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The phenomenon of ischemic postconditioning (PostC) is known to be neuroprotective against ischemic reperfusion (I/R) injury. One of the key processes in PostC is the opening of the mitochondrial ATP-dependent potassium (mito-K ATP ) channel and depolarization of the mitochondrial membrane, triggering the release of calcium ions from mitochondria through low-conductance opening of the mitochondrial permeability transition pore. Mitochondrial calcium uniporter (MCU) is known as a highly sensitive transporter for the uptake of Ca 2+ present on the inner mitochondrial membrane. The MCU has attracted attention as a new target for treatment in diseases, such as neurodegenerative diseases, cancer, and ischemic stroke. We considered that the MCU may be involved in PostC and trigger its mechanisms. This research used the whole-cell patch-clamp technique on hippocampal CA1 pyramidal cells from C57BL mice and measured changes in spontaneous excitatory post-synaptic currents (sEPSCs), intracellular Ca 2+ concentration, mitochondrial membrane potential, and N -methyl- d -aspartate receptor (NMDAR) currents under inhibition of MCU by ruthenium red 265 (Ru265) in PostC. Inhibition of MCU increased the occurrence of sEPSCs ( p  = 0.014), NMDAR currents ( p  < 0.001), intracellular Ca 2+ concentration ( p  < 0.001), and dead cells ( p  < 0.001) significantly after reperfusion, reflecting removal of the neuroprotective effects in PostC. Moreover, mitochondrial depolarization in PostC with Ru265 was weakened, compared to PostC ( p  = 0.004). These results suggest that MCU affects mitochondrial depolarization in PostC to suppress NMDAR over-activation and prevent elevation of intracellular Ca 2+ concentrations against I/R injury. Graphical Abstract

To preserve language function, intraoperative functional brain mapping (IFBM) in and near the speech center is essential. We present a case of a 73-year-old right-handed woman with colon cancer. She presented with mild speech disturbance. Magnetic resonance imaging revealed a ringed enhancing lesion in the frontal operculum. The preservation of language function was critical; therefore, she underwent awake craniotomy using IFBM. Thus, the speech site was elicited by cortical electrical stimulation at the surface, near the location of the tumor. We made a safe corticotomy on the surface of the lesion and performed the resection of brain metastasis (BM) via a safety corridor. We achieved gross total resection of the BM while preserving the language function. After surgery, she recovered from speech disturbance. She returned to her normal life with improved language function. IFBM is a useful tool to undertake a safe approach via the speech center, avoiding permanent language deficits.

Background/Aim: Post-transplant lymphoproliferative disorder (PTLD) is a heterogeneous lymphoid cell disorder that occurs after solid organ and hematopoietic stem cell transplantation. Primary occurrence in the central nervous system PTLD (PCNS PTLD) is rare. We present a rare case of PCNS-PTLD misdiagnosed as glioblastoma (GBM). Case Report: A 62-year-old man underwent living-related kidney transplantation at the age of 49. He was introduced to our Department because of transient speech disturbance. Computed tomography scan of the head showed a mass at the right frontal lobe. Magnetic resonance imaging (MRI) of the head showed a ring-enhancing lesion with a small, homonymous enhanced lesion in the right frontal lobe, invading the corpus callosum. Because the pathological analysis of an intraoperative frozen section of the tumour indicated high-grade glioma, the tumour was completely resected and BCNU wafers were implanted at the resection site. However, postoperative pathological analysis indicated a diffuse large, CD20 positive B-cell lymphoma. In addition, the patient was positive for Epstein Barr virus-encoded small RNA, and therefore, diagnosis of PCNS PTLD was confirmed. The dose of the immunosuppressant therapy was reduced, and rituximab monotherapy was begun. Conclusion: Both imaging and pathological findings on intraoperative frozen section of PCNS PTLD are similar to those of GBM. Therefore, in such cases, surgeons should consider PCNS-PTLD when the diagnosis indicates GBM.

