogenic signals?
Full text in Research Archive
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Hanson, Ingunn; Juvkam, Inga; Zlygosteva, Olga & Edin, Nina Frederike Jeppesen
(2023).
TGF-β3 increases the severity of radiation-induced oral mucositis and salivary gland fibrosis in a mouse model.
Full text in Research Archive
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Hanson, Ingunn; Juvkam, Inga; Zlygosteva, Olga & Edin, Nina Frederike Jeppesen
(2023).
TGF-β3 increases the severity of radiation-induced oral mucositis and salivary gland fibrosis in a mouse model.
Full text in Research Archive
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Hanson, Ingunn & Edin, Nina Frederike Jeppesen
(2022).
Shielding of the Femur Reduces the Severity of the Gastrointestinal Subsyndrome of ARS and Increases Survival in Mice.
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Hanson, Ingunn & Edin, Nina Frederike Jeppesen
(2022).
Shielding of the femur reduces the severity of the gastrointestinal subsyndrome of ARS and increases survival in mice.
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Edin, Nina Frederike Jeppesen
(2022).
PROCCA: Late effects after radiotherapy of the head and neck - from cells to persons.
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Nattudurai, Ravikumar; Arous, Delmon; Edin, Nina Frederike Jeppesen; Pandey, Anant & Malinen, Eirik
(2022).
Investigation of BaSO4:Eu nanophosphors for thermoluminescence dosimetry of X-ray and proton beams.
Radiotherapy and Oncology.
ISSN 0167-8140.
170,
p. S1356–S1356.
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Bousquet, Paula; Sandvik, Joe Alexander; Edin, Nina Frederike Jeppesen & Krengel, Ute
(2022).
Corrigendum to: Hypothesis: Hypoxia induces de novo synthesis of NeuGc gangliosides in humans through CMAH domain substitute (Biochemical and Biophysical Research Communications (2018) 495(1) (1562–1566), (S0006291X17323616), (10.1016/j.bbrc.2017.11.183)).
Biochemical and Biophysical Research Communications - BBRC.
ISSN 0006-291X.
587,
p. 166–166.
doi:
10.1016/j.bbrc.2021.11.074.
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Rykkelid, Anne Marit; Sørensen, Brita Singers; Horsman, Michael; Malinen, Eirik & Edin, Nina Frederike Jeppesen
(2022).
Effect of the Combination of Proton Radiotherapy and Immunotherapy on the MOC1/MOC2 tumor models in C57B16/Jrj mice.
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Nattudurai, Ravikumar; Arous, Delmon; Edin, Nina Frederike Jeppesen; Pandey, Anant & Malinen, Eirik
(2022).
Dosimetric characterization of BaSO4 phosphors activated by Eu for proton, gamma and X-ray beams.
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Grigalavicius, Mantas; Mastrangelopoulou, Maria; Berg, K.; Arous, Delmon; Ménard, M. & Raabe-Henriksen, T.
[Show all 12 contributors for this article]
(2021).
Publisher Correction: Proton-dynamic therapy following photosensitiser activation by accelerated protons demonstrated through fluorescence and singlet oxygen production (Nature Communications, (2019), 10, 1, (3986), 10.1038/s41467-019-12042-7).
Nature Communications.
12(1).
doi:
10.1038/s41467-021-27175-x.
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Nattudurai, Ravikumar; Arous, Delmon; Edin, Nina Frederike Jeppesen & Malinen, Eirik
(2021).
Estimating linear energy transfer in proton beams using alanine/EPR dosimetry.
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Nattudurai, Ravikumar; Arous, Delmon; Edin, Nina Frederike Jeppesen & Malinen, Eirik
(2021).
Alanine dosimeters for determining linear energy transfer in proton beams.
Radiotherapy and Oncology.
ISSN 0167-8140.
161,
p. 229–229.
Full text in Research Archive
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Hanson, Ingunn; Pitman, Kathinka Elinor; Thiede, Bernd; Cai, Yiqing & Edin, Nina Frederike Jeppesen
(2021).
Proteomic Analysis of Low Dose-Rate Primed Cells and Extracellular Exosomes.
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Hanson, Ingunn; Edin, Nina Frederike J; Thiede, Bernd & Altanerova, Ursula
(2020).
