Phaseâ amplitude coupling between interictal highâ frequency activity and slow waves in epilepsy surgery

ObjectiveWe hypothesized that the modulation index (MI), a summary measure of the strength of phaseâ amplitude coupling between highâ frequency activity (>150 Hz) and the phase of slow waves (3â 4 Hz), would serve as a useful interictal biomarker for epilepsy presurgical evaluation.MethodsWe investigated 123 patients who underwent focal cortical resection following extraoperative electrocorticography recording and had at least 1 year of postoperative followâ up. We examined whether consideration of MI would improve the prediction of postoperative seizure outcome. MI was measured at each intracranial electrode site during interictal slowâ wave sleep. We compared the accuracy of prediction of patients achieving International League Against Epilepsy class 1 outcome between the full multivariate logistic regression model incorporating MI in addition to conventional clinical, seizure onset zone (SOZ), and neuroimaging variables, and the reduced logistic regression model incorporating all variables other than MI.ResultsNinety patients had class 1 outcome at the time of most recent followâ up (mean followâ up = 5.7 years). The full model had a noteworthy outcome predictive ability, as reflected by regression model fit R2 of 0.409 and area under the curve (AUC) of receiver operating characteristic plot of 0.838. Incomplete resection of SOZ (P < 0.001), larger number of antiepileptic drugs at the time of surgery (P = 0.007), and larger MI in nonresected tissues relative to that in resected tissue (P = 0.020) were independently associated with a reduced probability of class 1 outcome. The reduced model had a lower predictive ability as reflected by R2 of 0.266 and AUC of 0.767. Anatomical variability in MI existed among nonepileptic electrode sites, defined as those unaffected by magnetic resonance imaging lesion, SOZ, or interictal spike discharges. With MI adjusted for anatomical variability, the full model yielded the outcome predictive ability of R2 of 0.422, AUC of 0.844, and sensitivity/specificity of 0.86/0.76.SignificanceMI during interictal recording may provide useful information for the prediction of postoperative seizure outcome.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146440/1/epi14544_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146440/2/epi14544.pd

Experimental model for the irradiation-mediated abscopal effect and factors influencing this effect

Radiotherapy (RT) is the primary treatment for cancer. Ionizing radiation from RT induces tumor damage at the irradiated site, and, although clinically infrequent, may cause regression of tumors distant from the irradiated site-a phenomenon known as the abscopal effect. Recently, the abscopal effect has been related to prolongation of overall survival time in cancer patients, though the factors that influence the abscopal effect are not well understood. The aim of this study is to clarify the factors influencing on abscopal effect. Here, we established a mouse model in which we induced the abscopal effect. We injected MC38 (mouse colon adenocarcinoma) cells subcutaneously into C57BL/6 mice at two sites. Only one tumor was irradiated and the sizes of both tumors were measured over time. The non-irradiated-site tumor showed regression, demonstrating the abscopal effect. This effect was enhanced by an increase in the irradiated-tumor volume and by administration of anti-PD1 antibody. When the abscopal effect was induced by a combination of RT and anti-PD1 antibody, it was also influenced by radiation dose and irradiated-tumor volume. These phenomena were also verified in other cell line, B16F10 cells (mouse melanoma cells). These findings provide further evidence of the mechanism for, and factors that influence, the abscopal effect in RT

Combination treatment with highly bioavailable curcumin and NQO1 inhibitor exhibits potent antitumor effects on esophageal squamous cell carcinoma

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most intractable cancers, so the development of novel therapeutics has been required to improve patient outcomes. Curcumin, a polyphenol from Curcuma longa, exhibits various health benefits including antitumor effects, but its clinical utility is limited because of low bioavailability. Theracurmin® (THC) is a highly bioavailable curcumin dispersed with colloidal submicron particles. Methods: We examined antitumor effects of THC on ESCC cells by cell viability assay, colony and spheroid formation assay, and xenograft models. To reveal its mechanisms, we investigated the levels of reactive oxygen species (ROS) and performed microarray gene expression analysis. According to those analyses, we focused on NQO1, which involved in the removal of ROS, and examined the effects of NQO1-knockdown or overexpression on THC treatment. Moreover, the therapeutic effect of THC and NQO1 inhibitor on ESCC patient-derived xenografts (PDX) was investigated. Results: THC caused cytotoxicity in ESCC cells, and suppressed the growth of xenografted tumors more efficiently than curcumin. THC increased ROS levels and activated the NRF2–NMRAL2P–NQO1 expressions. Inhibition of NQO1 in ESCC cells by shRNA or NQO1 inhibitor resulted in an increased sensitivity of cells to THC, whereas overexpression of NQO1 antagonized it. Notably, NQO1 inhibitor significantly enhanced the antitumor effects of THC in ESCC PDX tumors. Conclusions: These findings suggest the potential usefulness of THC and its combination with NQO1 inhibitor as a therapeutic option for ESCC

HER2 G776S mutation promotes oncogenic potential in colorectal cancer cells when accompanied by loss of APC function

