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C1q tumor necrosis factor-related peptide 8 (CTRP8) is the least studied member of the C1Q-TNF-related peptide family. We identified CTRP8 as a ligand of the G protein-coupled receptor relaxin family peptide receptor 1 (RXFP1) in glioblastoma multiforme (GBM). The CTRP8-RXFP1 ligand-receptor system protects human GBM cells against the DNA-alkylating damage-inducing temozolomide (TMZ), the drug of choice for the treatment of patients with GBM. The DNA protective role of CTRP8 was dependent on a functional RXFP1-STAT3 signaling cascade and targeted the monofunctional glycosylase N-methylpurine DNA glycosylase (MPG) for more efficient base excision repair of TMZ-induced DNA-damaged sites. CTRP8 also improved the survival of GBM cells by upregulating anti-apoptotic BCl-2 and BCL-XL. Here, we have identified Janus-activated kinase 3 (JAK3) as a novel member of a novel CTRP8-RXFP1-JAK3-STAT3 signaling cascade that caused an increase in cellular protein content and activity of the small Rho GTPase Cdc42. This is associated with significant F-actin remodeling and increased GBM motility. Cdc42 was critically important for the upregulation of the actin nucleation complex N-Wiskott-Aldrich syndrome protein/Arp3/4 and actin elongation factor profilin-1. The activation of the RXFP1-JAK3-STAT3-Cdc42 axis by both RXFP1 agonists, CTRP8 and relaxin-2, caused extensive filopodia formation. This coincided with enhanced activity of ezrin, a key factor in tethering F-actin to the plasma membrane, and inhibition of the actin filament severing activity of cofilin. The F-actin remodeling and pro-migratory activities promoted by the novel RXFP1-JAK3-STAT3-Cdc42 axis were blocked by JAK3 inhibitor tofacitinib and STAT3 inhibitor STAT3 inhibitor VI. This provides a new rationale for the design of JAK3 and STAT3 inhibitors with better brain permeability for clinical treatment of the pervasive brain invasiveness of GBM., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: The role of high-field 3-Tesla intraoperative magnetic resonance imaging (I-MRI) during awake craniotomy (AC) has not been extensively studied. We report the feasibility and safety of AC during 3-Tesla I-MRI., Methods: This retrospective descriptive report compared 3 groups: AC with minimal sedation and I-MRI; I-MRI-guided craniotomy under general anesthesia (GA), and; AC without I-MRI. Perioperative factors, surgical, anesthetic and radiologic complications, and postoperative morbidity and mortality were recorded., Results: Overall, 85 patients are included in this report. Five of 23 patients (22%) who underwent AC with I-MRI had anesthetic complications (nausea/vomiting and conversion to GA) compared with 3 of 40 (8%) who underwent I-MRI-guided craniotomy under GA (nausea/vomiting during extubation, and arrhythmia). Intraoperative surgical complications (seizures and speech deficits) occurred in 5 patients (22%) who underwent AC and I-MRI, excessive intraoperative bleeding occurred in 2 patients (5%) who had I-MRI-guided craniotomy under GA, and 4 of 22 (18%) patients who underwent AC without I-MRI experienced neurological complications (seizures, motor deficits, and transient loss of consciousness). Eight patients (20%) who had I-MRI with GA had postoperative complications, largely neurological. The duration of surgery and anesthesia were shortest in the group of patients receiving AC without I-MRI. Seventy-three percent of the patients in this group had residual tumor postoperatively compared with 44% and 38% in those having I-MRI with AC or GA, respectively. Patients who underwent I-MRI-guided craniotomy with GA had the highest morbidity (8%) at hospital discharge., Conclusions: Our institutional experience suggests that AC under 3-Tesla I-MRI could be an option for glioma resection, although firm conclusions cannot be drawn given the limited and heterogenous nature of our data. Future multicenter trials comparing anesthetic and imaging modalities for glioma resection are recommended., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Malignant gliomas derive from brain glial cells and represent >75% of primary brain tumors. This includes anaplastic astrocytoma (grade III; AS), the most common and fatal glioblastoma multiforme (grade IV; GBM), and oligodendroglioma (ODG). We have generated patient-derived AS, GBM, and ODG cell models to study disease mechanisms and test patient-centered therapeutic strategies. We have used an aptamer-based high-throughput SOMAscan ® 1.3K assay to determine the proteomic profiles of 1307 different analytes. SOMAscan ® proteomes of AS and GBM self-organized into closely adjacent proteomes which were clearly distinct from ODG proteomes. GBM self-organized into four proteomic clusters of which SOMAscan ® cluster 4 proteome predicted a highly inter-connected proteomic network. Several up- and down-regulated proteins relevant to glioma were successfully validated in GBM cell isolates across different SOMAscan ® clusters and in corresponding GBM tissues. Slow off-rate modified aptamer proteomics is an attractive analytical tool for rapid proteomic stratification of different malignant gliomas and identified cluster-specific SOMAscan ® signatures and functionalities in patient GBM cells.

