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1.  Ototoxicity in Children With High-Risk Neuroblastoma: Prevalence, Risk Factors, and Concordance of Grading Scales—A Report From the Children's Oncology Group 
Journal of Clinical Oncology  2014;32(6):527-534.
Purpose
Platinum-based therapy is the mainstay for management of high-risk neuroblastoma. Prevalence of platinum-related ototoxicity has ranged from 13% to 95% in previous reports; variability is attributable to small samples and disparate grading scales. There is no consensus regarding optimal ototoxicity grading. Furthermore, prevalence and predictors of hearing loss in a large uniformly treated high-risk neuroblastoma population are unknown. We address these gaps in our study.
Patients and Methods
Audiologic testing was completed after administration of cisplatin alone (< 400 mg/m2; exposure one) or after cisplatin (400 mg/m2) plus carboplatin (1,700 mg/m2; exposure two). Hearing loss was graded using four scales (American Speech-Language-Hearing Association; Brock; Chang; and Common Terminology Criteria for Adverse Events, version 3 [CTCAEv3]).
Results
Of 489 eligible patients, 333 had evaluable audiologic data. Median age at diagnosis was 3.3 years. Prevalence of severe hearing loss differed by scale. For those in the exposure-one group, prevalence ranged from 8% per Brock to 47% per CTCAEv3 (Brock v CTCAEv3 and Chang, P < .01; CTCAEv3 v Chang, P = .16); for those in the exposure-two group, prevalence ranged from 30% per Brock to 71% per CTCAEv3 (all pair-wise comparisons, P < .01). In patients requiring hearing aids, hearing loss was graded as severe in 49% (Brock), 91% (Chang), and 100% (CTCAEv3). Risk factors for severe hearing loss included exposure to cisplatin and carboplatin compared with cisplatin alone and hospitalization for infection.
Conclusion
Severe hearing loss is prevalent among children with high-risk neuroblastoma. Exposure to cisplatin combined with myeloablative carboplatin significantly increases risk. The Brock scale underestimates severe hearing loss and should be used with caution in this setting.
doi:10.1200/JCO.2013.51.2038
PMCID: PMC3918536  PMID: 24419114
2.  Mitochondrial genome of Hypoderaeum conoideum – comparison with selected trematodes 
Parasites & Vectors  2015;8:97.
Background
Hypoderaeum conoideum is a neglected but important trematode. The life cycle of this parasite is complex: snails serve as the first intermediate hosts: bivalves, fishes or tadpoles serve as the second intermediate hosts, and poultry (such as chickens and ducks) act as definitive hosts. In recent years, H. conoideum has caused significant economic losses to the poultry industry in some Asian countries. Despite its importance, little is known about the molecular ecology and population genetics of this parasite. Knowledge of mitochondrial (mt) genome of H. conoideum can provide a foundation for phylogenetic studies as well as epidemiological investigations.
Methods
The entire mt genome of H. conoideum was amplified in five overlapping fragments by PCR and sequenced, annotated and compared with mt genomes of selected trematodes. A phylogenetic analysis of concatenated mt amino acid sequence data for H. conoideum, eight other digeneans (Clonorchis sinensis, Fasciola gigantica, F. hepatica, Opisthorchis felineus, Schistosoma haematobium, S. japonicum, S. mekongi and S. spindale) and one tapeworm (Taenia solium; outgroup) was conducted to assess their relationships.
Results
The complete mt genome of H. conoideum is 14,180 bp in length, and contains 12 protein-coding genes, 22 transfer RNA genes, two ribosomal RNA genes and one non-coding region (NCR). The gene arrangement is the same as in Fasciola spp, with all genes being transcribed in the same direction. The phylogenetic analysis showed that H. conoideum had a relatively close relationship with F. hepatica and other members of the Fasciolidae, followed by the Opisthorchiidae, and then the Schistosomatidae.
Conclusions
The mt genome of H. conoideum should be useful as a resource for comparative mt genomic studies of trematodes and for DNA markers for systematic, population genetic and epidemiological studies of H. conoideum and congeners.
doi:10.1186/s13071-015-0720-x
PMCID: PMC4331133
Hypoderaeum conoideum; Mitochondrial genome
3.  Novel Inhibitors Induce Large Conformational Changes of GAB1 Pleckstrin Homology Domain and Kill Breast Cancer Cells 
PLoS Computational Biology  2015;11(1):e1004021.
The Grb2-associated binding protein 1 (GAB1) integrates signals from different signaling pathways and is over-expressed in many cancers, therefore representing a new therapeutic target. In the present study, we aim to target the pleckstrin homology (PH) domain of GAB1 for cancer treatment. Using homology models we derived, high-throughput virtual screening of five million compounds resulted in five hits which exhibited strong binding affinities to GAB1 PH domain. Our prediction of ligand binding affinities is also in agreement with the experimental KD values. Furthermore, molecular dynamics studies showed that GAB1 PH domain underwent large conformational changes upon ligand binding. Moreover, these hits inhibited the phosphorylation of GAB1 and demonstrated potent, tumor-specific cytotoxicity against MDA-MB-231 and T47D breast cancer cell lines. This effort represents the discovery of first-in-class GAB1 PH domain inhibitors with potential for targeted breast cancer therapy and provides novel insights into structure-based approaches to targeting this protein.
