Biology subjects

Soland, T. M.

Publications and source records attributed to Soland, T. M..

4 recordsLinked to original sources

bioRxiv2023

TGF-β3 increases the severity of radiation-induced oral mucositis and salivary gland fibrosis in a mouse model

PurposeToxicities 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-{beta}) family are key players in the fibrotic response. While TGF-{beta}1 is known to be pro-fibrotic, TGF-{beta}3 has mainly been considered anti-fibrotic. Moreover, TGF-{beta}3 has been shown to act protective against acute toxicities after radio- and chemotherapy. In the present study, we investigated the effect of TGF-{beta}3 treatment during fractionated H&N RT in a mouse model. Materials and methods30 C57BL/6J mice were assigned to three treatment groups. The RT + TGF-{beta}3 group received local fractionated H&N RT with 66 Gy over five days, combined with TGF-{beta}3-injections at 24-hour intervals. Animals in the RT reference group received identical RT without TGF-{beta}3 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 days after the first RT fraction. Submandibular and sublingual glands were preserved, sectioned, and stained with Massons trichrome to visualize collagen. ResultsA subset of mice in the RT + TGF-{beta}3 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-{beta}3 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-{beta}3 treatment did not impact saliva production. ConclusionsWhen repeatedly administered during fractionated RT at the current dose, TGF-{beta}3 treatment increased acute H&N radiation toxicities and increased mortality. Furthermore, TGF-{beta}3 treatment may increase the severity of radiation-induced salivary gland fibrosis.

biophysics↗

bioRxiv2023

Synergistic effects of combing proton- or X-irradiation with anti-PDL1 immunotherapy in two murine oral cancers

Background and purposeCombining radiation therapy with immunotherapy may be beneficial in treatment of head and neck cancer (HNC), but the combined effect may depend on tumor characteristics and the type of radiation. The purpose was to compare responses for two syngeneic tumor models in mice following X-ray or proton irradiation with or without immune checkpoint inhibition (ICI). Materials and methodsMOC1 and MOC2 tumors were inoculated in the right hind leg of each mouse (C57BL/6J, n=159). Single-dose irradiation with X-rays or protons and administration of anti-PDL1 started when the tumors reached 200 mm3. Doses of 5-30 Gy were given. Time-dependent tumor volume data were analyzed with a regression model yielding the growth rate {gamma} without irradiation and the reduction in growth rate per dose {eta}. Relative biological effectiveness (RBE) was calculated as the ratio of {eta} for X-rays to that of protons. Synergy between radiation and ICI was estimated as the ratio of {eta}s. ResultsMOC2 tumors grew faster and were more radioresistant than MOC1 tumors. ICI reduced the growth rate for MOC1 with 20{+/-}2% compared to controls, while no reduction was seen for MOC2. RBE for MOC1 wo/w ICI was 0.89{+/-}0.04 and 0.93{+/-}0.06, respectively, while it was 1.15{+/-}0.12 and 1.60{+/-}0.17, respectively, for MOC2. Combination synergy for X-rays was 1.22{+/-}0.08 and 0.96{+/-}0.11 in MOC1 and MOC2, respectively, while was it 1.27{+/-}0.06 and 1.33 {+/-}0.13, respectively, for protons. ConclusionsRBE for protons was dependent on use of ICI and tumor type. A greater synergy may be achieved when combining protons with ICI compared to X-rays and ICI.

cancer biology↗

bioRxiv2023

Fractionated irradiation of murine salivary glands resulted in focal acinar cell atrophy, immune cell infiltration, fibrosis, and hyposalivation

BackgroundRadiotherapy of head and neck cancer may cause detrimental late side effects such as fibrosis and hyposalivation. Our aim was to investigate late radiation-induced cellular and molecular changes of the salivary glands after fractionated irradiation to the head and neck in a murine model. Methods12-week-old female C57BL/6J 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. Salivary gland function was assessed by collecting saliva at baseline and at various time points after irradiation. The submandibular (SMG), sublingual (SLG), and parotid glands (PG) were dissected at day 105. Using different staining techniques, morphological, cellular, and molecular changes were investigated in the salivary glands. ResultsSaliva production was significantly reduced in irradiated compared to control mice at day 35, 80, and 105. We observed a significant decrease in total gland area and a significant increase in fibrotic area in irradiated compared to control SMG at day 105. Atrophy of acinar cells was observed in all irradiated SMG and SLG. Increased amount of chronic inflammatory cells, increased cell proliferation and altered expression of apoptotic markers were found in atrophic areas of irradiated glands. ConclusionAcinar and duct cells in irradiated salivary glands show increased cell proliferation and altered expression of apoptotic markers, proposing an attempt to overcome or withstand tissue damage caused by irradiation. This suggests a potential for regeneration of salivary glands after radiation therapy.

cell biology↗

bioRxiv2022

A Preclinical Model to Investigate Normal Tissue Damage Following Fractionated Radiotherapy to the Head and Neck

Radiotherapy of head and neck 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/6J 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 head and neck 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 what is observed in cancer patients.

cancer biology↗