| 1. |
- AHLSTEDT, JONATAN, et al.
(författare)
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Effect of Blockade of Indoleamine 2, 3-dioxygenase in Conjunction with Single Fraction Irradiation in Rat Glioma
- 2015
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Ingår i: Jacobs journal of radiation oncology. - 2376-9424. ; 2:3
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma (GBM), or WHO Astrocytoma grade IV, is the most common primary brain tumour in adults. GBM is shown to escape host immune surveillance through many paths, of which expression of indoleamine 2,3-dioxygenase (IDO), leading to induction and accumulation of regulatory T-cells in the tumour microenvironment, has been shown to be of importance. 1-Methyl tryptophan (1-MT) is an inhibitor of IDO that has been shown to have a positive effect on survival in experimental models of GBM. In this study, we evaluate the effect of combined single-fraction irradiation of 8 Gy with 1-MT treatment in Fischer rats carrying the RG2 glioma model. We also investigate expression of IDO in the RG2 model before and after irradiation. Thirty-three Fischer 344 rats received intracranial inoculations of RG2 tumour cells, and were treated with either intraperito-neal 1-MT, 8 Gy single-fraction radiotherapy, or a combination of the two. Survival in the combined treatment group (29 days ± 0.75) was significantly better than controls (20 ± 0.99, p=0.015) and radiation only (17 ± 2.75, p=0.014). Survival was also better with combined treatment compared to 1-MT only but the difference was non-significant (18 ± 0.28, p=0.215).Our results add to the growing base of evidence suggesting 1-methyl-tryptophan is an attractive candidate for clinical investi-gation in patients carrying highly malignant astrocytoma, especially in combination with radiation treatment, even in singular fraction settings.
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| 2. |
- Ahlstedt, Jonatan, et al.
(författare)
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Evaluating vacquinol-1 in rats carrying glioblastoma models RG2 and NS1
- 2018
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 9:9, s. 8391-8399
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor, and available experimental and routine therapies result in limited survival benefits. A vulnerability of GBM cells to catastrophic vacuolization and cell death, a process termed methuosis, induced by Vacquinol-1 (VQ-1) has been described earlier. In the present study, we investigate the efficacy of VQ-1 treatment in two syngeneic rat GBM models, RG2 and NS1. VQ-1 treatment affected growth of both RG2 and NS1 cells in vitro. Intracranially, significant reduction in RG2 tumor size was observed, although no effect was seen on overall survival. No survival advantage or effect on tumor size was seen in animals carrying the NS1 models compared to untreated controls. Furthermore, immunological staining of FOXP3, CD4 and CD8 showed no marked difference in immune cell infiltrate in tumor environment following treatment. Taken together, a survival advantage of VQ-1 treatment alone could not be demonstrated here, even though some effect upon tumor size was seen. Staining for immune cell markers did not indicate that VQ-1 either reduced or increased host anti-tumor immune response.
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| 3. |
- Ahlstedt, Jonatan, et al.
(författare)
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Growth pattern of experimental glioblastoma
- 2020
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Ingår i: Histology and Histopathology. - 1699-5848. ; 35:8, s. 871-886
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma multiforme (GBM) is an aggressive primary brain malignancy with a very poor prognosis. Researchers employ animal models to develop potential therapies. It is important that these models have clinical relevance. This means that old models, propagated for decades in cultures, should be questioned. Parameters to be evaluated include whether animals are immune competent or not, the infiltrative growth pattern of the tumor, tumor volume resulting in symptoms and growth rate.We here describe the growth pattern of an experimental glioblastoma model in detail with GFP positive glioblastoma cells in fully immune competent animalsand study tumor growth rate and tumor mass as a function of time from inoculation.We were able to correlate findings made with classical immunohistochemistry and MR findings. The tumor growth rate was fitted by a Gompertz function. The model predicted the time until onset of symptoms for 5000 inoculated cells to 18.7±0.4 days, and the tumor mass at days 10 and 14, which are commonly used as the start of treatment in therapeutic studies, were 5.97±0.62 mg and 29.1±3.0 mg, respectively.We want to raise the question regarding the clinical relevance of the outline of glioblastoma experiments, where treatment is ofteninitiated at a very early stage. The approach presented here could potentially be modified to gain information also from other tumor models.
