Mitochondrial Calcium Uniporter (MCU) is Involved in an Ischemic Postconditioning Effect Against Ischemic Reperfusion Brain Injury in Mice.

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-KATP) 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 Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ concentrations against I/R injury.

Embolic stroke induced by rotational persistent 1st intersegmental artery compression.

A 45-year-old man suffered multiple cerebral infarctions in the vertebrobasilar artery territory, followed by second stroke against conservative treatment. Radiological examinations revealed intra-arterial defect in left persistent 1st intersegmental artery (PFIA) at C1 level, suggesting mural thrombus, and mechanical compression of left PFIA at the level with head rotation to the right clearly revealed by reconstructed 3-dimensional radiological images, but no findings of atlantoaxial instability. One month after the second stroke, posterior fixation was performed. Postoperative course was uneventful without subsequent stroke for 24 months. This unique case demonstrated that PFIA might associate with cerebral stroke as a clinical condition of bow hunter's stroke even in middle age. Reconstructed 3-dimensional radiological images might be useful for clear demonstration of the pathophysiology in this complex clinical entity.

Therapeutic Anti-KIR Antibody of 1-7F9 Attenuates the Antitumor Effects of Expanded and Activated Human Primary Natural Killer Cells on In Vitro Glioblastoma-like Cells and Orthotopic Tumors Derived Therefrom.

Glioblastoma (GBM) is the leading malignant intracranial tumor, where prognosis for which has remained extremely poor for two decades. Immunotherapy has recently drawn attention as a cancer treatment, including for GBM. Natural killer (NK) cells are immune cells that attack cancer cells directly and produce antitumor immunity-related cytokines. The adoptive transfer of expanded and activated NK cells is expected to be a promising GBM immunotherapy. We previously established an efficient expansion method that produced highly purified, activated primary human NK cells, which we designated genuine induced NK cells (GiNKs). The GiNKs demonstrated antitumor effects in vitro and in vivo, which were less affected by blockade of the inhibitory checkpoint receptor programmed death 1 (PD-1). In the present study, we assessed the antitumor effects of GiNKs, both alone and combined with an antibody targeting killer Ig-like receptor 2DLs (KIR2DL1 and DL2/3, both inhibitory checkpoint receptors of NK cells) in vitro and in vivo with U87MG GBM-like cells and the T98G GBM cell line. Impedance-based real-time cell growth assays and apoptosis detection assays revealed that the GiNKs exhibited growth inhibitory effects on U87MG and T98G cells by inducing apoptosis. KIR2DL1 blockade attenuated the growth inhibition of the cell lines in vitro. The intracranial administration of GiNKs prolonged the overall survival of the U87MG-derived orthotopic xenograft brain tumor model. The KIR2DL1 blockade did not enhance the antitumor effects; rather, it attenuated it in the same manner as in the in vitro experiment. GiNK immunotherapy directly administered to the brain could be a promising immunotherapeutic alternative for patients with GBM. Furthermore, KIR2DL1 blockade appeared to require caution when used concomitantly with GiNKs.

[External Ocular Movement(EOM)Monitoring].

The intraoperative monitoring of extraocular motor nerves allows optimal skull base surgery by protecting the cranial nerves. For detecting cranial nerve function, several methods, such as external ocular movement monitoring with an electrooculogram(EOG), electromyogram(EMG), and piezoelectric device sensors, are present. While being valuable and useful, several problems related to its accurate monitoring persist when scanning from inside the tumor, which might be far from the cranial nerves. Here, we described three modalities, free-run EOG monitoring, trigger EMG monitoring, and piezoelectric sensor monitoring for monitoring external ocular movement. Improvement of these processes is essential for appropriately conducting these procedures during neurosurgical operations without harming the extraocular motor nerves.

Ischemic Postconditioning Reduces NMDA Receptor Currents Through the Opening of the Mitochondrial Permeability Transition Pore and KATP Channel in Mouse Neurons.

