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Due to the health and environmental risks posed by the presence of petroleum-contaminated areas around the world, remediation of petroleum-contaminated soil has drawn much attention from researchers. Combining Fenton reaction with a solvent has been proposed as a novel way to remediate contaminated soils. In this study, a green solvent, ethyl lactate (EL), has been used in conjunction with Fenton's reagents for the remediation of diesel-contaminated soil. The main aim of this research is to determine how the addition of EL affects Fenton reaction for the destruction of total petroleum hydrocarbons (TPHs) within the diesel range. Specifically, the effects of different parameters, including liquid phase volume-to-soil weight (L/S) ratio, hydrogen peroxide (H 2 O 2 ) concentration and EL% on the removal efficiency, have been studied in batch experiments. The results showed that an increase in H 2 O 2 resulted in an increase in removal efficiency of TPH from 68.41% at H 2 O 2  = 0.1 M to 90.21% at H 2 O 2  = 2 M. The lowest L/S, i.e. L/S = 1, had the highest TPH removal efficiency of 85.77%. An increase in EL% up to 10% increased the removal efficiency to 96.74% for TPH, and with further increase in EL%, the removal efficiency of TPH decreased to 89.6%. EL with an optimum value of 10% was found to be best for TPH removal in EL-based Fenton reaction. The power law and pseudo-first order equations fitted well to the experimental kinetic data of Fenton reactions.

This research investigated the potential of palm kernel shell (PKS), empty fruit bunch (EFB) and palm oil sludge (POS), abundantly available agricultural wastes, as feedstock for biochar production by slow pyrolysis (50mLmin -1 N 2 at 500°C). Various characterization tests were performed to establish the thermochemical properties of the feedstocks and obtained biochars. PKS and EFB had higher lignin, volatiles, carbon and HHV, and lower ash than POS. The thermochemical conversion had enhanced the biofuel quality of PKS-char and EFB-char exhibiting increased HHV (26.18-27.50MJkg -1 ) and fixed carbon (53.78-59.92%), and decreased moisture (1.03-2.26%). The kinetics of pyrolysis were evaluated by thermogravimetry at different heating rates (10-40°C). The activation energies determined by Kissinger-Akahira-Sunose and Flynn-Wall-Ozawa models were similar, and comparable with literature data. The findings implied that PKS and EFB are very promising sources for biochars synthesis, and the obtained chars possessed significant biofuel potential., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Exposure to different environments has been reported to change aggressive behavior, but previous research did not consider the underlying elements that caused such an effect. Based on previous work on environmental perception, we examined the role of environmental resource and security in altering aggression level. In three experiments, participants were exposed to environments that varied in resource (High vs. Low) and security (High vs. Low) levels, after which aggression was measured. The environments were presented through visual priming (Experiments 1-2) and a first-person gameplay (Experiment 3). We observed a consistent resource-security interaction effect on aggression, operationalized as the level of noise blast (Experiment 1) and number of unpleasant pictures (Experiments 2-3) delivered to strangers by the participants. High resource levels associated with higher aggression in insecure conditions, but lower aggression in secure conditions. The findings suggest that the adaptive value of aggression varies under different environmental constraints. Implications are discussed in terms of the effects of adverse environments on aggression, and the nature's effects on social behavior. Aggr. Behav. 43:304-314, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

In the past decade, hundreds of genome-wide association studies have been conducted to detect the significant single-nucleotide polymorphisms that are associated with certain diseases. However, most of the data from the X chromosome were not analyzed and only a few significant associated single-nucleotide polymorphisms from the X chromosome have been identified from genome-wide association studies. This is mainly due to the lack of powerful statistical tests. In this paper, we propose a novel statistical approach that combines the information of single-nucleotide polymorphisms on the X chromosome from both males and females in an efficient way. The proposed approach avoids the need of making strong assumptions about the underlying genetic models. Our proposed statistical test is a robust method that only makes the assumption that the risk allele is the same for both females and males if the single-nucleotide polymorphism is associated with the disease for both genders. Through simulation study and a real data application, we show that the proposed procedure is robust and have excellent performance compared to existing methods. We expect that many more associated single-nucleotide polymorphisms on the X chromosome will be identified if the proposed approach is applied to current available genome-wide association studies data.

Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 × 10 -7 , range P = 9.2 × 10 -8 to 6.0 × 10 -46 ; n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 × 10 -6 , range P = 5.5 × 10 -6 to 6.1 × 10 -35 , n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 × 10 -54 ). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.

We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Protein-protein interactions (PPIs) are increasingly important targets for drug discovery. Efficient fragment-based drug discovery approaches to tackle PPIs are often stymied by difficulties in the production of stable, unliganded target proteins. Here, we report an approach that exploits protein engineering to "humanise" thermophilic archeal surrogate proteins as targets for small-molecule inhibitor discovery and to exemplify this approach in the development of inhibitors against the PPI between the recombinase RAD51 and tumour suppressor BRCA2. As human RAD51 has proved impossible to produce in a form that is compatible with the requirements of fragment-based drug discovery, we have developed a surrogate protein system using RadA from Pyrococcus furiosus. Using a monomerised RadA as our starting point, we have adopted two parallel and mutually instructive approaches to mimic the human enzyme: firstly by mutating RadA to increase sequence identity with RAD51 in the BRC repeat binding sites, and secondly by generating a chimeric archaeal human protein. Both approaches generate proteins that interact with a fourth BRC repeat with affinity and stoichiometry comparable to human RAD51. Stepwise humanisation has also allowed us to elucidate the determinants of RAD51 binding to BRC repeats and the contributions of key interacting residues to this interaction. These surrogate proteins have enabled the development of biochemical and biophysical assays in our ongoing fragment-based small-molecule inhibitor programme and they have allowed us to determine hundreds of liganded structures in support of our structure-guided design process, demonstrating the feasibility and advantages of using archeal surrogates to overcome difficulties in handling human proteins., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Treatment of oil-contaminated soil is a major environmental concern worldwide. The aim of this study is to examine the applicability of a green solvent, ethyl lactate (EL), in desorption of diesel aliphatic fraction within total petroleum hydrocarbons (TPH) in contaminated soil and to determine the associated desorption kinetics. Batch desorption experiments were carried out on artificially contaminated soil at different EL solvent percentages (%). In analysing the diesel range of TPH, TPH was divided into three fractions and the effect of solvent extraction on each fraction was examined. The experimental results demonstrated that EL has a high and fast desorbing power. Pseudo-second order rate equation described the experimental desorption kinetics data well with correlation coefficient values, R 2 , between 0.9219 and 0.9999. The effects of EL percentage, initial contamination level of soil and liquid to solid ratio (L/S (v/w)) on initial desorption rate have also been evaluated. The effective desorption performance of ethyl lactate shows its potential as a removal agent for remediation of TPH-contaminated soil worldwide.

Parkinson's disease (PD) is a neurodegenerative disease with the absence of markers for diagnosis. Several studies on PD reported the elements imbalance in biofluids as biomarkers. However, their results remained inconclusive. This study integrates metallomics, multivariate and artificial neural network (ANN) to understand element variations in CSF and serum of PD patients from the largest cohort of Indian population to solve the inconsistent results of previous studies. Also, this study is aimed to (1) ascertain a common element signature between CSF and serum. (2) Assess cross sectional element variation with clinical symptoms. (3) Develop ANN models for rapid diagnosis. A metallomic profile of 110 CSF and 530 serum samples showed significant variations in 10 elements of CSF and six in serum of patients compared to controls. Consistent variations in elements pattern were noticed for Calcium, Magnesium and Iron in both the fluids of PD, which provides feasible diagnosis from serum. Furthermore, implementing multivariate analyses showed clear classification between normal and PD in both the fluids. Also, ANN provides 99% accuracy in detection of disease from CSF and serum. Overall, our analyses demonstrate that elements profile in biofluids of PD will be useful in development of diagnostic markers for PD.

