Changes in Brain Energy and Membrane Metabolism in Glioblastoma following Chemoradiation.
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ABSTRACT:
SUBMITTER: Grams AE
PROVIDER: S-EPMC8700426 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionThere is growing evidence that the subventricular zone (SVZ) plays a key role in glioblastoma (GBM) tumorigenesis. However, little is known regarding how the SVZ, which is a harbor for adult neural stem cells, may be influenced by chemoradiation. The current diffusion-weighted imaging (DWI) study explored ipsilateral and contralateral alterations in the anterior SVZ in GBM patients with posterior enhancing lesions following chemoradiation.MethodsForty GBM patients with tumor involvement in the posterior SVZ (mean age = 57 ± 10; left-hemisphere N = 25; right-hemisphere N = 15) were evaluated using DWI before and after chemoradiation. Regions-of-interest were drawn on the ipsilesional and contralesional anterior SVZ on apparent diffusion coefficient (ADC) maps for both timepoints. ADC histogram analysis was performed by modeling a bimodal, double Gaussian distribution to obtain ADCL, defined as the mean of the lower Gaussian distribution.ResultsThe ipsilesional SVZ had lower ADCL values compared to the contralesional SVZ before treatment (mean difference = 0.025 μm2/ms; P = 0.007). Following chemoradiation, these changes were no longer observed (mean difference = 0.0025 μm2/ms; P > 0.5), as ADCL values of the ipsilesional SVZ increased (mean difference = 0.026 μm2/ms; P = 0.037). An increase in ipsilesional ADCL was associated with shorter progression-free (P = 0.0119) and overall survival (P = 0.0265).ConclusionsThese preliminary observations suggest baseline asymmetry as well as asymmetric changes in the SVZ proximal (ipsilesional) to the tumor with respect to contralesional SVZ regions may be present in GBM, potentially implicating this region in tumorigenesis and/or treatment resistance.
| S-EPMC7769136 | biostudies-literature
Project description:ObjectiveTo investigate the effects of chemotherapy and cranial irradiation on normal brain tissue using in vivo neuroimaging in patients with glioblastoma.MethodsWe used longitudinal MRI to monitor structural brain changes during standard treatment in patients newly diagnosed with glioblastoma. We assessed volumetric and diffusion tensor imaging measures in 14 patients receiving 6 weeks of chemoradiation, followed by up to 6 months of temozolomide chemotherapy alone. We examined changes in whole brain, gray matter (GM), white matter (WM), anterior lateral ventricle, and hippocampal volumes. Normal-appearing GM, WM, and hippocampal analyses were conducted within the hemisphere of lowest/absent tumor burden. We examined diffusion tensor imaging measures within the subventricular zone.ResultsWhole brain (F = 2.41; p = 0.016) and GM (F = 2.13; p = 0.036) volume decreased during treatment, without significant WM volume change. Anterior lateral ventricle volume increased significantly (F = 65.51; p < 0.001). In participants analyzed beyond 23 weeks, mean ventricular volume increased by 42.2% (SE: 8.8%; t = 4.94; p < 0.005). Apparent diffusion coefficient increased within the subventricular zone (F = 7.028; p < 0.001). No significant changes were identified in hippocampal volume.ConclusionsWe present evidence of significant and progressive treatment-associated structural brain changes in patients with glioblastoma treated with standard chemoradiation. Future studies using longitudinal neuropsychological evaluation are needed to characterize the functional consequences of these structural changes.
| S-EPMC4553035 | biostudies-literature
Project description:Background: Glioblastoma multiforme (GBM) is a highly malignant primary brain tumor with infiltration of, on conventional imaging, normal-appearing brain parenchyma. Phosphorus magnetic resonance spectroscopy (31P-MRS) enables the investigation of different energy and membrane metabolites. The aim of this study is to investigate regional differences of 31P-metabolites in GBM brains. Methods: In this study, we investigated 32 patients (13 female and 19 male; mean age 63 years) with naïve GBM using 31P-MRS and conventional MRI. Contrast-enhancing (CE), T2-hyperintense, adjacent and distant ipsilateral areas of the contralateral brain and the brains of age- and gender-matched healthy volunteers were assessed. Moreover, the 31P-MRS results were correlated with quantitative diffusion parameters. Results: Several metabolite ratios between the energy-dependent metabolites and/or the membrane metabolites differed significantly between the CE areas, the T2-hyperintense areas, the more distant areas, and even the brains of healthy volunteers. pH values and Mg2+ concentrations were highest in visible tumor areas and decreased with distance from them. These results are in accordance with the literature and correlated with quantitative diffusion parameters. Conclusions: This pilot study shows that 31P-MRS is feasible to show regional differences of energy and membrane metabolism in brains with naïve GBM, particularly between the different "normal-appearing" regions and between the contralateral hemisphere and healthy controls. Differences between various genetic mutations or clinical applicability for follow-up monitoring have to be assessed in a larger cohort.
