Development and validation of a novel overhead method for anteroposterior radiographs of fractured rat femurs.

We aimed to establish a new method of obtaining femur anteroposterior radiographs from live rats. We used five adult male Sprague-Dawley rats and created a femoral fracture model with an 8 mm segmental fragment. After the surgery, we obtained two femoral anteroposterior radiographs, a novel overhead method, and a traditional craniocaudal view. We obtained the overhead method three times, craniocaudal view once, and anteroposterior radiograph of the isolated femoral bone after euthanasia. We compared the overhead method and craniocaudal view with an isolated femoral anteroposterior view. We used a two-sample t-test and intraclass correlation coefficient (ICC) to estimate the intra-observer reliability. The overhead method had significantly smaller differences than the craniocaudal view for nail length (1.53 ± 1.26 vs. 11.4 ± 3.45, p < 0.001, ICC 0.96) and neck shaft angle (5.82 ± 3.8 vs. 37.8 ± 5.7, p < 0.001, ICC 0.96). No significant differences existed for intertrochanteric length/femoral head diameter (0.23 ± 0.13 vs. 0.23 ± 0.13, p = 0.96, ICC 0.98) or lateral condyle/medial condyle width (0.15 ± 0.16 vs. 0.13 ± 0.08, p = 0.82, ICC 0.99). A fragment displacement was within 0.11 mm (2.4%). The overhead method was closer to the isolated femoral anteroposterior view and had higher reliability.

Microbiota-dependent activation of CD4+ T cells induces CTLA-4 blockade-associated colitis via Fcγ receptors.

Immune checkpoint inhibitors can stimulate antitumor immunity but can also induce toxicities termed immune-related adverse events (irAEs). Colitis is a common and severe irAE that can lead to treatment discontinuation. Mechanistic understanding of gut irAEs has been hampered because robust colitis is not observed in laboratory mice treated with checkpoint inhibitors. We report here that this limitation can be overcome by using mice harboring the microbiota of wild-caught mice, which develop overt colitis following treatment with anti-CTLA-4 antibodies. Intestinal inflammation is driven by unrestrained activation of IFNγ-producing CD4+ T cells and depletion of peripherally induced regulatory T cells through Fcγ receptor signaling. Accordingly, anti-CTLA-4 nanobodies that lack an Fc domain can promote antitumor responses without triggering colitis. This work suggests a strategy for mitigating gut irAEs while preserving antitumor stimulating effects of CTLA-4 blockade.

Signal conversion as tumor micro environment (TME) specifically activated cytokine.

Targeted cytokine delivery has been gaining popularity in cancer immunotherapy since systemic recombinant cytokine treatment has not been successful due to low response rate and systemic toxicities in the clinical studies. In order to address these issues, we propose a new concept that cytokine signal is specifically activated at tumor-micro-environment (TME) by delivering two protein subunits of heterodimeric cytokine fused with a tumor targeting antibody respectively to TME and by bridging the two subunits into active heterodimeric form.Interleukin-12 (IL-12) is one of the major cytokines which can induce immune activation. IL-12 consists of two protein subunits which are p35 and p40. IL-12 signaling is initiated when it forms as the heterodimeric protein and binds to IL-12 receptor complex. We made fusion proteins of both IL-12p35 and IL-12p40 targeting specific tumor associated antigens (TAAs) and demonstrated the formation of bioactive IL12p70 with TME targeting antibody toward both p35 and p40 to form as the active molecule. We describe our concept validation in an in vitro based functional assay.

Factors Related to the Delayed Cure of Hemifacial Spasm after Microvascular Decompression: An Analysis of 175 Consecutive Patients.

