| 1. |
- Paul-Visse, Gesine, et al.
(author)
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The adult human brain harbors multipotent perivascular mesenchymal stem cells.
- 2012
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:4
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Journal article (peer-reviewed)abstract
- Blood vessels and adjacent cells form perivascular stem cell niches in adult tissues. In this perivascular niche, a stem cell with mesenchymal characteristics was recently identified in some adult somatic tissues. These cells are pericytes that line the microvasculature, express mesenchymal markers and differentiate into mesodermal lineages but might even have the capacity to generate tissue-specific cell types. Here, we isolated, purified and characterized a previously unrecognized progenitor population from two different regions in the adult human brain, the ventricular wall and the neocortex. We show that these cells co-express markers for mesenchymal stem cells and pericytes in vivo and in vitro, but do not express glial, neuronal progenitor, hematopoietic, endothelial or microglial markers in their native state. Furthermore, we demonstrate at a clonal level that these progenitors have true multilineage potential towards both, the mesodermal and neuroectodermal phenotype. They can be epigenetically induced in vitro into adipocytes, chondroblasts and osteoblasts but also into glial cells and immature neurons. This progenitor population exhibits long-term proliferation, karyotype stability and retention of phenotype and multipotency following extensive propagation. Thus, we provide evidence that the vascular niche in the adult human brain harbors a novel progenitor with multilineage capacity that appears to represent mesenchymal stem cells and is different from any previously described human neural stem cell. Future studies will elucidate whether these cells may play a role for disease or may represent a reservoir that can be exploited in efforts to repair the diseased human brain.
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| 2. |
- Badn, Wiaam, et al.
(author)
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Inhibition of Inducible Nitric Oxide Synthase Enhances Anti-tumour Immune Responses in Rats Immunized with IFN-gamma-Secreting Glioma Cells.
- 2007
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In: Scandinavian Journal of Immunology. - : Wiley. - 1365-3083 .- 0300-9475. ; 65:3, s. 289-297
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Journal article (peer-reviewed)abstract
- Interferon gamma (IFN-gamma) has successfully been used in immunotherapy of different experimental tumours. Mechanistically, IFN-gamma has extensive effects on the immune system including release of nitric oxide (NO) by upregulation of the inducible nitric oxide synthase (iNOS). NO has putative immunosuppressive effects but could also play a role in killing of tumour cells. Therefore, the aim of the present study was to clarify whether inhibition of iNOS in rats immunized with glioma cells (N32) producing IFN-gamma (N32-IFN-gamma), could enhance the anti-tumour immune response. Initially, both a selective iNOS, L-N-6-(I-Iminoethyl)-L-lysine (L-NIL), and non-selective, N-nitro-L-arginine methyl ester (L-NAME), inhibitor of NOS were tested in vitro. After polyclonal stimulation with LPS and SEA, both L-NIL and L-NAME enhanced proliferation and production of IFN-gamma from activated rat splenocytes and this effect was inversely correlated to the production of NO. However, L-NIL had a broader window of efficacy and a lower minimal effective dose. When rats were immunized with N32-IFN-gamma), and administered NOS inhibitors by intraperitoneal (i.p.) mini-osmotic pumps, only splenocytes of rats treated with L-NIL, but not L-NAME, displayed an enhanced proliferation and production of IFN-gamma when re-stimulated with N32 tumour cells. Based on these findings, L-NIL was administered concurrently with N32-IFN-gamma cells to rats with intracerebral (i.c.) tumours resulting in a prolonged survival. These results show that inhibition of iNOS can enhance an IFN-gamma-based immunotherapy of experimental i.c. tumours implying that NO released after immunization has mainly immunosuppressive net effects.
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| 3. |
- Badn, Wiaam, et al.
(author)
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Postimmunization with IFN-gamma-secreting glioma cells combined with the inducible nitric oxide synthase inhibitor mercaptoethylguanidine prolongs survival of rats with intracerebral tumors
- 2007
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In: Journal of Immunology. - 1550-6606. ; 179:6, s. 4231-4238
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Journal article (peer-reviewed)abstract
- High-grade gliomas are one of the most aggressive human tumors with <1% of patients surviving 5 years after surgery. Immunotherapy could offer a possibility to eradicate remnant tumor cells after conventional therapy. Experimental immunotherapy can induce partial cure of established intracerebral tumors in several rodent models. One reason for the limited therapeutic effects could be immunosuppression induced by both the growing tumor and the induced immune reaction. NO has been implicated in tumor-derived immune suppression in tumor-bearing hosts, and unspecific inhibitors of NO synthase have been shown to boost antitumor immunity. In this study, we show that the inducible NO synthase (iNOS)-specific inhibitor mercaptoethylguanidine (MEG) superiorly enhanced lymphocyte reactivity after polyclonal stimulation compared with the iNOS-specific inhibitor L-NIL and the unspecific NO synthase inhibitor L-NAME. Both iNOS inhibitors increased the number and proliferation of T cells but not of B cells. When combined during postimmunization with IFN-gamma-secreting N32 rat glioma cells of rats harboring intracerebral tumors, only MEG increased the cure rate. However, this was only achieved when MEG was administered after immunizations. These findings implicate that NO has both enhancing and suppressive effects after active immunotherapy.
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| 4. |
- Cederberg, David, et al.
(author)
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Prolonged and intense neuroinflammation after severe traumatic brain injury assessed by cerebral microdialysis with 300 kDa membranes
- 2023
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In: Journal of Neuroimmunology. - : Elsevier BV. - 0165-5728. ; 377
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Journal article (peer-reviewed)abstract
- Background: A neuroinflammatory response that may lead to edema and secondary brain damage is elicited in severe traumatic brain injury (TBI). Previous studies using microdialysis (MD) membranes with 100 k Dalton (kDa) cut-off found a transient intracerebral release of cytokines and chemokines without significant correlations to clinical course, intracranial pressure (ICP) or metabolites. In this study, a (300 kDa) MD probe was used to measure the levels of cytokines and chemokines in relation to ICP and metabolites. Methods: Seven patients with severe TBI received 2 MD catheters. In four patients sufficient dialysate could be retrieved for analysis from both catheters. MD samples were analyzed bedside, then frozen and analyzed for chemokines and cytokines using a multiplex assay (Mesoscale Discovery). Results: MD sampling was performed from 9 to 350 h. In total, 17 chemokines and cytokines were detected. Of these, IL-6, IL-8, IP-10, MCP-1 and MIP-1β were consistently elevated, and investigated further in relation to metabolites, and ICP. Levels of chemokines and cytokines were higher than previously reported from TBI patients, and partially higher than those reported in patients with cytokine release syndrome. There were no significant differences between the two catheters regarding cytokine/chemokine concentrations, except for IL-6 which was higher in the peri-contusional area. No correlation with metabolites and ICP was observed. No significant increase or decline of chemokine or cytokine secretion was observed during the study period. Conclusion: Our data suggest that cytokine and chemokine levels reflect a perpetual, potent and pan-cerebebral inflammatory response that persists beyond 15 days following TBI.
