| 1. |
- Berg, Tracy J., et al.
(författare)
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The Irradiated Brain Microenvironment Supports Glioma Stemness and Survival via Astrocyte-Derived Transglutaminase 2
- 2021
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Ingår i: Cancer Research. - : American Association For Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 81:8, s. 2101-2115
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Tidskriftsartikel (refereegranskat)abstract
- The tumor microenvironment plays an essential role in supporting glioma stemness and radioresistance. Following radiotherapy, recurrent gliomas form in an irradiated microenvironment. Here we report that astrocytes, when pre-irradiated, increase stemness and survival of cocultured glioma cells. Tumor-naive brains increased reactive astrocytes in response to radiation, and mice subjected to radiation prior to implantation of glioma cells developed more aggressive tumors. Extracellular matrix derived from irradiated astrocytes were found to be a major driver of this phenotype and astrocyte-derived transglutaminase 2 (TGM2) was identified as a promoter of glioma stemness and radioresistance. TGM2 levels increased after radiation in vivo and in recurrent human glioma, and TGM2 inhibitors abrogated glioma stemness and survival. These data suggest that irradiation of the brain results in the formation of a tumor-supportive microenvironment. Therapeutic targeting of radiation-induced, astrocyte-derived extracellular matrix proteins may enhance the efficacy of standard-of-care radiotherapy by reducing stemness in glioma. Significance: These findings presented here indicate that radiotherapy can result in a tumor-supportive microenvironment, the targeting of which may be necessary to overcome tumor cell therapeutic resistance and recurrence.
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| 2. |
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| 3. |
- F., Durmo, et al.
(författare)
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Multivoxel 1H MR spectroscopy biometrics for preoprerative differentiation between brain tumors
- 2018
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Ingår i: Neuroradiology. - : Springer Science and Business Media LLC. - 1432-1920 .- 0028-3940. ; 60:S2, s. 444-444
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Konferensbidrag (refereegranskat)abstract
- Purpose To investigate multivoxel proton Magnetic Resonance Spectroscopy (1HMRS) biometrics for preoperative differentiation and prognosis of patients with brain metastases (MET), low-(LGG) and high grade glioma (HGG). Methods Thirty-five patients (15 HGG, 9 LGG and 11 MET) were included. Proton Magnetic Resonance Spectroscopy Imaging(1H-MRSI) data was assessed and neurochemical profiles for metabolites (NAA+NAAG, Cr+PCr, Glu+Gln (Glx), Lac, Ins, GPC+PCho) and total Lipids (tLip) and macromolecule (tMM) signals were estimated. Concentrations were reported as either absolute or ratios to total choline (tCho=GPC+PCho) and creatine (tCr=Cr+PCr) levels. Voxels of interest (VOIs) in a MRSI matrix were labelled accordingly to contrast-enhancing/nonenhancing lesional, edema, ipsi- or contralateral healthy appearing tissue and the metabolite averages were reported for each tissue type. Multi-biometric analysis with logistic regression, ROC- and Kaplan-Meier survival analysis was performed in SPSS v.24 and postprocessing with LC Model. Results Across HGG/LGG/MET; the average Ins/tCho was shown to be prognostic for overall survival (OS): with low values (≤1.29) in affected hemisphere predicting worse OS than high values (>1.29), (Log Rank
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| 4. |
- Pratt, G D, et al.