Natural killer (NK) cells are considered potential antitumor effector cells. The aim of this study was to establish a novel type of a chimeric antigen receptor (CAR) NK cell line (CAR-KHYG-1) specific for epidermal growth factor receptor variant III (EGFRvIII)-expressing tumors and investigate the anti-tumor activity of EGFRvIII-specific-CAR-KHYG-1 (EvCAR-KHYG-1). EvCAR-KHYG-1 was established by self-inactivated lentiviral-based transduction of the EvCAR gene and magnetic bead-based purification of EvCAR-expressing NK cells. The anti-tumor effects of EvCAR-KHYG-1 were evaluated using growth inhibition and apoptosis detection assays in glioblastoma (GBM) cell lines (EGFRvIII-expressing and non-expressing U87MG). The findings demonstrated that EvCAR-KHYG-1 inhibited GBM cell-growth via apoptosis in an EGFRvIII-expressing specific manner. This is the first study to establish a CAR NK cell line based on the human NK cell line KHYG-1. Therapy with EvCAR-KHYG-1 may be an effective treatment option for GBM patients.

Mitochondrial membrane potential regulation through the mitochondrial permeability transition pore (mPTP) is reportedly involved in the ischemic postconditioning (PostC) phenomenon. Melatonin is an endogenous hormone that regulates circadian rhythms. Its neuroprotective effects via mitochondrial melatonin receptors (MTs) have recently attracted attention. However, details of the neuroprotective mechanisms associated with PostC have not been clarified. Using hippocampal CA1 pyramidal cells from C57BL mice, we studied the involvement of MTs and the mPTP in melatonin-induced PostC mechanisms similar to those of ischemic PostC. We measured changes in spontaneous excitatory postsynaptic currents (sEPSCs), intracellular calcium concentration, mitochondrial membrane potential, and N-methyl-D-aspartate receptor (NMDAR) currents after ischemic challenge, using the whole-cell patch-clamp technique. Melatonin significantly suppressed increases in sEPSCs and intracellular calcium concentrations. The NMDAR currents were significantly suppressed by melatonin and the MT agonist, ramelteon. However, this suppressive effect was abolished by the mPTP inhibitor, cyclosporine A, and the MT antagonist, luzindole. Furthermore, both melatonin and ramelteon potentiated depolarization of mitochondrial membrane potentials, and luzindole suppressed depolarization of mitochondrial membrane potentials. This study suggests that melatonin-induced PostC via MTs suppressed the NMDAR that was induced by partial depolarization of mitochondrial membrane potential by opening the mPTP, reducing excessive release of glutamate and inducing neuroprotection against ischemia-reperfusion injury.

Background and purpose Poststroke epilepsy is a common problem in clinical practice. This study aimed to determine the predictors of poststroke epilepsy and to identify the risk factors. Methods A total of 436 patients were enrolled for this study. Baseline characteristics were recorded. Patients were followed up for 3 years. According to the occurrence of late seizures (i.e., seizure occurring 8 days or later after the stroke), the patients were separated into two groups: a seizure group and a seizure-free group. Baseline characteristics were compared between the groups. Univariate and multivariate Cox regression analysis was used to identify the risk factors for occurrence of poststroke epilepsy. The study was registered in the University Hospital Medical Information Network Center Clinical Trials Registry (registration number UMIN000009659, date 28/December/2012). Results Among the 436 patients, 26 developed late seizures—an incidence rate of 5.96%. In univariate analysis, female, subarachnoid hemorrhage, hemorrhagic lesion, lesion affecting the cortex, lesion affecting the frontal lobe, and absence of comorbidities were the significant risk factors for occurrence of epilepsy. In multivariate analysis, the independent predictors of poststroke epilepsy were hemorrhagic lesion (hazard ratio (HR) = 3.03) and lesion location in the cortex (HR = 4.64). The incidence of poststroke epilepsy in patients with both two risk factors was 15.4%. Conclusions Poststroke epilepsy occurs in almost 6% of patients within 3 years after stroke onset. Hemorrhagic stroke and subcortical lesion appear to be significantly associated with likelihood of developing epilepsy. Thus, prophylactic administration of antiepileptic drugs could be useful for stroke patients with these two risk factors.