Author Summary
In this paper, we described the identification and evaluation of a set of first-in-class potent inhibitors targeting a new cancer target, Grb2-associated binder-1 (GAB1), which integrates signals from different signaling pathways, and is frequently over-expressed in cancer cells. To achieve our goals, we have employed intensive computational modeling to understand the structure of the GAB1 pleckstrin homology (PH) domain and screened five million compounds. Upon biological evaluation, we found that several inhibitors that induced large conformational changes of the target structure exhibited strong selective binding to GAB1 PH domain. Particularly, these inhibitors demonstrated potent and tumor-specific cytotoxicity in breast cancer cells. This represents a groundbreaking discovery in targeting GAB1 signaling which may be used for cancer therapy, especially for triple negative breast cancer patients.
doi:10.1371/journal.pcbi.1004021
PMCID: PMC4287437  PMID: 25569504
4.  Mechanical and Anticorrosive Properties of Graphene/Epoxy Resin Composites Coating Prepared by in-Situ Method 
The graphene nanosheets-based epoxy resin coating (0, 0.1, 0.4 and 0.7 wt %) was prepared by a situ-synthesis method. The effect of polyvinylpyrrolidone/reduced graphene oxide (PVP-rGO) on mechanical and thermal properties of epoxy resin coating was investigated using nanoindentation technique and thermogravimetric analysis, respectively. A significant enhancement (ca. 213% and 73 °C) in the Young modulus and thermal stability of epoxy resin coating was obtained at a loading of 0.7 wt %, respectively. Furthermore, the erosion resistance of graphene nanosheets-based epoxy resin coating was investigated by electrochemical measurement. The results showed also that the Rrcco (ca. 0.3 mm/year) of graphene nanosheets-based epoxy resin coating was far lower than neat epoxy resin (1.3 mm/year). Thus, this approach provides a novel route for improving erosion resistance and mechanical-thermal stability of polymers coating, which is expected to be used in mechanical-thermal-corrosion coupling environments.
doi:10.3390/ijms16012239
PMCID: PMC4307360  PMID: 25608656
graphene; epoxy resin; composite coating; mechanical properties; erosion resistance
5.  Incidence, Risk Factors and Consequences of Emergence Agitation in Adult Patients after Elective Craniotomy for Brain Tumor: A Prospective Cohort Study 
PLoS ONE  2014;9(12):e114239.
Emergence agitation is a frequent complication that can have serious consequences during recovery from general anesthesia. However, agitation has been poorly investigated in patients after craniotomy. In this prospective cohort study, adult patients were enrolled after elective craniotomy for brain tumor. The sedation-agitation scale was evaluated during the first 12 hours after surgery. Agitation developed in 35 of 123 patients (29%). Of the agitated patients, 28 (80%) were graded as very and dangerously agitated. By multivariate stepwise logistic regression analysis, independent predictors for agitation included male sex, history of long-term use of anti-depressant drugs or benzodiazepines, frontal approach of the operation, method and duration of anesthesia and presence of endotracheal intubation. Total intravenous anesthesia and balanced anesthesia with short duration were protective factors. Emergence agitation was associated with self-extubation (8.6% vs 0%, P = 0.005). Sedatives were administered more in agitated patients than non-agitated patients (85.7% vs 6.8%, P<0.001). In conclusion, emergence agitation was a frequent complication in patients after elective craniotomy for brain tumors. The clarification of risk factors could help to identify the high-risk patients, and then to facilitate the prevention and treatment of agitation. For patients undergoing craniotomy, greater attention should be paid to those receiving a frontal approach for craniotomy and those anesthetized under balanced anesthesia with long duration. More researches are warranted to elucidate whether total intravenous anesthesia could reduce the incidence of agitation after craniotomy.
Trial Registration
ClinicalTrials.gov NCT00590499.
doi:10.1371/journal.pone.0114239
PMCID: PMC4262354  PMID: 25493435
6.  HOTAIR, a cell cycle–associated long noncoding RNA and a strong predictor of survival, is preferentially expressed in classical and mesenchymal glioma 
Neuro-Oncology  2013;15(12):1595-1603.
Background
Long noncoding RNA Hox transcript antisense intergenic RNA (HOTAIR) has been characterized as a negative prognostic factor in breast and colon cancer patients. The clinical significance and function of HOTAIR in glioma remains unclear.
Methods
We analyzed the clinical significance of HOTAIR in 3 different glioma cohorts with gene expression data, including correlation with tumor grade, prognosis, and molecular subtype. The function of HOTAIR in glioma was explored by performing gene set enrichment analysis and in vitro and in vivo experiments.
Results
HOTAIR expression was closely associated with glioma grade and poor prognosis. Multivariate Cox regression analysis revealed that HOTAIR was an independent prognostic factor in glioblastoma multiforme patients. HOTAIR expression correlated with glioma molecular subtype, including those of The Cancer Genome Atlas. HOTAIR was preferentially expressed in the classical and mesenchymal subtypes compared with the neural and proneural subtypes. A gene set enrichment analysis designed to show gene set differences between patients with high and low HOTAIR expression indicated that HOTAIR expression was associated with gene sets involved in cell cycle progression. HOTAIR reduction induced colony formation suppression, cell cycle G0/G1 arrest, and orthotopic tumor growth inhibition.