Ischemic postconditioning (PostC) is known to reduce cerebral ischemia/reperfusion (I/R) injury; however, whether the opening of mitochondrial ATP-dependent potassium (mito-KATP) channels and mitochondrial permeability transition pore (mPTP) cause the depolarization of the mitochondrial membrane that remains unknown. We examined the involvement of the mito-KATP channel and the mPTP in the PostC mechanism. Ischemic PostC consisted of three cycles of 15 s reperfusion and 15 s re-ischemia, and was started 30 s after the 7.5 min ischemic load. We recorded N-methyl-D-aspartate receptors (NMDAR)-mediated currents and measured cytosolic Ca2+ concentrations, and mitochondrial membrane potentials in mouse hippocampal pyramidal neurons. Both ischemic PostC and the application of a mito-KATP channel opener, diazoxide, reduced NMDAR-mediated currents, and suppressed cytosolic Ca2+ elevations during the early reperfusion period. An mPTP blocker, cyclosporine A, abolished the reducing effect of PostC on NMDAR currents. Furthermore, both ischemic PostC and the application of diazoxide potentiated the depolarization of the mitochondrial membrane potential. These results indicate that ischemic PostC suppresses Ca2+ influx into the cytoplasm by reducing NMDAR-mediated currents through mPTP opening. The present study suggests that depolarization of the mitochondrial membrane potential by opening of the mito-KATP channel is essential to the mechanism of PostC in neuroprotection against anoxic injury.

Simple sutureless closure of a thoracic ventral dural defect in a patient with superficial siderosis: technical report.

BACKGROUND: Closure of the ventral dura mater of the thoracic spinal cord is challenging because it requires both avoiding spinal cord damage and obtaining sufficient working space in an anatomically narrow area. We report a case of superficial siderosis (SS) due to chronic bleeding from a thoracic ventral dural defect in which we preformed dural repair using as a simple sutureless method and obtained good results. CASE DESCRIPTION: A 75-year-old man complained of slowly progressive gait, speech, and hearing disturbances over 5 years. Magnetic resonance imaging (MRI) showed SS in the brain and the spinal cord and a dural defect ventral to the spinal cord at the T2 level. Neurological examination revealed bilateral cerebellar ataxia and mild motor weakness in left iliopsoas muscle. T2 and T3 hemi-laminectomy was performed in the prone position. Transdurally, a dural defect on the ventral side of the spinal cord and a fluid-filled space beyond it could be observed. With endoscopic assistance, a blood clot in the space was confirmed. For dural closure, we performed a simple manipulation using a collagen-based dural graft. The graft was cut into pieces, softened with saline, and simply packed into the space with minimal strain on the spinal cord despite the narrow space. The postoperative clinical course was uneventful. Postoperative MRI at 1 year showed the space had disappeared. CONCLUSION: In patients with SS, sutureless dural closure using a collagen-based dural graft allows for effective, minimally invasive dural closure, even for thoracic ventral lesions.

Melatonin-Induced Postconditioning Suppresses NMDA Receptor through Opening of the Mitochondrial Permeability Transition Pore via Melatonin Receptor in Mouse Neurons.

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.

Capability of Human Dendritic Cells Pulsed with Autologous Induced Pluripotent Stem Cell Lysate to Induce Cytotoxic T Lymphocytes against HLA-A33-Matched Cancer Cells.

Irradiated murine induced-pluripotent stem cells (iPSCs) elicit the antitumor response in vivo. However, it is unclear whether human iPSCs would elicit antitumor effects. In the present study, we investigated the capability of human iPSC lysate (iPSL)-pulsed dendritic cells (DCs) (iPSL/DCs) to induce cancer-responsive cytotoxic T lymphocytes (CTLs) in vitro. iPSCs and DCs were induced from peripheral blood mononuclear cells isolated from a human leukocyte antigen (HLA)-A33 homozygous donor. The iPSL was pulsed with immature DCs, which were then stimulated to allow full maturation. The activated DCs were co-cultured with autologous CTLs and their responses to SW48 colorectal carcinoma cells (HLA-A32/A33), T47D breast cancer cells (HLA-A33/A33), and T98G glioblastoma cells (HLA-A02/A02) were tested with enzyme-linked immunospot (ELISPOT) assays. Comprehensive gene expression analysis revealed that the established iPSCs shared numerous tumor-associated antigens with the SW48 and T47D cells. Immunofluorescent analysis demonstrated that the fluorescent-labeled iPSL was captured by the immature DCs within 2 h. iPSL/DCs induced sufficient CTL numbers in 3 weeks for ELISPOT assays, which revealed that the induced CTLs responded to SW48 and T47D cells. Human iPSL/DCs induced cancer-responsive CTLs on HLA-A33-matched cancer cells in vitro and could be a promising universal cancer vaccine for treating and preventing cancer.