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| 4. |
- Förnvik, Karolina, et al.
(författare)
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Anti-C1-inactivator treatment of glioblastoma
- 2018
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 9:100, s. 37421-37428
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Glioblastoma multiforme (GBM) or astrocytoma grade IV is the most common type of primary brain tumor in adults. In the present study, we investigate the role of the complement system in the glioblastoma situation in an experimental model, since we have previously been able to show a blockade of this system in the glioblastoma setting. Technique and results: A GFP-positive glioblastoma cell line was used to induce glioblastomas subcutaneously in rats (n=42). Antibodies against C1-Inactivator (C1-IA) were used to try to re-activate the complement system. We were able to demonstrate an increased survival in rats treated with anti-C1-IA with an intratumoral route, and we could establish the same the results in a second series. Serum analyses revealed decreased levels of IL-1b and GM-CSF in animals 24 days after tumor cell inoculation in the anti-C1-IA group when compared to controls. Immunohistochemistry revealed decreased expression of C1-IA following treatment. Interpretation: These results are in line with our previous work showing an upregulation of C1-IA, which is able to block the classical complement pathway, in glioblastomas. Treatment with antibodies against C1-IA seems to be beneficial in the glioblastoma situation, and no side effects could be seen in our experiments.
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| 5. |
- Förnvik, Karolina, et al.
(författare)
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C1-inactivator is upregulated in glioblastoma
- 2017
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Glioblastoma is the most common and aggressive type of primary brain tumor in adults. A key problem is the capacity of glioma cells to inactivate the body’s immune response. The complement system acts as a functional bridge between the innate and adaptive immune response. Still, the role of the complement system has almost been forgotten in glioma research. In our present study, we hypothesize that C1 inactivator (C1-IA) is upregulated in astrocytoma grade IV, and that its inhibition of the complement system has beneficial effects upon survival. Methods and results: We have explored this hypothesis both on gene and protein levels and found an upregulation of C1-IA in human glioblastoma cells using data from a publicly available database and our own mRNA material from glioblastoma patients. Furthermore, we demonstrated the presence of C1-IA by using immunohistochemistry on glioma cells from both humans and rats in vitro. Finally, we could demonstrate a significantly increased survival in vivo in animals inoculated intracerebrally with glioma cells pre-coated with C1-IA antibodies as compared to control animals. Conclusions: Our findings indicate that overexpression of C1-IA is present in glioblastomas. This could be demonstrated both at the gene level from patients with glioblastoma, on mRNA level and with immunohistochemistry. Treatment with antibodies against C1-IA had beneficial effects on survival when tested in vivo.
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| 6. |
- Förnvik, Karolina, et al.
(författare)
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ITPP treatment of RG2 glioblastoma in a rat model
- 2016
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Ingår i: Anticancer research. - : Anticancer Research USA Inc.. - 0250-7005 .- 1791-7530. ; 36:11, s. 5751-5755
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Tidskriftsartikel (refereegranskat)abstract
- Background: Inositol trispyrophosphate (ITPP) has been shown to reduce tumour growth in different animal cancer models, as well as of human U87 glioma cells grafted onto chick chorioallantoic membrane (CAM). The aim of this study was to establish whether ITPP crosses the blood-brain barrier and whether it halts the growth of RG2 glioblastoma tumour. Materials and Methods: A model comprising of Fischer 344 rats was chosen and RG2 cells were implanted either intracranially, or subcutaneously on the left hind leg, and the animals were treated with ITPP either intraperitoneally, intravenously or both routes combined. Overall survival was then calculated. Results: No prolonged survival was seen in animals treated with ITPP. The route of ITPP administration did not affect outcome. Conclusion: ITPP had no favourable effect upon survival in our animal model with RG2 glioblastoma tumours in Fischer 344 rats.
