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Background and ObjectivesThere is growing evidence that bilingualism can induce neuroplasticity and modulate neural efficiency, resulting in greater resistance to neurologic disease. However, whether bilingualism is beneficial to neural health in the presence of epilepsy is unknown. We tested whether bilingual individuals with temporal lobe epilepsy (TLE) have improved whole-brain structural white matter network organization.MethodsHealthy controls and individuals with TLE recruited from 2 specialized epilepsy centers completed diffusion-weighted MRI and neuropsychological testing as part of an observational cohort study. Whole-brain connectomes were generated via diffusion tractography and analyzed using graph theory. Global analyses compared network integration (path length) and specialization (transitivity) in TLE vs controls and in a 2 (left vs right TLE) × 2 (bilingual vs monolingual) model. Local analyses compared mean local efficiency of predefined frontal-executive and language (i.e., perisylvian) subnetworks. Exploratory correlations examined associations between network organization and neuropsychological performance.ResultsA total of 29 bilingual and 88 monolingual individuals with TLE matched on several demographic and clinical variables and 81 age-matched healthy controls were included. Globally, a significant interaction between language status and side of seizure onset revealed higher network organization in bilinguals compared with monolinguals but only in left TLE (LTLE). Locally, bilinguals with LTLE showed higher efficiency in frontal-executive but not in perisylvian networks compared with LTLE monolinguals. Improved whole-brain network organization was associated with better executive function performance in bilingual but not monolingual LTLE.DiscussionHigher white matter network organization in bilingual individuals with LTLE suggests a neuromodulatory effect of bilingualism on whole-brain connectivity in epilepsy, providing evidence for neural reserve. This may reflect attenuation of or compensation for epilepsy-related dysfunction of the left hemisphere, potentially driven by increased efficiency of frontal-executive networks that mediate dual-language control. This highlights a potential role of bilingualism as a protective factor in epilepsy, motivating further research across neurologic disorders to define mechanisms and develop interventions.

Identifying neoadjuvant chemotherapy (NAC) response in patients with muscle invasive bladder cancer (MIBC) has had limited success based on clinicopathological features and molecular subtyping. Identification of chemotherapy responsive cohorts would facilitate delivery to those most likely to benefit.Develop a molecular signature that can identify MIBC NAC responders (R) and non-responders (NR) using a cohort of known NAC response phenotypes, and better understand differences in molecular pathways and subtype classifications between NAC R and NR.Presented are the messenger RNA (mRNA) and microRNA (miRNA) differential expression profiles from initial transurethral resection of bladder tumor (TURBT) specimens of a discovery cohort of MIBC patients consisting of 7 known NAC R and 11 NR, and a validation cohort consisting of 3 R and 5 NR. Pathological response at time of cystectomy after NAC was used to classify initial TURBT specimens as R (pT0) versus NR (≥pT2). RNA and miRNA from FFPE blocks were sequenced using RNAseq and qPCR, respectively.The discovery cohort had 2309 genes, while the validation cohort had 602 genes and 13 miRNA differentially expressed between R and NR. Gene set enrichment analysis identified mitochondrial gene expression, DNA replication initiation, DNA unwinding in the R discovery cohort and positive regulation of vascular associated smooth muscle cell proliferation in the NR discovery cohort. Canonical correlation (CC) analysis was applied to differentiate R versus NR. 3 CCs (CC13, CC16, and CC17) had an AUCgt;0.65 in the discovery and validation dataset. Gene ontology enrichment showed CC13 as nucleoside triphosphate metabolic process, CC16 as cell cycle and cellular response to DNA damage, CC17 as DNA packaging complex. All patients were classified using established molecular subtypes: Baylor, UNC, CIT, Lund, MD Anderson, TCGA, and Consensus Class. The MD Anderson p53-like subtype, CIT MC4 subtype and Consensus Class stroma rich subtype had the strongest correlation with a NR phenotype, while no subtype had a strong correlation with the R phenotype.Our results identify molecular signatures that can be used to differentiate MIBC NAC R versus NR, salient molecular pathway differences, and highlight the utility of molecular subtyping in relation to NAC response.

