Sodium-fluorescein-guided awake surgery for cerebral metastases located in eloquent brain areas: technical notes and preliminary experiences.

Background/aim: Awake craniotomy (AC) maximizes the resection of lesions in eloquent brain areas while preserving functionality. Tumor delineation with intraoperative use of sodium fluorescein (NaFl) facilitates total resection. When used with AC, it may allow for safe resection without increasing the risk of postoperative neurologic deficits. This study investigated the efficacy and safety of the combined use of NaFl and AC for maximum safe resection in patients with brain metastases. Material and methods: Patients who underwent AC due to brain metastasis in the Department of Neurosurgery of Uludag University's Faculty of Medicine between January 1, 2018 and August 1, 2022, were retrospectively analyzed. The study comprised 2 patient groups: plain AC (pAC) and NaFl-guided AC (NaFlg-AC). Surgical outcomes related to fluorescence intensity, degree of resection, perioperative complications, and postoperative neurological factors were evaluated. Results: The pAC group included 16 patients (12 males, 4 females), and the NaFlg-AC group comprised 21 (13 males, 7 females). The mean patient ages for males and females were 61.4 years (61.4 ± 9.5 years) and 60.4 years (60.6 ± 12 years), respectively. The most common origin of the metastatic lesion was the lung in both the pAC and NaFlg-AC groups (n = 12 vs. n = 14, respectively). Gross total resection (GTR) was achieved in 85.7% of the patients in the NaFlg-AC group, whereas the GTR rate was 68.7% in the pAC group. There was no significant difference in GTR rates between the 2 groups (p = 0.254). The mean duration of the resection time was significantly shorter in the NaFlg-AC group (45.95 ± 7.00 min vs. 57.5 ± 12.51 min; p = 0.002). The patients' Karnofsky Performance Status (KPS) score did not reach statistical significance at 6-month follow-up in either group compared to their preoperative baseline scores (p = 0.374). KPS did not show a significant difference between the 2 groups at any time. Conclusion: Fluorescence-guided resection in AC for metastatic tumors in sensory, motor, and cognitive areas is a feasible, safe, and convenient technique that significantly increases GTR rates and shortens operative time compared to conventional white light surgery without fluorescence guidance. It also does not increase the incidence of postoperative complications. With the combined use of AC and NaFl, ensuring clear and visible tumor margins during surgery and controlling patients' neurological function in real-time are possible.

NEAT1 Is a Novel Oncogenic LncRNA and Correlated with miR-143 in Pediatric Oligodendrogliomas.

INTRODUCTION: The noncoding RNAs (ncRNAs) play a role in biological processes of various cancers including gliomas. The majority of these transcripts are uniquely expressed in differentiated tissues or specific glioma types. Pediatric oligodendroglioma (POG) is a rare subtype of diffuse glioma and accounts for <1% of pediatric brain tumors. Because histologically POG resembles adult OG, the same treatment is applied as adults. However, the significance in predicting outcomes in POG patients is unclear. In this study, we aimed to investigate the prognostic significance of expression -profiles of microRNA (miRNA) and long noncoding RNA -(LncRNA) in POGs. METHODS: We investigated the levels of 13 known miRNAs and 6 LncRNAs in tumor samples from 9 patients with primary POG by using RT-PCR and analyzed their association with outcomes. RESULTS: The expression levels of miR-21, miR-106a, miR-10b, and LncRNA NEAT1 were higher, and the expression level of miR-143 was lower in POG tissues compared with normal brain tissues (p = 0.006, p = 0.032, p = 0.034, p = 0.002, and p = 0.001, respectively). High levels of NEAT1 and low expression of miR-143 were associated with decreased probability of short disease-free survival (p = 0.018 and p = 0.022, respectively). DISCUSSION: NEAT1 and miR-143 levels could serve as reciprocal prognostic predictors of disease progression in patients with POG. New treatment models to regulate the expression levels of NEAT1 and miR-143 will bring a new approach to the therapy of POG.

CT-Guided Percutaneous Trigeminal Tractotomy-Nucleotomy for Intractable Craniofacial Pain.