Conclusion
Our data establish that HOTAIR is an important long noncoding RNA that primarily serves as a prognostic factor for glioma patient survival, as well as a biomarker for identifying glioma molecular subtypes, a critical regulator of cell cycle progression.
doi:10.1093/neuonc/not131
PMCID: PMC3829598  PMID: 24203894
cell cycle; glioma; HOTAIR; molecular subtype; survival
7.  An atlas of genetic influences on human blood metabolites 
Nature genetics  2014;46(6):543-550.
Genome-wide association scans with high-throughput metabolic profiling provide unprecedented insights into how genetic variation influences metabolism and complex disease. Here we report the most comprehensive exploration of genetic loci influencing human metabolism to date, including 7,824 adult individuals from two European population studies. We report genome-wide significant associations at 145 metabolic loci and their biochemical connectivity regarding more than 400 metabolites in human blood. We extensively characterize the resulting in vivo blueprint of metabolism in human blood by integrating it with information regarding gene expression, heritability, overlap with known drug targets, previous association with complex disorders and inborn errors of metabolism. We further developed a database and web-based resources for data mining and results visualization. Our findings contribute to a greater understanding of the role of inherited variation in blood metabolic diversity, and identify potential new opportunities for pharmacologic development and disease understanding.
doi:10.1038/ng.2982
PMCID: PMC4064254  PMID: 24816252
8.  PREDOSE: A Semantic Web Platform for Drug Abuse Epidemiology using Social Media 
Journal of biomedical informatics  2013;46(6):10.1016/j.jbi.2013.07.007.
Objectives
The role of social media in biomedical knowledge mining, including clinical, medical and healthcare informatics, prescription drug abuse epidemiology and drug pharmacology, has become increasingly significant in recent years. Social media offers opportunities for people to share opinions and experiences freely in online communities, which may contribute information beyond the knowledge of domain professionals. This paper describes the development of a novel Semantic Web platform called PREDOSE (PREscription Drug abuse Online Surveillance and Epidemiology), which is designed to facilitate the epidemiologic study of prescription (and related) drug abuse practices using social media. PREDOSE uses web forum posts and domain knowledge, modeled in a manually created Drug Abuse Ontology (DAO) (pronounced dow), to facilitate the extraction of semantic information from User Generated Content (UGC). A combination of lexical, pattern-based and semantics-based techniques is used together with the domain knowledge to extract fine-grained semantic information from UGC. In a previous study, PREDOSE was used to obtain the datasets from which new knowledge in drug abuse research was derived. Here, we report on various platform enhancements, including an updated DAO, new components for relationship and triple extraction, and tools for content analysis, trend detection and emerging patterns exploration, which enhance the capabilities of the PREDOSE platform. Given these enhancements, PREDOSE is now more equipped to impact drug abuse research by alleviating traditional labor-intensive content analysis tasks.
Methods
Using custom web crawlers that scrape UGC from publicly available web forums, PREDOSE first automates the collection of web-based social media content for subsequent semantic annotation. The annotation scheme is modeled in the DAO, and includes domain specific knowledge such as prescription (and related) drugs, methods of preparation, side effects, routes of administration, etc. The DAO is also used to help recognize three types of data, namely: 1) entities, 2) relationships and 3) triples. PREDOSE then uses a combination of lexical and semantic-based techniques to extract entities and relationships from the scraped content, and a top-down approach for triple extraction that uses patterns expressed in the DAO. In addition, PREDOSE uses publicly available lexicons to identify initial sentiment expressions in text, and then a probabilistic optimization algorithm (from related research) to extract the final sentiment expressions. Together, these techniques enable the capture of fine-grained semantic information from UGC, and querying, search, trend analysis and overall content analysis of social media related to prescription drug abuse. Moreover, extracted data are also made available to domain experts for the creation of training and test sets for use in evaluation and refinements in information extraction techniques.
Results
A recent evaluation of the information extraction techniques applied in the PREDOSE platform indicates 85% precision and 72% recall in entity identification, on a manually created gold standard dataset. In another study, PREDOSE achieved 36% precision in relationship identification and 33% precision in triple extraction, through manual evaluation by domain experts. Given the complexity of the relationship and triple extraction tasks and the abstruse nature of social media texts, we interpret these as favorable initial results. Extracted semantic information is currently in use in an online discovery support system, by prescription drug abuse researchers at the Center for Interventions, Treatment and Addictions Research (CITAR) at Wright State University.
Conclusion
A comprehensive platform for entity, relationship, triple and sentiment extraction from such abstruse texts has never been developed for drug abuse research. PREDOSE has already demonstrated the importance of mining social media by providing data from which new findings in drug abuse research were uncovered. Given the recent platform enhancements, including the refined DAO, components for relationship and triple extraction, and tools for content, trend and emerging pattern analysis, it is expected that PREDOSE will play a significant role in advancing drug abuse epidemiology in future.
doi:10.1016/j.jbi.2013.07.007
PMCID: PMC3844051  PMID: 23892295
Entity Identification; Relationship Extraction; Triple Extraction; Sentiment Extraction; Semantic Web; Drug Abuse Ontology; Prescription Drug Abuse; Epidemiology
9.  Genome Architecture and Its Roles in Human Copy Number Variation 
Genomics & Informatics  2014;12(4):136-144.