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| 7. |
- Förnvik, Karolina
(författare)
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Novel treatments of glioblastoma in experimental models
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- One of the major problems with malignant brain tumours, such as glioblastoma multiforme, is that despite being able to remove the major bulk of the tumour through surgery and treating the patients with chemotherapy and radiotherapy, we know that tumour cells have already spread throughout the brain. Furthermore, we now know that the glioblastoma cells effectively suppress the patients’ own anti-tumour response. One key part of the immune response, the complement system, acts as a functional bridge between innate and adaptive immunity. Here we wanted to further investigate the complement system in both glioblastoma patients and in laboratory animals by looking at the role of CRP and C1-inhibitor (C1-INH). In order not to rely solely on old glioblastoma models, which have been passed in vitro for decades, we also developed a new glioblastoma model.Initially we studied an experimental treatment, ITPP, which had previously shown promising results in other cancer models. This was done using the old glioblastoma model RG2. Subsequently we went on to develop a new GFPpositive glioblastoma model called NS1. The NS1 cell line was then used to further investigate the role of the complement system, both in vitro and in vivo, by treating the cells and animals with anti-C1-INH and anti-CRP. The in vivo experiments involved intratumoral treatment of both intracranial and subcutaneous tumours. Additionally, tumour material from glioblastoma patients was examined on the gene and protein level and compared to tumour data available from public databases.Treatment with ITPP showed no survival advantage in the RG2 model, and the route of ITPP administration did not affect outcome. The NS1 model turned out to generate infiltrative CNS tumours with perivascular growth and characteristics of a glioblastoma upon histopathological examination. With MRI tumour could easily be detected within 14 days after inoculation. We could demonstrate a significantly increased survival in vivo in animals inoculated intracerebrally with NS1 glioblastoma cells pre-coated with anti-C1-INH antibodies. On the contrary no effect of coating glioblastoma cells with anti-CRP antibodies prior to intracranial inoculation was seen. In the subcutaneous NS1 tumour model, intratumoral anti-C1-INH treatment showed a significant survival advantage andthere was a significant decrease in tumour size over time following treatment with anti-C1-INH. Using data fram a publicly available database and our own mRNA material from glioblastoma patients, we found an upregulation ofC1-INH in human glioblastoma cells. Furthermore, by using immunohistochemistry, we could demonstrate the presence of both C1-INH and CRP on glioma cells in vitro from humans and rats.We could conclude that C1-INH seems to play an important role in glioblastoma. This could possibly be explained by effects on the complement system, but also other effects are possible, since C1-INH has many biological functions. The exact role and mechanisms of anti-C1-INH treatment are topics for future studies.
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| 8. |
- Förnvik, Karolina, et al.
(författare)
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What is the role of CRP in glioblastoma?
- 2021
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Ingår i: Cancer Treatment and Research Communications. - : Elsevier BV. - 2468-2942. ; 26
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Tidskriftsartikel (refereegranskat)abstract
- Background: Glioblastoma is the most common primary malignant brain tumor in adults. Previous studies have suggested that CRP (C-reactive protein) could serve as a biomarker candidate as well as a prognostic factor in glioblastoma patients, and we here further investigate its potential role. Materials and methods: Publicly available datasets were used to compare gene expression between brain samples from glioblastoma patients and non-tumor tissue. The structure of CRP was compared between humans and rats. Glioblastoma cells from humans and rats were stained with anti-CRP. Fischer 344 rats were inoculated with syngeneic glioblastoma cells pre-coated with anti-CRP, and survival was monitored. CRP concentration in rats carrying glioblastoma was followed. Results: CRP was upregulated on one locus on gene level in glioblastoma tissue as compared to non-tumor brain tissue, but not in glioma stem cells as compared to neural stem cells. The structure of the CRP protein was a characteristic pentamer in both humans and rats. Both human and rat glioblastoma cells were clearly positive for anti-CRP staining. Pre-coating of glioblastoma cells with anti-CRP antibodies did not affect survival in rats with intracranial tumors. Serum levels of CRP increased during tumor progression but did not reach significantly different levels. Conclusions: Both human and rat glioblastoma cells could be stained with anti-CRP antibodies in vitro. In a syngeneic glioblastoma rat model we could see an increase in serum CRP during tumor progression, but coating glioblastoma cells with anti-CRP antibodies did not provide any survival change for the animals.