Communication of radioprotective efects by TGF-β3.
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Edin, Nina Frederike Jeppesen
(2020).
Increased immunogenic calreticulin signaling at the distal end of the proton Bragg peak.
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Hanson, Ingunn; Altanerova, Ursula; Thiede, Bernd & Edin, Nina Frederike J
(2020).
Radioprotector TGF-β3 is secreted in exosomes and activated by LDR priming.
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The biological effects of ionizing radiation in the low-dose region is important for diagnostic imaging, healthy tissue in radiation therapy and environmental radiation. For a majority of tested cell lines, the low dose hyper-radiosensitive (HRS) response has been shown to be default. We have previously shown that cells primed with a low dose-rate (⁓0.3 Gy/h) ionizing radiation permanently loses the HRS response. We have also shown that the transforming growth factor (TGF)-β3 is responsible for this effect. Here, we investigated the secretion mechanism of TGF-β3 from LDR primed cells, and theorize regarding the way it is activated.
Exosomes were isolated from LDR primed cells, and were shown to remove HRS in reporter cells when co-cultured with these. Adding a TGF-β3 inhibitor to the medium restored the HRS response in reporter cells, confirming that TGF-β3 was the factor in the exosomes responsible for removing HRS. Mass spectrometry was performed on the content of exosomes from primed and control cells. Proteomic analysis confirmed the presence of exosome-specific proteins in exosomes from primed and control groups. TGF-β3 along with latency-associated protein (LAP), the protein that TGF-β3 is bound to in its inactive form, was present in similar amounts in both groups, indicating that TGF-β3 was secreted in its inactive form, regardless of LDR priming. Three proteins were significantly upregulated in the primed exosomes. These proteins will be investigated further in future experiments.
We conclude that TGF-β3 is secreted in its inactive form in exosomes from LDR primed and unprimed cells, and that the priming is responsible for its activation. We will further investigate three significantly upregulated proteins with regards to their role in the activation of TGF-β3.
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Rykkelid, Anne Marit; Siem, Sunniva; Ytre-Hauge, Kristian; Malinen, Eirik & Edin, Nina Frederike J
(2018).
Very high relative biological effectiveness found at the distal end of the proton Bragg peak.
Radiotherapy and Oncology.
ISSN 0167-8140.
127,
p. 1259–1259.
Full text in Research Archive
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Dahle, Tordis Johnsen; Rykkelid, Anne Marit; Stokkevåg, Camilla Hanquist; Görgen, Andreas; Edin, Nina Frederike J & Malinen, Eirik
[Show all 7 contributors for this article]
(2017).
Monte Carlo simulations of a low-energy proton beam and estimation of LET distributions.
Radiotherapy and Oncology.
ISSN 0167-8140.
123,
p. 179–180.
Full text in Research Archive
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Hole, Eli Olaug; Edin, Nina Frederike J; Malinen, Eirik; Pettersen, Erik O & Sagstuen, Einar
(2017).
Biophysics and medical physics at UiO: Research and education. An incomplete overview.
Full text in Research Archive
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Frettem, Åshild Kvammen; Edin, Nina Frederike J; Galtung, Hilde & Søland, Tine Merete
(2016).
Tumour associated Aquaporin-3 and hypoxia in an oral squamous cell carcinoma cell line.
Full text in Research Archive
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Edin, Nina Frederike J; altaner, cestmir; Altanerova, Veronica & Ebbesen, Peter
(2014).
TGF-3 IN PROTECTION AGAINST RADIATION DAMAGE.
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Christoffersen, Stine; Sandvik, Joe Alexander; Pettersen, Erik O & Edin, Nina Frederike J
(2012).
Cell respiration, hypoxia and low dose rate radiation.
Full text in Research Archive
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Edin, Nina Frederike J & Ebbesen, Peter
(2012).
Effect of small doses whole-body γ-radiation given at low dose-rate to mice with normal micro-flora.
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Grødem, Edvard Olaf Sætersdal; Fjell, Anders Martin; Bjørnerud, Atle; MacIntosh, Bradley & Edin, Nina Frederike Jeppesen
(2025).
Characterizing Brain MRI with Machine Learning Methods with Applications to Alzheimer’s Disease.