Detailed studies assessing the factors related to delayed cure of hemifacial spasm (HFS) after microvascular decompression (MVD) are sparse. We aimed to evaluate the effect of 11 clinical factors on the time until the patient became spasm free after MVD. We enrolled 175 consecutive patients with HFS who underwent MVD between 2012 and 2018. The end point was defined as the time point at which the patient became spasm free based on the outpatient interview. Patients were divided into six groups depending on when they became spasm free after the operation, as follows: <7 days ( n = 62), 7 days to 1 month ( n = 28), 1 to 3 months ( n = 38), 3 to 6 months ( n = 25), 6 to 12 months ( n = 17), and >12 months ( n = 5). The median time to become spasm free after MVD was 30.0 days. Association of 11 factors (age, sex, laterality, number of offending arteries, vertebral artery compression, number of compression sites, compression at root detachment zone, preoperative Botox treatment, indentation of the brain stem on preoperative magnetic resonance image, transposition, and interposition) with spasm-free rate was assessed using the Cox's proportional hazards model. Spasm-free rate curve after MVD for the significant factor was obtained using the Kaplan-Meier method. In univariate and multivariate analyses, nontransposition was significantly related to delayed HFS cure after MVD (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.42, 0.87; p = 0.0068 and HR, 0.60; CI, 0.43, 0.85; p = 0.042, respectively). The spasm-free rate was higher in the transposition than in the nontransposition group ( p = 0.0013). As shortening the time until spasm free after MVD improves patients' quality of life, transposition should be recommended. Prediction of spasm-free time could relieve the anxiety of postoperative patients.

Visualization of ictal networks using gamma oscillation regularity correlation analysis in focal motor epilepsy: Illustrative cases.

Background: Focal motor epilepsy is difficult to localize within the epileptogenic zone because ictal activity quickly spreads to the motor cortex through ictal networks. We previously reported the usefulness of gamma oscillation (30-70 Hz) regularity (GOR) correlation analysis using interictal electrocorticographic (ECoG) data to depict epileptogenic networks. We conducted GOR correlation analysis using ictal ECoG data to visualize the ictal networks originating from the epileptogenic zone in two cases - a 26-year-old woman with negative motor seizures and a 53-year-old man with supplementary motor area (SMA) seizures. Case Description: In both cases, we captured several habitual seizures during monitoring after subdural electrode implantation and performed GOR correlation analysis using ictal ECoG data. A significantly high GOR suggestive of epileptogenicity was identified in the SMA ipsilateral to the lesions, which were connected to the motor cortex through supposed ictal networks. We resected the high GOR locations in the SMA and the patients' previously identified tumors were removed. The patients were seizure-free without any neurological deficits after surgery. Conclusion: The GOR correlation analysis using ictal ECoG data could be a powerful tool for visualizing ictal networks in focal motor epilepsy.

Interictal High Gamma Oscillation Regularity as a Marker for Presurgical Epileptogenic Zone Localization.

BACKGROUND: To ensure that epilepsy surgery is effective, accurate presurgical localization of the epileptogenic zone is essential. Our previous reports demonstrated that interictal high gamma oscillation (30-70 Hz) regularity (GOR) on intracranial electroencephalograms is related to epileptogenicity. OBJECTIVE: To examine whether preoperative GOR analysis with interictal high-density electroencephalography (HD-EEG) improves the accuracy of epileptogenic focus localization and enhances postoperative seizure control. METHODS: We calculated GOR from 20 seconds of HD-EEG data for 21 patients with refractory focal epilepsy (4 with nonlesional temporal lobe epilepsy) scheduled for epilepsy surgery. Low-resolution brain electromagnetic tomography was used to analyze the high GOR source. To validate our findings, we made comparisons with other conventional localization methods and postoperative seizure outcomes. RESULTS: In all patients, the areas of interictal high GOR were identified and resected. All patients were seizure-free after the operation. The concordance between the results of interictal high GOR on HD-EEG and those of source estimation of interictal discharge was fully overlapping in 10 cases, partially overlapping in 8 cases, and discordant in 3 cases. The concordance between the results of interictal high GOR on HD-EEG and those of interictal 123 I-iomazenil single-photon emission computed tomography was fully overlapping in 8 cases, partially overlapping in 11 cases, and discordant in 2 cases. In 4 patients with nonlesional temporal lobe epilepsy, the interictal high GOR on HD-EEG was useful in confirming the epileptogenic zone. CONCLUSION: The interictal high GOR on HD-EEG is an excellent marker for presurgical epileptogenic zone localization.

Fc-independent functions of anti-CTLA-4 antibodies contribute to anti-tumor efficacy.