OBJECT: In this report, we aimed to analyze the outcome results of our patients who underwent percutaneous trigeminal tractotomy (TR) and nucleotomy (NC) procedures, which are defined as destructive procedures targeting the descending trigeminal tractus and nucleus caudalis of the spinal trigeminal nucleus, respectively, for intractable craniofacial pain. METHODS: The medical records of a total of 12 patients who underwent a total of 14 computed tomography (CT)-guided TR-NC procedures at our clinics between 2005 and 2017 were retrospectively reviewed. RESULTS: A significant increase in patients' performance status (p = 0.015) as well as a significant decrease in the VAS score (p < 0.001) were achieved. Grade I pain relief (VAS = 0, no pain) was established in 66.7% of the patients, whereas grade II pain relief was observed in the remaining patients. Two of the patients suffered from recurrent pain after the initial procedure. Both patients underwent a second trigeminal TR-NC procedure, and grade I pain relief was re-established. The mean VAS score at 3-month follow-up was 1.4 ± 1.1, whereas this score at 6-month follow-up was 2 ± 1.3. The trigeminal TR-NC procedure resulted in a significant decrease in patients' VAS scores at 3- and 6-month follow-up visits compared with preoperative VAS scores (p < 0.001). Transient ataxia was noted in only one patient (8.3%) early after the procedure. CONCLUSIONS: The results presented in the current study support the efficacy of the percutaneous CT-guided trigeminal TR-NC procedure in the management of intractable facial pain in selected patients. The use of CT guidance allows direct visualization of the target area, thereby enhancing the safety and success of the procedure.

Nuances to provide ideas for radiologic diagnosis in primary spinal paragangliomas: report of two cases.

Spinal paragangliomas are rarely-observed neuroendocrine benign tumors in the extra-adrenal paraganglionic system. Primary spinal involvement is even rarer. Radiologic differential diagnosis is not easy. This paper presents 2 lumbar paraganglioma cases and focuses on nuances to provide ideas for radiological differential diagnosis.

Olea europaea Leaf Extract Improves the Efficacy of Temozolomide Therapy by Inducing MGMT Methylation and Reducing P53 Expression in Glioblastoma.

Unmethylated O6-methylguanine-DNA-methyltransferase (MGMT) promoter leads to Temozolomide (TMZ) resistance in most of the glioblastoma multiforme (GBM) patients. We previously investigated the synergistic effect of Olea europaea leaf extract (OLE) on TMZ cytotoxicity through modulating microRNA expression. To date, knowledge about the effect of OLE on MGMT methylation is insufficient. The aim of the current study was to evaluate the potential modulating effect of OLE on the TMZ response of GBM tumors through MGMT methylation. Exposure to 1 mg/mL OLE caused a significant induction of CpG island methylation in the MGMT gene using Methyl quantitative PCR assay (P < 0.001). In WST-1 analysis, the use of 350 µM TMZ plus 1 mg/mL OLE significantly increased the TMZ response of MGMT unmethylated cells (P = 0.003). Using the comet assay, the impact of 1 mg/mL OLE plus 350 µM TMZ on the formation of DNA strand breaks was significantly higher than that of 450 µM TMZ alone (P < 0.001) and Western blot analysis revealed that, when cells are treated with 1-mg/mL OLE, the total p53 protein levels tended to decrease. The results presented in this study uniquely demonstrated that OLE synergistically increased the TMZ response of GBM tumors by regulating MGMT gene methylation and p53 expression. However, further studies to validate our findings are required.

CDP-choline modulates matrix metalloproteinases in rat sciatic injury.

BACKGROUND: CDP-choline (cytidine-5'-diphosphocholine) improves functional recovery, promotes nerve regeneration, and decreases perineural scarring in rat peripheral nerve injury. The aim of the present study was to investigate the mechanism of action of CDP-choline with regard to matrix metalloproteinase (MMP) activity in the rat-transected sciatic nerve injury model. MATERIALS AND METHODS: Male Wistar rats were randomized into Sham, Saline, and CDP-choline groups. Rats in Sham group received Sham surgery, whereas rats in Saline and CDP-choline groups underwent right sciatic nerve transection followed by immediate primary saturation and injected intraperitoneally with 0.9% NaCl (1 mL/kg) and CDP-choline (600 µg/kg), respectively. Sciatic nerve samples were obtained 1, 3, and 7 d after the surgery and analyzed for levels and activities of MMP-2 and MMP-9, levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) and TIMP-3, and axonal regeneration. RESULTS: CDP-choline treatment decreased the levels and activities of MMP-2 and MMP-9, whereas increasing levels of TIMP-1 and TIMP-3 significantly on the third and seventh day after injury compared to Saline group. In addition, CDP-choline administration resulted in new axon formation and formation and advancement of myelination on newly formed islets (compartments) of axonal regrowth. CONCLUSIONS: Our data show, for the first time, that CDP-choline modulates MMP activity and promotes the expression of TIMPs to stimulate axonal regeneration. These data help to explain one mechanism by which CDP-choline provides neuroprotection in peripheral nerve injury.