Besides single-nucleotide variants in the human genome, large-scale genomic variants, such as copy number variations (CNVs), are being increasingly discovered as a genetic source of human diversity and the pathogenic factors of diseases. Recent experimental findings have shed light on the links between different genome architectures and CNV mutagenesis. In this review, we summarize various genomic features and discuss their contributions to CNV formation. Genomic repeats, including both low-copy and high-copy repeats, play important roles in CNV instability, which was initially known as DNA recombination events. Furthermore, it has been found that human genomic repeats can also induce DNA replication errors and consequently result in CNV mutations. Some recent studies showed that DNA replication timing, which reflects the high-order information of genomic organization, is involved in human CNV mutations. Our review highlights that genome architecture, from DNA sequence to high-order genomic organization, is an important molecular factor in CNV mutagenesis and human genomic instability.
doi:10.5808/GI.2014.12.4.136
PMCID: PMC4330246
DNA copy number variations; DNA replication; genetic recombination; genomic instability
10.  Analysis of Current Status and Strategies of Retinopathy of Prematurity Screening during 6 Years in Local Regions of China: Implication and Caution 
Journal of Ophthalmology  2014;2014:756059.
Purpose. To understand the current status of retinopathy of prematurity (ROP) screening in a province of North China. Methods. We retrospectively analyzed 5651 cases with ROP screening in the Provincial Screening Center of Hebei Province from January 2008 to December 2013. Results. 14.98% of all ROP patients and 1.56% of severe ROP patients required treatment. All the severe ROP patients met the criteria of screening. Severe ROP patients were detected at recommended initial screening time (4–6 weeks after birth). The frequency of other ocular diseases was 8.03%, in which the main disease was fundus hemorrhage. In 2665 more mature and unqualified infants, only 2 retinoblastoma and 2 familial exudative vitreoretinopathy were detected, which indicates the advantage of early diagnosis and treatment based on fundus examination. Conclusions. It is suggested that the standard of GA < 32 weeks and/or BW < 1800 g could be served as the screening criteria in the local region for ROP screening. 4 weeks after birth is the most appropriate time for initial screening.
doi:10.1155/2014/756059
PMCID: PMC4236892  PMID: 25538849
11.  Role of Angiopoietin-2 in Corneal Lymphangiogenesis 
Purpose.
Lymphatic research has progressed rapidly in recent years. Lymphatic dysfunction has been found in myriad disorders from cancer metastasis to transplant rejection; however, effective treatment for lymphatic disorders is still limited. This study investigates the role of angiopoietin-2 (Ang-2) in corneal inflammatory lymphangiogenesis (LG) in vivo and in lymphatic endothelial cell (LEC) functions in vitro.
Methods.
Standard suture placement model was used to study Ang-2 expression in inflamed cornea, and corneal LG and hemangiogenesis (HG) responses in Ang-2 knockout mice. Moreover, human LEC culture system was used to examine the effect of Ang-2 gene knockdown on LEC functions using small interfering RNAs (siRNAs). The effect of siRNA treatment on corneal LG was also assessed in vivo.
Results.
Angiopoietin-2 was expressed on lymphatic vessels and macrophages in inflamed cornea. While corneal LG response was abolished in Ang-2 knockout mice, the HG response was also significantly suppressed with disorganized patterning. Moreover, anti-Ang-2 treatment inhibited LEC proliferation and capillary tube formation in vitro and corneal LG in vivo.
Conclusions.
Angiopoietin-2 is critically involved in lymphatic processes in vivo and in vitro. Further investigation of the Ang-2 pathway may provide novel insights and therapeutic strategies for lymphatic-related disorders, which occur both inside and outside the eye.
This study reveals Ang-2 gene deficiency leads to marked suppression of lymphangiogenesis in vivo and lymphatic endothelial cell functions in intro. Future investigation on Ang-2 pathway may provide novel therapeutic strategies for lymphatic-related diseases.
doi:10.1167/iovs.13-13779
PMCID: PMC4039380  PMID: 24781940
corneal lymphangiogenesis; Ang-2; knockout mice; small interfering RNA; lymphatic endothelial cells
12.  A Cluster Analytic Examination of Acculturation and Health Status among Asian Americans in the Washington DC Metropolitan Area, United States 
Previous studies reported mixed findings on the relationship between acculturation and health status among Asian Americans due to different types of acculturation measures used or different Asian subgroups involved in various studies. We aim to fill the gap by applying multiple measures of acculturation in a diverse sample of Asian subgroups.