The C1q/TNF-related peptide 8 (CTRP8) has recently emerged as a novel ligand of the G protein-coupled receptor RXFP1 in the fatal brain tumor glioblastoma (GBM). We previously demonstrated that the CTRP8-RXFP1 ligand-receptor system promotes motility and matrix invasion of patient GBM and U87 MG cells by specific phosphorylation of PI3 kinase and protein kinase C. Here, we demonstrate a novel role for CTRP8 in protecting human GBM cells against the DNA alkylating damage of temozolomide (TMZ), the standard chemotherapy drug used to treat GBM. This DNA protective role of CTRP8 required a functional RXFP1-STAT3 signaling cascade in GBM cells. We identified N-methylpurine DNA glycosylase (MPG), a monofunctional glycosylase that initiates base excision repair pathway by generating an apurinic/apyrimidinic (AP) site, as a new CTRP8-RXFP1-STAT3 target in GBM. Upon TMZ exposure, treatment with CTRP8 reduced the formation of AP sites and double-strand DNA breaks in GBM cells. This CTRP8 effect was independent of cellular MGMT levels and was associated with decreased caspase 3/7 activity and increased survival of human GBM. CTRP8-induced RXFP1 activation caused an increase in cellular protein levels of the anti-apoptotic Bcl members and STAT3 targets Bcl-2 and Bcl-XL in human GBM. Collectively, our results demonstrate a novel multipronged and clinically relevant mechanism by which the CTRP8-RXFP1 ligand-receptor system exerts a DNA protective function against TMZ chemotherapeutic stress in GBM. This CTRP8-RXFP1-STAT3 axis is a novel determinant of TMZ responsiveness/chemoresistance and an emerging new drug target for improved treatment of human GBM., (© 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Background: This is the first case to our knowledge of a serious adverse event following the Epley maneuver, which is the treatment of choice for benign paroxysmal positional vertigo (BPPV), the most common vestibular disorder in adults., Case Presentation: A 77 year old female presented for outpatient evaluation of vertigo at a tertiary otolaryngology clinic. She was found to have BPPV clinically, and elected to have a particle repositioning maneuver (Epley maneuver) performed in clinic. Immediately following Epley maneuver, she had severe nausea and vomiting, with evolving visual changes. A CT angiogram of the brain was performed urgently through the emergency department and demonstrated an acute intraparenchymal hemorrhage in the occipital lobe. After medical stabilization and rehabilitation, the patient continues to have a permanent visual field deficit., Conclusion: The Epley maneuver is safe and effective, and there are no prior reports of serious adverse events associated with its use. This case, in which a patient experienced a hemorrhagic stroke after undergoing the Epley maneuver, is the first and sole case in the medical literature of an Epley-associated serious adverse event. The indirect causation and extreme rarity of this event do not warrant any change to patterns of practice.

The multikinase inhibitor and FDA-approved drug dovitinib (Dov) crosses the blood-brain barrier and was recently used as single drug application in clinical trials for GB patients with recurrent disease. The Dov-mediated molecular mechanisms in GB cells are unknown. We used GB patient cells and cell lines to show that Dov downregulated the stem cell protein Lin28 and its target high-mobility group protein A2 (HMGA2). The Dov-induced reduction in pSTAT3 Tyr705 phosphorylation demonstrated that Dov negatively affects the STAT3/LIN28/Let-7/HMGA2 regulatory axis in GB cells. Consistent with the known function of LIN28 and HMGA2 in GB self-renewal, Dov reduced GB tumor sphere formation. Dov treatment also caused the downregulation of key base excision repair factors and O 6 -methylguanine-DNA-methyltransferase (MGMT), which are known to have important roles in the repair of temozolomide (TMZ)-induced alkylating DNA damage. Combined Dov/TMZ treatment enhanced TMZ-induced DNA damage as quantified by nuclear γH2AX foci and comet assays, and increased GB cell apoptosis. Pretreatment of GB cells with Dov ('Dov priming') prior to TMZ treatment reduced GB cell viability independent of p53 status. Sequential treatment involving 'Dov priming' and alternating treatment cycles with TMZ and Dov substantially reduced long-term GB cell survival in MGMT+ patient GB cells. Our results may have immediate clinical implications to improve TMZ response in patients with LIN28 + /HMGA2 + GB, independent of their MGMT methylation status., (© 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