Ficus carica latex prevents invasion through induction of let-7d expression in GBM cell lines.

Glioblastoma multiforme (GBM) is one of the deadliest human malignancies. A cure for GBM remains elusive, and the overall survival time is less than 1 year. Thus, the development of more efficient therapeutic approaches for the treatment of these patients is required. Induction of tumor cell death by certain phytochemicals derived from medicinal herbs and dietary plants has become a new frontier for cancer therapy research. Although the cancer suppressive effect of Ficus carica (fig) latex (FCL) has been determined in a few cancer types, the effect of this latex on GBM tumors has not been investigated. Therefore, in the current study, the anti-proliferative activity of FCL and the effect of the FCL-temozolomide (TMZ) combination were tested in the T98G, U-138 MG, and U-87 MG GBM cell lines using the WST-1 assay. The mechanism of cell death was analyzed using Annexin-V/FITC and TUNEL assays, and the effect of FCL on invasion was tested using the chick chorioallantoic membrane assay. To determine the effect of FCL on GBM progression, the expression levels of 40 GBM associated miRNAs were analyzed in T98G cells using RT-qPCR. According to the obtained data, FCL causes cell death in GBM cells with different responses to TMZ, and this effect is synergistically increased in combination with TMZ. In addition, the current study is the first to demonstrate the effect of FCL on modulation of let-7d expression, which may be an important underlying mechanism of the anti-invasive effect of this extract.

Statistical shape analysis of temporal lobe in mesial temporal sclerosis patients.

BACKGROUND: Surgery is regarded as a common treatment option for patients with mesial temporal lobe epilepsy due to hippocampal sclerosis but sometimes deciding this diagnosis can be very difficult. We aim to investigate the shape differences in the temporal lobe of mesial temporal sclerosis epilepsy patients compared with healthy controls, investigating the side difference and, if present, assessing the clinical application of this situation. METHOD: The MRI scans of mesial TLE patients and controls were retrospectively reviewed. Temporal lobe data were collected from the two-dimensional digital images. Standard anthropometric landmarks were selected and marked on each digital image using TPSDIG 2.04 software. Eight anatomic landmarks were marked on images. A generalized Procrustes analysis was used to evaluate the shape difference. The shape deformation of the temporal lobe from control to patient was evaluated using the TPS method. RESULTS: There were statistically significant TL shape differences between groups. High level deformations for the left and right side from the control to patient group were seen in the TPS graphic. The highest deformation was determined at the inferior lateral temporal midpoint of the middle temporal gyri and superior temporal landmark points of both the right and left sides. CONCLUSION: Our study for the first time demonstrated temporal shape differences in TLE patients using a landmark-based geometrical morphometric method by taking into consideration the topographic distribution of TL.

microRNA expression pattern modulates temozolomide response in GBM tumors with cancer stem cells.

Temozolomide (TMZ) is widely used to treat glioblastoma multiforme (GBM). Although the MGMT gene methylation status is postulated to correlate with TMZ response, some patients with a methylated MGMT gene still do not benefit from TMZ therapy. Cancer stem cells (CSCs) may be one of the causes of therapeutic resistance, but the molecular mechanism underlying this resistance is unclear. microRNA (miRNA) deregulation has been recognized as another chemoresistance modulating mechanism. Thus, we aimed to evaluate the miRNA expression patterns associated with chemoresistance that is dependent on the CSC status in GBM tumors to identify therapeutic biomarkers. CSCs were identified in 5 of 20 patients' tumor tissues using magnetic separation. CSC (+) tumors displayed a significant induction of CpG island methylation in the MGMT gene promoter (p = 0.009). Using real-time reverse transcription polymerase chain reaction (qRT-PCR), 9 miRNAs related to GBM (mir-181b, miR-153, miR-137, miR-145, miR-10a, miR-10b, let-7d, miR-9, and miR-455-3p), which are associated with cell cycle and invasion was analyzed in tumor samples. Low miR-181b and high miR-455-3p expression levels were detected (p = 0.053, p = 0.004; respectively) in CSC (+) tumors. Analysis revealed a significant correlation between miR-455-3p expression and Smad2 protein levels as analyzed by immunohistochemistry in CSC (+) tumors (p = 0.002). Thus, miR-455-3p may be involved in TMZ resistance in MGMT methylated CSC (+) GBM patients. Further studies and evaluations are required, but this miRNA may provide novel therapeutic molecular targets for GBM treatment and new directions for the development of anticancer drugs.