| S-EPMC8199363 | biostudies-literature
Project description:GSK3β is a serine threonine kinase implicated in the progression of Alzheimer's disease. Although the role of GSK3β in growth and pathology has been extensively studied, little is known about the metabolic consequences of GSK3β manipulation, particularly in the brain. Here, we show that GSK3β regulates mitochondrial energy metabolism in human H4 neuroglioma cells and rat PC12-derived neuronal cells and that inhibition of GSK3β in mice in vivo alters metabolism in the hippocampus in a region-specific manner. We demonstrate that GSK3β inhibition increases mitochondrial respiration and membrane potential and alters NAD(P)H metabolism. These metabolic effects are associated with increased PGC-1α protein stabilization, enhanced nuclear localization, and increased transcriptional co-activation. In mice treated with the GSK3β inhibitor lithium carbonate, changes in hippocampal energy metabolism are linked to increased PGC-1α. These data highlight a metabolic role for brain GSK3β and suggest that the GSK3β/PGC-1α axis may be important in neuronal metabolic integrity.
| S-EPMC6082412 | biostudies-literature
Project description:Precise assessment of treatment response in glioblastoma during combined anti-angiogenic and chemoradiation remains a challenge. In particular, early detection of treatment response by standard anatomical imaging is confounded by pseudo-response or pseudo-progression. Metabolic changes may be more specific for tumor physiology and less confounded by changes in blood-brain barrier permeability. We hypothesize that metabolic changes probed by magnetic resonance spectroscopic imaging can stratify patient response early during combination therapy. We performed a prospective longitudinal imaging study in newly diagnosed glioblastoma patients enrolled in a phase II clinical trial of the pan-vascular endothelial growth factor receptor inhibitor cediranib in combination with standard fractionated radiation and temozolomide (chemoradiation). Forty patients were imaged weekly during therapy with an imaging protocol that included magnetic resonance spectroscopic imaging, perfusion magnetic resonance imaging, and anatomical magnetic resonance imaging. Data were analyzed using receiver operator characteristics, Cox proportional hazards model, and Kaplan-Meier survival plots. We observed that the ratio of total choline to healthy creatine after 1 month of treatment was significantly associated with overall survival, and provided as single parameter: (1) the largest area under curve (0.859) in receiver operator characteristics, (2) the highest hazard ratio (HR = 85.85, P = 0.006) in Cox proportional hazards model, (3) the largest separation (P = 0.004) in Kaplan-Meier survival plots. An inverse correlation was observed between total choline/healthy creatine and cerebral blood flow, but no significant relation to tumor volumetrics was identified. Our results suggest that in vivo metabolic biomarkers obtained by magnetic resonance spectroscopic imaging may be an early indicator of response to anti-angiogenic therapy combined with standard chemoradiation in newly diagnosed glioblastoma.
| S-EPMC5708878 | biostudies-literature
Project description:Regional brain glucose use was measured in rats with streptozotocin-induced diabetes (65 mg/kg intravenously) of 1 or 4 weeks duration, by using [6-14C]glucose and quantitative autoradiography. The concentrations of several metabolites were measured in plasma and brain. Results were compared with those from normal untreated rats. Glucose concentrations were increased in both plasma and brain, to similar degrees in both diabetic groups. Plasma ketone-body concentrations were 0.25, 1.0, and 3.15 mumol/ml in the control, 1-week and 4-week groups respectively (sum of acetoacetate and 3-hydroxybutyrate). Glucose use was increased throughout the brain (differences were statistically significant in 55 of 59 brain areas) after 1 week of diabetes, with an increase of 25% for the brain as a whole. In contrast, normal rates were found throughout the brain after 4 weeks of diabetes. None of the brain areas was affected significantly differently from the others, in either diabetic group. There was no significant loss of 14C as lactate or pyruvate during the experimental period, nor was there any indication of net production of lactate in any of the groups. Other methodological considerations that could have affected the results obtained in the diabetic rats were likewise ruled out. Because the ketone bodies are expected to supplement glucose as a metabolic fuel for the brain, our results indicate that brain energy consumption is increased during streptozotocin-diabetes.
| S-EPMC1148665 | biostudies-other
Project description:Introduction: Temozolomide (TMZ) is part of the standard of care for treating glioblastoma multiforme (GBM), an aggressive primary brain tumor. New approaches are needed to enhance therapeutic efficacy and reduce toxicity. GBM tumor cells are dependent on glucose and glutamine while relying heavily on aerobic fermentation for energy metabolism. Restricted availability of glucose and glutamine may therefore reduce disease progression. Calorically restricted ketogenic diets (KD-R), which reduce glucose and elevate ketone bodies, offer a promising alternative in targeting energy metabolism because cancer cells cannot effectively burn ketones due to defects in the number, structure, and function of mitochondria. Similarly, oxaloacetate, which participates in the deamination of glutamate, has the potential to reduce the negative effects of excess glutamate found in many brain tumors, while hyperbaric oxygen therapy can reverse the hypoxic phenotype of tumors and reduce growth. We hypothesize that the combinatorial therapy of KD-R, hyperbaric oxygen, and oxaloacetate, could reduce or eliminate the need for TMZ in GBM patients. Methods: Our proposed approach for inhibiting tumor metabolism involved various combinations of the KD-R, oxaloacetate (2 mg/g), hyperbaric oxygen, and TMZ (20 mg/kg). This combinatorial therapy was tested on adult VM/Dk mice bearing the VM-M3/Fluc preclinical GBM model grown orthotopically. After 14 days, tumor growth was quantified via bioluminescence. A survival study was performed and the data were analyzed and portrayed in a Kaplan Meier plot. Preliminary dosage studies were used and strict diet and drug administration was maintained throughout the study. Results: The therapeutic effect of all treatments was powerful when administered under KD-R. The most promising survival advantage was seen in the two groups receiving oxaloacetate without TMZ. The survival of mice receiving TMZ was diminished due to its apparent toxicity. Among all groups, those receiving TMZ had the most significant reduction in tumor growth. The most powerful therapeutic effect was evident with combinations of these therapies. Conclusion: This study provides evidence for a potentially novel therapeutic regimen of hyperbaric oxygen, oxaloacetate, and the KD-R for managing growth and progression of VM-M3/Fluc GBM.