Ipilimumab, a monoclonal antibody that recognizes cytotoxic T-lymphocyte associated protein 4 (CTLA-4), was the first immune checkpoint inhibitor approved by the FDA to treat metastatic melanoma patients. Multiple preclinical studies have proposed that Fc effector functions of anti-CTLA-4 therapy are required for anti-tumor efficacy, in part, through the depletion of intratumoral regulatory T cells (Tregs). However, the contribution of the Fc-independent functions of anti-CTLA-4 antibodies to the observed efficacy is not fully understood. H11, a non-Fc-containing single-domain antibody (VHH) against CTLA-4, has previously been demonstrated to block CTLA-4-ligand interaction. However, in vivo studies demonstrated lack of anti-tumor efficacy with H11 treatment. Here, we show that a half-life extended H11 (H11-HLE), despite the lack of Fc effector functions, induced potent anti-tumor efficacy in mouse syngeneic tumor models. In addition, a non-Fc receptor binding version of ipilimumab (Ipi-LALAPG) also demonstrated anti-tumor activity in the absence of Treg depletion. Thus, we demonstrate that Fc-independent functions of anti-CTLA-4 antibodies contributed to anti-tumor efficacy, which may indicate that non-Treg depleting activity of anti-CTLA-4 therapy could benefit cancer patients in the clinic.

TAK-676: A Novel Stimulator of Interferon Genes (STING) Agonist Promoting Durable IFN-dependent Antitumor Immunity in Preclinical Studies.

Oncology therapies targeting the immune system have improved patient outcomes across a wide range of tumor types, but resistance due to an inadequate T-cell response in a suppressive tumor microenvironment (TME) remains a significant problem. New therapies that activate an innate immune response and relieve this suppression may be beneficial to overcome this hurdle. TAK-676 is a synthetic novel stimulator of interferon genes (STING) agonist designed for intravenous administration. Here we demonstrate that TAK-676 dose-dependently triggers activation of the STING signaling pathway and activation of type I interferons. Furthermore, we show that TAK-676 is a highly potent modulator of both the innate and adaptive immune system and that it promotes the activation of dendritic cells, natural killer cells, and T cells in preclinical models. In syngeneic murine tumor models in vivo, TAK-676 induces dose-dependent cytokine responses and increases the activation and proliferation of immune cells within the TME and tumor-associated lymphoid tissue. We also demonstrate that TAK-676 dosing results in significant STING-dependent antitumor activity, including complete regressions and durable memory T-cell immunity. We show that TAK-676 is well tolerated, exhibits dose-proportional pharmacokinetics in plasma, and exhibits higher exposure in tumor. The intravenous administration of TAK-676 provides potential treatment benefit in a broad range of tumor types. Further study of TAK-676 in first-in-human phase I trials is ongoing. Significance: TAK-676 is a novel systemic STING agonist demonstrating robust activation of innate and adaptive immune activity resulting in durable antitumor responses within multiple syngeneic tumor models. Clinical investigation of TAK-676 is ongoing.

Tumor-immune profiling of CT-26 and Colon 26 syngeneic mouse models reveals mechanism of anti-PD-1 response.

BACKGROUND: Immune checkpoint blockade (ICB) therapies have changed the paradigm of cancer therapies. However, anti-tumor response of the ICB is insufficient for many patients and limited to specific tumor types. Despite many preclinical and clinical studies to understand the mechanism of anti-tumor efficacy of ICB, the mechanism is not completely understood. Harnessing preclinical tumor models is one way to understand the mechanism of treatment response. METHODS: In order to delineate the mechanisms of anti-tumor activity of ICB in preclinical syngeneic tumor models, we selected two syngeneic murine colorectal cancer models based on in vivo screening for sensitivity with anti-PD-1 therapy. We performed tumor-immune profiling of the two models to identify the potential mechanism for anti-PD-1 response. RESULTS: We performed in vivo screening for anti-PD-1 therapy across 23 syngeneic tumor models and found that CT-26 and Colon 26, which are murine colorectal carcinoma derived from BALB/c mice, showed different sensitivity to anti-PD-1. CT-26 tumor mice were more sensitive to the anti-PD-1 antibody than Colon 26, while both models show similarly sensitivity to anti-CTLA4 antibody. Immune-profiling showed that CT-26 tumor tissue was infiltrated with more immune cells than Colon 26. Genomic/transcriptomic analyses highlighted thatWnt pathway was one of the potential differences between CT-26 and Colon 26, showing Wnt activity was higher in Colon 26 than CT-26. . CONCLUSIONS: CT-26 and Colon 26 syngeneic tumor models showed different sensitivity to anti-PD-1 therapy, although both tumor cells are murine colorectal carcinoma cell lines from BALB/c strain. By characterizing the mouse cells lines and tumor-immune context in the tumor tissues with comprehensive analysis approaches, we found that CT-26 showed "hot tumor" profile with more infiltrated immune cells than Colon 26. Further pathway analyses enable us to propose a hypothesis that Wnt pathway could be one of the major factors to differentiate CT-26 from Colon 26 model and link to anti-PD-1 response. Our approach to focus on preclinical tumor models with similar genetic background but different sensitivity to anti-PD-1 therapy would contribute to illustrating the potential mechanism of anti-PD-1 response and to generating a novel concept to synergize current anti-PD-1 therapies for cancer patients.