A comparison of spinal anesthesia characteristics following intrathecal bupivacaine or levobupivacaine in lumbar disc surgery.

PURPOSE: While bupivacaine is the most frequently used local anesthetic for spinal anesthesia, use of levobupivacaine in clinical practice has advanced recently. The aim of our study was to compare the clinical and anesthetic effects of isobaric bupivacaine and isobaric levobupivacaine when administered intrathecally in patients undergoing lumbar disc surgery. METHODS: ASA I-III, 60 patients were enrolled in this study. Only patients with unilateral single-level (L4-5) lumbar disc hernia were selected and operated in each group and all were operated by the same surgeon. Patients were randomized into two groups, as group B (n = 30): 15 mg 0.5% isobaric bupivacaine, or group L (n = 30): 15 mg 0.5% isobaric levobupivacaine received intrathecally. The level of sensory block dermatome, degree of motor block, intraoperative sensory and motor block characteristics, and postoperative recovery times of spinal anesthesia were evaluated. The satisfaction scores of the surgeon and patients, intraoperative hemodynamic changes, intraoperative and postoperative complications were recorded. RESULTS: The maximum level of sensory blockade was significantly higher in the levobupivacaine group (group L 7 ± 1.63, group B 8.6 ± 1.76 thoracic dermatome, p < 0.05). There was no significant difference in the onset time of sensory (group L 6 ± 3 min, group B 9 ± 4 min) and motor (in group L 7 ± 3 min, in group B 10 ± 4 min) blockade (p > 0.05). There was no significant difference between the groups regarding duration of operation (group L 49 ± 7.3 min, group B 52 ± 8.1, p > 0.05). Recovery times of sensory (175 ± 57 min) and motor (216 ± 59 min) blockade were significantly shorter in the levobupivacaine group (p < 0.05). Mobilization was also earlier in the levobupivacaine group (339 ± 90 min, p < 0.05). Patients' satisfaction and intraoperative, postoperative complications were similar between the two groups. CONCLUSIONS: Our results showed that block recovery time was shorter in the levobupivacaine group, this may be a disadvantage for longer operative procedures. But with proper patient selection this can be eliminated. Recovery time was shorter in levobupivacaine group. Therefore, postoperative neurological examination can be done earlier. In addition, early mobilization can be an advantage for postoperative recovery.

Extraforaminal Microdiscectomy for Upper Lumbar Disc Herniations: A Minimally Invasive Alternative Surgical Approach.

BACKGROUND: Various methods and techniques have been developed for extraforaminal decompression, particularly for far lateral lumbar disc herniation. Distinct anatomical differences are noticeable in the upper levels of the lumbar spine, which may complicate the related surgical approach. This study aimed to determine the safety and efficiency of the far lateral extraforaminal approach for the upper lumbar disc. METHODS: L1-2 and L2-3 migrated lumbar disc herniations were defined as upper lumbar disc herniations. 31 consecutive patients with upper lumbar disk herniation who underwent extraforaminal lumbar microdiscectomy between January 2018 and March 2022 were retrospectively investigated. The patients were assessed using the interval history, follow-up lower back and leg pain visual analog scale scores (0-100 mm), the Oswestry Disability Index (%), and modified MacNab criteria. RESULTS: 31 consecutive patients with upper lumbar disk herniation (20 men and 11 women) with a mean age of 52.8 ± 10.8 years (range 31-70 years) underwent extraforaminal lumbar microdiscectomy. The preoperative and postoperative visual analog scale scores and Oswestry Disability Index were significantly different (P < 0.001). According to the modified MacNab criteria, 23 patients showed excellent improvement, 5 showed good improvement, and 3 showed fair improvement; thus, the rate of satisfactory improvement was 90.3% at the 2-year follow-up. No patients required reoperation at the operative level during follow-up. CONCLUSIONS: Extraforaminal lumbar microdiscectomy is a safe and effective minimally invasive surgical technique for treating upper lumbar disc herniation.

