inguhans

• 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. Full text in Research Archive Show summary

  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.

• 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. Full text in Research Archive Show summary

  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.

• 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. Full text in Research Archive Show summary

  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.

• 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. Full text in Research Archive
• 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. Full text in Research Archive Show summary

  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.

• Sulheim, Einar; Hanson, Ingunn; Snipstad, Sofie; Vikedal, Krister; Mørch, Ýrr Asbjørg & Boucher, Yves [Show all 7 contributors for this article] (2021). Sonopermeation with nanoparticle-stabilized microbubbles reduces solid stress and improves nanomedicine delivery to tumors. Advanced therapeutics. 4(10). doi: 10.1002/adtp.202100147. Full text in Research Archive Show summary

  Drug delivery to tumors is challenging due to biological barriers obstructing effective delivery. Sonopermeation with ultrasound and microbubbles has been shown to improve therapeutic effect of many classes of drugs, but the underlying mechanism is not fully understood. In this study, two subcutaneous xenograft tumor models, that differed substantially in blood vessel density and stiffness, is treated with poly(alkyl cyanoacrylate) nanoparticles and nanoparticle-stabilized microbubbles combined with ultrasound. Improved nanoparticle accumulation and extracellular matrix (ECM) penetration is found. The stiffness and solid stress in the tumors are measured and it is discovered that sonopermeation can reduce the solid stress in both models, with the highest effect in the stiffest tumor model. This suggests that sonopermeation affects not only the blood vessel wall which has been described previously, but also the ECM to reduce solid stress and increase diffusion and transport of nanomedicines.

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• Hanson, Ingunn; Pitman, Kathinka Elinor & Edin, Nina Frederike Jeppesen (2024). Mechanisms of TGF- β3 induced modulation of low dose hyperradiosensitivity. Full text in Research Archive
• Pitman, Kathinka Elinor; Hanson, Ingunn & Edin, Nina Frederike Jeppesen (2024). Mechanisms of TGFb3 induced modulation of low dose hyper-radiosensitivity. Full text in Research Archive
• 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
• 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
• 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. Full text in Research Archive
• Hanson, Ingunn & Edin, Nina Frederike Jeppesen (2022). The role of TGF-β3 in modification of radiation response. Full text in Research Archive
• 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. Full text in Research Archive
• Hanson, Ingunn & Edin, Nina Frederike Jeppesen (2021). The role of TGF-B3 in modification of radiation response. Full text in Research Archive
• 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. Full text in Research Archive
• Hanson, Ingunn; Edin, Nina Frederike J; Thiede, Bernd & Altanerova, Ursula (2020). Communication of radioprotective efects by TGF-β3. Full text in Research Archive
• Hanson, Ingunn; Altanerova, Ursula; Thiede, Bernd & Edin, Nina Frederike J (2020). Radioprotector TGF-β3 is secreted in exosomes and activated by LDR priming. Full text in Research Archive Show summary

  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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