| S-EPMC6186985 | biostudies-literature
Project description:Glioblastoma is a high-grade glial neoplasm with a patient survival of 12-18 months. Therefore, the identification of novel therapeutic targets is an urgent need. RAB38 is a GTPase protein implicated in regulating cell proliferation and survival in tumors. The role of RAB38 in glioblastoma is relatively unexplored. Here, we test the hypothesis that RAB38 regulates glioblastoma growth using human glioblastoma cell lines. We found that genetic interference of RAB38 resulted in a decrease in glioblastoma growth through inhibition of proliferation and cell death induction. Transcriptome analysis showed that RAB38 silencing leads to changes in genes related to mitochondrial metabolism and intrinsic apoptosis (e.g., Bcl-xL). Consistently, rescue experiments demonstrated that loss of RAB38 causes a reduction in glioblastoma viability through downregulation of Bcl-xL. Moreover, RAB38 knockdown inhibited both glycolysis and oxidative phosphorylation. Interference with RAB38 enhanced cell death induced by BH3-mimetics. RAB38 antagonists are under development, but not yet clinically available. We found that FDA-approved statins caused a rapid reduction in RAB38 protein levels, increased cell death, and phenocopied some of the molecular changes elicited by loss of RAB38. In summary, our findings suggest that RAB38 is a potential therapeutic target for glioblastoma treatment.
| S-EPMC8306361 | biostudies-literature
Project description:PurposeTo evaluate the time course of changes in the thickness of retinal layers after epiretinal membrane (ERM) removal surgery.MethodsA retrospective cohort study of patients following surgery for idiopathic ERM. We used new specialized image analysis software to create a thickness map of each retinal layer and analyzed changes during one year follow-up. Healthy fellow eyes were used as negative controls and the retina prior to surgery as positive control.ResultsTwenty-one patients were included with a mean age of 68±13 years. Central macular thickness decreased steadily until 6 months after surgery (25% decrease, 516±76 to 386±73 μm, P<0.001) with no further decrease between 6 and 12 months (386±73 to 390±73 μm, P=0.291). The retinal nerve fiber layer (RNFL), and the ganglion cell and inner plexiform layer (GCIPL) were most affected (57%, P<0.001 and 27%, P=0.010, respectively). The thickest region showed a more abrupt decrease of 21% at first follow-up (504±61 to 399±58 μm, P=0.001) with subsequent decrements of about 3%. Prior to surgery all retinal layers were thicker in study eyes compared with healthy control eyes (6-63%, all P<0.05).ConclusionsFollowing ERM surgery, in the course of 6 months, the macula gradually becomes thinner after which a stable state is reached. All layers appear to be affected, with the RNFL and GCIPL impacted the most. Our results provide a unique view on how the thickness of different retinal layers changes following ERM surgery.
| S-EPMC5848276 | biostudies-literature
Project description:The processing and perception of individual internal bodily signals (interoception) has been differentiated to comprise different levels and processes involved. The so-called heartbeat-evoked potential (HEP) offers an additional possibility to examine automatic processing of cardiac signals. Knowledge on neural structures potentially supporting different facets of interoception is still sparse. One way to get insights into neuroanatomical function is to manipulate the activity of different brain structures. In this study, we used repetitive transcranial magnetic stimulation (rTMS) and a continuous theta-burst protocol to inhibit specific central locations of the interoceptive network including the right anterior insula and the right somatosensory cortices and assessed effects on interoceptive facets and the HEP in 18 male participants. Main results were that inhibiting anterior insula resulted in a significant decline in cardiac and respiratory interoceptive accuracy (IAc) and in a consistent decrease in perception confidence. Continuous theta-burst stimulation (cTBS) over somatosensory cortices reduced only cardiac IAc and affected perception confidence. Inhibiting right anterior insula and right somatosensory cortices increased interoceptive sensibility and reduced the HEP amplitude over frontocentral locations. Our findings strongly suggest that cTBS is an effective tool to investigate the neural network supporting interoceptive processes.This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'.
| S-EPMC5062104 | biostudies-literature