Although 1p/19q codeletion is the genetic hallmark defining oligodendrogliomas, approximately 30-40% of oligodendroglial tumors have intact 1p/19q in the literature and they demonstrate a worse prognosis. This group of 1p/19q intact oligodendroglial tumors is frequently suggested to be astrocytic in nature with TP53 and ATRX mutations but actually remains under-investigated. In the present study, we provided evidence that not all 1p/19q intact oligodendroglial tumors are astrocytic through histologic and molecular approaches. We examined 1p/19q status by FISH in a large cohort of 337 oligodendroglial tumors and identified 39.8% lacking 1p/19q codeletion which was independently associated with poor prognosis. Among this 1p/19q intact oligodendroglial tumor cohort, 58 cases demonstrated classic oligodendroglial histology which showed older patient age, better prognosis, association with grade III histology, PDGFRA expression, TERTp mutation, as well as frequent IDH mutation. More than half of the 1p/19q intact oligodendroglial tumors showed lack of astrocytic defining markers, p53 expression and ATRX loss. TP53 mutational analysis was additionally conducted in 45 cases of the 1p/19q intact oligodendroglial tumors. Wild-type TP53 was detected in 71.1% of cases which was associated with classic oligodendroglial histology. Importantly, IDH and TERTp co-occurred in 75% of 1p/19q intact, TP53 wild-type oligodendrogliomas, highlighting the potential of the co-mutations in assisting diagnosis of oligodendrogliomas in tumors with clear cell morphology and non-codeleted 1p/19q status. In summary, our study demonstrated that not all 1p/19q intact oligodendroglial tumors are astrocytic and co-evaluation of IDH and TERTp mutation could potentially serve as an adjunct for diagnosing 1p/19q intact oligodendrogliomas.

Background: Strategies to screen colorectal cancers (CRCs) for Lynch syndrome are evolving rapidly; the optimal strategy remains uncertain., Aim: We compared targeted versus universal screening of CRCs for Lynch syndrome., Methods: In 2010-2011, we employed targeted screening (age < 60 and/or Bethesda criteria). From 2012 to 2014, we screened all CRCs. Immunohistochemistry for the four mismatch repair proteins was done in all cases, followed by other diagnostic studies as indicated. We modeled the diagnostic costs of detecting Lynch syndrome and estimated the 5-year costs of preventing CRC by colonoscopy screening, using a system dynamics model., Results: Using targeted screening, 51/175 (29 %) cancers fit criteria and were tested by immunohistochemistry; 15/51 (29 %, or 8.6 % of all CRCs) showed suspicious loss of ≥1 mismatch repair protein. Germline mismatch repair gene mutations were found in 4/4 cases sequenced (11 suspected cases did not have germline testing). Using universal screening, 17/292 (5.8 %) screened cancers had abnormal immunohistochemistry suspicious for Lynch syndrome. Germline mismatch repair mutations were found in only 3/10 cases sequenced (7 suspected cases did not have germline testing). The mean cost to identify Lynch syndrome probands was ~$23,333/case for targeted screening and ~$175,916/case for universal screening at our institution. Estimated costs to identify and screen probands and relatives were: targeted, $9798/case and universal, $38,452/case., Conclusions: In real-world Lynch syndrome management, incomplete clinical follow-up was the major barrier to do genetic testing. Targeted screening costs 2- to 7.5-fold less than universal and rarely misses Lynch syndrome cases. Future changes in testing costs will likely change the optimal algorithm.

The involvement of secretin (SCT) and secretin receptor (SCTR) in regulating body water homeostasis is well established. Identified as one of the vasopressin (Vp)-independent mechanisms in fluid balance, SCT regulates aquaporin 2 (AQP2) in the kidney distal collecting duct cells through activating intracellular cAMP production. This ability to bypass Vp-mediated water reabsorption in kidney implicates SCT's potential to treat nephrogenic diabetes insipidus (NDI). Research on NDI in the past has largely been focused on the searching for mutations in vasopressin receptor 2 (AVPR2), while the functional relationship between SCTR, AVPR2 and NDI remains unclear. Here, we demonstrate the interaction between SCTR and AVPR2 to modulate cellular signaling in vitro. Interestingly, we show in this report that upon heteromer formation with SCTR, R137H, a NDI-causing AVPR2 mutant that is defective in trafficking to cell surface, can functionally be rescued. Our data may provide an explanation for this clinically mild case of NDI, and insights into the pathological development of NDI in the future., Competing Interests: The authors have declared that no competing interests exist.

Studies have showed the involvement of ubiquitin-like with PHD and RING finger domains 1 (UHRF1) in tumorigenesis and progression. This study focused on the relationships between UHRF1 and medulloblastoma (MB). Immunostaining and western blotting demonstrated differential expression of UHRF1 in MB tissues and no UHRF1 expression in normal cerebellum tissues. Univariate survival analysis revealed MB patients with high UHRF1 expression had significantly shorter OS and PFS than patients with low UHRF1 (OS p = 0.009, PFS p = 0.003). Multivariate analysis illustrated that UHRF1 expression level is an independent prognostic factor influencing the OS and PFS (OS p = 0.038, PFS p = 0.014). UHRF1 expression levels were significantly different among molecular subgroups of MB (p = 0.003). Down-regulation of UHRF1 by RNAi inhibited proliferation and clonogenic ability of MB cell lines with cell cycle arrest in G1/G2-phase. Meanwhile, cells transfected with lenti-shUHRF1 showed increased p16 expression and location shift of CDK4 in MB cells. These findings indicate UHRF1 may promote cell proliferation and be a potential biomarker that can be used as a prognostic parameter and a therapeutic target for MB.

Background and Purpose: High signal on T1-weighted fat-suppressed images in middle cerebral artery plaques on ex vivo magnetic resonance imaging was verified to be intraplaque hemorrhage histologically. However, the underlying plaque component of low signal on T1-weighted fat-suppressed images (LST1) has never been explored. Based on our experience, we hypothesized that LST1 might indicate the presence of lipid core within intracranial plaques., Methods: 1.5 T magnetic resonance imaging was performed in the postmortem brains to scan the cross sections of bilateral middle cerebral arteries. Then middle cerebral artery specimens were removed for histology processing. LST1 presence was identified on magnetic resonance images, and lipid core areas were measured on the corresponding histology sections., Results: Total 76 middle cerebral artery locations were included for analysis. LST1 showed a high specificity (96.9%; 95% confidence interval, 82.0%-99.8%) but a low sensitivity (38.6%; 95% confidence interval, 24.7%-54.5%) for detecting lipid core of all areas. However, the sensitivity increased markedly (81.2%; 95% confidence interval, 53.7%-95.0%) when only lipid cores of area ≥0.80 mm(2) were included. Mean lipid core area was 5× larger in those with presence of LST1 than in those without (1.63±1.18 mm(2) versus 0.32±0.31 mm(2); P=0.003)., Conclusions: LST1 is a promising imaging biomarker of identifying intraplaque lipid core, which may be useful to distinguish intracranial atherosclerotic disease from other intracranial vasculopathies and to assess plaque vulnerability for risk stratification of patients with intracranial atherosclerotic disease. In vivo clinical studies are required to explore the correlation between LST1 and clinical outcomes of patients with intracranial atherosclerotic disease., (© 2016 The Authors.)

