The synergistic effect of radiation and inhibition of SPAK/OSR1 in the reduction of cell proliferation and clonogenic potential in patient-derived GBM cells in vitro

Glioblastoma (GBM) is the most aggressive brain tumor in adults. Cell invasion, migration and proliferation into the heathy brain parenchyma it’s one of the most important challenges in the treatment of this deadly tumor. One potential mechanism that GBM cells can utilize to enhance cell migration and evade pro-apoptotic signals is the tight regulation of cell volume by the STE20/SPS1-Related Proline-Alanine-Rich Protein Kinase (SPAK) and (Oxidative Stress Responsive Kinase 1) OSR1 kinases. Dynamic changes in cell volume can be used by GBM cells to disseminate through the narrow perivascular spaces of the brain. In addition, cancer cells could counteract pro-apoptotic reduction of cell volume by increasing the activity of these kinases. The objective of this project is to test the efficacy of SPAK and OSR1 inhibition alone or in combination with radiotherapy. For this purpose we evaluated the impact of this novel therapy on the proliferation, clonogenicity and apoptosis of primary patient-derived GBM cells in vitro. To achieve our goal we tested a novel SPAK/OSR1 inhibitor (a small molecule called YU566) in two patient derived GBM lines. Cell proliferation and colony formation were determined after treatment using 1uM YU566 alone or in combination with radiotherapy (at different doses 2, 4 Gray (Gy)). We found that radiation and inhibition of SPAK/OSR1 could act in a synergistic fashion, decreasing cell proliferation and clonogenic potential. The next steps in our research will be to determine the mechanisms of cell death and the implications of this therapy in vivo

Use of Mesenchymal Stem Cells in Pre-Clinical Models of Spinal Cord Injury

Spinal Cord Injury (SCI) is a devastating disease that causes disruption of sensorimotor function below the site of injury. Current management is based on surgical decompression of the neural tissue and pharmacotherapy; however, there is no gold standard treatment readily available for patients in the clinic. This indicates that novel therapeutic strategies for the treatment are still needed in the clinical setting. There are several alternatives that are currently under investigation for the treatment of this disease, with increasing focus in regenerative medicine treatments. Mesenchymal stem cells (MSCs) are one of the most promising candidates for stem cell therapy in SCI, as they are easily obtained, have high safety profiles, and help with neural regeneration in SCI mainly via release of trophic factors, neovascularization, and immunomodulation. In this work, authors provide an insight of the available MSC for neural regeneration, their therapeutic role, and the potential MSC-based therapies for SCI

Primary and Specialist Palliative Care in Neurosurgery: A Narrative Review and Bibliometric Analysis of Glioblastoma and Stroke

OBJECTIVE: Due to the increased demand for palliative care (PC) in recent years, a model has been proposed to divide PC into primary PC and specialist PC. This article aimed to delineate the indications for primary and specialist PC within 2 common neurosurgical conditions-glioblastoma (GBM) and stroke. METHODS: A systematic review and bibliometric analysis was conducted to better appreciate the practice trends in PC utilization for GBM and stroke patients using several databases. RESULTS: There were 70 studies on PC for GBM, the majority of which related to patient preference (22 [31%]). During 1999-2022, there was significant growth in publications per year on this topic at a rate of approximately 0.3 publications per year (P \u3c 0.01). There were 44 studies on PC for stroke, the majority of which related to communication strategies (14 [32%]). During 1999-2022, there was no significant growth in stroke publications per year (P = 0.22). CONCLUSIONS: Due to the progressively disabling neurological course of GBM, we suggest that a specialty PC team be used in conjunction with the neurosurgical team early in the disease trajectory while patients are still able to communicate their preferences, goals, and values. In contrast, short-term and long-term stages of management of stroke have differing implications for PC needs, with the short-term stage necessitating adept, time-sensitive communication between the patient, family, and care teams. Thus, we propose that primary PC should be included as a core competency in neurosurgery training, among other stroke specialists

Influence of Platelet Count on Procedure-Related Outcomes After Mechanical Thrombectomy for Large Vessel Occlusion: A Systematic Review and Meta-Analysis

To compare outcomes between patients who underwent mechanical thrombectomy for large vessel occlusion based on platelet count: low versus normal. Three studies were included with a pooled cohort of 1125 patients. Data points were collected and pooled by meta-analysis of proportions via a logit transformation to provide a summary statistic. Both fixed-effect and random-effects models were recruited for the analysis. In this meta-analysis, risk of developing symptomatic intracranial hemorrhage, unfavorable clinical outcomes (modified Rankin Scale score >3), and mortality of patients with low platelet counts were compared with patients with normal platelet counts according to the criteria for inclusion used by each study. Of patients, 50 (4.7%) had low platelet count, and 1075 (95.3%) had normal platelet count. Patients in the low platelet count group had a substantially higher risk of mortality (risk ratio 1.93, 95% confidence interval 1.43–2.60, P < 0.0001, I2 = 0%), but no differences in clinical outcomes (risk ratio 0.66, 95% confidence interval 0.40–1.11, P = 0.12, I2 = 0%) or symptomatic intracranial hemorrhage (risk ratio 2.03, 95% confidence interval 0.87–4.70, P = 0.10, I2 = 15%) were noted. Patients with low platelet counts had increased mortality compared with patients with normal platelet counts following mechanical thrombectomy for large vessel occlusion

Melatonin Treatment Triggers Metabolic and Intracellular pH Imbalance in Glioblastoma

Metabolic rewiring in glioblastoma (GBM) is linked to intra- and extracellular pH regulation. In this study, we sought to characterize the role of melatonin on intracellular pH modulation and metabolic consequences to identify the mechanisms of action underlying melatonin oncostatic effects on GBM tumor initiating cells. GBM tumor initiating cells were treated at different times with melatonin (1.5 and 3.0 mM). We analyzed melatonin’s functional effects on GBM proliferation, cell cycle, viability, stemness, and chemo-radiosensitivity. We then assessed the effects of melatonin on GBM metabolism by analyzing the mitochondrial and glycolytic parameters. We also measured the intracellular and extracellular pH. Finally, we tested the effects of melatonin on a mouse subcutaneous xenograft model. We found that melatonin downregulated LDHA and MCT4, decreasing lactate production and inducing a decrease in intracellular pH that was associated with an increase in ROS and ATP depletion. These changes blocked cell cycle progression and induced cellular death and we observed similar results in vivo. Melatonin’s cytotoxic effects on GBM were due, at least in part, to intracellular pH modulation, which has emerged as a newly identified mechanism, providing new insights into the oncostatic effect of melatonin on GBM