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| 5. |
- Eberstål, Sofia, et al.
(author)
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Immunizations with unmodified tumor cells and simultaneous COX-2 inhibition eradicate malignant rat brain tumors and induce a long-lasting CD8(+) T cell memory.
- 2014
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In: Journal of Neuroimmunology. - : Elsevier BV. - 1872-8421 .- 0165-5728. ; 274:1-2, s. 161-167
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Journal article (peer-reviewed)abstract
- Malignant brain tumors induce pronounced immunosuppression, which diminishes immune responses generated by immunotherapy. Here we report that peripheral immunotherapy, using irradiated unmodified whole tumor cells, and systemic cyclooxygenase-2 inhibition induce cure in glioma-bearing rats (60% cure rate), whereas neither monotherapy was sufficient to cure any animal. Moreover, the combined therapy protected against secondary tumor challenges (89% cure rate) and the secondary immune response was correlated with increased plasma interferon-gamma levels and CD8(+) T cells systemically and intratumorally. In conclusion, we demonstrate that cyclooxygenase-2 inhibition is sufficient to render unmodified tumor cells immunogenic in immunotherapy of experimental brain tumors.
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| 6. |
- Eberstål, Sofia, et al.
(author)
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Inhibition of cyclooxygenase-2 enhances immunotherapy against experimental brain tumors.
- 2012
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In: Cancer immunology, immunotherapy. - : Springer Science and Business Media LLC. - 1432-0851 .- 0340-7004. ; 61:8, s. 1191-1199
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Journal article (peer-reviewed)abstract
- Glioblastoma multiforme is the most common and aggressive malignant brain tumor in humans, and the prognosis is very poor despite conventional therapy. Immunotherapy represents a novel treatment approach, but the effect is often weakened by release of immune-suppressive molecules such as prostaglandins. In the current study, we investigated the effect of immunotherapy with irradiated interferon-γ (IFN-γ)-secreting tumor cells and administration of the selective cyclooxygease-2 (COX-2) inhibitor parecoxib as treatment of established rat brain tumors. COX-2 inhibition and immunotherapy significantly enhanced the long-term cure rate (81% survival) compared with immunotherapy alone (19% survival), and there was a significant increase in plasma IFN-γ levels in animals treated with the combined therapy, suggesting a systemic T helper 1 immune response. COX-2 inhibition alone, however, did neither induce cure nor prolonged survival. The tumor cells were identified as the major source of COX-2 both in vivo and in vitro, and unmodified tumor cells produced prostaglandin E(2) in vitro, while the IFN-γ expressing tumor cells secreted significantly lower levels. In conclusion, we show that immunotherapy of experimental brain tumors is greatly potentiated when combined with COX-2 inhibition. Based on our results, the clinically available drug parecoxib may be added to immunotherapy against human brain tumors. Furthermore, the discovery that IFN-γ plasma levels can be used to determine the ongoing in vivo immune response has translational potential.
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| 7. |
- Eberstål, Sofia, et al.
(author)
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Intratumoral COX-2 inhibition enhances GM-CSF immunotherapy against established mouse GL261 brain tumors.
- 2014
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In: International Journal of Cancer. - : Wiley. - 0020-7136. ; 134:11, s. 2748-2753
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Journal article (peer-reviewed)abstract
- Immunotherapy has shown effectiveness against experimental malignant brain tumors, but the clinical results have been less convincing most likely due to immunosuppression. Prostaglandin E2 (PGE2 ) is the key immunosuppressive product of cyclooxygenase-2 (COX-2) and increased levels of PGE2 and COX-2 have been shown in several tumor types including brain tumors. In the current study, we report enhanced cure rate of mice with established mouse GL261 brain tumors when immunized with granulocyte macrophage-colony stimulating factor (GM-CSF) secreting tumor cells and simultaneously treated with the selective COX-2 inhibitors parecoxib systemically (5 mg/kg/day; 69% cure rate) or valdecoxib intratumorally (5.3 µg/kg/day; 63% cure rate). Both combined therapies induced a systemic anti-tumor response of proliferating CD4(+) and CD8(+) T cells and further analysis revealed T helper 1 (Th 1) cell supremacy. The GL261 tumor cell line produced very low levels of PGE2 in vitro and co-staining at the tumor site demonstrated that a large fraction of the COX-2(+) cells were derived from CD45(+) immune cells and more specifically macrophages (F4/80(+) ), indicating that tumor-infiltrating immune cells constitute the primary source of COX-2 and PGE2 in this model. We conclude that intratumoral COX-2 inhibition potentiates GM-CSF immunotherapy against established brain tumors at substantially lower doses than systemic administration. These findings underscore the central role of targeting COX-2 during immunotherapy and implicate intratumoral COX-2 as the primary target. © 2013 Wiley Periodicals, Inc.
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| 8. |
- Ehinger, Erik, et al.
(author)
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Antisecretory factor is safe to use as add-on treatment in newly diagnosed glioblastoma
- 2023
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In: BMC Neurology. - : BioMed Central (BMC). - 1471-2377. ; 23:1
-
Journal article (peer-reviewed)abstract
- PurposeGlioblastoma (GBM) is the most common primary malignant brain tumor in adults. Despite the best available treatment, prognosis remains poor. Current standard therapy consists of surgical removal of the tumor followed by radiotherapy and chemotherapy with the alkylating agent temozolomide (TMZ). Experimental studies suggest that antisecretory factor (AF), an endogenous protein with proposed antisecretory and anti-inflammatory properties, may potentiate the effect of TMZ and alleviate cerebral edema. Salovum is an egg yolk powder enriched for AF and is classified as a medical food in the European Union. In this pilot study, we evaluate the safety and feasibility of add-on Salovum in GBM patients.MethodsEight patients with newly diagnosed, histologically confirmed GBM were prescribed Salovum during concomitant radiochemotherapy. Safety was determined by the number of treatment-related adverse events. Feasibility was determined by the number of patients who completed the full prescribed Salovum treatment.ResultsNo serious treatment-related adverse events were observed. Out of 8 included patients, 2 did not complete the full treatment. Only one of the dropouts was due to issues directly related to Salovum, which were nausea and loss of appetite. Median survival was 23 months.ConclusionsWe conclude that Salovum is safe to use as an add-on treatment for GBM. In terms of feasibility, adherence to the treatment regimen requires a determined and independent patient as the large doses prescribed may cause nausea and loss of appetite.