OBJECTIVE Risk for memory decline is a common concern for individuals with temporal lobe epilepsy (TLE) undergoing surgery. Global and local network abnormalities are well documented in TLE. However, it is less known whether network abnormalities predict postsurgical memory decline. The authors examined the role of preoperative global and local white matter network organization and risk of postoperative memory decline in TLE. METHODS One hundred one individuals with TLE (n = 51 with left TLE and 50 with right TLE) underwent preoperative T1-weighted MRI, diffusion MRI, and neuropsychological memory testing in a prospective longitudinal study. Fifty-six age- and sex-matched controls completed the same protocol. Forty-four patients (22 with left TLE and 22 with right TLE) subsequently underwent temporal lobe surgery and postoperative memory testing. Preoperative structural connectomes were generated via diffusion tractography and analyzed using measures of global and local (i.e., medial temporal lobe [MTL]) network organization. Global metrics measured network integration and specialization. The local metric was calculated as an asymmetry of the mean local efficiency between the ipsilateral and contralateral MTLs (i.e., MTL network asymmetry). RESULTS Higher preoperative global network integration and specialization were associated with higher preoperative verbal memory function in patients with left TLE. Higher preoperative global network integration and specialization, as well as greater leftward MTL network asymmetry, predicted greater postoperative verbal memory decline for patients with left TLE. No significant effects were observed in right TLE. Accounting for preoperative memory score and hippocampal volume asymmetry, MTL network asymmetry uniquely explained 25%–33% of the variance in verbal memory decline for left TLE and outperformed hippocampal volume asymmetry and global network metrics. MTL network asymmetry alone produced good diagnostic classification of memory decline in left TLE (i.e., an area under the receiver operating characteristic curve of 0.80–0.84 and correct classification of 65%–76% of cases with cross-validation). CONCLUSIONS These preliminary data suggest that global white matter network disruption contributes to verbal memory impairment preoperatively and predicts postsurgical verbal memory outcomes in left TLE. However, a leftward asymmetry of MTL white matter network organization may confer the highest risk for verbal memory decline. Although this requires replication in a larger sample, the authors demonstrate the importance of characterizing preoperative local white matter network properties within the to-be-operated hemisphere and the reserve capacity of the contralateral MTL network, which may eventually be useful in presurgical planning.

Supplementary Figure 5. Assessment of citric acid cycle activity by protein expression analysis of PDHE1a.

Supplementary Table 1 - 7. Supplementary Table 1: Clinical and histopathological data associated with all spinal ependymomas analyzed in this study, along with molecular subgroup assignment; Supplementary Table 2: Table of all antibodies used in this study, their commercial sources, and dilutions used; Supplementary Table 3: Table of differentially expressed genes between spinal grade II and myxopapillary ependymoma; Supplementary Table 4: Summary of focal amplifications detected in spinal ependymoma by GISTIC2; Supplementary Table 5: Summary of focal deletions detected in spinal ependymoma by GISTIC2; Supplementary Table 6: List of significant pathways enriched by Gene Set Enrichment Analysis in spinal grade II ependymoma; Supplementary Table 7: List of significant pathways enriched by Gene Set Enrichment Analysis in spinal myxopapillary ependymoma

Supplementary Figure 1. Unsupervised consensus hierarchical clustering and non-negative matrix factorization of 35 spinal ependymoma gene expression signatures from a rank 2 to 4 classification.

Supplementary Figure 2. Summary of focal copy number alterations detected by GISTIC2 in spinal Grade II and Myxopapillary Ependymoma.

Supplementary Figure 3. Analysis of HIF-1a expression in Spinal Grade II versus Myxopapillary Ependymoma in additional to single sample GSEA analysis of HIF1a transcriptional targets.

Supplementary Figure 4. Metabolic protein expression analysis supporting Figure 4 along with lactate measurements in normal spinal tissue, Grade II spinal ependymoma, and myxopapillary ependymoma.

Purpose: Myxopapillary ependymoma (MPE) is a distinct histologic variant of ependymoma arising commonly in the spinal cord. Despite an overall favorable prognosis, distant metastases, subarachnoid dissemination, and late recurrences have been reported. Currently, the only effective treatment for MPE is gross-total resection. We characterized the genomic and transcriptional landscape of spinal ependymomas in an effort to delineate the genetic basis of this disease and identify new leads for therapy.Experimental Design: Gene expression profiling was performed on 35 spinal ependymomas, and copy number profiling was done on an overlapping cohort of 46 spinal ependymomas. Functional validation experiments were performed on tumor lysates consisting of assays measuring pyruvate kinase M activity (PKM), hexokinase activity (HK), and lactate production.Results: At a gene expression level, we demonstrate that spinal grade II and MPE are molecularly and biologically distinct. These are supported by specific copy number alterations occurring in each histologic variant. Pathway analysis revealed that MPE are characterized by increased cellular metabolism, associated with upregulation of HIF1α. These findings were validated by Western blot analysis demonstrating increased protein expression of HIF1α, HK2, PDK1, and phosphorylation of PDHE1A. Functional assays were performed on MPE lysates, which demonstrated decreased PKM activity, increased HK activity, and elevated lactate production.Conclusions: Our findings suggest that MPE may be driven by a Warburg metabolic phenotype. The key enzymes promoting the Warburg phenotype: HK2, PKM2, and PDK are targetable by small-molecule inhibitors/activators, and should be considered for evaluation in future clinical trials for MPE. Clin Cancer Res; 21(16); 3750–8. ©2015 AACR.

Supplementary Figure 6. A schematic of the glycolytic pathway in myxopapillary ependymoma illustrating deregulation of proteins and metabolites and possible targets for therapeutic intervention.

Supplementary Figure and Table Legends. Legends describing in detail the data shown in supplementary figures and tables pertaining to this manuscript.

PDF file - 65K, Supplementary Figure 6. A schematic drawing of full length N1ICD in mouse, N1ICD allele analyzed in this study, and the ACTB-Notch1 allele previously published (Yang et al., 2004) and analyzed in Supplementary Figure 6.

Supplementary Figure Legends from Epigenetic States of Cells of Origin and Tumor Evolution Drive Tumor-Initiating Cell Phenotype and Tumor Heterogeneity