A cross sectional study was conducted among Chinese, Korean and Vietnamese Americans in Washington D.C. Metropolitan Area to examine the association between health status and acculturation using multiple measures including the Suinn-Lew Asian Self-Identity Acculturation (SL-ASIA) scale, clusters based on responses to SL-ASIA, language preference, length of stay, age at arrival in the United Sates and self-identity. Three clusters (Asian (31%); Bicultural (47%); and American (22%)) were created by using a two-step hierarchical method and Bayesian Information Criterion values. Across all the measures, more acculturated individuals were significantly more likely to report good health than those who were less acculturated after adjusting for covariates. Specifically, those in the American cluster were 3.8 times (95% Confidence Interval (CI): 2.2, 6.6) more likely and those in the Bicultural cluster were 1.7 times more likely (95% CI: 1.1, 2.4) to report good health as compared to those in the Asian cluster. When the conventional standardized SL-ASIA summary score (range: −1.4 to 1.4) was used, a one point increase was associated with 2.2 times greater odds of reporting good health (95% CI: 1.5, 3.2). However, the interpretation may be challenging due to uncertainty surrounding the meaning of a one point increase in SL-ASIA summary score.
Among all the measures used, acculturation clusters better approximated the acculturation process and provided us with a more accurate test of the association in the population. Variables included in this measure were more relevant for our study sample and may have worked together to capture the multifaceted acculturation process.
doi:10.1016/j.socscimed.2013.07.007
PMCID: PMC4143184  PMID: 24034947
acculturation; health status; Asian Americans; United States; clusters; measures
13.  Clinical diagnostic utility of CA 15-3 for the diagnosis of malignant pleural effusion: A meta-analysis 
Malignant pleural effusion (MPE) is one of the most common pleura-associated conditions observed in clinical practice. The development of MPE usually defines advanced cancer with a poor prognosis. Carbohydrate antigen 15-3 (CA 15-3), as an effective pleural fluid biomarker, has been an object of ongoing research in the detection of MPE. The aim of this meta-analysis was to establish the overall diagnostic accuracy of the measurement of pleural CA 15-3 for diagnosing MPE. The databases Medline (using PubMed as the search engine), Embase, Ovid, Web of Science and Cochrane database (up to December 2013) were searched to identify relevant studies. No lower date limit was applied. All literature published in English was reviewed. Sensitivity, specificity, likelihood ratio and diagnostic odds ratio (DOR) were pooled using a random-effect model. Summary receiver operating characteristic (SROC) curve analysis was conducted to evaluate the overall diagnostic value. The methodological quality was assessed in line with the Quality Assessment for Studies of Diagnostic Accuracy statement. Twenty-one studies with a total of 2,861 cases were included in present meta-analysis. The sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and DOR of CA 15-3 in the diagnosis of MPE were 0.58 [95% confidence interval (CI), 0.56–0.61], 0.91 (95% CI, 0.90–0.93), 8.93 (95% CI, 4.45–17.93), 0.46 (95% CI, 0.37–0.56) and 24.89 (95% CI, 10.39–59.63), respectively. In addition, the area under the curve (AUC) was 0.84. In conclusion, due to the significantly high specificity of pleural CA 15-3 in detecting MPE, it may play a pivotal role in screening to identify patients who may benefit from further invasive pathologic examination, particularly in those presenting clinical manifestations of MPE but with negative cytological findings of the pleural fluid. However, ruling out MPE by testing CA15-3 alone is not recommended due to its limited sensitivity, and it is recommended that the results of CA15-3 assays are interpreted in parallel with conventional test results and other clinical findings.
doi:10.3892/etm.2014.2039
PMCID: PMC4247302  PMID: 25452808
CA 15-3; malignant pleural effusion; diagnosis; meta-analysis
14.  Income-related children’s health inequality and health achievement in China 
Introduction
This study assessed income–related health inequality and health achievement in children in China, and additionally, examined province-level variations in health achievement.
Methods
Longitudinal data on 19,801 children under 18 years of age were derived from the China Health and Nutrition Survey. Income–related health inequality and health achievement were measured by the Health Concentration and Health Achievement Indices, respectively. Panel data with a fixed effect multiple regression model was employed to examine province-level variations in health achievement.
Results
A growing trend was towards greater health inequality among Chinese children over the last two decades. Although health achievement was getting better over time, the pro-rich inequality component has lessened the associated gain in achievement. Health achievement was positively impacted by middle school enrollments, the urbanization rate, inflation-adjusted per capita gross domestic product, and per capita public health spending.
Conclusion
This study has provided evidence that average health status of Chinese children has improved, but inequality has widened. Widening inequality slowed the growth in health achievement for children over time. There were wide variations in health achievement throughout China.
doi:10.1186/s12939-014-0102-6
PMCID: PMC4229621  PMID: 25359568
Child health inequality; Concentration index; Health achievement
15.  Accelerated Experience-dependent Pruning of Cortical Synapses in Ephrin-A2 Knockout Mice 
Neuron  2013;80(1):64-71.