(författare)
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Differential regulation of N-methyl-D-aspartate receptor subunit messenger RNAs in kindling-induced epileptogenesis
- 1993
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Ingår i: Neuroscience. - 0306-4522. ; 57:2, s. 18-307
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Tidskriftsartikel (refereegranskat)abstract
- N-methyl-D-aspartate-receptors are implicated in several neuropathological conditions including epilepsy. As a model of complex partial seizures, rapid hippocampal kindling was chosen to investigate changes in the expression of messenger RNAs encoding the N-methyl-D-aspartate-receptor subunits NR1, NR2A and NR2B both during and in the period immediately following the induction of the kindled state. The study demonstrates a cell-specific, time-dependent modulation of the N-methyl-D-aspartate-receptor subunit messenger RNAs almost entirely restricted to the granule cells of the dentate gyrus. In partially kindled animals (10 stimulations), while the NR1 subunit messenger RNA remained unaltered after a period of 2 h, the NR2A and NR2B subunit messenger RNAs were bilaterally reduced in dentate gyrus granule cells by around 50% below control values. In fully kindled animals (40 stimulations), a progressive reduction in NR1 subunit messenger RNA levels in the dentate gyrus was observed, being maximal after 4 h (-67%). At the same time point, NR2A and NR2B transcript levels were transiently increased by 102% and 46% above control values, respectively. These data point to a differential regulation of N-methyl-D-aspartate-receptor subunit messenger RNAs. No alterations were detected in pyramidal cells. Long-term maintenance of the kindled state was not associated with alterations in N-methyl-D-aspartate-receptor subunit messenger RNAs since control levels of messenger RNA were attained by 12 h and persisted for at least five days. The early changes in messenger RNAs described in this study indicate that the expression of N-methyl-D-aspartate-receptor subunits is under independent regulatory control. This phenomenon may contribute to epileptogenesis and to kindling-associated plasticity by mediating a structural reorganization of N-methyl-D-aspartate-receptors, leading to an altered excitability of dentate gyrus granule cells.
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| 5. |
- Rydelius, A., et al.
(författare)
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Predictive value of diffusion MRI-based parametric response mapping for prognosis and treatment response in glioblastoma
- 2023
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Ingår i: Magnetic Resonance Imaging. - 0730-725X. ; 104, s. 88-96
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Tidskriftsartikel (refereegranskat)abstract
- Background: Early detection of treatment response is important for the management of patients with malignant brain tumors such as glioblastoma to assure good quality of life in relation to therapeutic efficacy. Aim: To investigate whether parametric response mapping (PRM) with diffusion MRI may provide prognostic information at an early stage of standard therapy for glioblastoma. Materials and methods: This prospective study included 31 patients newly diagnosed with glioblastoma WHO grade IV, planned for primary standard postoperative treatment with radiotherapy 60Gy/30 fractions with concomitant and adjuvant Temozolomide. MRI follow-up including diffusion and perfusion weighting was performed at 3 T at start of postoperative chemoradiotherapy, three weeks into treatment, and then regularly until twelve months postoperatively. Regional mean diffusivity (MD) changes were analyzed voxel-wise using the PRM method (MD-PRM). At eight and twelve months postoperatively, after completion of standard treatment, patients were classified using conventional MRI and clinical evaluation as either having stable disease (SD, including partial response) or progressive disease (PD). It was assessed whether MD-PRM differed between patients having SD versus PD and whether it predicted the risk of disease progression (progression-free survival, PFS) or death (overall survival, OS). A subgroup analysis was performed that compared MD-PRM between SD and PD in patients only undergoing diagnostic biopsy. MGMT-promotor methylation status (O6-methylguanine-DNA methyltransferase) was registered and analyzed with respect to PFS, OS and MD-PRM. Results: Of the 31 patients analyzed: 21 were operated by resection and ten by diagnostic biopsy. At eight months, 19 patients had SD and twelve had PD. At twelve months, ten patients had SD and 20 had PD, out of which ten were deceased within twelve months and one was deceased without known tumor progression. Median PFS was nine months, and median OS was 17 months. Eleven patients had methylated MGMT-promotor, 16 were MGMT unmethylated, and four had unknown MGMT-status. MD-PRM did not significantly predict patients having SD versus PD neither at eight nor at twelve months. Patients with an above median MD-PRM reduction had a slightly longer PFS (P = 0.015) in Kaplan-Maier analysis, as well as a non-significantly longer OS (P = 0.099). In the subgroup of patients only undergoing biopsy, total MD-PRM change at three weeks was generally higher for patients with SD than for patients with PD at eight months, although no tests were performed. MGMT status strongly predicted both PFS and OS but not MD-PRM change. Conclusion: MD-PRM at three weeks was not demonstrated to be predictive of treatment response, disease progression, or survival. Preliminary results suggested a higher predictive value in non-resected patients, although this needs to be evaluated in future studies.