Background: Certain hand activities cause deformation and displacement of the median nerve at the carpal tunnel due to the gliding motion of tendons surrounding it. As smartphone usage escalates, this raises the public's concern whether hand activities while using smartphones can lead to median nerve problems., Objective: The aims of this study were to 1) develop kinematic graphs and 2) investigate the associated deformation and rotational information of median nerve in the carpal tunnel during hand activities., Methods: Dominant wrists of 30 young adults were examined with ultrasonography by placing a transducer transversely on their wrist crease. Ultrasound video clips were recorded when the subject performing 1) thumb opposition with the wrist in neutral position, 2) thumb opposition with the wrist in ulnar deviation and 3) pinch grip with the wrist in neutral position. Six still images that were separated by 0.2-second intervals were then captured from the ultrasound video for the determination of 1) cross-sectional area (CSA), 2) flattening ratio (FR), 3) rotational displacement (RD) and 4) translational displacement (TD) of median nerve in the carpal tunnel, and these collected information of deformation, rotational and displacement of median nerve were compared between 1) two successive time points during a single hand activity and 2) different hand motions at the same time point. Finally, kinematic graphs were constructed to demonstrate the mobility of median nerve during different hand activities., Results: Performing different hand activities during this study led to a gradual reduction in CSA of the median nerve, with thumb opposition together with the wrist in ulnar deviation causing the greatest extent of deformation of the median nerve. Thumb opposition with the wrist in ulnar deviation also led to the largest extent of TD when compared to the other two hand activities of this study. Kinematic graphs showed that the motion pathways of median nerve during different hand activities were complex., Conclusion: We observed that the median nerve in the carpal tunnel was rotated, deformed and displaced during the hand activities that people may be performed when using a smartphone, suggesting an increased risk of carpal tunnel syndrome (CTS). In addition, the kinematic graphs of median nerve developed in the present study provide new clues for further studies on the pathophysiology of CTS, and alerting smartphone users to establish proper postural habits when using handheld electronic devices.

Background: The current World Health Organization (WHO) classification of nasopharyngeal carcinoma (NPC) conveys little prognostic information. This study aimed to propose an NPC histopathologic classification that can potentially be used to predict prognosis and treatment response., Methods: We initially developed a histopathologic classification based on the morphologic traits and cell differentiation of tumors of 2716 NPC patients who were identified at Sun Yat-sen University Cancer Center (SYSUCC) (training cohort). Then, the proposed classification was applied to 1702 patients (retrospective validation cohort) from hospitals outside SYSUCC and 1613 patients (prospective validation cohort) from SYSUCC. The efficacy of radiochemotherapy and radiotherapy modalities was compared between the proposed subtypes. We used Cox proportional hazards models to estimate hazard ratios (HRs) with 95% confidence intervals (CI) for overall survival (OS)., Results: The 5-year OS rates for all NPC patients who were diagnosed with epithelial carcinoma (EC; 3708 patients), mixed sarcomatoid-epithelial carcinoma (MSEC; 1247 patients), sarcomatoid carcinoma (SC; 823 patients), and squamous cell carcinoma (SCC; 253 patients) were 79.4%, 70.5%, 59.6%, and 42.6%, respectively (P < 0.001). In multivariate models, patients with MSEC had a shorter OS than patients with EC (HR = 1.44, 95% CI = 1.27-1.62), SC (HR = 2.00, 95% CI = 1.76-2.28), or SCC (HR = 4.23, 95% CI = 3.34-5.38). Radiochemotherapy significantly improved survival compared with radiotherapy alone for patients with EC (HR = 0.67, 95% CI = 0.56-0.80), MSEC (HR = 0.58, 95% CI = 0.49-0.75), and possibly for those with SCC (HR = 0.63; 95% CI = 0.40-0.98), but not for patients with SC (HR = 0.97, 95% CI = 0.74-1.28)., Conclusions: The proposed classification offers more information for the prediction of NPC prognosis compared with the WHO classification and might be a valuable tool to guide treatment decisions for subtypes that are associated with a poor prognosis.

Background: Patients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner., Methods: We retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (<1·5 cm(2) tumour remaining), or sub-total resection (≥1·5 cm(2) tumour remaining). We did multivariable analyses of overall survival and progression-free survival using the variables molecular subgroup (WNT, SHH, group 4, and group 3), age (<3 vs ≥3 years old), metastatic status (metastases vs no metastases), geographical location of therapy (North America/Australia vs rest of the world), receipt of chemotherapy (yes vs no) and receipt of craniospinal irradiation (<30 Gy or >30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival., Findings: We included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable Cox models of progression-free and overall survival. We found that the prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. We identified a progression-free survival benefit for gross total resection over sub-total resection (hazard ratio [HR] 1·45, 95% CI 1·07-1·96, p=0·16) but no overall survival benefit (HR 1·23, 0·87-1·72, p=0·24). We saw no progression-free survival or overall survival benefit for gross total resection compared with near-total resection (HR 1·05, 0·71-1·53, p=0·8158 for progression-free survival and HR 1·14, 0·75-1·72, p=0·55 for overall survival). No significant survival benefit existed for greater extent of resection for patients with WNT, SHH, or group 3 tumours (HR 1·03, 0·67-1·58, p=0·89 for sub-total resection vs gross total resection). For patients with group 4 tumours, gross total resection conferred a benefit to progression-free survival compared with sub-total resection (HR 1·97, 1·22-3·17, p=0·0056), especially for those with metastatic disease (HR 2·22, 1·00-4·93, p=0·050). However, gross total resection had no effect on overall survival compared with sub-total resection in patients with group 4 tumours (HR 1·67, 0·93-2·99, p=0·084)., Interpretation: The prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. Although maximum safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high because there is no definitive benefit to gross total resection compared with near-total resection., Funding: Canadian Cancer Society Research Institute, Terry Fox Research Institute, Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, and the Garron Family Chair in Childhood Cancer Research., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The statistical analysis of genome-wide association studies (GWASs) with multiple diseases and shared controls (SCs) is discussed. The usual method for analyzing data from these studies is to compare each individual disease with either the SCs or the pooled controls which include other diseases. We observed that applying individual association tests can be problematic because these tests may suffer from power loss in detecting significant associations between diseases and single-nucleotide polymorphism or copy number variant. We propose here a two-stage procedure wherein we first apply an overall chi-square test for multiple diseases with SCs; if the overall test is rejected, then individual tests using the chi-square partition method will be applied to each disease against SCs. A real GWAS data set with SCs and a Monte Carlo simulation study are used to demonstrate that the proposed method is more effective and preferable than other existing methods for analyzing data from GWASs with multiple diseases and SCs., (© The Author(s) 2013.)