[Surgical Site Infection in Spine and Spinal Cord Surgery].

Surgical site infection(SSI)is among the most serious complications of spinal surgery in terms of patient health status and clinical outcomes. The use of prophylactic antimicrobials does not eliminate SSIs. Risk factors for SSI exist during not only the intraoperative period, but also all perioperative periods. In addition to intraoperative surgical risk factors, patient-related factors such as age, nutritional status, diabetes, smoking, obesity, coexistent infections in a remote part of the body, and colonization with microorganisms have also been reported. Therefore, it is important to reduce the risk of SSIs even before surgery, which requires knowledge about SSIs and prevention efforts. Spinal surgery can cause deep SSIs, instrumented infections, and meningitis resulting from cerebrospinal fluid infection. Spinal SSIs can be predicted by detecting changes in wound sites, pain and fever, and trends in hematological examination. However, special attention should be given to instrumented surgeries because of the subclinical nature of bacterial biofilm formation on the surface of implants. Therefore, it is important to aim for early detection and treatment of SSIs while reducing perioperative risks to decrease the potential for poor outcomes due to spinal SSIs.

Lipid Core Burden Index Assessed by Near-Infrared Spectroscopy of Symptomatic Carotid Plaques: Association with Magnetic Resonance T1-Weighted Imaging.

INTRODUCTION: Vulnerable plaques are a strong predictor of cerebrovascular ischemic events, and high lipid core plaques (LCPs) are associated with an increased risk of embolic infarcts during carotid artery stenting (CAS). Recent developments in magnetic resonance (MR) plaque imaging have enabled noninvasive assessment of carotid plaque vulnerability, and the lipid component and intraplaque hemorrhage (IPH) are visible as high signal intensity areas on T1-weighted MR images. Recently, catheter-based near-infrared spectroscopy (NIRS) has been shown to accurately distinguish LCPs without IPH. This study aimed to determine whether the results of assessment of high LCPs by catheter-based NIRS correlate with the results of MR plaque imaging. METHODS: We recruited 82 consecutive symptomatic carotid artery stenosis patients who were treated with CAS under NIRS and MR plaque assessment. Maximum lipid core burden index (max-LCBI) at minimal luminal areas (MLA), defined as max-LCBIMLA, and max-LCBI for any 4-mm segment in a target lesion, defined as max-LCBIAREA, were assessed by NIRS. Correlations were investigated between max-LCBI and MR T1-weighted plaque signal intensity ratio (T1W-SIR) and MR time-of-flight signal intensity ratio (TOF-SIR) in the same regions as assessed by NIRS. RESULTS: Both T1W-SIRMLA and T1W-SIRAREA were significantly lower in the high LCP group (max-LCBI >504, p < 0.001 for both), while TOF-SIRMLA and TOF-SIRAREA were significantly higher in the high LCP group (p < 0.001 and p = 0.004, respectively). A significant linear correlation was present between max-LCBIMLA and both TIW-SIRMLA and TOF-SIRMLA (r = -0.610 and 0.452, respectively, p < 0.0001 for both). Furthermore, logistic regression analysis revealed that T1W-SIRMLA and TOF-SIRMLA were significantly associated with a high LCP assessed by NIRS (OR, 44.19 and 0.43; 95% CI: 6.55-298.19 and 0.19-0.96; p < 0.001 and = 0.039, respectively). CONCLUSIONS: A high LCP assessed by NIRS correlates with the signal intensity ratio of MR imaging in symptomatic patients with unstable carotid plaques.

Cough syncope and hyperventilation-induced convulsion in Chiari 1.5 malformation.