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| 6. |
- Silverberg, E., et al.
(författare)
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Comparison of citrated and fresh whole blood for viscoelastic coagulation testing during elective neurosurgery
- 2017
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Ingår i: Thrombosis Research. - : Elsevier BV. - 0049-3848. ; 156, s. 73-79
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Tidskriftsartikel (refereegranskat)abstract
- Background Previous viscoelastic haemostatic tests studies have often indicated a hypercoagulative test signal with citrated blood, which could influence clinical decision makings. Purpose The aim of this study was to compare fresh and citrated whole blood using two non-automated viscoelastic ROTEM and Sonoclot tests. Our hypothesis was that citrated blood would demonstrate a hypercoagulative response in this setting, not tested before. Methods Perioperative viscoelastic coagulation changes were evaluated with a ROTEM and Sonoclot in 38 patients undergoing elective brain tumor surgery. The citrated samples were recalcified with CaCl2. Wilcoxon nonparametric-paired tests and Bland-Altman plots were performed to compare the fresh and citrated blood analyses. Results The citrated blood showed a hypercoagulative response in ROTEM NATEM-clot formation time and α-angle, Sonoclot-clot rate and platelet function, as compared to fresh blood (p < 0.0001). Conclusions Fresh whole blood may theoretically reflect in vivo haemostasis more closely than citrated analyses, which indicated a hypercoagulative response as compared to the fresh whole blood analyses Bland-Altman plots also indicated that ROTEM reference ranges in patients undergoing brain surgery should be redefined. Future studies must establish the correlation between viscoelastic test results using fresh or citrate anticoagulated blood and clinical outcomes, such as bleeding, transfusion or reoperation for postoperative haematoma.
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| 7. |
- Wickham, J., et al.
(författare)
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Prolonged life of human acute hippocampal slices from temporal lobe epilepsy surgery
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Resected hippocampal tissue from patients with drug-resistant epilepsy presents a unique possibility to test novel treatment strategies directly in target tissue. The post-resection time for testing and analysis however is normally limited. Acute tissue slices allow for electrophysiological recordings typically up to 12 hours. To enable longer time to test novel treatment strategies such as, e.g., gene-therapy, we developed a method for keeping acute human brain slices viable over a longer period. Our protocol keeps neurons viable well up to 48 hours. Using a dual-flow chamber, which allows for microscopic visualisation of individual neurons with a submerged objective for whole-cell patch-clamp recordings, we report stable electrophysiological properties, such as action potential amplitude and threshold during this time. We also demonstrate that epileptiform activity, monitored by individual dentate granule whole-cell recordings, can be consistently induced in these slices, underlying the usefulness of this methodology for testing and/or validating novel treatment strategies for epilepsy.
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| 8. |
- Bengzon, J, et al.