Background and Purpose: Clinical trial studies show that plaque eccentricity (symmetry) is among the plaque features that have been associated with more frequent cerebrovascular events. Plaque eccentricity of intracranial atherosclerotic disease is unclear because of lacking of cerebral artery specimens., Methods: 1.5T magnetic resonance imaging was performed in the postmortem brains to scan the cross sections of middle cerebral artery. Plaque eccentricity of histology-verified middle cerebral artery atherosclerosis was calculated on T1-weighted fat-suppressed sequence., Results: Validated by histology, concentric atherosclerotic plaques were identified in 46 middle cerebral arteries (63.9%) on magnetic resonance imaging and eccentric plaques in 26 arteries (26.1%). Eccentric plaques showed higher maximum wall thickness and lower minimum wall thickness than concentric plaques (both P<0.001). Plaque burden and brain infarctions were similar between concentric and eccentric plaques., Conclusions: Intracranial atherosclerosis presents as eccentric or concentric in geometry, which may be not linked to intracranial plaque risk. Further in vivo imaging studies are needed to identify morphological features of intracranial plaques and to verify its association with brain infarctions., (© 2015 American Heart Association, Inc.)

While the predominant elderly and the pediatric glioblastomas have been extensively investigated, young adult glioblastomas were understudied. In this study, we sought to stratify young adult glioblastomas by BRAF, H3F3A and IDH1 mutations and examine the clinical relevance of the biomarkers. In 107 glioblastomas aged from 17 to 35 years, mutually exclusive BRAF-V600E (15%), H3F3A-K27M (15.9%), H3F3A-G34R/V (2.8%) and IDH1-R132H (16.8%) mutations were identified in over half of the cases. EGFR amplification and TERTp mutation were only detected in 3.7% and 8.4% in young adult glioblastomas, respectively. BRAF-V600E identified a clinically favorable subset of glioblastomas with younger age, frequent CDKN2A homozygous deletion, and was more amendable to surgical resection. H3F3A-K27M mutated glioblastomas were tightly associated with midline locations and showed dismal prognosis. IDH1-R132H was associated with older age and favorable outcome. Interestingly, tumors with positive PDGFRA immunohistochemical expression exhibited poorer prognosis and identified an aggressive subset of tumors among K27M mutated glioblastomas. Combining BRAF, H3F3A and IDH1 mutations allowed stratification of young adult glioblastomas into four prognostic subgroups. In summary, our study demonstrates the clinical values of stratifying young adult glioblastomas with BRAF, H3F3A and IDH1 mutations, which has important implications in refining prognostic classification of glioblastomas.

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

IDH mutations frequently occur in WHO grade II and III diffuse gliomas and have favorable prognosis compared to wild-type tumors. However, whether IDH mutations in WHO grade II and II diffuse gliomas predict enhanced sensitivity to adjuvant radiation (RT) or chemotherapy (CHT) is still being debated. Recent studies have identified recurrent mutations in the promoter region of telomerase reverse transcriptase (TERT) in gliomas. We previously demonstrated that TERT promoter mutations may be promising biomarkers in glioma survival prognostication when combined with IDH mutations. This study analyzed IDH and TERT promoter mutations in 295 WHO grade II and III diffuse gliomas treated with or without adjuvant therapies to explore their impact on the sensitivity of tumors to genotoxic therapies. IDH mutations were found in 216 (73.2%) patients and TERT promoter mutations were found in 112 (38%) patients. In multivariate analysis, IDH mutations (p < 0.001) were independent prognostic factors for PFS and OS in patients receiving genotoxic therapies while TERT promoter mutations were not. In univariate analysis, IDH and TERT promoter mutations were not significant prognostic factors in patients who did not receive genotoxic therapies. Adjuvant RT and CHT were factors independently impacting PFS (RT p = 0.001, CHT p = 0.026) in IDH mutated WHO grade II and III diffuse gliomas but not in IDH wild-type group. Univariate and multivariate analyses demonstrated TERT promoter mutations further stratified IDH wild-type WHO grade II and III diffuse gliomas into two subgroups with different responses to genotoxic therapies. Adjuvant RT and CHT were significant parameters influencing PFS in the IDH wt/TERT mut subgroup (RT p = 0.015, CHT p = 0.015) but not in the IDH wt/TERT wt subgroup. Our data demonstrated that IDH mutated WHO grade II and III diffuse gliomas had better PFS and OS than their IDH wild-type counterparts when genotoxic therapies were administered after surgery. Importantly, we also found that TERT promoter mutations further stratify IDH wild-type WHO grade II and III diffuse gliomas into two subgroups with different responses to adjuvant therapies. Taken together, TERT promoter mutations may predict enhanced sensitivity to genotoxic therapies in IDH wild-type WHO grade II and III diffuse gliomas and may justify intensified treatment in this subgroup.

The promoter region of telomerase reverse transcriptase (TERTp) and isocitrate dehydrogenase (IDH) have been regarded as biomarkers with distinct clinical and phenotypic features. Investigated the possible correlations between tumor location and genetic alterations would enhance our understanding of gliomagenesis and heterogeneity of glioma. We examined mutations of TERTp and IDH by direct sequencing and fluorescence in-situ hybridization in a cohort of 225 grades II and III diffuse gliomas. Correlation analysis between molecular markers and tumor locations was performed by Chi-square tests/Fisher's exact test and multivariate logistic regression analysis. We found gliomas in frontal lobe showed higher frequency of TERTp mutation (P=0.0337) and simultaneously mutations of IDH and TERTp (IDH (mut)-TERTp(mut)) (P=0.0281) than frequency of biomarkers mutation of tumors in no-Frontal lobes, while lower frequency of TERTp mutation (P<0.0001) and simultaneously wild type of IDH and TERTp (IDH (wt)-TERTp(wt)) (P<0.0001) in midline than no-midline lobes. Logistic regression analysis indicated that locations of tumors associated with TERTp mutation (OR=0.540, 95% CI 0.324-0.900, P=0.018) and status of combinations of IDH and TERTp (IDH (mut)-TERTp (mut) vs. IDH (wt)-TERTp (wt) OR=0.162, 95% CI 0.075-0.350, P<0.001). In conclusion, grades II and III gliomas harboring TERTp mutation were located preferentially in the frontal lobe and rarely in midline. Association of IDH-TERTp status and tumor location suggests their potential values in molecular classification of grades II and III gliomas.

We studied if combination genetic signature potentially stratifies lower-grade gliomas better than histology by investigating 214 lower-grade gliomas for IDH1/2 and TERTp mutations, 1p/19q codeletion and EGFR amplification as to their impact on prognostication. Prognostic association of grading was independent of other prognostic variables including age, histological type, IDH1/2, 1p/19q and TERTp status. No single marker, including IDH1/2, superseded grading in prognostication, indicating grading was still a very important tool. Prognosis was most favorable in 31.7% of patients with IDH1/2 mutation and either 1p/19q codeletion or TERTp mutation (IDHmut-OT), intermediate in 45.8% of patients with IDH1/2 mutation only (IDHmut) and 16.9% of patients without any of the alterations (IDHwt), and poorest in 5.6% of patients with wild-type IDH1/2 and either TERTp mutation or EGFR amplification (IDHwt-ET). Our results suggested not all IDH1/2 wild-type lower-grade gliomas are aggressive and additional biomarkers are required to identify glioblastoma-equivalent tumors. Multivariate analysis revealed independent prognostic values of grading and genetic signature. Grade II IDHwt-ET gliomas exhibited shorter survival than IDH1/2 mutated grade III gliomas, suggesting combination genetic signature potentially superseded grading in prognostication. In summary, biomarker-based stratification is useful in the diagnosis and prognostication of lower-grade gliomas, and should be used together with grading.