Chiari malformation type I (CM1) is defined as cerebellar tonsillar herniation below the level of the foramen magnum. Syncope, especially cough syncope, is a rare but important symptom of CM1 patients. Here, we report a CM1 patient, in combination with brainstem herniation (CM1.5), presenting with repetitive syncope who was successfully treated by decompressive surgery. A 43-year-old right-handed male, with 5-year history of repeated episodes of loss of consciousness in association with cough, was investigated. Neurological examination revealed slight muscle weakness, clumsiness, and sensory disturbance in the left upper limb. There was no sign of orthostatic hypotension or orthostatic intolerance. Cranial and spinal magnetic resonance imaging revealed a herniation of the cerebellar tonsils and a syringomyelia. Forced hyperventilation during electroencephalogram (EEG) induced brief generalized symmetric clonic convulsions with preserved consciousness, but no overt EEG seizure patterns or slow activities were found. Based on the diagnosis of CM1.5 with recurrent episodes of loss of consciousness, he underwent foramen magnum decompression. He has no recurrence of the episode after the surgery on 1 year follow-up. Decompressive surgery was an effective procedure for cough syncope and other symptoms of the current patient with CM1.5. Dissociation of cerebrospinal fluid pressure between the cranial and spinal compartments which leads further herniation of the cerebellar tonsils and subsequent compression on the cerebellum and the brainstem is considered to be the major mechanism of his cough syncope. Analysis of EEG can be useful not only to diagnose epileptic seizures but also to elucidate mechanisms of syncope and concurrent involuntary movements.

Efficacy and safety of intraventricular fibrinolytic therapy for post-intraventricular hemorrhagic hydrocephalus in extreme low birth weight infants: a preliminary clinical study.

PURPOSE: To evaluate the efficacy and safety of our unique therapy for treating post-intraventricular hemorrhagic hydrocephalus (PIVHH) in low birth weight infants (LBWls) through an early stage fibrinolytic therapeutic strategy involving urokinase (UK) injection into the lateral ventricle, called the "Ventricular Lavage (VL) therapy." METHODS: Overall, 43 consecutive infants with PIVHH were included. Most were extremely LBWIs (n = 39). Other cases included very LBWIs (n = 2) and full-term infants (n = 2). VL therapy involved continuous external ventricular drainage (EVD) management using a very fine catheter and intermittent slow injection of 6000 IU of UK every 3-6 h to actively dissolve hematomas. RESULTS: Early EVD management (within 3 weeks of IVH onset) was performed in 25 infants, with combination VL therapy in 21 infants. Five initiated late EVD management (≥ 3 weeks after IVH onset); the remaining 13 were treated conservatively for several weeks, delaying surgical intervention. Eighteen of 21 (86%) infants who received VL therapy did not require permanent shunt surgery. There were no serious complications, including the absence of secondary hemorrhage and infection. Two-thirds of the infants treated in the late stages required permanent shunt, and various shunt-related complications frequently occurred. A good outcome occurred in 13/17 infants in the early treatment group, despite most subjects having an IVH grade IV, and in 6/15 in the late treatment group. CONCLUSIONS: Permanent shunt surgery needs were dramatically reduced following early VL therapy, and functional outcomes were favorable. VL therapy might be a promising strategy that could lead to the development of new treatments for PIVHH.

Hinge and floating decompressive craniotomy for infantile acute subdural hematoma: technical note.

Cranioplasty complications after decompressive craniectomy (DC) in infants are not fully recognized. We aimed to devise and assess the efficacy of a hinge and floating DC (HFDC) technique for treating infantile acute subdural hematoma. Five infants, aged 2-20 months, were included. Intracranial pressure was controlled below 20 mmHg, no additional surgery was required, and there was no incidence of surgical site infection or bone graft resorption.

Diagnostic impact of monitoring transcranial motor-evoked potentials to prevent ischemic complications during endovascular treatment for intracranial aneurysms.