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| 9. |
- Enell Smith, Karin, et al.
(author)
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Cure of established GL261 mouse gliomas after combined immunotherapy with GM-CSF and IFNgamma is mediated by both CD8(+) and CD4(+) T-cells.
- 2009
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 124:3, s. 630-637
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Journal article (peer-reviewed)abstract
- We were the first to demonstrate that combined immunotherapy with GM-CSF producing GL261 cells and recombinant IFNgamma of preestablished GL261 gliomas could cure 90% of immunized mice. To extend these findings and to uncover the underlying mechanisms, the ensuing experiments were undertaken. We hypothesized that immunizations combining both GM-CSF and IFNgamma systemically would increase the number of immature myeloid cells, which then would mature and differentiate into dendritic cells (DCs) and macrophages, thereby augmenting tumor antigen presentation and T-cell activation. Indeed, the combined therapy induced a systemic increase of both immature and mature myeloid cells but also an increase in T regulatory cells (T-regs). Cytotoxic anti-tumor responses, mirrored by an increase in Granzyme B-positive cells as well as IFNgamma-producing T-cells, were augmented after immunizations with GM-CSF and IFNgamma. We also show that the combined therapy induced a long-term memory with rejection of intracerebral (i.c.) rechallenges. Depletion of T-cells showed that both CD4(+) and CD8(+) T-cells were essential for the combined GM-CSF and IFNgamma effect. Finally, when immunizations were delayed until day 5 after tumor inoculation, only mice receiving immunotherapy with both GM-CSF and IFNgamma survived. We conclude that the addition of recombinant IFNgamma to immunizations with GM-CSF producing tumor cells increased the number of activated tumoricidal T-cells, which could eradicate established intracerebral tumors. These results clearly demonstrate that the combination of cytokines in immunotherapy of brain tumors have synergistic effects that have implications for clinical immunotherapy of human malignant brain tumors. (c) 2008 Wiley-Liss, Inc.
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| 10. |
- Enríquez Pérez, Julio, et al.
(author)
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Convection-enhanced delivery of temozolomide and whole cell tumor immunizations in GL261 and KR158 experimental mouse gliomas
- 2020
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In: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 20
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Glioblastomas (GBM) are therapy-resistant tumors with a profoundly immunosuppressive tumor microenvironment. Chemotherapy has shown limited efficacy against GBM. Systemic delivery of chemotherapeutic drugs is hampered by the difficulty of achieving intratumoral levels as systemic toxicity is a dose-limiting factor. Although some of its effects might be mediated by immune reactivity, systemic chemotherapy can also inhibit induced or spontaneous antitumor immune reactivity. Convection-enhanced delivery of temozolomide (CED-TMZ) can tentatively increase intratumoral drug concentration while reducing systemic side effects. The objective of this study was to evaluate the therapeutic effect of intratumorally delivered temozolomide in combination with immunotherapy and whether such therapy can generate a cellular antitumor immune response. METHODS: Single bolus intratumoral injection and 3-day mini-osmotic pumps (Alzet®) were used to deliver intratumoral TMZ in C57BL6 mice bearing orthotopic gliomas. Immunotherapy consisted of subcutaneous injections of irradiated GL261 or KR158 glioma cells. Tumor size and intratumoral immune cell populations were analyzed by immunohistochemistry. RESULTS: Combined CED-TMZ and immunotherapy had a synergistic antitumor effect in the GL261 model, compared to CED-TMZ or immunotherapy as monotherapies. In the KR158 model, immunization cured a small proportion of the mice whereas addition of CED-TMZ did not have a synergistic effect. However, CED-TMZ as monotherapy prolonged the median survival. Moreover, TMZ bolus injection in the GL261 model induced neurotoxicity and lower cure rate than its equivalent dose delivered by CED. In addition, we found that T-cells were the predominant cells responsible for the TMZ antitumor effect in the GL261 model. Finally, CED-TMZ combined with immunotherapy significantly reduced tumor volume and increased the intratumoral influx of T-cells in both models. CONCLUSIONS: We show that immunotherapy synergized with CED-TMZ in the GL261 model and cured animals in the KR158 model. Single bolus administration of TMZ was effective with a narrower therapeutic window than CED-TMZ. Combined CED-TMZ and immunotherapy led to an increase in the intratumoral influx of T-cells. These results form part of the basis for the translation of the therapy to patients with GBM but the dosing and timing of delivery will have to be explored in depth both experimentally and clinically.
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| 11. |
- Enríquez Pérez, Julio, et al.
(author)
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The effect of locally delivered cisplatin is dependent on an intact immune function in an experimental glioma model
- 2019
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
-
Journal article (peer-reviewed)abstract
- Several chemotherapeutic drugs are now considered to exert anti-tumour effects, by inducing an immune-promoting inflammatory response. Cisplatin is a potent chemotherapeutic agent used in standard medulloblastoma but not glioblastoma protocols. There is no clear explanation for the differences in clinical efficacy of cisplatin between medulloblastomas and glioblastomas, despite the fact that cisplatin is effective in vitro against the latter. Systemic toxicity is often dose limiting but could tentatively be reduced by intratumoral administration. We found that intratumoral cisplatin can cure GL261 glioma-bearing C57BL/6 mice and this effect was abolished in GL261-bearing NOD-scid IL2rγ null (NSG) mice. Contrary to previous results with intratumoral temozolomide cisplatin had no additive or synergistic effect with whole cell either GL261 wild-type or GM-CSF-transfected GL261 cells whole cell vaccine-based immunotherapy. While whole tumour cell immunizations increased CD8 + T-cells and decreased F4/80 + macrophages intratumorally, cisplatin had no effect on these cell populations. Taken together, our results demonstrate that intratumoral cisplatin treatment was effective with a narrow therapeutic window and may be an efficient approach for glioma or other brain tumour treatment.
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| 12. |
- Fritzell, Sara, et al.
(author)
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IFNγ in combination with IL-7 enhances immunotherapy in two rat glioma models.
- 2013
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In: Journal of Neuroimmunology. - : Elsevier BV. - 1872-8421 .- 0165-5728. ; 258:1-2, s. 91-95
-
Journal article (peer-reviewed)abstract
- Peripheral immunization, using a combination of interferon-gamma (IFNγ)- and interleukin-7 (IL-7)-producing tumor cells, eradicated 75% of pre-established intracerebral N32 rat glioma tumors, and prolonged survival in the more aggressive RG2 model. Rats immunized with IFNγ- and IL7-transduced N32 cells displayed increases in IFNγ plasma levels and proliferating circulating T cells when compared with rats immunized with N32-wild type cells. Following irradiation, the expression of MHC I and II was high on N32-IFNγ cells, but low on RG2-IFNγ cells. In conclusion, IFNγ and IL-7 immunizations prolong survival in two rat glioma models.