Clinical cancer genome sequencing detects oncogenic variants that are potential targets for cancer treatment, but it also detects variants of unknown significance. These variants may interact with each other to influence tumor pathophysiology, however, such interactions have not been fully elucidated. Additionally, the effect of target therapy for those variants also unclarified. In this study, we investigated the biological functions of a HER2 mutation (G776S mutation) of unknown pathological significance, which was detected together with APC mutation by cancer genome sequencing of samples from a colorectal cancer (CRC) patient. Transfection of the HER2 G776S mutation alone slightly increased the kinase activity and phosphorylation of HER2 protein, but did not activate HER2 downstream signaling or alter the cell phenotype. On the other hand, the HER2 G776S mutation was shown to have strong oncogenic potential when loss of APC function was accompanied. We revealed that loss of APC function increased Wnt pathway activity but also increased RAS-GTP, which increased ERK phosphorylation triggered by HER2 G776S transfection. In addition, afatinib, a pan-HER tyrosine kinase inhibitor, suppressed tumor growth in xenografts derived from HER2 G776S-transfected CRC cells. These findings suggest that this HER2 mutation in CRC may be a potential therapeutic target

Effect of extracted garlic powder ingestion for two months on exercise-induced immunological responses

Introduction. Exhaustive exercise is associated with an increased risk of upper respiratory tract infection. Previously, allicin supplementation has been reported to reduce the incidence of common cold symptoms and production of exercise-induced interleukin (IL)-6. However, it is not clear if daily ingestion of the edible portion of whole garlic (Allium sativum) alters the exercise-induced immunological response. The present study investigated the effects of extracted garlic powder ingestion for 2 months on immune cell counts, natural killer cell activity (NKCA), as well as changes in cytokines, cortisol, and lactic acid in response to high-intensity cycling exercise. Methods. The present study employed a before-after study design. Six sedentary male participants (age, 22.0±0.3 years) consumed extracted garlic powder for 2 months, and underwent 45 minutes of cycling exercise at 80% of the heart rate reserve once before and once after the supplementation period. A thousand milligrams of extracted garlic powder, comparable to 6 g (1 clove) of raw garlic, was ingested every day. Blood samples were obtained at the following five time points: before exercise, 0 min, 30 min, 60 min, and 120 min after exercise. We measured NKCA, leukocyte counts, neutrophil counts, lymphocyte counts, as well as levels of serum IL-6, IL-10, cortisol, and lactic acid. Repeated measures ANOVA was used for statistical analyses. When interaction effects were significant, measurement values at the various time points were compared between pre- and post-supplementation period using the paired t-test. Changes were deemed statistically significant when p\u3c0.05. Results. We observed no significant difference in pre-exercise measurements between pre- and post-supplementation periods. In addition, we found no significant interaction effect for leukocytes, neutrophils, NKCA, IL-10, and cortisol. However, we did identify a significant interaction effect for lymphocytes, IL-6, and lactic acid (p=0.033, p=0.030, and p\u3c0.001, respectively). Lymphocyte counts were significantly lower post-supplementation relative to pre-supplementation immediately after exercise (p=0.014). In addition, IL-6 was significantly lower post-supplementation relative to pre-supplementation immediately and 30 minutes after exercise (p=0.015 and p=0.018, respectively). Lactic acid levels were significantly lower post-supplementation relative to pre-supplementation immediately after exercise (p=0.018). Conclusions. The extracted garlic powder did not significantly influence exercise-induced responses by leukocytes, neutrophils, NKCA, IL-10, or cortisol. However, exercise-induced responses by lymphocytes, IL-6, and lactic acid were suppressed after ingestion of extracted garlic powder. Thus, daily ingestion of the edible portion of whole garlic may suppress exercise-induced immunological responses and lactic acid levels

Pemafibrate prevents choroidal neovascularization in a mouse model of neovascular age-related macular degeneration

Background Pathological choroidal neovascularization (CNV) is one of the major causes of visual impairment in neovascular age-related macular degeneration (AMD). CNV has been suppressed by using anti-vascular endothelial growth factor (VEGF) antibodies. However, some clinical cases have demonstrated the failure of anti-VEGF therapies. Furthermore, anti-VEGF agents might induce the development of ocular atrophy. Recently, peroxisome proliferator-activated receptor alpha (PPARα) activation using pemafibrate treatment was suggested as one of the promising therapeutic targets in the prevention of ocular ischemia. However, the preventive role of pemafibrate remains unclear in CNV. We aimed to examine the preventive role of pemafibrate on laser-induced pathological CNV. Methods Adult male C57BL/6 mice were orally supplied pemafibrate (0.5 mg/kg) for four days, followed by laser irradiation. Then, pemafibrate was consecutively given to mice with the same condition. CNV was visualized with isolectin-IB4. The eye (retina and/or retinal pigment epithelium [RPE]-choroid), liver, and serum were used for biomolecular analyses. Results We found that pemafibrate administration suppressed CNV volumes. Pemafibrate administration activated PPARα downstream genes in the liver and eye (especially, RPE-choroid). Furthermore, pemafibrate administration elevated serum fibroblast growth factor 21 levels and reduced serum levels of triglycerides. Conclusions Our data suggest a promising pemafibrate therapy for suppressing CNV in AMD