The present study aimed to determine the incidence of intraprocedural motor-evoked potential (MEP) changes and to correlate them with intraprocedural ischemic complications and postprocedural neurological deficits in patients after endovascular intracranial aneurysm treatment. This study analyzed data from 164 consecutive patients who underwent endovascular coil embolization to treat intracranial aneurysms under transcranial MEP monitoring. We analyzed associations between significant changes in MEP defined as > 50% decrease in amplitude, and intraprocedural complications as well as postoperative neurological deficits. Factors associated with postprocedural neurological deficits were also assessed. The treated aneurysms were predominantly located in the anterior circulation (71%). Fourteen (9%) were located at perforators or branches that supplied the pyramidal tract. Intraprocedural complications developed in eight (5%) patients, and four of eight (50%) patients occurred postprocedural neurological deficits. Significant intraprocedural MEP changes occurred during seven of eight endovascular procedures associated with intraprocedural complications and salvage procedures were performed immediately. Among these changes, four transient MEP changes, recovered within 10 min, were not associated with postprocedural neurological deficits, whereas three permanent MEP changes were associated with postprocedural neurological deficits and mRS ≥ 1 at discharge. Aneurysms located at perforators/branches supplying the pyramidal tract, and permanent intraprocedural MEP changes were associated with postprocedural neurological deficits. We conclude that intraprocedural transcranial MEP monitoring can reliably identify ischemic changes and can initiate prompt salvage procedures during endovascular aneurysm treatment.

Ocular blood flow by laser speckle flowgraphy to detect cerebral ischemia during carotid endarterectomy.

Laser speckle flowgraphy (LSFG) is a noninvasive technique that can measure relative blood flow velocity in the optic fundus contributed by the ophthalmic artery, the main first branch originating from the internal carotid artery (ICA). The aim of this study was to assess the feasibility of ocular blood flow measurement by LSFG to detect ischemic stress due to carotid clamping during carotid endarterectomy (CEA). Nineteen patients undergoing CEA with ocular blood flow measurement by LSFG and intraoperative monitoring (IOM) were prospectively enrolled between August 2016 and March 2019. The mean blur rate (MBR) of ocular blood flow by LSFG, representing relative blood flow of the branch of the retinal artery originating from the optic nerve head, was compared between before and after carotid clamping during CEA. The correlation between the reduction ratio of MBR and the regional saturation oxygen (rSO2) index by near infrared spectroscopy was investigated. Ocular blood flow measurement by LSFG could not be performed in one patient with a severe cataract. In the other 18 patients, LSFG could be performed in all 106 sessions during surgery. The MBR reduction ratio between before and after carotid clamping ranged from - 12 to 100%. The MBR reduction ratio was positively correlated with the rSO2 index (r = 0.694, 95% confidence interval: 0.336-0.877, p = 0.001). The MBR reduction ratio of ocular blood flow by LSFG after carotid clamping was significantly correlated with the rSO2 index. The ocular blood flow by LSFG could be considered an adjunct modality for evaluating cerebral ischemic tolerance during CEA.

Motor evoked potential monitoring can evaluate ischemic tolerance to carotid artery occlusion during surgery.

Balloon test occlusion (BTO) is a useful examination for evaluating ischemic tolerance to internal carotid artery (ICA) occlusion. The aim of this study was to investigate the relationships between intraoperative motor evoked potential (MEP) monitoring and the results of preoperative BTO. Between 2013 and 2017, 32 patients undergoing surgery under general anesthesia with intraoperative MEP monitoring, in whom preoperative BTO was performed, were identified. A receiver operator characteristic (ROC) analysis was performed to determine the appropriate cutoff value of MEP amplitude for BTO-positive. Furthermore, the accuracy of MEP monitoring for BTO-positive was compared with electroencephalogram (EEG) and somatosensory evoked potential (SEP) monitoring. Four of 32 (12.5%) patients were BTO-positive. The cutoff value of MEP amplitude for BTO-positive was a > 80% reduction from the baseline level, which showed sensitivity of 100% and specificity of 100%. Thus, the sensitivity and specificity for BTO-positive were significantly higher for MEP than for EEG (100% and 72.0%, p = 0.02) in 28 patients, but they were not significantly different compared with SEP (33.3% and 100%, p = 0.48) in 21 patients. MEP monitoring might be one of the alternatives for evaluating ischemic tolerance to ICA occlusion during surgery. The cutoff value of MEP amplitude was a > 80% reduction.

CRISPR-Cas9-Mediated TIM3 Knockout in Human Natural Killer Cells Enhances Growth Inhibitory Effects on Human Glioma Cells.