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| 13. |
- Fritzell, Sara, et al.
(author)
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Intratumoral temozolomide synergizes with immunotherapy in a T cell-dependent fashion.
- 2013
-
In: Cancer Immunology and Immunotherapy. - : Springer Science and Business Media LLC. - 1432-0851 .- 0340-7004. ; 62:9, s. 1463-1474
-
Journal article (peer-reviewed)abstract
- Despite temozolomide (TMZ) treatment, the prognosis for patients with glioblastoma multiforme is still dismal. As dose escalation of TMZ is limited by systemic toxicity, intratumoral delivery emerges as an attractive treatment modality, which may sustain cytotoxic drug concentrations intratumorally and induce immunogenic cell death. Both clinical and experimental gliomas have responded to immunotherapy, but the benefit of simultaneous chemo- and immunotherapy is inadequately studied. Here, we monitored survival of GL261-bearing C57BL/6 mice following a 3-day treatment with either intratumoral TMZ (micro-osmotic pump, 4.2 mg/kg/day) or systemic TMZ (i.p. injections, 50 mg/kg/day) alone, or combined with immunization using GM-CSF secreting GL261 cells. Peripheral and intratumoral leukocytes were analyzed by flow cytometry and immunohistochemistry. Intratumoral TMZ induced higher survival rate than systemic TMZ (45 vs. 8 %). When T cells were depleted following intratumoral TMZ, the therapeutic effect was completely abrogated (0 % survival). Intratumoral TMZ synergistically increased survival rate of immunized mice (from 25 to 83 %), while systemic TMZ failed (0 %). While systemic TMZ induced a transient leukopenia, intratumoral TMZ and immunotherapy sustained the proliferation of CD8(+) T cells and decreased the number of intratumoral immunosuppressive cells. In conclusion, intratumoral TMZ alone or in combination with immunotherapy could cure glioma-bearing mice, due to attenuation of local immunosuppression and increase in potential effector immune cells.
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| 14. |
- Godina, Christopher, et al.
(author)
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Interplay between Caveolin-1 and body and tumor size affects clinical outcomes in breast cancer
- 2022
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In: Translational Oncology. - : Elsevier. - 1944-7124 .- 1936-5233. ; 22
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Journal article (peer-reviewed)abstract
- Background: Caveolin-1 (CAV1) is associated with cholesterol-rich membrane raft domains and is a master regulator of cell signaling and membrane transport. Here, we investigated CAV1's role in cellular compartments of breast cancer in relation to signaling pathways, clinicopathological features, and clinical outcomes.Methods: CAV1 levels were evaluated with immunohistochemistry in cytoplasm of invasive tumor cells and stromal cells in tumor tissue microarrays from a cohort of 1018 breast cancer patients (inclusion 2002-2012, Sweden). Cytoplasmic and stromal CAV1 were categorized as positive/negative and strong/not strong, respectively. CAV1 expression in relation to clinical outcomes was assessed with Cox regression. Investigations into CAV1 functional pathways was conducted in the STRING, GOBO, and TCGA databases.Results: CAV1 expression was associated with non-luminal subtypes, cell cycle control, inflammation, epithelialmesenchymal transition, and the IGF/Insulin system. Generally, CAV1 was not associated with recurrence risk. Stromal CAV1's impact on recurrence risk was modified by BMI > 25 kg/m(2) (P-interaction = 0.002), waist > 80 cm (P-interaction = 0.005), and invasive tumor size (pT2/3/4) (P-interaction = 0.028). In low-risk patients only, strong stromal CAV1 significantly increased recurrence risk (HRs(adj) > 1.61). In all patients, positive cytoplasmic CAV1 conferred > 2-fold risk for contralateral disease HRadj 2.63 (95% CI 1.36-5.10). Strong stromal CAV1 conferred nearly 2-fold risk for locoregional recurrence HRadj 1.88 (95% CI 1.09-3.24).Conclusions: CAV1's prognostic impact depended on its localization, anthropometric, and tumor factors. Stromal CAV1 predicted high recurrence risk in a group of supposedly "low-risk' patients. Cytoplasmic CAV1 predicted metachronous contralateral disease. If confirmed, CAV1 could be used as treatment target and for risk stratification.
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| 15. |
- Godina, Christopher, et al.
(author)
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Prognostic impact of tumor-specific insulin-like growth factor binding protein 7 (IGFBP7) levels in breast cancer : A prospective cohort study
- 2021
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In: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 42:11, s. 1314-1325
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Journal article (peer-reviewed)abstract
- The prognostic impact of insulin-like growth factor binding protein 7 (IGFBP7) in breast cancer is unclear. Host factors, including lifestyle, anthropometry and metabolic profile, might influence tumor-specific IGFBP7. This study aimed to investigate whether IGFBP7 levels and messenger ribonucleic acid (mRNA) expression are associated with the patient and tumor characteristics and prognosis in breast cancer. Patients with primary breast cancer in Lund, Sweden, were included preoperatively in the study between 2002 and 2012 (n = 1018). Tumor-specific IGFBP7 protein levels were evaluated with immunohistochemistry using tissue microarrays in tumors from 878 patients. IGFBP7 mRNA expression and its corresponding clinical data were obtained from The Cancer Genome Atlas and analyzed for 809 patients. Tumor-specific IGFBP7 protein levels were categorized based on Histo 300 scores into IGFBP7low (6.2%), IGFBP7intermediate (75.7%) and IGFBP7high (18.1%). Both low IGFBP7 protein levels and mRNA expression were associated with less aggressive tumor characteristics. Overall, IGFBP7low conferred low recurrence risk. The prognostic impact of IGFBP7high varied according to any alcohol consumption and tamoxifen treatment. IGFBP7high was associated with low recurrence risk in alcohol consumers but high recurrence risk in alcohol abstainers (Pinteraction= 0.039). Moreover, the combination of IGFBP7high and estrogen receptor-positive tumors was associated with low recurrence risk only in tamoxifen-treated patients (Pinteraction= 0.029). To conclude, IGFBP7low might be a good, independent prognosticator in breast cancer. The prognostic impact of IGFBP7high depends on host factors and treatment. IGFBP7 merits further investigation to confirm whether it could be a suitable biomarker for treatment selection.
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| 16. |
- Janelidze, Shorena, et al.
(author)
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Activation of purified allogeneic CD4(+) T cells by rat bone marrow-derived dendritic cells induces concurrent secretion of IFN-gamma, IL-4, and IL-10.