The interplay between neuroinflammatory pathways and Parkinson's disease.

Parkinson's disease, a progressive neurodegenerative disorder predominantly affecting elderly, is marked by the gradual degeneration of the nigrostriatal dopaminergic pathway, culminating in neuronal loss within the substantia nigra pars compacta (SNpc) and dopamine depletion. At the molecular level, neuronal loss in the SNpc has been attributed to factors including neuroinflammation, impaired protein homeostasis, as well as mitochondrial dysfunction and the resulting oxidative stress. This review focuses on the interplay between neuroinflammatory pathways and Parkinson's disease, drawing insights from current literature.

Insights into neuroinflammatory mechanisms of deep brain stimulation in Parkinson's disease.

Parkinson's disease, a progressive neurodegenerative disorder, involves gradual degeneration of the nigrostriatal dopaminergic pathway, leading to neuronal loss within the substantia nigra pars compacta and dopamine depletion. Molecular factors, including neuroinflammation, impaired protein homeostasis, and mitochondrial dysfunction, contribute to the neuronal loss. Deep brain stimulation, a form of neuromodulation, applies electric current through stereotactically implanted electrodes, effectively managing motor symptoms in advanced Parkinson's disease patients. Deep brain stimulation exerts intricate effects on neuronal systems, encompassing alterations in neurotransmitter dynamics, microenvironment restoration, neurogenesis, synaptogenesis, and neuroprotection. Contrary to initial concerns, deep brain stimulation demonstrates antiinflammatory effects, influencing cytokine release, glial activation, and neuronal survival. This review investigates the intricacies of deep brain stimulation mechanisms, including insertional effects, histological changes, and glial responses, and sheds light on the complex interplay between electrodes, stimulation, and the brain. This exploration delves into understanding the role of neuroinflammatory pathways and the effects of deep brain stimulation in the context of Parkinson's disease, providing insights into its neuroprotective capabilities.

Neurosurgery training camp for medical student: experience of the Turkish neurosugery academy and Bursa Uludag University.

Introduction: To highlight the importance of hands-on experiences and mentorship in shaping the future workforce of specialized medical professionals via a Neurosurgery Training Camp. Methods: Responses of the questionnaire regarding the Neurosurgery Training Camp organized by Bursa Uludag University's Faculty of Medicine and the Turkish Neurosurgery Academy were reviewed retrospectively. A one-day program was organized to introduce neurosurgery to medical students. During the camp, the students participated in interactive presentations delivered by faculty members, had lunch together, became acquainted with neurosurgical tools and technologies, and performed interventions. With pre and postworkshop questionnaire, student's expectations and thoughts about camp was evaluated. Results: Forty-one students from 10 medical schools, spanning every year of study, attended the camp. Approximately 39% of the attendees (n = 16) were women and 61% (n = 25) were men. The post-workshop survey results demonstrated that 73% of the students (n = 30) were inclined to pursue a career in neurosurgery after the camp, 21.9% (n = 9) remained undecided, and 4.8% (n = 2) chose not to pursue neurosurgery. Feedback from the post-workshop questionnaire highlighted that all students perceived the camp as beneficial in providing insights into their future careers and aiding in making a decision regarding their career paths. Discussion: The neurosurgical training camp effectively inspired and educated medical students about the discipline of neurosurgery. Furthermore, the camp effectively altered the career aspirations and perceptions of neurosurgery among the participating students.

Repeat Microvascular Decompression for Recurrent Trigeminal Neuralgia.