Influences of Lavender Essential Oil Inhalation on Stress Responses during Short-Duration Sleep Cycles: A Pilot Study.

Lavender essential oil (LEO) was reported to improve sleep quality. We investigated the influence of aromatherapy by testing the effects of LEO on stress responses during a short-duration sleep in a single-blind, randomized, crossover trial. The subjects were twelve healthy adults who were nonsmokers without any known disease and who were not prescribed medications, and nine of these completed the study. After the subjects had fallen asleep, they were sprayed with LEO using an aroma diffuser. Before and after 90 min of sleep, α-amylase, chromogranin A (CgA), and cortisol levels in saliva were measured as objective stress indicators, and the Japanese version of the UWIST Mood Adjective Checklist was used as a subjective indicator. A comparison of changes before and after sleep, with and without LEO, revealed that the cortisol level did not significantly change; however, α-amylase (p < 0.05) and CgA (p < 0.01) levels significantly decreased after LEO inhalation. A mood test indicated no change in mood before and after sleep, with or without LEO. Since α-amylase and CgA reflect the sympathetic nervous system response, these results indicate that LEO aromatherapy during a short-duration sleep cycle suppresses the stress response, especially that of the sympathetic nervous system.

Intraoperative epileptogenic network visualization using gamma oscillation regularity correlation analysis in epilepsy surgery.

BACKGROUND: We have recently demonstrated that gamma oscillation (30-70 Hz) regularity (GOR) analysis accurately localized epileptogenic focus using intraoperative electrocorticographic data. In this report, we assessed whether GOR correlation analysis could depict epileptogenic networks intraoperatively. Dual foci in temporal lobe epilepsy without hippocampal structural abnormalities are difficult to diagnose. Using our GOR correlation analysis, we aimed to intraoperatively visualize such dual foci and epileptogenic networks. CASE DESCRIPTION: A 56-year-old man suffered from pharmacoresistant focal impaired awareness seizures. Magnetic resonance imaging demonstrated an 8 × 12-mm cavernoma in the right inferior temporal gyrus without any structural changes in the hippocampus. Since ictal semiology indicated a high probability of epileptogenicity in the right hippocampus, we reached the hippocampus using a transsylvian approach and assessed intraoperative GOR correlation analysis in the lateral temporal lobe where the cavernoma was located and the hippocampus, simultaneously. High GORs suggestive of epileptogenicity were identified in both the lateral temporal lobe and the hippocampus. Furthermore, they were connected using GOR correlation networks. When the high GOR locations in the lateral temporal lobe and the cavernoma were removed, high GORs and those networks were found within the hippocampus only. After additional hippocampal transection, high GORs and these networks were absent. The patient became seizure-free after the surgery. CONCLUSION: Our GOR correlation analysis may be a powerful tool for intraoperative evaluation of epileptogenic networks in epilepsy surgery.

Identification of Novel Carbocyclic Pyrimidine Cyclic Dinucleotide STING Agonists for Antitumor Immunotherapy Using Systemic Intravenous Route.

Stimulator of Interferon Genes (STING) plays an important role in innate immunity by inducing type I interferon production upon infection with intracellular pathogens. STING activation can promote increased T-cell activation and inflammation in the tumor microenvironment, resulting in antitumor immunity. Natural and synthetic cyclic dinucleotides (CDNs) are known to activate STING, and several synthetic CDN molecules are being investigated in the clinic using an intratumoral administration route. Here, we describe the identification of STING agonist 15a, a cyclic dinucleotide structurally diversified from natural ligands with optimized properties for systemic intravenous (iv) administration. Our studies have shown that STING activation by 15a leads to an acute innate immune response as measured by cytokine secretion and adaptive immune response via activation of CD8+ cytotoxic T-cells, which ultimately provides robust antitumor efficacy.