- 2005
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In: Immunology Letters. - : Elsevier BV. - 0165-2478. ; 101:2, s. 193-201
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Journal article (peer-reviewed)abstract
- Dendritic cells (DCs) are highly specialized antigen-presenting cells that play a key role in the initiation and regulation of immune responses. The ability of DCs to process antigens and the outcome of their interaction with T cells are largely dependent on phenotype as well as maturation state of DCs. In this study, we generated DCs from rat bone marrow precursors. Bone marrow cells cultured in the presence of granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-4, and Flt-3 ligand (FL) produced immature DCs that expressed intermediate levels of major histocompatibility complex (MHC) class II, low levels of CD80 and CD86 molecules and displayed a high capacity of endocytosis. Bone marrow-derived DCs (BMDCs) matured in the presence of lipopolysaccharide (LPS) upregulated expression of MHC class II, CD80 and CD86, while their phagocytic capacity was dramatically reduced. Mature BMDCs stimulated vigorous proliferation of purified allogeneic CD4(+) T cells in a primary mixed leukocyte reaction (MLR) and elicited a mixed cytokine profile in allogeneic CD4(+) T cells: DCs activated CD4(+) T cells to produce interferon (IFN)-gamma, IL-4, and IL-10. Thus, rat BMDCs effectively internalize antigens and stimulate T cell proliferation but fail to induce an unidirectional polarization of T helper (T-H) cells and in this respect differ from both human and mouse DCs. (c) 2005 Elsevier B.V. All rights reserved.
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| 17. |
- Janelidze, Shorena, et al.
(author)
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Immunizations With IFN gamma Secreting Tumor Cells can Eliminate Fully Established and Invasive Rat Gliomas
- 2009
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In: Journal of Immunotherapy. - 1524-9557. ; 32:6, s. 593-601
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Journal article (peer-reviewed)abstract
- Immunotherapy of malignant primary brain tumors holds the potential to improve the dismal prognosis after current clinical therapy. Although immunotherapy of experimental gliomas has been demonstrated to have the capacity to cure intracerebral tumors no convincing effects of immunotherapy have been shown in clinical trials. One reason for this could be that some of the models used do not display full features of human glioblastomas. The N29 rat gliomas exhibited all the histologic features of human glioblastoma multiforme including nuclear atypia, mitotic figures, necrosis, and diffuse infiltration into the normal brain tissue. Surprisingly, immunotherapy with autologous interferon gamma producing tumor cells against preestablished intracerebral N29 turners yielded a higher cure rate than immunotherapy against less invasive tumors. Furthermore, when immunizations were postponed until day 5 after tumor establishment 50% of the animals survived. When immunizations were postponed until day 11 after tumor establishment no glioma-bearing animals were cured but survival was significantly prolonged. The superior effect of immunotherapy in the invasive N29 model compared with the less invasive tumors could depend oil combined effects of up-regulation of major histocompatibility complex I and induction of major histocompatibility complex II plus CD80 after transfection and irradiation of the tumor cells used for immunizations. This study demonstrates that immunotherapy against experimental brain tumors indeed is feasible even against highly invasive and established tumors. These results strengthen the translational potential of immunotherapy against malignant brain tumors.
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| 18. |
- Johansson, Anna C, et al.
(author)
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Enhanced expression of iNOS intratumorally and at the immunization site after immunization with IFNgamma-secreting rat glioma cells
- 2002
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In: Journal of Neuroimmunology. - 1872-8421. ; 123:1-2, s. 135-143
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Journal article (peer-reviewed)abstract
- Nitric oxide (NO) can modulate both tumor growth and antitumor immune responses. In order to elucidate the mechanism of curative therapeutic immunization with IFNgamma-producing glioma cells, we examined the expression of inducible nitric oxide synthase (iNOS) in tissue sections from immunized animals. There was a significantly enhanced iNOS expression both intratumorally and at the immunization site. Although the mechanisms behind this dual expression of iNOS most probably are different, our results suggest a role for NO in both the induction and execution of the antitumor response.
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| 19. |
- Kopecky, Jan, et al.
(author)
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Intratumoral administration of the antisecretory peptide AF16 cures murine gliomas and modulates macrophage functions
- 2022
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In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 12:1
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Journal article (peer-reviewed)abstract
- Glioblastoma has remained the deadliest primary brain tumor while its current therapy offers only modest survival prolongation. Immunotherapy has failed to record notable benefits in routine glioblastoma treatment. Conventionally, immunotherapy relies on T cells as tumor-killing agents; however, T cells are outnumbered by macrophages in glioblastoma microenvironment. In this study, we explore the effect of AF16, a peptide from the endogenous antisecretory factor protein, on the survival of glioma-bearing mice, the tumor size, and characteristics of the tumor microenvironment with specific focus on macrophages. We elucidate the effect of AF16 on the inflammation-related secretome of human and murine macrophages, as well as human glioblastoma cells. In our results, AF16 alone and in combination with temozolomide leads to cure in immunocompetent mice with orthotopic GL261 gliomas, as well as prolonged survival in immunocompromised mice. We recorded decreased tumor size and changes in infiltration of macrophages and T cells in the murine glioma microenvironment. Human and murine macrophages increased expression of proinflammatory markers in response to AF16 treatment and the same effect was seen in human primary glioblastoma cells. In summary, we present AF16 as an immunomodulatory factor stimulating pro-inflammatory macrophages with a potential to be implemented in glioblastoma treatment protocols.
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| 20. |
- Réen, Linus, et al.
(author)
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Low Morbidity and Mortality in Children with Severe Traumatic Brain Injury Treated According to the Lund Concept : A Population-Based Study
- 2023
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In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 40:7-8, s. 720-729
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Journal article (peer-reviewed)abstract
- Previous reports of mortality and morbidity in pediatric severe traumatic brain injury (TBI) vary considerably, with few population-based studies. Mortality rates from 3-33 % and varying morbidity have been reported, most commonly using the Extended Glasgow Outcome Scale (eGOS). The Lund concept is a treatment algorithm for severe TBI aiming at controlling intracranial pressure (ICP) by reducing cerebral perfusion pressure (CPP). The aim of the present study was to retrospectively assess mortality and morbidity in a population of pediatric TBI treated according to the Lund concept. All cases of severe pediatric TBI (age <18 years) in the southern region of Sweden during 19 years were identified. Patients were treated according to the Lund concept. Mortality, eGOS, ICP, CPP, time in the neurosurgical intensive care unit (NICU), drugs delivered and surgical procedures were recorded. Data were analyzed both by dichotomized outcomes and by ordinal statistics. A total of 135 cases of severe TBI <18 years of age were recorded (incidence 2.0/100000) and 86 patients were admitted to the tertiary NICU. Mortality including all cases was 43% (mortality rate 0.7/100,000) and in NICU 10%. Outcome was good in 60%, moderate in 25%, unfavorable in 15%, with none in a vegetative status. In both dichotomized and ordinal analyses, CPP <40 mm Hg and ICP >15 were associated with poor outcome, supporting current guidelines. However, high CPP also was associated with increased mortality and morbidity, supporting that elevated CPP might increase cerebral edema. In this study, the Lund concept resulted in low mortality and a favorable outcome in a majority of severe pediatric TBI patients; however, randomized controlled trials are warranted to verify this.