AIM: This study aimed to review our experience with patients who suffered from recurrent trigeminal neuralgia (TN) and underwent repeat microvascular decompression surgery (rMVD). MATERIAL AND METHODS: This observational study is based on retrospective analysis and was conducted at the Department of Neurosurgery in a university hospital. It included patients who initially experienced complete pain relief after the first MVD but later had a recurrence of TN symptoms and subsequently underwent rMVD. Pain control outcomes were evaluated based on the Barrow Neurological Institute (BNI) scale score. RESULTS: Out of a total of 375 patients who underwent MVD for TN over a 20-year period, 19 patients (6 females, 13 males) with a mean age of 57.68 ± 9.78 years suffered from recurrent symptoms necessitating rMVD (%5.06). The average duration of symptoms before rMVD was 16.1 ± 19.36 months. The mean BNI score of the patients before rMVD was 4.5 ± 0.5. recurrence was primarily attributed to compression by a new offending vessel (n=9, 47.4%) and Teflon granuloma formation (n=8, 42.1%). Two patients (10.5%) showed no compression. During a follow-up period of 106.3 ± 58.3 months, excellent pain relief (BNI-I) was achieved in 10 patients (52.6%). Eight patients (42.1%) experienced a good outcome (BNI-III), while one patient (5.3%) had a poor outcome (BNI-IV). CONCLUSIONS: Recurrence of TN symptoms can occur even after initially successful MVD procedures. Repeat MVD should be considered as the primary treatment option in recurrent cases, as it can lead to significant pain control with low morbidity.

Hemorrhagic presentation of previously silent brain tumors.

INTRODUCTION AND OBJECTIVES: Acute presentation with intracranial hemorrhage owing to a previously silent brain tumor (BT) is rare. Although any BT can bleed, the frequency and type of bleeding varies across tumor types. MATERIALS AND METHODS: We aimed to retrospectively review our experience with 55 patients with BTs presenting with ICH. RESULTS: Signs of increased intracranial pressure were the most common symptoms. The temporal lobe was the most common lesion site (n=22). Hemorrhages were mainly confined to the tumor margins (HCTs) (n=34). Extensive intraparenchymal hemorrhages (EIHs) were mainly associated with moderately/severely decreased levels of consciousness (LOCs) (n=15/16). High-grade glioma (HGGT) (n=25) was the leading pathological diagnosis followed by metastasis (MBT) (n=16/55). The hemorrhage type was associated with the pathological diagnosis of the tumor. Patients with HGGT (n=19/25) and MBT (n=9/16) mainly presented with HCTs, whereas low-grade gliomas (LGGT) primarily caused EIHs (n=6/7). CONCLUSIONS: Hemorrhagic presentation is a rare occurrence in BTs. Among all, MBT and HGGT are responsible for majority of the cases. Importantly, despite their relatively benign characteristics, LGGTs mainly result in extensive parenchymal destruction once they bleed. Maximum surgical resection of hemorrhagic BTs and decompression of the affected brain regions followed by histological confirmation of the diagnosis should be the main goals of treatment in cases with hemorrhagic BTs.

Diabetes Mellitus-Mediated MALAT1 Expression Induces Glioblastoma Aggressiveness.

AIM: To describe the role of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in glioblastoma (GB) progression in patients concurrently diagnosed with diabetes mellitus (DM). MATERIAL AND METHODS: Formalin-fixed paraffin-embedded (FFPE) tumor samples of 47 patients diagnosed with GB only and 13 patients diagnosed with GB and DM (GB-DM) were enrolled in this study. Data for p53 and Ki67 immunohistochemical staining of the tumors and blood HbA1c levels of patients with DM were retrospectively collected. MALAT1 expression was assessed using quantitative real-time polymerase chain reaction. RESULTS: The coexistence of GB and DM induced the nuclear expression of p53 and Ki67 compared with GB only. MALAT1 expression was higher in GB-DM tumors than in GB only tumors. The expression of MALAT1 and HbA1c levels were positively correlated. Additionally, MALAT1 was positively correlated with tumoral p53 and Ki67. The disease-free survival of patients with GB-DM with high MALAT1 expression was shorter than that of those diagnosed with GB only and with a lower MALAT1 expression. CONCLUSION: Our findings suggest that one of the mechanisms of the facilitating effect of DM on GB tumor aggressiveness is via MALAT1 expression.

Olea europaea Leaf Phenolics Oleuropein, Hydroxytyrosol, Tyrosol, and Rutin Induce Apoptosis and Additionally Affect Temozolomide against Glioblastoma: In Particular, Oleuropein Inhibits Spheroid Growth by Attenuating Stem-like Cell Phenotype.