SUMMARY
Refinement of mammalian neural circuits involves substantial experience-dependent synapse elimination. Using in vivo two-photon imaging, we found that experience-dependent elimination of postsynaptic dendritic spines in the cortex was accelerated in ephrin-A2 knockout (KO) mice, resulting in fewer adolescent spines integrated into adult circuits. Such increased spine removal in ephrin-A2 KOs depended on activation of glutamate receptors, as blockade of the N-methyl-D-aspartate (NMDA) receptors eliminated the difference in spine loss between wild-type and KO mice. We also showed that ephrin-A2 in the cortex colocalized with glial glutamate transporters, which were significantly down-regulated in ephrin-A2 KOs. Consistently, glial glutamate transport was reduced in ephrin-A2 KOs, resulting in an accumulation of synaptic glutamate. Finally, inhibition of glial glutamate uptake promoted spine elimination in wild-type mice, resembling the phenotype of ephrin-A2 KOs. Together, our results suggest that ephrin-A2 regulates experience-dependent, NMDA receptor-mediated synaptic pruning through glial glutamate transport during maturation of the mouse cortex.
doi:10.1016/j.neuron.2013.07.014
PMCID: PMC3792401  PMID: 24094103
16.  Phase II study of cilengitide in the treatment of refractory or relapsed high-grade gliomas in children: A report from the Children's Oncology Group 
Neuro-Oncology  2013;15(10):1438-1444.
Background
Cilengitide, an αv integrin antagonist, has demonstrated activity in recurrent adult glioblastoma (GBM). The Children's Oncology Group ACNS0621 study thus evaluated whether cilengitide is active as a single agent in the treatment of children with refractory high-grade glioma (HGG). Secondary objectives were to investigate the pharmacokinetics and pharmacogenomics of cilengitide in this population.
Methods
Cilengitide (1800 mg/m2/dose intravenous) was administered twice weekly until evidence of disease progression or unacceptable toxicity. Thirty patients (age range, 1.1–20.3 years) were enrolled, of whom 24 were evaluable for the primary response end point.
Results
Toxicity was infrequent and mild, with the exception of one episode of grade 2 pain possibly related to cilengitide. Two intratumoral hemorrhages were reported, but only one (grade 2) was deemed to be possibly related to cilengitide and was in the context of disease progression. One patient with GBM received cilengitide for 20 months and remains alive with continuous stable disease. There were no other responders, with median time to tumor progression of 28 days (range, 11–114 days). Twenty-one of the 24 evaluable patients died, with a median time from enrollment to death of 172 days (range, 28–325 days). The 3 patients alive at the time of this report had a follow-up time of 37, 223, and 1068 days, respectively.
Conclusions
We conclude that cilengitide is not effective as a single agent for refractory pediatric HGG. However, further study evaluating combination therapy with cilengitide is warranted before a role for cilengitide in the treatment of pediatric HGG can be excluded.
doi:10.1093/neuonc/not058
PMCID: PMC3779033  PMID: 24014381
childhood; cilengitide; high-grade glioma
17.  Screening of Duchenne Muscular Dystrophy (DMD) Mutations and Investigating Its Mutational Mechanism in Chinese Patients 
PLoS ONE  2014;9(9):e108038.
Duchenne muscular dystrophy (DMD) is a common X-linked recessive disease of muscle degeneration and death. In order to provide accurate and reliable genetic counseling and prenatal diagnosis, we screened DMD mutations in a cohort of 119 Chinese patients using multiplex ligation-dependent probe amplification (MLPA) and denaturing high performance liquid chromatography (DHPLC) followed by Sanger sequencing. In these unrelated DMD patients, we identified 11 patients with DMD small mutations (9.2%) and 81 patients with DMD deletions/duplications (del/dup) (68.1%), of which 64 (79.0%) were deletions, 16 (19.8%) were duplications, and one (1.2%) was both deletion and duplication. Furthermore, we analyzed the frequency of DMD breakpoint in the 64 deletion cases by calculating exon-deletion events of certain exon interval that revealed a novel mutation hotspot boundary. To explore why DMD rearrangement breakpoints were predisposed to specific regions (hotspot), we precisely characterized junction sequences of breakpoints at the nucleotide level in 21 patients with exon deleted/duplicated in DMD with a high-resolution SNP microarray assay. There were no exactly recurrent breakpoints and there was also no significant difference between single-exon del/dup and multiple-exon del/dup cases. The data from the current study provided a comprehensive strategy to detect DMD mutations for clinical practice, and identified two deletion hotspots at exon 43–55 and exon 10–23 by calculating exon-deletion events of certain exon interval. Furthermore, this is the first study to characterize DMD breakpoint at the nucleotide level in a Chinese population. Our observations provide better understanding of the mechanism for DMD gene rearrangements.
doi:10.1371/journal.pone.0108038
PMCID: PMC4171529  PMID: 25244321
18.  Intraspinal transplantation of mouse and human neural precursor cells 
Current protocols in stem cell biology  2013;26:2D.16.1-2D.16.16.
This unit describes the preparation and transplantation of human neural precursor cells (hNPCs) and mouse neural precursor cells (mNPCs) into the thoracic region of the mouse spinal cord. The techniques in this unit also describe how to prepare the mouse for surgery by performing a laminectomy to expose the spinal cord for transplantation. Here we show NPCs genetically labeled with eGFP transplanted into the spinal cord of a mouse following viralmediated demyelination can efficiently be detected via eGFP expression. Transplantation of these cells into the spinal cord is an efficacious way to determine their effects in neurological disorders such as multiple sclerosis, Alzheimer's disease, and spinal cord injury.
doi:10.1002/9780470151808.sc02d16s26
PMCID: PMC3920297  PMID: 24510791
19.  Interleukin-8 Can Reduce Post-Surgical Lymphedema Formation by Promoting Lymphatic Vessel Regeneration 
Angiogenesis  2012;16(1):29-44.