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| 21. |
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| 22. |
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| 23. |
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| 24. |
- Salford, Leif, et al.
(author)
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Search for effective therapy against glioblastoma multiforme - Clinical immunisation with autologous glioma cells transduced with the human interferon-gamma gene
- 2002
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In: Developments in Neuroscience. Proceedings of the 2nd International Mt Bandai Symposium for Neuroscience 2001. - 0531-5131. ; 1247, s. 211-220
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Conference paper (peer-reviewed)abstract
- Based upon earlier experimental work by our group, we have started a human immuno-gene therapy study. The goal is to study the effects of immunisation with autologous tumour cells expressing gene sequences for human interferon-gamma For more than two decades we have sought for efficient treatment against malignant gliomas. Our most successful treatment in the animal models is immuno-gene therapy where murine genes for the cytokines IFN-gamma, IL-7 and B7-1 were chosen for their ability to stimulate different stages of the pathway for cytotoxic T lymphocyte (CTL) activation. Rats of the syngeneic inbred strain Fischer 344 had rat glioma cells of the N32 line inoculated in the right caudate nucleus, and 1 or 3 days later N32 cells transfected with either IFN-gamma, IL-7 or B7-1 genes were injected subcutaneously (and in some studies intraperitoneally). This treatment was repeated three to four times with 7- to 14-day interval and resulted in significantly improved survival compared with treatment with wild-type rat glioma cells (e.g. not transfected with the cytokine genes). The continued work concentrated on treatment with IFN-gamma secreting tumour cells of both the N32 line and also a newly developed ENU-induced rat glioma cell line called N29. This work proved the effectiveness of the technique. Cure was achieved in 72% of the animals treated with the IFN-gamma cells. Tumour-infiltrating leukocytes from N32-IFN-gamma-immunised animals showed a significantly stronger infiltration by CD8+ T-cells, significantly more NK cells, and an increased number of CD25-expressing T-cells. These results confirmed the possible usefulness of IFN-gamma-transfected tumour cells in the immune-therapy of rat brain tumours. The animal experiments have motivated us to start a human immuno-gene therapy study including 20 patients with glioblastoma multiforme (GBM), where >80% of the tumour can be surgically removed. The goal is to ascertain whether immunisation with autologous tumour cells expressing gene sequences for human interferon-gamma is safe for the patients, gives rise to an immunological response, and adds any beneficial effect to conventional therapy (tumour growth, prolonged survival). Hitherto, nine patients have been included in the study, two of which have received 6 and 10 immunisations, respectively. Two patients have died from their disease before cells have been ready for immunisation; in two cases no malignant cells have appeared in the cell cultures and three patients are ready to start their immunisation shortly. The immunisation takes place in the dermis of the upper arm. Seven days after each immunisation, a skin biopsy is taken from the centre of one of the injection sites. The composition of the cellular infiltration in the skin is studied by markers for T lymphocytes (CD3); helper cells, subset of T cells (CD4); killer cells, subset of T cells (CD8); natural killer cells (CD16) and B lymphocytes, B cells (CD20). Also the expression of cytokines for functional T cell subsets are studied: IL-2, IL-4, IL-10, IL-12, IL-18, TNF-alpha and IF-gamma and TGF-beta(1,2 and 3-) Peripheral blood is sampled both before and after operation and also after each immunisation event. Co-culture of this blood with tumour cells from the patient allows for a selection of T-cells that can recognise tumour-specific antigens. The results from the first human treatments are presented. (C) 2002 Published by Elsevier Science B.V.
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| 25. |
- Sandén, Emma, et al.
(author)
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A standardized and reproducible protocol for serum-free monolayer culturing of primary paediatric brain tumours to be utilized for therapeutic assays.
- 2015
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
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Journal article (peer-reviewed)abstract
- In vitro cultured brain tumour cells are indispensable tools for drug screening and therapeutic development. Serum-free culture conditions tentatively preserve the features of the original tumour, but commonly comprise neurosphere propagation, which is a technically challenging procedure. Here, we define a simple, non-expensive and reproducible serum-free cell culture protocol for establishment and propagation of primary paediatric brain tumour cultures as adherent monolayers. The success rates for establishment of primary cultures (including medulloblastomas, atypical rhabdoid tumour, ependymomas and astrocytomas) were 65% (11/17) and 78% (14/18) for sphere cultures and monolayers respectively. Monolayer culturing was particularly feasible for less aggressive tumour subsets, where neurosphere cultures could not be generated. We show by immunofluorescent labelling that monolayers display phenotypic similarities with corresponding sphere cultures and primary tumours, and secrete clinically relevant inflammatory factors, including PGE2, VEGF, IL-6, IL-8 and IL-15. Moreover, secretion of PGE2 was considerably reduced by treatment with the COX-2 inhibitor Valdecoxib, demonstrating the functional utility of our newly established monolayer for preclinical therapeutic assays. Our findings suggest that this culture method could increase the availability and comparability of clinically representative in vitro models of paediatric brain tumours, and encourages further molecular evaluation of serum-free monolayer cultures.
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| 26. |
- Sandén, Emma, et al.
(author)
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Aberrant immunostaining pattern of the CD24 glycoprotein in clinical samples and experimental models of pediatric medulloblastomas
- 2015
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In: Journal of Neuro-Oncology. - : Springer Science and Business Media LLC. - 0167-594X .- 1573-7373. ; 123:1, s. 1-13
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Journal article (peer-reviewed)abstract
- The CD24 glycoprotein is a mediator of neuronal proliferation, differentiation and immune suppression in the normal CNS, and a proposed cancer biomarker in multiple peripheral tumor types. We performed a comparative analysis of CD24 gene expression in a large cohort of pediatric and adult brain tumors (n = 813), and further characterized protein expression in tissue sections (n = 39), primary brain tumor cultures (n = 12) and a novel orthotopic group 3 medulloblastoma xenograft model. Increased CD24 gene expression was demonstrated in ependymomas, medulloblastomas, anaplastic astrocytomas and glioblastomas, although medulloblastomas displayed higher expression than all other tumor entities. Preferential expression of CD24 in medulloblastomas was confirmed at protein level by immunostaining and computerized image analysis of cryosections. Morphologies and immunophenotyping of CD24(+) cells in tissue sections tentatively suggested disparate functions in different tumor subsets. Notably, protein staining of medulloblastoma cells was associated with prominent cytoplasmic and membranous granules, enabling rapid and robust identification of medulloblastoma cells in clinical tissue samples, as well as in experimental model systems. In conclusion, our results implicate CD24 as a clinically and experimentally useful medulloblastoma immunomarker. Although our results encourage further functional studies of CD24 as a potential molecular target in subsets of brain tumors, the promiscuous expression of CD24 in vivo highlights the importance of specificity in the future design of such targeted treatment.