The effects of Olea europaea leaf extract (OLE) phenolics, including oleuropein (OL), hydroxytyrosol (HT), tyrosol (TYR), and rutin against glioblastoma (GB), independently and in combination with temozolomide (TMZ), were investigated in T98G and A172 cells. Cell growth was assessed by WST-1, real-time cell analysis, colony formation, and cell cycle distribution assays. A dual acridine orange propidium iodide (AO/PI) staining and annexin V assay determined cell viability. A sphere-forming assay, an intracellular oxidative stress assay, and the RNA expression of CD133 and OCT4 investigated the GB stem-like cell (GSC) phenotype. A scratch wound-healing assay evaluated migration capacity. OL was as effective as OLE in terms of apoptosis promotion (p < 0.001) and GSC inhibition (p < 0.001). HT inhibited cell viability, GSC phenotype, and migration rate (p < 0.001), but its anti-GB effect was less than the total effect of OLE alone. Rutin decreased reactive oxygen species production and inhibited colony formation and cell migration (p < 0.001). TYR demonstrated the least effect. The additive effects of OL, HT, TYR and rutin with TMZ were significant (p < 0.001). Our data suggest that OL may represent a novel therapeutic approach against GB cells, while HT and rutin show promise in increasing the efficacy of TMZ therapy.

Co-loading of Temozolomide with Oleuropein or rutin into polylactic acid core-shell nanofiber webs inhibit glioblastoma cell by controlled release.

Glioblastoma (GB) has susceptibility to post-surgical recurrence. Therefore, local treatment methods are required against recurrent GB cells in the post-surgical area. In this study, we developed a nanofiber-based local therapy against GB cells using Oleuropein (OL), and rutin and their combinations with Temozolomide (TMZ). The polylactic acid (PLA) core-shell nanofiber webs were encapsulated with OL (PLAOL), rutin (PLArutin), and TMZ (PLATMZ) by an electrospinning process. A SEM visualized the morphology and the total immersion method determined the release characteristics of PLA webs. Real-time cell tracking analysis for cell growth, dual Acridine Orange/Propidium Iodide staining for cell viability, a scratch wound healing assay for migration capacity, and a sphere formation assay for tumor spheroid aggressiveness were used. All polymeric nanofiber webs had core-shell structures with an average diameter between 133 ± 30.7-139 ± 20.5 nm. All PLA webs promoted apoptotic cell death, suppressed cell migration, and spheres growth (p < 0.0001). PLAOL and PLATMZ suppressed GB cell viability with a controlled release that increased over 120 h, while PLArutin caused rapid cell inhibition (p < 0.0001). Collectively, our findings suggest that core-shell nano-webs could be a novel and effective therapeutic tool for the controlled release of OL and TMZ against recurrent GB cells.

The promoter hypermethylation status of GATA6, MGMT, and FHIT in glioblastoma.

Glioblastoma (GBM) is an aggressive and lethal cancer, accounting for the majority of primary brain tumors in adults. GBMs are characterized by large and small alterations in genes that control cell growth, apoptosis, angiogenesis, and invasion. Epigenetic alterations also affect the expression of cancer genes, either alone or in combination with genetic mechanisms. The current evidence suggests that hypermethylation of promoter CpG islands is a common epigenetic event in a variety of human cancers. A subset of GBMs is also characterized by a locus-specific and genome-wide decrease in DNA methylation. Epigenetic alterations are important in the molecular pathology of GBM. However, there are very limited data about these epigenetic alterations in GBM. Alterations in promoter methylations are important to understand because histone deacetylases are targets for drugs that are in clinical trial for GBMs. The aim of the current study was to investigate whether the promoter hypermethylation of putative tumor suppressor genes was involved in GBM. We examined the methylation status at the promoter regions of GATA6, MGMT, and FHIT using the methylation-specific polymerase chain reaction in 61 primary GBMs. Our results reveal that there is no promoter hypermethylation of FHIT in the examined GBM tissue specimens. In contrast, the promoter hypermethylation of GATA6 and MGMT was detected in 42.8 and 11.11% of GBMs, respectively. The frequency of MGMT promoter hypermethylation was low in the group of patients we evaluated. In conclusion, our study demonstrates that promoter hypermethylation of MGMT is a common event in GBMs, whereas GATA6 is epigenetically affected in GBMs. Furthermore, inactivation of FHIT by epigenetic mechanisms in GBM may not be associated with brain tumorigenesis.