Epileptogenic zone localization using intraoperative gamma oscillation regularity analysis in epilepsy surgery for cavernomas: patient series.

BACKGROUND: In epilepsy surgery for cavernoma with intractable focal epilepsy, removal of the cavernoma with its surrounding hemosiderin deposition and other extended epileptogenic zone has been shown to improve postsurgical seizures. However, there has been no significant association between such an epileptogenic zone and intraoperative electrocorticography (ECoG) findings. The authors recently demonstrated that high regular gamma oscillation (30-70 Hz) regularity (GOR) significantly correlates with epileptogenicity. OBSERVATIONS: The authors evaluated the utility of intraoperative GOR analysis in epilepsy surgery for cavernomas. The authors also analyzed intraoperative ECoG data from 6 patients with cavernomas. The GOR was calculated using a sample entropy algorithm. In 4 patients, the GOR was significantly high in the area with the pathological hemosiderin deposition. In 2 patients with temporal cavernoma, the GOR was significantly high in both the hippocampus and the area with the pathological hemosiderin deposition. ECoG showed no obvious epileptic waveforms in 3 patients, whereas extensive spikes were observed in 3 patients. All patients underwent cavernoma removal plus resection of the area with significantly high GOR. The 2 patients with temporal cavernomas underwent additional hippocampal transection. All patients were seizure free after surgery. LESSONS: The high GOR may be a novel intraoperative marker of the epileptogenic zone in epilepsy surgery for cavernomas.

Potential Efficacy of Multimodal Mixed Reality in Epilepsy Surgery.

BACKGROUND: Mixed reality (MR) technology, which can fuse things in real and virtual space in real time, has been used mainly for simulation in neurosurgical training. OBJECTIVE: To develop MR technology into multimodal MR for intraoperative guidance during epilepsy surgery. METHODS: A 33-yr-old male patient suffered from intractable general tonic seizures due to left temporal meningoencephalocele. Preoperative scalp electroencephalograms localized interictal epileptic activity on the left temporal lobe. Iomazenil single photon emission tomography revealed temporal lobe lateralization. Magnetic resonance imaging (MRI) demonstrated left basal temporal meningoencephalocele extending into the pterygopalatine fossa through a bone defect at the base of the greater sphenoid wing. A 3-dimensional model was created for MR based on multimodal data including computed tomography, MRI tractography, and digital subtraction angiography, which enabled 3-dimensional visualization of abnormal subcortical fiber connections between the meningoencephalocele and the epileptic focus. RESULTS: By using intraoperative multimodal MR, we were able to safely remove the meningoencephalocele and perform epileptic focus resection. The patient was seizure-free postoperatively, and no adverse effects were noted. CONCLUSION: Intraoperative multimodal MR was a feasible and effective technique, and it can be applied for a wide range of epilepsy surgeries.

[Impact of Aperture Shape Controller on Volumetric Modulated Arc Therapy Treatment Planning for Nasopharyngeal Cancer].

PURPOSE: The aperture shape controller (ASC) decreases the complexity of the multi-leaf collimator (MLC) aperture for volumetric modulated arc therapy (VMAT). The purpose of this study was to evaluate the effect of ASC settings on the VMAT plan quality. METHOD: First, VMAT plans were created (ASC=off) for three test patterns of The American Association of Physicists in Medicine (AAPM) Task Group 119 (TG-119) and 20 cases of nasopharyngeal cancer. Next, for these VMAT plans, only the ASC settings were changed from very low (complexity reduction: low) to very high (complexity reduction: high) in five steps, and VMAT plans were created respectively. To evaluate the created VMAT plans per each ASC settings, we analyzed the modulation complexity score (MCSV) and dosimetric parameters for the planning target volume (PTV) and organ at risk (OAR). RESULT: In three test patterns, there were no major dosimetric differences between the VMAT plans. In nasopharyngeal cancer, the mean MCSV were 0.413, 0.325, 0.320, 0.307, 0.303, and 0.272 for very high, high, moderate, low, very low, off settings, respectively. Therefore, the most complex MLC aperture was off, followed by very low, low, moderate, high, and very high. In terms of dosimetric parameters, the VMAT plans created using the very high setting showed an increase of D2% in the PTV and worse OAR sparing than that using other ASC settings. On the other hand, the dosimetric results for the very low to moderate setting obtained similar results to those for the off setting, respectively. CONCLUSION: The ASC was able to decrease the complexity of the MLC aperture according to the setting level. From very low to moderate settings, a plan equivalent to the off setting could be created in terms of dose parameters.