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| 9. |
- Liljedahl, Emma, et al.
(författare)
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Combined anti-C1-INH and radiotherapy against glioblastoma
- 2023
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: A more effective immune response against glioblastoma is needed in order to achieve better tumor control. Radiotherapy can induce anti-tumor mediated immune reactions, in addition to its dose response effects. The complement system can function as a bridge between innate and adaptive immune responses. Combining radiotherapy and complement activating therapy is theoretically interesting. Methods: Radiotherapy at 8 Gy × 2 was combined with treatment against C1-inhibitor (C1-INH), a potent inhibitor of activation of the classical pathway of the complement system. Anti-C1-INH was delivered as intratumoral injections. Fully immunocompetent Fischer 344 rats with NS1 glioblastoma tumors were treated. Survival was monitored as primary outcome. Models with either intracranial or subcutaneous tumors were evaluated separately. Results: In the intracranial setting, irradiation could prolong survival, but there was no additional survival gain as a result of anti-C1-INH treatment. In animals with subcutaneous tumors, combined radio-immunotherapy with anti-C1-INH and irradiation at 8 Gy × 2 significantly prolonged survival compared to control animals, whereas irradiation or anti-C1-INH treatment as single therapies did not lead to significantly increased survival compared to control animals. Conclusions: Anti-C1-INH treatment could improve the efficacy of irradiation delivered at sub-therapeutic doses and delay tumor growth in the subcutaneous tumor microenvironment. In the intracranial setting, the doses of anti-C1-INH were not enough to achieve any survival effect in the present setting.
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| 10. |
- Liljedahl, Emma, et al.
(författare)
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Long-term anti-tumor effects following both conventional radiotherapy and FLASH in fully immunocompetent animals with glioblastoma
- 2022
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1, s. 12285-12285
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Tidskriftsartikel (refereegranskat)abstract
- Radiotherapy can induce an immunological response. One limiting factor is side effects on normal tissue. Using FLASH radiotherapy, side effects could possibly be reduced. The efficacy of FLASH in relation to conventional radiotherapy (CONV-RT) has not been extensively explored in fully immunocompetent animals. Fully immunocompetent Fischer 344 rats were inoculated with NS1 glioblastoma cells subcutaneously or intracranially. Radiotherapy was delivered with FLASH or CONV-RT at 8 Gy × 2 (subcutaneous tumors) and 12.5 Gy × 2 (intracranial tumors). Cured animals were re-challenged in order to explore long-term anti-tumor immunity. Serum analytes and gene expression were explored. The majority of animals with subcutaneous tumors were cured when treated with FLASH or CONV-RT at 8 Gy × 2. Cured animals could reject tumor re-challenge. TIMP-1 in serum was reduced in animals treated with FLASH 8 Gy × 2 compared to control animals. Animals with intracranial tumors survived longer when treated with FLASH or CONV-RT at 12.5 Gy × 2, but cure was not reached. CONV-RT and FLASH were equally effective in fully immunocompetent animals with glioblastoma. Radiotherapy was highly efficient in the subcutaneous setting, leading to cure and long-term immunity in the majority of the animals.
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