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| 27. |
- Sandén, Emma, et al.
(author)
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ANALYSIS OF CLUSTER OF DIFFERENTIATION (CD) MARKERS IN PEDIATRIC BRAIN TUMORS CAN BE USED AS A DIAGNOSTIC AND PROGNOSTIC TOOL
- 2012
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In: Neuro-Oncology. - : Oxford University Press (OUP). - 1523-5866 .- 1522-8517. ; 14:suppl. 1, s. 43-48
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Conference paper (peer-reviewed)abstract
- BACKGROUND: Malignant pediatric brain tumors constitute a heterogeneic group of central nervous system tumors, and general markers of diagnosis and prognosis are not available. Recently, a panel of CD markers (CD15, CD24, CD29) was used to define increasing neural differentiation of embryonic stem cells. Although these CD markers have been associated with worse prognosis due to presence of tumor propagating cells, alterations in adhesion and migration in various cancer types, no studies of multiple CD markers in pediatric brain tumors have been performed. METHODS: We have collected tumors, including medulloblastomas (MB), ependymomas (EP) and juvenile astrocytomas, from >20 pediatric brain tumor patients. Frozen tumor sections and cultured tumor cells were stained for CD15, CD24 and CD29 and analyzed using fluorescence microscopy or flowcytometry. RESULTS: MB contained a mixture of cells with strong CD15 labeling inside vessels and cells with diffuse CD15 staining in the parenchyma of the tumor tissue. Cells strongly labeled with CD15 were also positive for the leukocyte marker CD45. The previously proposed association between CD15 expression and prognosis in MB could instead of reflecting abundance of tumor propagating cells depend on infiltrating immune cells. In low-grade pediatric tumors and EP, larger areas stained weakly for CD15 while few cells displayed strong staining. CD24 was expressed on the vast majority of cells in pediatric brain tumors, despite grade of malignancy. MB, however, displayed an intense and aberrant staining for CD24. Computerized image analysis of frozen tumor sections showed that proliferation of cells and the expression of CD29 correlated in a sub-group of MB. CONCLUSIONS: Our preliminary data show that CD15, CD24 and CD29 are differentially expressed in high- and low-malignant pediatric brain tumors in vivo. By defining the patterns of CD antigen expression in different pediatric tumors their relationship to biological behavior and thus prognosis can be established.
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| 28. |
- Sandén, Emma, et al.
(author)
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Establishment and characterization of an orthotopic patient-derived Group 3 medulloblastoma model for preclinical drug evaluation
- 2017
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7, s. 46366-
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Journal article (peer-reviewed)abstract
- Medulloblastomas comprise a heterogeneous group of tumours and can be subdivided into four molecular subgroups (WNT, SHH, Group 3 and Group 4) with distinct prognosis, biological behaviour and implications for targeted therapies. Few experimental models exist of the aggressive and poorly characterized Group 3 tumours. In order to establish a reproducible transplantable Group 3 medulloblastoma model for preclinical therapeutic studies, we acquired a patient-derived tumour sphere culture and inoculated low-passage spheres into the cerebellums of NOD-scid mice. Mice developed symptoms of brain tumours with a latency of 17–18 weeks. Neurosphere cultures were re-established and serially transplanted for 3 generations, with a negative correlation between tumour latency and numbers of injected cells. Xenografts replicated the phenotype of the primary tumour, including high degree of clustering in DNA methylation analysis, high proliferation, expression of tumour markers, MYC amplification and elevated MYC expression, and sensitivity to the MYC inhibitor JQ1. Xenografts maintained maintained expression of tumour-derived VEGFA and stromal-derived COX-2. VEGFA, COX-2 and c-Myc are highly expressed in Group 3 compared to other medulloblastoma subgroups, suggesting that these molecules are relevant therapeutic targets in Group 3 medulloblastoma.
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| 29. |
- Sandén, Emma, et al.
(author)
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Preoperative systemic levels of VEGFA, IL-7, IL-17A, and TNF-beta delineate two distinct groups of children with brain tumors
- 2016
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In: Pediatr Blood Cancer. - : Wiley. - 1545-5009 .- 1545-5017. ; 63:12, s. 2112-2122
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Journal article (peer-reviewed)abstract
- BackgroundPrimary brain tumors are the most common solid tumors in children. Increasing evidence demonstrates diverse intratumoral immune signatures, which are tentatively reflected in peripheral blood. ProcedureTwenty cytokines were analyzed in preoperative plasma samples from five healthy children and 45 children with brain tumors, using a multiplex platform (MesoScale Discovery V-PLEX (R)). Tumor types included medulloblastoma (MB), ependymoma, sarcoma, high-grade glioma, pilocytic astrocytoma, and other low-grade gliomas. ResultsA panel of four cytokines [VEGFA, interleukin (IL)-7, IL-17A, and tumor necrosis factor (TNF)-] delineated two distinct patient groups, identified as VEGFA(high)IL-7(high)IL-17A(low)TNF-(low) (Group A) and VEGFA(low)IL-7(low)IL-17A(high)TNF-(high) (Group B). Healthy controls and the vast majority of patients with MB were found within Group A, whereas patients with other tumor types were equally distributed between the two groups. Unrelated to A/B affiliation, we detected trends toward increased IL-10 and decreased IL-12/23 and TNF- in several tumor types. Finally, a small number of patients displayed evidence of enhanced systemic immune activation, including elevated levels of interferon-, granulocyte monocyte colony-stimulating factor, IL-6, IL-12/23, and TNF-. Following tumor resection, cytokine levels in a MB patient approached the levels of healthy controls. ConclusionsWe identify common features and individual differences in the systemic immune profiles of children with brain tumors. Overall, patients with MB displayed a uniform cytokine profile, whereas other tumor diagnoses did not predict systemic immunological status in single patients. Future characterization and monitoring of systemic immune responses in children with brain tumors will have important implications for the development and implementation of immunotherapy.
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| 30. |
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| 31. |
- Smith, Karin E, et al.
(author)
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Synergism between GM-CSF and IFNgamma: Enhanced immunotherapy in mice with glioma.