Whole-Field Indocyanine Green Intensity Analysis to Intraoperatively Predict Cerebral Hyperperfusion Syndrome Following Superficial Temporal Artery-Middle Cerebral Artery Bypass: A Retrospective Case-Control Study in 7-Year Experience With 112 Cases.

BACKGROUND: Intraoperative prediction of postoperative cerebral hyperperfusion syndrome (CHS) after cerebrovascular bypass surgery is challenging. OBJECTIVE: To conduct a retrospective case-control study with indocyanine green (ICG) intensity analysis of the superficial temporal artery-middle cerebral artery (STA-MCA) bypass and investigate whether its washout pattern might be a marker for intraoperative prediction of CHS. METHODS: Between 2012 and 2018, 6 of 112 patients (5.4%) that underwent STA-MCA bypass exhibited CHS. We selected 5 patients with CHS (3 with atherosclerotic cerebrovascular disease [ASCVD] and 2 with moyamoya) and 15 patients without CHS (60% ASCVD and 40% moyamoya) as a matched control group. During prebypass and postbypass, washout times (WTs) for the first 10%, 25%, 50%, and 75% of maximum ICG intensity measured in the whole-camera field were compared between groups. The changes in WT (ΔWT) from prebypass to postbypass for each ICG intensity level were compared between groups. The cutoff ΔWTs, sensitivities, and specificities were also calculated. RESULTS: Postbypass WTs were significantly longer in the CHS group than the control group at all ICG intensities (P < .05). ΔWT was significantly greater in the CHS group than the control group for the first 10%, 25%, and 50% ICG intensities (P < .001). A cutoff ΔWT of ≥2.66 s for the first 50% ICG intensity showed a sensitivity of 100% and specificity of 100%. CONCLUSION: We found that a ΔWT ≥2.66 s for the first 50% ICG intensity could be an intraoperative predictive factor for CHS.

[Influence of Respiratory Phase during Image Acquisition on Prescribed Dose in Image Guided Radiation Therapy Using Implant Marker for Prostate Cancer].

In image guided radiation therapy (IGRT) using implanted fiducial marker by two-dimensional radiography for prostate cancer, temporal positional relationship during treatment between the isocenter and the prostate is changed by respiratory phase at the time of image acquisition. We examined influence of the respiratory phase in the IGRT on dose variation by interplay effect. Intra-fractional prostate motions of patients who were implanted fiducial marker were measured using fluoroscopy, then we reconstructed plans considering for the respiratory phase in IGRT and the respiratory motion during volumetric modulated arc therapy. Averages of the intra-fractional prostate motion in left-right, anterior-posterior and superior-inferior direction were 0.039, 0.49 and 1.6 mm respectively. There was a patient whose intra-fractional prostate motion was larger than 4 mm that was planning target volume margin. By changing the respiratory phase like inspiration, exhalation and dispersing respiratory phase in each fraction, dose variation from original plan became smaller in order of the inspiration, exhalation and dispersion. The largest variations of dose indices in clinical target volume, bladder and rectum were 8.0%, 4.5% and 9.1% respectively when IGRT was done in inspiration. When the IGRT is performed by the same respiratory phase in each fraction, systematic dose variations may occur even if the respiratory phase at the timing of irradiation is changed. By dispersing the respiratory phase in each fraction, the variations in all dose indices were<1% from original plan. We realized that dispersing the respiratory phase in IGRT by each fraction is effective to reduce the dose variation caused by the respiratory phase in IGRT.

Low entropy of interictal gamma oscillations is a biomarker of the seizure onset zone in focal cortical dysplasia type II.