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults. Natural Killer (NK) cells are potent cytotoxic effector cells against tumor cells inducing GBM cells; therefore, NK cell based- immunotherapy might be a promising target in GBM. T cell immunoglobulin mucin family member 3 (TIM3), a receptor expressed on NK cells, has been suggested as a marker of dysfunctional NK cells. We established TIM3 knockout in NK cells, using the clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9). Electroporating of TIM3 exon 2- or exon 5-targeting guide RNA- Cas9 protein complexes (RNPs) inhibited TIM3 expression on NK cells with varying efficacy. T7 endonuclease I mutation detection assays showed that both RNPs disrupted the intended genome sites. The expression of other checkpoint receptors, i.e., programmed cell death 1 (PD1), Lymphocyte-activation gene 3 (LAG3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), and TACTILE (CD96) were unchanged on the TIM3 knockout NK cells. Real time cell growth assays revealed that TIM3 knockout enhanced NK cell-mediated growth inhibition of GBM cells. These results demonstrated that TIM3 knockout enhanced human NK cell mediated cytotoxicity on GBM cells. Future, CRISPR-Cas9 mediated TIM3 knockout in NK cells may prove to be a promising immunotherapeutic alternative in patient with GBM.

Ex Vivo Expanded and Activated Natural Killer Cells Prolong the Overall Survival of Mice with Glioblastoma-like Cell-Derived Tumors.

Glioblastoma (GBM) is the leading malignant intracranial tumor and is associated with a poor prognosis. Highly purified, activated natural killer (NK) cells, designated as genuine induced NK cells (GiNKs), represent a promising immunotherapy for GBM. We evaluated the anti-tumor effect of GiNKs in association with the programmed death 1(PD-1)/PD-ligand 1 (PD-L1) immune checkpoint pathway. We determined the level of PD-1 expression, a receptor known to down-regulate the immune response against malignancy, on GiNKs. PD-L1 expression on glioma cell lines (GBM-like cell line U87MG, and GBM cell line T98G) was also determined. To evaluate the anti-tumor activity of GiNKs in vivo, we used a xenograft model of subcutaneously implanted U87MG cells in immunocompromised NOG mice. The GiNKs expressed very low levels of PD-1. Although PD-L1 was expressed on U87MG and T98G cells, the expression levels were highly variable. Our xenograft model revealed that the retro-orbital administration of GiNKs and interleukin-2 (IL-2) prolonged the survival of NOG mice bearing subcutaneous U87MG-derived tumors. PD-1 blocking antibodies did not have an additive effect with GiNKs for prolonging survival. GiNKs may represent a promising cell-based immunotherapy for patients with GBM and are minimally affected by the PD-1/PD-L1 immune evasion axis in GBM.

[Variations in Cervical Degenerative Diseases:What are the Key-points in Diagnosis?]

Degenerative cervical spine diseases are caused by age-related changes in the spine and often lead to impairment of neurological function, resulting in reduced quality of life. Multiple cervical spine degenerative diseases are known, such as cervical spondylosis, cervical disc herniation, and ossification of the posterior longitudinal ligament, which often coexist in a single patient. In degenerative cervical spine disease, many lesions are noted on radiographs but are often asymptomatic; hence, caution is required in clinical practice. Therefore, for the treatment of the disease, it is important to diagnose and identify the phenomenon or location causing the disorder. For this purpose, it is important to focus on the type and extent of neurological symptoms; mechanism of nerve compression, radiculopathy or myelopathy; and presence or absence of spinal instability, static or dynamic.

C2 extradural schwannoma compressing the dominant internal jugular vein: a case report.

We describe a rare case of extradural schwannoma in the upper cervical spine compressing the dominant internal jugular vein (IJV) presenting with atypical headaches. A 50-year-old woman complained of a subcutaneous neck mass associated with atypical headaches. Radiological examinations revealed the right IJV was compressed anteriorly by C2 extradural mass and occluded with markedly dilated collateral cerebral venous drainage through deep cervical veins. Subtotal removal was performed via the posterolateral approach and the atypical headaches resolved immediately. This case demonstrates that extradural schwannoma in the upper cervical spine could compress the IJV and manifest as cerebral venous circulation disturbances.