- 2007
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 120:1, s. 75-80
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Journal article (peer-reviewed)abstract
- Glioblastoma multiforme is the most common malignant primary brain tumor and also one of the most therapy-resistant tumors. Because of the dismal prognosis, various therapies modulating the immune system have been developed in experimental models. Previously, we have shown a 37-70% cure in a rat glioma model where rats were peripherally immunized with tumor cells producing IFN. On the basis of these results, we wanted to investigate whether a combination of GM-CSF and IFN could improve the therapeutic effect in a mouse glioma model, GL261 (GL-wt). Three biweekly intraperitoneal (i.p.) immunizations with irradiated GM-CSF-transduced GL261 cells (GL-GM) induced a 44% survival in mice with intracranial glioma. While treatment of GL-wt and GL-GM with IFN in vitro induced upregulation of MHC I and MHC II on the tumor cells, it could not enhance survival after immunization. However, immunizations with GL-GM combined with recombinant IFN at the immunization site synergistically enhanced survival with a cure rate of 88%. Tumors from mice receiving only 1 immunization on Day 10 after tumor inoculation were sectioned on Day 20 for analysis of leukocyte infiltration. Tumor volume was reduced and the infiltration of macrophages was denser in mice immunized with GL-GM combined with IFN compared with that of both wildtype and nonimmunized mice. To our knowledge, this is the first study to demonstrate a synergy between GM-CSF and IFN in experimental immunotherapy of tumors, by substantially increasing survival as well as inducing a potent anti-tumor response after only 1 postponed immunization.
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| 32. |
- Tabatabaei, Pedram, et al.
(author)
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Radiotherapy induces an immediate inflammatory reaction in malignant glioma : a clinical microdialysis study
- 2017
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In: Journal of Neuro-Oncology. - : Springer. - 0167-594X .- 1573-7373. ; 131:1, s. 83-92
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Journal article (peer-reviewed)abstract
- The knowledge of response to radiation in the immuno-microenvironment of high grade gliomas is sparse. In vitro results have indicated an inflammatory response of myeloid cells after irradiation. Therefore, microdialysis was used to verify whether this is operative in tumor tissue and brain adjacent to tumor (BAT) after clinical radiotherapy of patients with high grade glioma. Stereotactic biopsies and implantation of microdialysis catheters in tumor tissue and BAT were performed in eleven patients with high-grade glioma. The patients were given daily radiation fractions of 2-3.4 Gy. Microdialysis samples were collected before radiotherapy and during the first five days of radiation. Cytokines, glucose metabolites, glutamate and glycerol were analyzed. Immunohistochemistry was performed to detect macrophages (CD68) and monocytes (CD163) as well as IL-6, IL-8 and MCP-1. A significant increase of IL-8, MCP-1 and MIP-1a were detected in tumor tissue already after the first dose of radiation and increased further during 5 days of radiation. IL-6 did also increase but after five fractions of radiation. In BAT, the cytokine response was modest with significant increase of IL-8 after third dose of radiation. We found a positive correlation between baseline IL-8 and IL-6 microdialysis levels in tumor tissue and survival. Glucose metabolites or glycerol and glutamate did not change during radiation. In all tumors staining for macrophages was demonstrated. IL-6 was found in viable tumor cells while MCP-1 was demonstrated in macrophages or tumor matrix. Our findings suggest that radiation induces a rapid enhancement of the prevailing inflammation in high-grade glioma tissue. The microdialysis technique is feasible for this type of study and could be used to monitor metabolic changes after different interventions.
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| 33. |
- Visse, Edward
(author)
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Immuno Gene Therapy of Rat Brain Tumors with interferon-gamma transfected glioma cells
- 2000
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Doctoral thesis (other academic/artistic)abstract
- Immunotherapy is a new promising approach in cancer treatment. In the future, it will hopefully offer an alternative to existing brain tumors treatments, which are unable to cure. We have established an experimental, low immunogenic, brain tumor model in the rat. We have increased tumor cell immunogenicity with mutagen treatment or transfection of IFN-g. Mutagen treated glioma cells (tum-) could cross protect for subsequent challenge of wild type tumor cells. Immunization with tum- cells pre-incubated with IFN-g could also reject wild type tumor after tumor grafting. Lymphocyte populations in draining lymph nodes after tum- immunization showed the number of CD8+ T cells to increase fastest and strongest. IFN-g and TNF-a induction was stronger (in the CD8+ T cell compartment), while IL-10 was weaker (in the CD4+ T cell compartment) after tum- immunization as compared to control immunization. Peripheral immunizations with IFN-g transfected glioma cells after tumor grafting, were able to induce total tumor rejection of 37 and 72% with the N32 and N29 glioma, respectively. B7 or IL-7 transfected tumor cells could also cure but were less effective. Analysis of tumor infiltrating leucocytes in N32-IFN-g immunized as compared to control animals, showed a significant higher infiltration density in CD8+ and CD4+ T cells, as well as NK cells. CD8+ T cells from tumors immunized with N32-IFN-g also had increased LFA-1 expression. CD25 expression was similar between immunization groups, with CD25low expression in both CD4+ and CD8+ T cells, as well as CD25high expression in a population of CD4+ T cells.
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| 34. |
- Visse, Edward, et al.
(author)
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The MAP kinases are differently utilized by CD28 and CD2 adhesion pathways in superantigen-activated Jurkat T cells
- 2003
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In: Biological Research. - 0717-6287. ; 36:2, s. 263-278
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Journal article (peer-reviewed)abstract
- To mimic the two-signal requirements for T cell activation mediated by ligands, we exposed the superantigens SEA or SEE (signal 1) to T cells incubated with HLA-DR/LFA-3 or HLA-DR/137-1-CHO transfected cells (signal 2). LFA-3 costimulation was able to induce T cell proliferation as well as IFN-gamma and IL-4 production at similar levels as in cells induced by B7-1. Analysis of the CD28RE of the IL-2 promoter showed specific transcription factor recruitment at the CD28RE element upon induction by B7-1/SEE. Further functional Studies with an IL-2 enhancer-promoter carrying either wild type or mutated versions of the CD28RE site revealed that this element is necessary for full activation upon B7-1 costimulation. While both CD28/B7-1 and CD2/LFA-3 costimulation resulted in the up-regulation of IL-4 and IFN-gamma promoters, IL-2 promoter activity and production of IL-2 were only seen after B7-1 costimulation. However, contrary to what has been previously proposed, we show that costimulation with either B7-1 or LFA-3 further enhanced the ERK-2 activity and strongly activated the p38 MAPK pathway, but only B7-1 costiniulation induced high levels of JNK-1 activity. These data Suggest that the differential effect of CD28 vs. CD2 can be related to the difference in the ability of the two pathways to induce JNK-1 activity.
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| 35. |
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