OBJECTIVE: Dynamic changes in the regularity of interictal gamma oscillations (GOs, 30-70 Hz) on intracranial electroencephalography (EEG) reflect focal ictogenesis with epileptogenic neuronal synchronization in focal cortical dysplasia (FCD). We investigated whether the regularity of interictal GOs is a biomarker of the seizure onset zone (SOZ) using multiscale entropy analysis. METHODS: We quantified the regularity of interictal GOs using intracranial EEG data from 1164 electrodes in 13 patients with FCD who were seizure-free postoperatively. The regularity of interictal GOs was quantified as entropy values. Low entropy represents high regularity. We standardized entropy values using Z values for each SOZ, resection area (RA), and the region outside the RA. The cutoff Z values, sensitivity, and specificity for detecting each area were calculated using area under the receiver operating characteristics curves (AUCs). RESULTS: Low Z values represent higher regularity of GOs. The cutoff Z value of ≤-2.09 for the SOZ had a sensitivity of 100% and specificity of 97.1% (AUC = 0.992 ±â€¯0.002). The cutoff Z value of ≤-0.12 for the RA had a sensitivity of 54.2% and specificity of 73.8% (AUC = 0.673 ±â€¯0.019). The cutoff Z value of ≥-0.11 for the region outside the RA had a sensitivity of 73.8% and specificity of 54.2% (AUC = 0.673 ±â€¯0.019). CONCLUSIONS: Low entropy of interictal GOs was a reliable biomarker for the SOZ. Maintained high entropy of interictal GOs may be an auxiliary biomarker for nonepileptogenic regions. SIGNIFICANCE: Low entropy of interictal GOs may be a biomarker for the SOZ in FCD type II.

Gene Signature-Based Approach Identified MEK1/2 as a Potential Target Associated With Relapse After Anti-TNFα Treatment for Crohn's Disease.

Background: Anti-tumor necrosis factor alpha (anti-TNFα) therapy has become the mainstay of therapy for Crohn's disease (CD). However, post-therapy, the recurrence rate is still high. The aim of this study was to dissect the molecular mechanism for recurrence of CD treated with anti-TNFα therapy and investigate novel therapeutic options that could induce complete remission. Methods: We re-analyzed publicly available mucosal gene expression data from CD patients pre- and post-infliximab therapy to extract the transcriptional differences between responders and healthy controls. We used a systematic computational approach based on identified differences to discover novel therapies and validated this prediction through in vitro and in vivo experimentation. Results: We identified a set of 3545 anti-TNFα therapy-untreatable genes (TUGs) that are significantly regulated in intestinal epithelial cells, which remain altered during remission. Pathway enrichment analysis of these genes clearly showed excessive growth state and suppressed terminal differentiation, whereas immune components were clearly resolved. Through in silico screening strategy, we observed that MEK inhibitors were predicted to revert expression of genes dysregulated in infliximab responders. In vitro transcriptome analysis demonstrated that selective MEK1/2 inhibitor significantly normalized reference genes from TUGs. In addition, in vitro functional study proved that MEK1/2 inhibitor facilitated intestinal epithelial differentiation. Finally, using murine colitis model, administration of MEK1/2 inhibitor significantly improved diarrhea and histological score. Conclusions: Our data revealed the abnormalities in anti-TNFα responders' CD colons that would be cause of recurrence of CD. Also, we provided evidence regarding MEK1/2 inhibitor as a potential treatment against CD to achieve sustainable remission.

Advanced dynamic statistical parametric mapping with MEG in localizing epileptogenicity of the bottom of sulcus dysplasia.

OBJECTIVE: To investigate whether advanced dynamic statistical parametric mapping (AdSPM) using magnetoencephalography (MEG) can better localize focal cortical dysplasia at bottom of sulcus (FCDB). METHODS: We analyzed 15 children with diagnosis of FCDB in surgical specimen and 3 T MRI by using MEG. Using AdSPM, we analyzed a ±50 ms epoch relative to each single moving dipole (SMD) and applied summation technique to estimate the source activity. The most active area in AdSPM was defined as the location of AdSPM spike source. We compared spatial congruence between MRI-visible FCDB and (1) dipole cluster in SMD method; and (2) AdSPM spike source. RESULTS: AdSPM localized FCDB in 12 (80%) of 15 children whereas dipole cluster localized six (40%). AdSPM spike source was concordant within seizure onset zone in nine (82%) of 11 children with intracranial video EEG. Eleven children with resective surgery achieved seizure freedom with follow-up period of 1.9 ±â€¯1.5 years. Ten (91%) of them had an AdSPM spike source in the resection area. CONCLUSION: AdSPM can noninvasively and neurophysiologically localize epileptogenic FCDB, whether it overlaps with the dipole cluster or not. SIGNIFICANCE: This is the first study to localize epileptogenic FCDB using MEG.