(författare)
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Regulation of neurotrophin and trkA, trkB and trkC tyrosine kinase receptor messenger RNA expression in kindling
- 1993
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Ingår i: Neuroscience. - 0306-4522. ; 53:2, s. 433-446
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Tidskriftsartikel (refereegranskat)abstract
- Levels of messenger RNA for nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and the tyrosine kinase receptors trkA, trkB and trkC have been studied using in situ hybridization in the rat brain 2 h and four weeks after kindling-induced seizures. Epileptiform activity evoked by hippocampal stimulation and exceeding 70 s lead to a concomitant and transient increase of brain- derived neurotrophic factor, nerve growth factor, trkB and trkC messenger RNA expression in dentate granule cells after both focal and generalized seizures. Brain-derived neurotrophic factor messenger RNA levels were also increased bilaterally in the CA1-CA3 regions, amygdala and the piriform, entorhinal, perirhinal, retrosplenial and temporal cortices after generalized seizures. The magnitude of the increases was similar throughout the development of kindling and in the fully kindled brain. No changes of trkA messenger RNA were observed. In amygdalar kindling, elevated brain-derived neurotrophic factor messenger RNA levels developed more rapidly in the amygdala-piriform cortex than after stimulation in the hippocampus but changes in the hippocampal formation were only seen in few animals. Intraventricular 6-hydroxydopamine or a bilateral fimbria-fornix lesion did not alter basal expression or seizure-evoked changes in messenger RNA levels for neurotrophins or trk receptors but increased the number of animals exhibiting elevated levels after the first stimulation, probably due to a prolongation of seizure activity. Both in sham-operated and fimbria-fornix-lesioned rats seizure activity caused a marked reduction of neurotrophin-3 messenger RNA levels in dentate granule cells. The results indicate that activation of the brain-derived neurotrophic factor gene, at least in dentate granule cells, is an "all-or-none" type of response and dependent on the duration but not the severity of seizures or the stage of kindling epileptogenesis. Changes in brain-derived neurotrophic factor, nerve growth factor, neurotrophin-3 and trkB and trkC were observed concomitantly in the dentate gyrus, which suggests that seizure activity sets in motion a cascade of genomic events possibly mediated via a common mechanism. Since altered messenger RNA levels outside hippocampus were detected only for brain-derived neurotrophic factor, neurotrophin and trk gene expression in these regions seems to be regulated differently.
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| 9. |
- Bengzon, Johan, et al.
(författare)
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Regulation of norepinephrine transporter and tyrosine hydroxylase mRNAs after kainic acid-induced seizures
- 1999
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Ingår i: Brain Research. - 0006-8993. ; 842:1, s. 239-242
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Tidskriftsartikel (refereegranskat)abstract
- Noradrenergic locus coeruleus (LC) efferents to the forebrain suppress seizures in several models of epilepsy. Using in situ hybridization, we demonstrate that tyrosine hydroxylase (TH) and norepinephrine transporter (NET) but not vesicular monoamine transporter 2 (VMAT2) mRNA levels are transiently elevated in LC neurons following kainic acid-induced status epilepticus. These increases of TH and NET mRNAs and presumably of the proteins themselves might enhance synthesis and reuptake of NE postictally.
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| 10. |
- Bexell, Daniel, et al.
(författare)
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Characterization of the subventricular zone neurogenic response to rat malignant brain tumors
- 2007
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Ingår i: Neuroscience. - : Elsevier BV. - 1873-7544 .- 0306-4522. ; 147:3, s. 824-832
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Tidskriftsartikel (refereegranskat)abstract
- The subventricular zone (SVZ) is one of the neurogenic regions of the adult brain. We characterized the neurogenic response of the SVZ to the growth of brain tumors in the rat striatum. Abundant nestin positive cells, most likely representing reactive astrocytes, were found surrounding the tumor. However, we observed no substantial migration of nestin positive cells from the SVZ toward the tumor. Tumor growth resulted in decreased numbers of bromodeoxyuridine positive and Ki-67 positive proliferating cells and a concomitant increase in doublecortin and polysialylated neural cell adhesion molecule immunoreactivity within the SVZ. Neuroblasts were observed in high numbers in the area between the SVZ and the tumor, most likely pointing to the SVZ as the principal source of these cells. Neuroblasts located between the SVZ and the tumor expressed the transcription factor Pbx, a marker for immature striatal neurons. However, no evidence of neuroblast differentiation into fully mature neurons was found. This study thus demonstrates increased neuroblast immunoreactivity within the SVZ ipsilateral to a brain tumor in the striatum. SVZ-derived neuroblasts attracted by the tumor adopt an immature striatal phenotype indicating a region specific reparative mechanism in response to a malignant tumor. (C) 2007 IBRO. Published by Elsevier Ltd. All rights reserved.
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