Lymphedema is mainly caused by lymphatic obstruction and manifested as tissue swelling, often in the arms and legs. Lymphedema is one of the most common post-surgical complications in breast cancer patients and presents a painful and disfiguring chronic illness that has few treatment options. Here, we evaluated the therapeutic potential of interleukin (IL)-8 in lymphatic regeneration independent of its pro-inflammatory activity. We found that IL-8 promoted proliferation, tube formation, and migration of lymphatic endothelial cells (LECs) without activating the VEGF signaling. Additionally, IL-8 suppressed the major cell cycle inhibitor CDKN1C/p57KIP2 by downregulating its positive regulator PROX1, which is known as the master regulator of LEC-differentiation. Animal-based studies such as matrigel plug and cornea micropocket assays demonstrated potent efficacy of IL-8 in activating lymphangiogenesis in vivo. Moreover, we have generated a novel transgenic mouse model (K14-hIL8) that expresses human IL-8 in the skin and then crossed with lymphatic-specific fluorescent (Prox1-GFP) mouse. The resulting double transgenic mice showed that a stable expression of IL-8 could promote embryonic lymphangiogenesis. Moreover, an immunodeficient IL-8-expressing mouse line that was established by crossing K14-hIL8 mice with athymic nude mice displayed an enhanced tumor-associated lymphangiogenesis. Finally, when experimental lymphedema was introduced, K14-hIL8 mice showed an improved amelioration of lymphedema with an increased lymphatic regeneration. Together, we report that IL-8 can activate lymphangiogenesis in vitro and in vivo with a therapeutic efficacy in post-surgical lymphedema.
doi:10.1007/s10456-012-9297-6
PMCID: PMC4166493  PMID: 22945845
20.  Corneal Lymphatic Valve Formation in Relation to Lymphangiogenesis 
Purpose.
We have recently provided evidence showing that luminal lymphatic valves are formed right after the onset of corneal inflammatory lymphangiogenesis (LG). The purpose of this study was to further characterize the long-term time course, spatial distribution, directional orientation, and functional implications of the valve formation in relation to corneal LG.
Methods.
Corneal LG was induced in normal adult BALB/c mice by a modified suture placement model with equal distribution in the nasal and temporal side. Whole-mount corneas were harvested every 2 weeks for up to 8 weeks post suturing for immunofluorescent microscopic assays. Quantitative analysis on both lymphatic vessels and valves was performed by using National Institutes of Health ImageJ software. Corneal lymphatic live imaging was performed to show functional drainage of the valves.
Results.
Lymphatic vessel invasion areas at 4, 6, and 8 weeks were significantly less than the peak at 2 weeks post corneal suturing. In contrast, the ratio of lymphatic valves to vessel invasion area was at its lowest at 2 weeks with a peak approximately at 6 weeks post suturing. Lymphatic valves were more localized in the nasal quadrant at all time points studied, and most of the well-formed valves were directionally oriented toward the limbus. The lymphatic valves function to guide lymphatic drainage outside the cornea.
Conclusions.
This study presents new insights into corneal lymphatic valve formation and function in inflammatory LG. Further investigation on lymphatic valves may provide novel strategies to interfere with lymphatic maturation and function and to treat lymphatic-related disorders.
This study provides the first evidence on the time course, spatial distribution, and directional orientation with functional relevance of corneal lymphatic valves in inflammatory lymphangiogenesis. Further investigation may offer new therapeutic strategies for lymphatic disorders.
doi:10.1167/iovs.13-12251
PMCID: PMC3968927  PMID: 24595382
lymphangiogenesis; lymphatic valve; corneal inflammation
21.  Enhancing mucosal immunity in mice by recombinant adenovirus expressing major epitopes of porcine circovirus-2 capsid protein delivered with cytosine-phosphate-guanosine oligodeoxynucleotides 
Journal of Veterinary Science  2014;15(3):399-407.
A recombinant replication-defective adenovirus expressing the major epitopes of porcine circovirus-2 (PCV-2) capsid protein (rAd/Cap/518) was previously constructed and shown to induce mucosal immunity in mice following intranasal delivery. In the present study, immune responses induced by intranasal immunization with a combination of rAd/Cap/518 and cytosine-phosphate-guanosine oligodeoxynucleotides (CpG ODN) were evaluated in mice. The levels of PCV-2-specific IgG in serum and IgA in saliva, lung, and intestinal fluids were significantly higher in the group immunized with rAd/Cap/518 and CpG ODN than animals immunized with rAd/Cap/518 alone. The frequencies of IL-2-secreting CD4+ T cells and IFN-γ-producing CD8+ T cells were significantly higher in the combined immunization group than mice immunized with rAd/Cap/518 alone. The frequencies of CD3+, CD3+CD4+CD8-, and CD3+CD4-CD8+ T cells in the combined immunization group were similar to that treated with CpG ODN alone, but significantly higher than mice that did not receive CpG ODN. PCV-2 load after challenge in the combined immunization group was significantly lower than that in the phosphate-buffered saline placebo group and approximately 7-fold lower in the group treated with CpG ODN alone. These results indicate that rAd/Cap/518 combined with CpG ODN can enhance systemic and local mucosal immunity in mice, and represent a promising synergetic mucosal vaccine against PCV-2.