ZFPM2, encoding a zinc finger protein and abundantly expressed in the brain, uterus and smooth muscles, plays important roles in cardiac and gonadal development. Abnormal expression of ZFPM2 in ovarian tumors and neuroblastoma has been reported but hitherto its genetic association with cancer and effects on gliomas have not been studied. In the present study, the hexamer insertion-deletion polymorphism rs71305152, located within a large haplotype block spanning intron 1 to intron 3 of ZFPM2, was genotyped in Chinese cohorts of glioma (n = 350), non-glioma cancer (n = 354) and healthy control (n = 463) by direct sequencing and length polymorphism in gel electrophoresis, and ZFPM2 expression in glioma tissues (n = 69) of different grades was quantified by real-time RT-PCR. Moreover, potential natural selection pressure acting on the gene was investigated. Disease-association analysis showed that the overall genotype of rs71305152 was significantly associated with gliomas (P = 0.016), and the heterozygous genotype compared to the combined homozygous genotypes was less frequent in gliomas than in controls (P = 0.005) or non-glioma cancers (P = 0.020). ZFPM2 mRNA expression was negatively correlated with the grades of gliomas (P = 0.002), with higher expression levels in the low-grade gliomas. In the astrocytoma subtype, higher ZFPM2 expression was also correlated with the rs71305152 heterozygous genotype (P = 0.028). In addition, summary statistics tests gave highly positive values, demonstrating that the gene is under the influence of balancing selection. These findings suggest that ZFPM2 is a glioma susceptibility gene, its genotype and expression showing associations with incidence and severity, respectively. Moreover, the balancing selection acting on ZFPM2 may be related to the important roles it has to play in multiple organ development or associated disease etiology.

Background: Indian Asians, who make up a quarter of the world's population, are at high risk of developing type 2 diabetes. We investigated whether DNA methylation is associated with future type 2 diabetes incidence in Indian Asians and whether differences in methylation patterns between Indian Asians and Europeans are associated with, and could be used to predict, differences in the magnitude of risk of developing type 2 diabetes., Methods: We did a nested case-control study of DNA methylation in Indian Asians and Europeans with incident type 2 diabetes who were identified from the 8-year follow-up of 25 372 participants in the London Life Sciences Prospective Population (LOLIPOP) study. Patients were recruited between May 1, 2002, and Sept 12, 2008. We did epigenome-wide association analysis using samples from Indian Asians with incident type 2 diabetes and age-matched and sex-matched Indian Asian controls, followed by replication testing of top-ranking signals in Europeans. For both discovery and replication, DNA methylation was measured in the baseline blood sample, which was collected before the onset of type 2 diabetes. Epigenome-wide significance was set at p<1 × 10(-7). We compared methylation levels between Indian Asian and European controls without type 2 diabetes at baseline to estimate the potential contribution of DNA methylation to increased risk of future type 2 diabetes incidence among Indian Asians., Findings: 1608 (11·9%) of 13 535 Indian Asians and 306 (4·3%) of 7066 Europeans developed type 2 diabetes over a mean of 8·5 years (SD 1·8) of follow-up. The age-adjusted and sex-adjusted incidence of type 2 diabetes was 3·1 times (95% CI 2·8-3·6; p<0·0001) higher among Indian Asians than among Europeans, and remained 2·5 times (2·1-2·9; p<0·0001) higher after adjustment for adiposity, physical activity, family history of type 2 diabetes, and baseline glycaemic measures. The mean absolute difference in methylation level between type 2 diabetes cases and controls ranged from 0·5% (SD 0·1) to 1·1% (0·2). Methylation markers at five loci were associated with future type 2 diabetes incidence; the relative risk per 1% increase in methylation was 1·09 (95% CI 1·07-1·11; p=1·3 × 10(-17)) for ABCG1, 0·94 (0·92-0·95; p=4·2 × 10(-11)) for PHOSPHO1, 0·94 (0·92-0·96; p=1·4 × 10(-9)) for SOCS3, 1·07 (1·04-1·09; p=2·1 × 10(-10)) for SREBF1, and 0·92 (0·90-0·94; p=1·2 × 10(-17)) for TXNIP. A methylation score combining results for the five loci was associated with future type 2 diabetes incidence (relative risk quartile 4 vs quartile 1 3·51, 95% CI 2·79-4·42; p=1·3 × 10(-26)), and was independent of established risk factors. Methylation score was higher among Indian Asians than Europeans (p=1 × 10(-34))., Interpretation: DNA methylation might provide new insights into the pathways underlying type 2 diabetes and offer new opportunities for risk stratification and prevention of type 2 diabetes among Indian Asians., Funding: The European Union, the UK National Institute for Health Research, the Wellcome Trust, the UK Medical Research Council, Action on Hearing Loss, the UK Biotechnology and Biological Sciences Research Council, the Oak Foundation, the Economic and Social Research Council, Helmholtz Zentrum Munchen, the German Research Center for Environmental Health, the German Federal Ministry of Education and Research, the German Center for Diabetes Research, the Munich Center for Health Sciences, the Ministry of Science and Research of the State of North Rhine-Westphalia, and the German Federal Ministry of Health., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Many facets of the tumor biology of medulloblastoma (MB) have not been fully elucidated. Collapsin response mediator protein 1 (CRMP1) is a member of cytoplasmic family of proteins that regulate the development of central nervous system. Recent studies demonstrated that CRMP1 could function as an invasion suppressor. We reported previously that high mobility group AT-hook 1 (HMGA1) contributed to development of MB and regulated its growth and migration/invasion. Transcriptional profiling and quantitative RT-PCR revealed increased expression of CRMP1 in HMGA1-depleted cells, suggesting that CRMP1 may be a downstream target of HMGA1 in MB. In this study, we showed HMGA1 can bind CRMP1 promoter by chromatin immunoprecipitation (ChIP) assay. Luciferase assay demonstrated a marked enhancement of CRMP1 transcription activity in HMGA1-depleted cells. Furthermore, quantitative RT-PCR revealed a negative correlation between HMGA1 and CRMP1 in 32 MB samples. To investigate the biological roles of CRMP1 in MB pathogenesis, we established MB clones stably expressing CRMP1. Functional analysis revealed that expression of CRMP1 significantly inhibited proliferation, migration, invasion and formation of filopodia and intense stress fiber of MB cells. Our data suggest that HMGA1 regulates CRMP1 expression and CRMP1 is implicated in MB pathogenesis.

Background: Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours., Methods: We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling., Findings: Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0·004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2·02 (95% CI 1·04-3·85; p=0·038) and 3·98 (1·71-9·26; p=0·001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes., Interpretation: An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours., Funding: C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

G-protein-coupled receptors (GPCRs) are classified into A to F subfamilies in which only families A, B, and C are present in mammals. Some of these GPCRs were found to form higher ordered structures such as oligomers with the discovery of interacting receptors in the form of homomers or heteromers. The importance of these oligomers on regulating receptor functions has recently been an intense research focus. It has been proposed that receptor oligomer formation has impact on its physiological importance on receptor trafficking, signaling, ligand-related regulation, and also is related to certain diseases. The present body of knowledge, however, comprises mainly intra-family oligomers formation and their consequences. Inter-family oligomers are recognized but there is limited information. This article aims to provide a current view regarding inter-family GPCR oligomerization in the subfamilies A, B, and C found in mammals.