Glioblastoma is the leading malignant glioma with a poor prognosis. This study aimed to investigate the antitumor effects of natural killer cells in combination with temozolomide as the standard chemotherapeutic agent for glioblastoma. Using a simple, feeder-less, and chemically defined culture method, we expanded human peripheral blood mononuclear cells and assessed the receptor expression, natural killer cell activity, and regulatory T cell frequency in expanded cells. Next, using the standard human glioblastoma cell lines (temozolomide-sensitive U87MG, temozolomide-resistant T98G, and LN-18), we assessed the ligand expressions of receptors on natural killer cells. Furthermore, the antitumor effects of the combination of the expanded natural killer cells and temozolomide were assessed using growth inhibition assays, apoptosis detection assays, and senescence-associated β-galactosidase activity assays in the glioblastoma cell lines. Novel culture systems were sufficient to attain highly purified (>98%), expanded (>440-fold) CD3-/CD56+ peripheral blood-derived natural killer cells. We designated the expanded population as genuine induced natural killer cells. Genuine induced natural killer cells exhibited a high natural killer activity and low regulatory T cell frequency compared with lymphokine-activated killer cells. Growth inhibition assays revealed that genuine induced natural killer cells inhibited the glioblastoma cell line growth but enhanced temozolomide-induced inhibition effects in U87MG. Apoptosis detection assays revealed that genuine induced natural killer cells induced apoptosis in the glioblastoma cell lines. Furthermore, senescence-associated β-galactosidase activity assays revealed that temozolomide induced senescence in U87MG. Genuine induced natural killer cells induce apoptosis in temozolomide-sensitive and temozolomide-resistant glioblastoma cells and enhances temozolomide-induced antitumor effects in different mechanisms. Hence, the combination of genuine induced natural killer cells and temozolomide may prove to be a promising immunochemotherapeutic approach in patients with glioblastoma if the antitumor effects in vivo can be demonstrated.

To avoid permanent neurologic deficits and preserve brain function, intraoperative electrical stimulation mapping (IESM) is essential for surgical resection. A 59-year-old right-handed woman with ovarian cancer who had undergone stereotactic radiotherapy for brain metastasis two years before, was introduced due to progressive left upper paresis. Magnetic resonance imaging showed a recurrence of the lesion. We performed awake surgery using IESM. Thus, the sensorimotor site was elicited on the precentral and postcentral gyrus. However, IESM elicited no disturbance of motor function on the surface of the posterior part of the precentral gyrus. We made a safe corticotomy on it, and performed the resection of recurrent BM. Preserving the motor and sensory function, we achieved the resection of BM. After surgery, she experienced a significant improvement in motor function. IESM is a useful tool to make a safe approach via the precentral gyrus avoiding permanent sensorimotor deficits.

Glioblastoma (GBM), which is the most common malignant brain tumor, is resistant to standard treatments. Immunotherapy might be a promising alternative for the treatment of this cancer. Chimeric antigen receptor (CAR) is an artificially modified fusion protein that can be engineered to direct the specificity and function of T cells against tumor antigens. However, the antitumor effects of EGFRvIII-targeting CAR-T (EvCAR-T) cells in GBM are limited. The inhibitory effect is induced by the interaction between programmed cell death protein 1 (PD-1) on activated EvCAR-T cells and its ligands on GBM cells. In the present study, PD-1-disrupted EvCAR-T cells were established using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9). The sgRNA/Cas9 expression vectors designed precisely disrupted the target region of PD-1 and inhibited the expression of PD-1 in EvCAR-T cells. The PD-1-disrupted EvCAR-T cells had an in vitro growth inhibitory effect on EGFRvIII-expressing GBM cells without altering the T-cell phenotype and the expression of other checkpoint receptors. In the future, the in vivo antitumor effect of this vector should be evaluated in order to determine if it could be applied clinically for improving the efficacy of EvCAR-T cell-based adoptive immunotherapy for GBM.