Universitetet i Oslo.
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The human brain undergoes lifelong structural changes that reflect both normal aging and pathological processes. Alzheimer’s disease (AD) is neurodegenerative disorder that causes pronounced structural changes in the brain in the form of atrophy. In AD, patients’ cognitive function is permanently reduced, and treatment options are limited. Magnetic resonance imaging (MRI) makes it possible to observe these structural changes in vivo. Over the past twenty years, large open imaging databases (e.g., the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and UK Biobank) have enabled studies involving tens of thousands of participants. At the same time, there have been major advances in machine-learning methods, for example in deep learning, Bayesian statistics and image processing. Together, large databases and new machine-learning techniques open up deeper insights into the brain’s evolving anatomy.
Nevertheless, challenges remain. There is considerable inter-individual anatomical differences, and distinguishing natural variation from pathology can be difficult. The MRI data themselves present additional hurdles: the mages are large three-dimensional scans that must be processed to obtain measurable quantities such as regional volume and cortical thickness. Although the imaging databases are extensive, scans often originate from many different scanners, leading to contrast differences that complicate direct comparisons. In longitudinal studies, the morphological changes of interest are often smaller than the measurement noise. Consequently, new methods are needed to analyze changes in brain MRI reliably.
In this thesis, the aim is to develop and improve machine-learning methods for analyzing brain MRI. These methods are intended to quantify changes in brain structures, to characterize the brain’s Natural development across the lifespan and to diagnose AD. The work comprises three papers.
In Paper I we use deep learning to diagnose Alzheimer’s disease from brain MRI. We investigate how the architecture of the deep convolutional network influences the classification outcome. MRI scans of individuals with AD and healthy controls from ADNI serve as material. We find that more complex and deeper architectures such as EfficientNet do not outperform simpler and shallower architectures such as the Simple Fully Convolutional Network (SFCN). Further analyses show that SFCN can be scaled down to very small sizes while still providing strong results. These findings indicate that straightforward preprocessing combined with simple convolutional networks yields classification performance comparable to the more elaborate methods reported in the literature.
In Paper II we study volume changes of various brain structures across the lifespan. We aim to determine when there are individual changes in the brain due to normal aging and to what extent these can be estimated at the individual level. A large dataset of longitudinal brain MRI collected from 14 studies is employed. We model the volume of the brain structures as a stochastic dynamical system and fit the model to the data using a Markov chain Monte Carlo approach. The results show that the brain changes throughout life, but up to the age of 50 there are only small individual differences in the rate of change. After 50 years we observe greater individual variation. From the model we calculate the explained variance from the structure volume at age 18 to the volume later in life, finding that up to 60 years almost all variance is explained by the young-adult volume. The lateral ventricles stand out: here, individual variation in change persists throughout life. We further estimate how accurately individual change can be inferred for single subjects. For individuals under 50 years there is virtually no correlation between an estimated change and the actual individualchange; after 50 years this correlation increases with age. Increasing the interval between volume measurements effectively increases this correlation, whereas adding more measurements within a given interval has a smaller effect.
Paper III examines medical image-registration algorithms, in which a deformation field that aligns two images is estimated so that anatomically identical regions overlap. This can be used both to compare images across individuals and to study anatomical changes over time. Registration is often performed by minimising the image-similarity loss Local Normalised Cross-Correlation (LNCC). We show that using LNCC can lead to erroneous deformation estimates in homogeneous regions where noise dominates the signal. Two new variants are proposed: Regularized-LNCC (R-LNCC) and Weighted-LNCC (W-LNCC). We use real MRI from a wide range of scanners and generate synthetic deformations to test how well the similarity metrics recover them. LNCC produces incorrect deformation estimates in low-variance regions, whereas R-LNCC and W-LNCC resolve this issue. We also find that R-LNCC generally yields significantly better deformation estimates than LNCC, even in more heterogeneous regions.
Together, Papers I, II and III constitute a framework for studying changes in the brain. Our aim is that these tools will be utilized to better understand Alzheimer’s disease and promote healthy aging.
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Published
Nov. 4, 2010 12:13 PM
- Last modified
Apr. 27, 2022 9:11 AM