Recurrent mutations in the promoter region of telomerase reverse transcriptase (TERT) have been found in various cancers including diffuse gliomas. Mutations lead to TERT upregulation and are associated with aggressive clinical behavior in glioblastomas. However, the clinical significance of TERT promoter mutations in lower-grade gliomas remains undetermined. The aim of this study is to evaluate the status of TERT promoter and the respective prognostic significance in a cohort of 237 lower-grade gliomas comprising grades II and III astrocytomas, oligodendrogliomas, and oligoastrocytomas. Mutually exclusive mutations in TERT promoter, C228T and C250T, were identified in 16/105 (15%) diffuse astrocytomas, 16/63 (25%) anaplastic astrocytomas, 13/18 (72%) oligodendrogliomas, 3/3 (100%) anaplastic oligodendrogliomas, 17/45 (38%) oligoastrocytomas, and 2/3 (67%) anaplastic oligoastrocytomas. Mutations co-occurred with 1p/19q codeletion (P<0.001) and are associated with oligodendroglial histology (P<0.001). Kaplan-Meier's survival analysis showed that TERT promoter mutation (P=0.037), Isocitrate dehydrogenase (IDH) mutation (P<0.001), and 1p/19q codeletion (P<0.001) were associated with favorable overall survival (OS). In the subset of 116 IDH-mutated lower-grade gliomas lacking 1p/19q codeletion, 19 TERT promoter-mutated tumors exhibited longer progression-free survival (PFS) (P=0.027) and OS (P=0.004). Consistent with this observation, in the subset of 97 IDH-mutated astrocytomas, 14 TERT promoter-mutated tumors showed longer PFS (P=0.001) and OS (P=0.001). In contrast, among the subset of 74 IDH wild-type lower-grade gliomas with intact 1p/19q, TERT promoter mutation was associated with shorter PFS (P=0.001) and OS (P=0.001). Similarly, in the subset of 65 IDH wild-type astrocytomas, 16 TERT promoter-mutated tumors exhibited unfavorable PFS (P=0.007) and OS (P=0.008). Our results indicate that when combined with IDH status, TERT promoter mutation contributes to prognostic subgroups of lower-grade astrocytic tumors or 1p/19q intact lower-grade gliomas and this may further refine future molecular classification of lower-grade gliomas.

Aims: MicroRNAs (miRNAs) are an abundant group of small non-coding RNAs that have been implicated in tumorigenesis. They regulate expression of target genes by complementary base pairing. The purposes of this study were to delineate miR-106b expression in medulloblastoma (MB) and to explore its functional contributions to MB pathogenesis., Methods: We analysed expression of miR-106b in 32 MB samples by quantitative RT-PCR. We applied gain- and loss-of-function strategies to delineate the functional roles of miR-106b in MB. Luciferase reporter assay was conducted to confirm target gene of miR-106b., Results: Expression of miR-106b was overexpressed in MB, and was significantly associated with its host gene MCM7 (P = 0.020). Transfection of miR-106b inhibitor in MB cell lines markedly reduced cell proliferation, migration and invasion potential, and tumour sphere formation. Cell cycle analysis indicated that miR-106b inhibition induced G1 arrest and apoptosis. The cell cycle regulators, p21 and cyclin D1, and apoptotic marker cleaved PARP were differentially expressed in miR-106b inhibitor-transfected cells. PTEN was identified as a direct target gene of miR-106b. Luciferase reporter assay confirmed miR-106b directly interacted with the 3' UTR of PTEN. We found miR-106b directly targeted PTEN at transcriptional and translational levels. Immunohistochemistry revealed a trend between PTEN and miR-106b in MB tumours (P = 0.07)., Conclusions: These data suggested the upregulation of miR-106b in MB and the involvement of miR-106b in MB biology., (© 2014 British Neuropathological Society.)

This study focuses on the feasibility of treating aged polycyclic aromatic hydrocarbons (PAHs)-contaminated soils using ethyl lactate (EL)-based Fenton treatment via a combination of parametric and kinetic studies. An optimised operating condition was observed at 66.7 M H2O2 with H2O2/Fe(2+) of 40:1 for low soil organic carbon (SOC) content and mildly acidic soil (pH 6.2), and 10:1 for high SOC and very acidic soil (pH 4.4) with no soil pH adjustment. The desorption kinetic was only mildly shifted from single equilibrium to dual equilibrium of the first-order kinetic model upon ageing. Pretreatment with EL fc = 0.60 greatly reduced the mass transfer coefficient especially for the slow desorbed fraction (kslow) of high molecular weight (HMW) PAHs, largely contributed by the concentration gradient created by EL-enhanced solubility. As the major desorption obstacle was almost fully overcome by the pretreatment, the pseudo-first-order kinetic reaction rate constant of PAHs degradation of aged soils was statistically discernible from that of freshly contaminated soils but slightly reduced in high SOC and high acidity soil. Stabilisation of H2O2 by EL addition in combination with reduced Fe(2+) catalyst were able to slow the decomposition rate of H2O2 even at higher soil pH.

Epidermoid cysts are benign slow growing extra-axial tumours that insinuate between brain structures, while their occurrences in intra-axial or intradiploic locations are exceptionally rare. We present the clinical, imaging, and pathological findings in two patients with atypical epidermoid cysts. CT and MRI findings for the first case revealed an intraparenchymal epidermoid cyst that demonstrated no restricted diffusion. The second case demonstrated an aggressive epidermoid cyst that invaded into the intradiploic spaces, transverse sinus, and the calvarium. The timing of ectodermal tissue sequestration during fetal development may account for the occurrence of atypical epidermoid cysts.

Objective: LGGs (low-grade gliomas) are sometimes encountered by chance during radiological examinations. These incidentally discovered LGGs (IDLGGs) were relatively under-studied in the literature. The purpose of current study is to review a cohort of patients with IDLGGs surgically treated in our institution for their clinical and histological aspects and determine their IDH1 and 1p19q status., Methods: All patients with hemispheric LGGs receiving operation in our institution between 2001 and 2004 were reviewed. Clinical, radiological and treatment data of the patients were collected and IDLGGs were retrieved and compared with symptomatic LGGs. Histological review was carried out and formalin-fixed paraffin embedded (FFPE) tissues of IDLGGs were examined for IDH1/IDH2 mutation and 1p/19q codeletion., Results: Twenty three IDLGGs (10.4%) were identified while 196 patients had symptomatic LGGs. The reasons for patients with IDLGGs having radiological examination included trauma (47.8%), dizziness (26.1%), unrelated headache (21.7%), and health checkup (4.4%). Clinically, patients with IDLGGs had higher preoperative KPS (P < 0.001), smaller tumor volume (P = 0.014), lower frequency of eloquent areas involvement (P < 0.001) and higher rate of complete resection (P = 0.037) comparing to those with symptomatic LGGs. Histologically, there is a preponderance of oligodendroglial differentiation with 6 oligodendrogliomas and 11 oligoastrocytomas but there were also 6 astrocytomas. IDH1 mutation and 1p/19q co-deletion were detected in 95.7% (22/23) and 69.6% (16/23) of IDLGGs, respectively. The latter encompassed all but one of the cases of oligodendroglial tumors. Patients with IDLGGs had longer overall survival than those with symptomatic LGGs (P = 0.027)., Conclusions: We conclude that the majority of IDLGGs are IDH1 mutated and are predominantly oligodendroglial tumors. With a median follow-up of 9.3 years to our series, we conclude that patients with IDLGGs had better prognosis than those with symptomatic LGGs. The favorable prognosis of IDLGGs may be accounted by the higher practicability of extensive resection, non-eloquent tumor location and smaller tumor volume. Frequent IDH1 mutation and 1p/19q co-deletion in IDLGGs may also contribute to the favorable prognosis of this subgroup of patients.