The accurate grading of malignant astrocytomas has significant prognostic and therapeutic implications. Traditional histopathological grading can be challenging due to regional tumor heterogeneity, especially in scenarios where small amounts of tissue are available for pathologic review. Here, we hypothesized that a critical tumor resection volume is needed for correct grading of astrocytomas by histopathology. For insufficient tissue sampling, IDH1 molecular testing can act as a complementary marker to improve diagnostic accuracy. Volumetric analyses were obtained using preoperative and postoperative MRI images. Histological specimens were gathered from 403 patients with malignant astrocytoma who underwent craniotomy. IDH1 status was assessed by immunohistochemistry and sequencing. Patients with >20 cubic centimeters (cc) of the total tumor volume resected on MRI have higher rate of GBM diagnosis compared to <20 cc [odds ratio (OR) 2.57, 95% confidence interval (CI) 1.6-4.06, P < 0.0001]. The rate of IDH1 status remained constant regardless of the tumor volume resected (OR 0.81, 95% CI 0.48-1.36, P < 0.43). The rate of GBM diagnosis is twofold greater for individual surgical specimen >10 cc than those of lower volume (OR 2.48, 95% CI 1.88-3.28, P < 0.0001). Overall survival for AA patients with >20 cc tumor resection on MRI is significantly better than those with <20 cc tumor resected (P < 0.05). No volume-dependent differences were observed in patients with GBM (P < 0.4), IDH1 wild type (P < 0.1) or IDH1 mutation (P < 0.88). IDH1 status should be considered when total resection volume is <20 cc based on MRI analysis and for surgical specimen <10 cc to complement histopathologic diagnosis of malignant astrocytomas. In these specimens, under-diagnosis of GBM may occur when analysis is restricted to histopathology alone.

Background: IDH1 gene mutations identify gliomas with a distinct molecular evolutionary origin. We sought to determine the impact of surgical resection on survival after controlling for IDH1 status in malignant astrocytomas-World Health Organization grade III anaplastic astrocytomas and grade IV glioblastoma., Methods: Clinical parameters including volumetric assessment of preoperative and postoperative MRI were recorded prospectively on 335 malignant astrocytoma patients: n = 128 anaplastic astrocytomas and n = 207 glioblastoma. IDH1 status was assessed by sequencing and immunohistochemistry., Results: IDH1 mutation was independently associated with complete resection of enhancing disease (93% complete resections among mutants vs 67% among wild-type, P < .001), indicating IDH1 mutant gliomas were more amenable to resection. The impact of residual tumor on survival differed between IDH1 wild-type and mutant tumors. Complete resection of enhancing disease among IDH1 wild-type tumors was associated with a median survival of 19.6 months versus 10.7 months for incomplete resection; however, no survival benefit was observed in association with further resection of nonenhancing disease (minimization of total tumor volume). In contrast, IDH1 mutants displayed an additional survival benefit associated with maximal resection of total tumor volume (median survival 9.75 y for >5 cc residual vs not reached for <5 cc, P = .025)., Conclusions: The survival benefit associated with surgical resection differs based on IDH1 genotype in malignant astrocytic gliomas. Therapeutic benefit from maximal surgical resection, including both enhancing and nonenhancing tumor, may contribute to the better prognosis observed in the IDH1 mutant subgroup. Thus, individualized surgical strategies for malignant astrocytoma may be considered based on IDH1 status.

Male rats outperform females in spatial tasks, such as the water maze (WM). Female rats are known to have higher basal serum corticosterone (CORT) levels and to manifest a more rapid and stronger CORT response to novel stressors. Sex differences in stress responses to the handling and forced swimming in the WM task might contribute to the sex difference in WM performance. In Experiment 1, naive females were found to be impaired relative to naive males in swimming to a visible platform in a WM pool due to strongly thigmotaxic swimming by females. In Experiment 2, serum CORT, a physiological measure of stress, was highly elevated during and after WM training, with female > male values and strong inverse correlations between CORT and measures of WM performance in females. Familiarization with the WM pool and test procedures by strategies pretraining prior to spatial training reduced or eliminated the sex differences in the stress response and WM performance. In Experiment 3, adrenalectomy to eliminate the stress response eliminated sex differences in WM performance. Taken together, the results suggest that male and female rats may harbor brain circuitry that is equally capable of accurate spatial navigation and memory in the WM but which may be impaired to different degrees by the differential stress responses triggered by WM testing., (Copyright 2003 Elsevier B.V.)