doi:10.4142/jvs.2014.15.3.399
PMCID: PMC4178141  PMID: 24675838
cytosine-phosphate-guanosine oligodeoxynucleotides; mucosal immunity; porcine circovirus-2; rAd/Cap/518
22.  The Wedelolactone Derivative Inhibits Estrogen Receptor-Mediated Breast, Endometrial, and Ovarian Cancer Cells Growth 
BioMed Research International  2014;2014:713263.
Estrogen and estrogen receptor (ER)-mediated signaling pathways play important roles in the etiology and progression of human breast, endometrial, and ovarian cancers. Attenuating ER activities by natural products and their derivatives is a relatively practical strategy to control and reduce breast, endometrial, and ovarian cancer risk. Here, we found 3-butoxy-1,8,9-trihydroxy-6H-benzofuro[3,2-c]benzopyran-6-one (BTB), a new derivative of wedelolactone, could effectively inhibit the 17-estradiol (E2)-induced ER transactivation and suppress the growth of breast cancer as well as endometrial and ovarian cancer cells. Our results indicate that 2.5 μM BTB effectively suppresses ER-positive, but not ER-negative, breast, endometrial, and ovarian cancer cells. Furthermore, our data indicate that BTB can modulate ER transactivation and suppress the expression of E2-mediated ER target genes (Cyclin D1, E2F1, and TERT) in the ER-positive MCF-7, Ishikawa, and SKOV-3 cells. Importantly, this BTB mediated inhibition of ER activity is selective since BTB does not suppress the activities of other nuclear receptors, including glucocorticoid receptor and progesterone receptor, suggesting that BTB functions as a selective ER signaling inhibitor with the potential to treat breast, endometrial, and ovarian cancers.
doi:10.1155/2014/713263
PMCID: PMC4157183  PMID: 25221777
24.  Research on Multirobot Pursuit Task Allocation Algorithm Based on Emotional Cooperation Factor 
The Scientific World Journal  2014;2014:864180.
Multirobot task allocation is a hot issue in the field of robot research. A new emotional model is used with the self-interested robot, which gives a new way to measure self-interested robots' individual cooperative willingness in the problem of multirobot task allocation. Emotional cooperation factor is introduced into self-interested robot; it is updated based on emotional attenuation and external stimuli. Then a multirobot pursuit task allocation algorithm is proposed, which is based on emotional cooperation factor. Combined with the two-step auction algorithm recruiting team leaders and team collaborators, set up pursuit teams, and finally use certain strategies to complete the pursuit task. In order to verify the effectiveness of this algorithm, some comparing experiments have been done with the instantaneous greedy optimal auction algorithm; the results of experiments show that the total pursuit time and total team revenue can be optimized by using this algorithm.
doi:10.1155/2014/864180
PMCID: PMC4132438  PMID: 25152925
25.  In the era of total mesorectal excision: adjuvant radiotherapy may be unnecessary for pT3N0 rectal cancer 
Background
Due to the Total Mesorectal Excision (TME) surgery made a good local control,the role of radiotherapy in the treatment of pT3N0 rectal cancer is debated and whether this group of patiens were overtreated has been a controversy recently. This study aimed to evaluate the value of adjuvant radiation after TME and survival outcome for patients with pT3N0 rectal adenocarcinoma.
Methods
From January 2003 to December 2011, a total of 141 patients with pT3N0 rectal cancer after radical resection with the principle of Total Mesorectal Excision (TME) were enrolled. Among them, 42 patients (29.8%) got adjuvant chemotherapy (CT) and the remaining cohort received chemoradiotherapy (CRT). The 5-year overall survival rate (OS), 5-year disease free survival rate (DFS), 5-year local recurrence free survival rate (LRFS), 5-year local recurrence rate (LRR) and the prognostic factor of this cohort were analyzed.
Results
The median follow-up interval time was 44 months. The 5-year OS and DFS rates were 82.4% and 71.9% for the whole group. There were no significant differences in 5-year OS (83.3% vs 72.4%, P = 0.931) or LRFS rates (81.7% vs 74.5%, P = 0.157) for patients between CT group and CRT group. Multivariate cox regression analysis suggests that preoperative serum CEA level, number of lymph nodes inspected, perirectal fat infiltration were independent prognostic factors for 5-year DFS. The recurrence rate was not affected by radiotherapy for patients with lower and midrectal cancer.
Conclusions
For the patients with pT3N0 rectal cancer, addition radiation after TME surgery made no significant differences in survival rate and local recurrence rate. The effect of adjuvant radiotherapy needs further evaluation.
doi:10.1186/1748-717X-9-159
PMCID: PMC4223727  PMID: 25052511
Rectal cancer; Post-operative radiotherapy; Prognosis factors

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