Background: Next generation sequencing (NGS) promises many benefits for clinical diagnostics. However, current barriers to its adoption include suboptimal amenability for low clinical throughputs and uncertainty over data accuracy and analytical procedures. We assessed the feasibility and performance of low-throughput NGS for detecting germline mutations for Lynch syndrome (LS)., Methods: Sequencing depth, time, and cost of 6 formats on the MiSeq and Personal Genome Machine platforms at 1-12 samples/run were calculated. Analytical performance was assessed from 3 runs of 3 DNA samples annotated for 7500 nucleotides by BeadChip arrays. The clinical performance of low-throughput NGS and 9 analytical processes were assessed through blinded analysis of DNA samples from 12 LS cases confirmed by Sanger sequencing, and 3 control cases., Results: The feasibility analysis revealed different formats were optimal at different throughputs. Detection was reproducible for 2619/2635 (99.39%) replicate variants, and sensitivity and specificity to array annotation were 99.42% and 99.99% respectively. Eleven of 16 inconsistently detected variants could be specifically identified by having allele frequencies ≤ 0.15, strand biases >-35, or genotype quality scores ≤ 80. Positive selection for variants in the Human Genome Mutation Database (colorectal cancer, nonpolyposis) and variants with ≤ 5% frequency in the Asian population gave the best clinical performance (92% sensitivity, 67% specificity)., Conclusions: Low-throughput NGS can be a cost-efficient and reliable approach for screening germline variants; however, its clinical utility is subject to the quality of annotation of clinically relevant variants., (© 2014 American Association for Clinical Chemistry.)

Major discoveries in the biology of nervous system tumors have raised the question of how non-histological data such as molecular information can be incorporated into the next World Health Organization (WHO) classification of central nervous system tumors. To address this question, a meeting of neuropathologists with expertise in molecular diagnosis was held in Haarlem, the Netherlands, under the sponsorship of the International Society of Neuropathology (ISN). Prior to the meeting, participants solicited input from clinical colleagues in diverse neuro-oncological specialties. The present "white paper" catalogs the recommendations of the meeting, at which a consensus was reached that incorporation of molecular information into the next WHO classification should follow a set of provided "ISN-Haarlem" guidelines. Salient recommendations include that (i) diagnostic entities should be defined as narrowly as possible to optimize interobserver reproducibility, clinicopathological predictions and therapeutic planning; (ii) diagnoses should be "layered" with histologic classification, WHO grade and molecular information listed below an "integrated diagnosis"; (iii) determinations should be made for each tumor entity as to whether molecular information is required, suggested or not needed for its definition; (iv) some pediatric entities should be separated from their adult counterparts; (v) input for guiding decisions regarding tumor classification should be solicited from experts in complementary disciplines of neuro-oncology; and (iv) entity-specific molecular testing and reporting formats should be followed in diagnostic reports. It is hoped that these guidelines will facilitate the forthcoming update of the fourth edition of the WHO classification of central nervous system tumors., (© 2014 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Amplification of the C19MC oncogenic miRNA cluster and high LIN28 expression has been linked to a distinctly aggressive group of cerebral CNS-PNETs (group 1 CNS-PNETs) arising in young children. In this study, we sought to evaluate the diagnostic specificity of C19MC and LIN28, and the clinical and biological spectra of C19MC amplified and/or LIN28+ CNS-PNETs. We interrogated 450 pediatric brain tumors using FISH and IHC analyses and demonstrate that C19MC alteration is restricted to a sub-group of CNS-PNETs with high LIN28 expression; however, LIN28 immunopositivity was not exclusive to CNS-PNETs but was also detected in a proportion of other malignant pediatric brain tumors including rhabdoid brain tumors and malignant gliomas. C19MC amplified/LIN28+ group 1 CNS-PNETs arose predominantly in children <4 years old; a majority arose in the cerebrum but 24 % (13/54) of tumors had extra-cerebral origins. Notably, group 1 CNS-PNETs encompassed several histologic classes including embryonal tumor with abundant neuropil and true rosettes (ETANTR), medulloepithelioma, ependymoblastoma and CNS-PNETs with variable differentiation. Strikingly, gene expression and methylation profiling analyses revealed a common molecular signature enriched for primitive neural features, high LIN28/LIN28B and DNMT3B expression for all group 1 CNS-PNETs regardless of location or tumor histology. Our collective findings suggest that current known histologic categories of CNS-PNETs which include ETANTRs, medulloepitheliomas, ependymoblastomas in various CNS locations, comprise a common molecular and diagnostic entity and identify inhibitors of the LIN28/let7/PI3K/mTOR axis and DNMT3B as promising therapeutics for this distinct histogenetic entity.

Intracranial germ cell tumours (IGCTs) are a group of rare heterogeneous brain tumours that are clinically and histologically similar to the more common gonadal GCTs. IGCTs show great variation in their geographical and gender distribution, histological composition and treatment outcomes. The incidence of IGCTs is historically five- to eightfold greater in Japan and other East Asian countries than in Western countries, with peak incidence near the time of puberty. About half of the tumours are located in the pineal region. The male-to-female incidence ratio is approximately 3-4:1 overall, but is even higher for tumours located in the pineal region. Owing to the scarcity of tumour specimens available for research, little is currently known about this rare disease. Here we report the analysis of 62 cases by next-generation sequencing, single nucleotide polymorphism array and expression array. We find the KIT/RAS signalling pathway frequently mutated in more than 50% of IGCTs, including novel recurrent somatic mutations in KIT, its downstream mediators KRAS and NRAS, and its negative regulator CBL. Novel somatic alterations in the AKT/mTOR pathway included copy number gains of the AKT1 locus at 14q32.33 in 19% of patients, with corresponding upregulation of AKT1 expression. We identified loss-of-function mutations in BCORL1, a transcriptional co-repressor and tumour suppressor. We report significant enrichment of novel and rare germline variants in JMJD1C, which codes for a histone demethylase and is a coactivator of the androgen receptor, among Japanese IGCT patients. This study establishes a molecular foundation for understanding the biology of IGCTs and suggests potentially promising therapeutic strategies focusing on the inhibition of KIT/RAS activation and the AKT1/mTOR pathway.

Recently, the survival rate of medulloblastoma patients has greatly improved; yet, patients undergoing current treatment regimes suffer from serious therapy-related side-effects. The aim of the present study was to investigate the anticancer effects of curcumin on medulloblastoma cells by testing its capacity to suppress proliferation and regulate the Wnt/β-catenin pathway. In the present study, cell proliferation was determined by MTT assay. Cell cycle was observed by flow cytometry. The changes in the Wnt/β-catenin pathway were analyzed by immunofluorescence, western blot analysis and RT-PCR. Curcumin treatment resulted in a dose- and time-dependent inhibition of proliferation in the medulloblastoma cell line. Curcumin treatment arrested the cell-cycle at the G2/M phase. Furthermore, curcumin treatment led to activation of GSK-3β, reduced expression of β-catenin and its downstream target cyclin D1. The attenuation of the Wnt/β‑catenin pathway was due to the loss of nuclear β-catenin. In conclusion, curcumin can inhibit cell growth by suppressing the Wnt/β-catenin signaling pathway, and it has the potential to be developed as a therapeutic agent for medulloblastoma.