Rationale: Ethanol impairs performance in the water maze in rats. A detailed behavioral analysis is required to fully evaluate the nature of the impairment., Objectives: A detailed behavioral analysis was carried out to evaluate the effect of ethanol on performance in the water maze task in male hooded rats given 2.0 or 6.0 g/kg ethanol by gavage. Multiple measures of water maze strategies learning and spatial learning were studied., Methods: Water maze trials were recorded on videotape and digitized for offline analysis. Some rats were naive at the start of spatial training, whereas other rats received water maze strategies pretraining prior to spatial training to familiarize them with the general behavioral strategies required in the task., Results: Naive ethanol-treated rats exhibited both spatial learning and water maze behavioral strategies impairments. There was no evidence of a spatial learning impairment that was independent of an associated behavioral strategies impairment. Further, ethanol impaired the ability of naive rats to swim to a stable visible platform. Pretrained ethanol-treated rats performed significantly better than naive ethanol-treated rats on almost all measures, and were indistinguishable from controls on most measures., Conclusions: These results suggest that ethanol may impair water maze performance in naive rats by interfering with their ability to acquire and use required water maze behavioral strategies and generate adaptive swim paths. Ethanol does not prevent robust spatial learning in rats that are familiar with required water maze behavioral strategies.

Successful performance of the water maze task requires that rats learn complex behavioral strategies for swimming in a pool of water, searching for and interacting with a hidden platform before its spatial location can be learned. To evaluate whether NMDA receptor-dependent long-term potentiation (NMDA-LTP) is required for learning the required behavioral strategies, rats with NMDA-LTP blocked by systemic pharmacological treatment were trained in the behavioral strategies using simplified and stepwise training methods. Despite the blockade of NMDA-LTP in the dentate gyrus and hippocampal area CA1, rats learned the required behavioral strategies and used them to learn both initial and reversed platform locations. This is the first evaluation of the role of NMDA-LTP specifically in behavioral strategy learning. Although hippocampal NMDA-LTP might contribute to the water maze task, this form of LTP is not essential for learning complex behavioral strategies or multiple hidden platform locations.

Long-term potentiation (LTP) is the principal model of synaptic plasticity often used to explain the changes that occur in the brain as a result of learning and memory. In this experiment the relationship between rat posterior parietal cortex (PPC) transcallosal evoked field potentials (TCEPs) and spatial training in the water maze was examined to determine if LTP-like changes (i.e. learning-induced LTP) in PPC TCEPs occur as a result of spatial training. Spatial training consisted of 10 trials per day for 10 consecutive days. The location of the hidden platform was changed over the course of spatial training to ensure the rats' acquisition of several different platform positions. TCEPs were taken 1 and 23 h after each training session. Upon completion of all water maze training, the animals were administered LTP-inducing trains to ensure that the recording arrangement and procedure was capable of detecting LTP. The results showed that the rats quickly acquired the water maze task and that the recording arrangement and procedure were capable of detecting LTP, even after the first session of induction. However, despite robust place learning, the TCEPs taken after water maze training did not differ from those taken before water maze training. Although the present results failed to provide any evidence for a role of neocortical LTP in learning and memory, further studies of this nature are required to determine if the present results generalize to different behavioural tasks and/or cortical areas.

A detailed behavioural analysis of water maze spatial performance in the rat was utilized to determine the effect of single and combined administration of p-chlorophenylalanine (PCPA; 1000 mg/kg, i.p.), an inhibitor of serotonin biosynthesis, and scopolamine hydrobromide (SCO; 1.0 mg/kg, i.p.), a muscarinic receptor antagonist. In some groups a water maze pretraining regimen known as non-spatial pretraining (NSP) was used to familiarize the animals with the general requirements of the task before spatial training was begun. The results showed that: (a) depletion of serotonin with PCPA had no effect on water maze performance and produced no sensorimotor disturbances; (b) antagonism of muscarinic receptors produced impairments in spatial and sensorimotor function in naive rats but neither effect was observed in rats first given NSP; (c) combined disruption of muscarinic and serotonergic function produced a severe deficit in spatial performance that was only partially alleviated by NSP; and (d) there was an association between poor maze acquisition scores and a high incidence of sensorimotor dysfunction. In addition to the water maze task the rats were also assessed for motoric performance on a beam walking test. The role of cholinergic and serotonergic systems in learning and memory is discussed.