Medulloblastoma (MB) is one of the most common primary central nervous system tumors in children. Data is lacking of a large cohort of medulloblastoma patients in China. Also, our knowledge on the sensitivity of different molecular subgroups of MB to adjuvant radiation therapy (RT) or chemotherapy (CHT) is still limited. The authors performed a retrospective study of 173 medulloblastoma patients treated at two institutions from 2002 to 2011. Formalin-fixed paraffin embedded (FFPE) tissues were available in all the cases and sections were stained to classify histological and molecular subgroups. Univariate and multivariate analyses were used to investigate prognostic factors. Of 173 patients, there were 118 children and 55 adults, 112 males and 61 females. Estimated 5-year overall survival (OS) rates for all patients, children and adults were 52%, 48% and 63%, respectively. After multivariate analysis, postoperative primary radiation therapy (RT) and chemotherapy (CHT) were revealed as favorable prognostic factors influencing OS and EFS. Postoperative primary chemotherapy (CHT) was found significantly improving the survival of children (p<0.001) while it was not a significant prognostic factor for adult patients. Moreover, patients in WNT subtype had better OS (p = 0.028) than others (SHH and Non-SHH/WNT subtypes) given postoperative adjuvant therapies. Postoperative primary RT was found to be a strong prognostic factor influencing the survival in all histological and molecular subgroups (p<0.001). Postoperative primary CHT was found significantly to influence the survival of classic medulloblastoma (CMB) (OS p<0.001, EFS p<0.001), SHH subgroup (OS p = 0.020, EFS p = 0.049) and WNT subgroup (OS p = 0.003, EFS p = 0.016) but not in desmoplastic/nodular medulloblastoma (DMB) (OS p = 0.361, EFS p = 0.834) and Non-SHH/WNT subgroup (OS p = 0.127, EFS p = 0.055). Our study showed postoperative primary CHT significantly influence the survival of CMB, SHH subgroup and WNT subgroup but not in DMB and Non-SHH/WNT subgroup of MB.

High-frequency action potentials are mediated by voltage-gated sodium channels, composed of one large α subunit and two small β subunits, encoded mainly by SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B genes in the brain. These play a key role in epilepsy, with the most commonly mutated gene in epilepsy being SCN1A. We examined whether polymorphisms in the above genes affect epilepsy risk in 1,529 epilepsy patients and 1,935 controls from four ethnicities or locations: Malay, Indian, and Chinese, all from Malaysia, and Chinese from Hong Kong. Of patients, 19 % were idiopathic, 42 % symptomatic, and 40 % cryptogenic. We genotyped 43 polymorphisms: 27 in Hong Kong, 28 in Malaysia, and 12 in both locations. The strongest association with epilepsy was rs3812718, or SCN1A IVS5N+5G>A: odds ratio (OR) = 0.85 for allele G (p = 0.0009) and 0.73 for genotype GG versus AA (p = 0.003). The OR was between 0.76 and 0.87 for all ethnicities. Meta-analysis confirmed the association (OR = 0.81 and p = 0.002 for G, and OR = 0.67 and p = 0.007 for GG versus AA), which appeared particularly strong for Indians and for febrile seizures. Allele G affects splicing and speeds recovery from inactivation. Since SCN1A is preferentially expressed in inhibitory neurons, G may decrease epilepsy risk. SCN1A rs10188577 displayed OR = 1.20 for allele C (p = 0.003); SCN2A rs12467383 had OR = 1.16 for allele A (p = 0.01), and displayed linkage disequilibrium with rs2082366 (r (2) = 0.67), whose genotypes tended toward association with SCN2A brain expression (p = 0.10). SCN1A rs2298771 was associated in Indians (OR = 0.56, p = 0.005) and SCN2B rs602594 with idiopathic epilepsy (OR = 0.62, p = 0.002). Therefore, sodium channel polymorphisms are associated with epilepsy.

Backgrounds: Intracranial germ cell tumors (GCTs) are rare and heterogeneous with very little is known about their pathogenesis and underlying genetic abnormalities., Procedures: In order to identify candidate genes and pathways which are involved in the pathogenesis of these tumors, we have profiled 62 intracranial GCTs for DNA copy number alterations (CNAs) and loss of heterozygosity (LOH) by using single nucleotide polymorphism (SNP) array and quantitative real time PCR (qPCR)., Results: Initially 27 cases of tumor tissues with matched blood samples were fully analyzed by SNP microarray and qPCR. Statistical analysis using the genomic identification of significant targets in cancer (GISTIC) tool identified 10 regions of significant copy number gain and 11 regions of significant copy number loss. While overall pattern of genomic aberration was similar between germinoma and nongerminomatous germ cell tumors (NGGCTs), a few subtype-specific peak regions were identified. Analysis by SNP array and qPCR was replicated using an independent cohort of 35 cases., Conclusions: Frequent aberrations of CCND2 (12p13) and RB1 (13q14) suggest that Cyclin/CDK-RB-E2F pathway might play a critical role in the pathogenesis of intracranial GCTs. Frequent gain of PRDM14 (8q13) implies that transcriptional regulation of primordial germ cell specification might be an important factor in the development of this tumor., (© 2013 Wiley Periodicals, Inc.)

Combined deletion of chromosomes 1p and 19q is a prognostic marker in oligodendroglial tumors. Recent studies in oligodendroglial tumors have unveiled recurrent mutations of CIC (homolog of Drosophila capicua) and FUBP1 (far upstream element binding protein 1) that are located on 19q13 and 1p31, respectively. However, the impact of CIC and FUBP1 mutations on their protein expressions has not been examined. The aims of this study were to correlate the expression patterns of CIC and FUBP1 with their mutation profiles and to evaluate the clinical relevance of these molecular markers in 55 oligodendroglial tumors diagnosed in 47 adult patients. Using direct sequencing, somatic mutations of CIC and FUBP1 were identified in 47% (22/47) and 16% (7/45) of oligodendroglial tumors, respectively. Immunohistochemical analysis revealed loss of CIC or FUBP1 protein expression in 36% (20/55) and 16% (9/55) of oligodendroglial tumors examined. Somatic mutation was significantly associated with absent protein expression for both genes (CIC, P=0.01; FUBP1, P=0.00001). Four tumors with undetectable CIC mutations exhibited absent CIC expression, suggesting that CIC inactivation could be mediated by mechanisms other than mutations and genomic loss. Univariate survival analysis revealed that 1p/19q codeletion was significantly associated with overall survival (P=0.05). Loss of CIC expression was significantly correlated with shorter progression-free survival (P=0.03), whereas CIC alteration (mutation or null expression) with worse overall survival (P=0.05). Absent FUBP1 expression was linked with unfavorable progression-free survival (P=0.02) and overall survival (P=0.01). In 16 tumors with 1p/19q codeletion, CIC mutation was associated with unfavorable survival (P=0.01). There was a correlation between lack of CIC or FUBP1 expression and poor progression-free survival (P=0.004; P=0.0003). No molecular markers showed association with survival in oligodendroglial tumors lacking 1p/19q codeletion. We conclude that absent CIC and FUBP1 expressions are potential markers of shorter time to recurrence and CIC mutation a potential marker of worse prognosis, especially in tumors carrying 1p/19q codeletion.