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1.  Neuropsychological functions and quality of life in survived patients with intracranial germ cell tumors after treatment 
Neuro-Oncology  2013;15(11):1543-1551.
Background
The notable survival chances of intracranial germ cell tumors (icGCTs) lead to a rising concern over long-term neurocognitive outcome. Yet, prior evidence related to this issue fails to provide a comprehensive examination of the effects of tumor location and radiotherapy. We attempt to explore their impacts on the neuropsychological functions and life quality in children with icGCT after multimodality treatments.
Methods
A retrospective review of 56 patients diagnosed with icGCTs at age <20 and treated at the Taipei Veterans General Hospital was provided. Intelligence, memory, visual organization, attention, and executive function were assessed by neurocognitive tests; adaptation to life, emotional and behavioral changes, interpersonal relationships, and impact on the family were evaluated by parent-report instruments. Effects of tumor locations (germinomas and nongerminomatous malignant germ cell tumors in the pineal, suprasellar, and basal ganglia) and irradiation on these measurements were examined.
Results
Patients with tumors in the basal ganglia region had lower full-scale IQs than those with tumors in the pineal or suprasellar regions. Subscores of intelligence scale and short-term retention of verbal and visual stimuli showed evident group differences, as did the quality of life and adaptive skills, particularly in psychosocial domains. Patients treated with whole-ventricular irradiation had better outcomes. Extensive irradiation field and high irradiation dosage influenced intellectual functions, concept crystallization, executive function, and memory.
Conclusions
Tumor location and irradiation field/dosage appear to be the crucial factors related to certain neuropsychological, emotional, and behavioral dysfunctions that in turn alter the quality of life in children with icGCTs who survive after treatment.
doi:10.1093/neuonc/not127
PMCID: PMC3813422  PMID: 24101738
basal ganglia; intracranial germ cell tumors; neurocognitive functions; quality of life; whole ventri-cular irradiation
2.  DriverDB: an exome sequencing database for cancer driver gene identification 
Nucleic Acids Research  2013;42(Database issue):D1048-D1054.
Exome sequencing (exome-seq) has aided in the discovery of a huge amount of mutations in cancers, yet challenges remain in converting oncogenomics data into information that is interpretable and accessible for clinical care. We constructed DriverDB (http://ngs.ym.edu.tw/driverdb/), a database which incorporates 6079 cases of exome-seq data, annotation databases (such as dbSNP, 1000 Genome and Cosmic) and published bioinformatics algorithms dedicated to driver gene/mutation identification. We provide two points of view, ‘Cancer’ and ‘Gene’, to help researchers to visualize the relationships between cancers and driver genes/mutations. The ‘Cancer’ section summarizes the calculated results of driver genes by eight computational methods for a specific cancer type/dataset and provides three levels of biological interpretation for realization of the relationships between driver genes. The ‘Gene’ section is designed to visualize the mutation information of a driver gene in five different aspects. Moreover, a ‘Meta-Analysis’ function is provided so researchers may identify driver genes in customer-defined samples. The novel driver genes/mutations identified hold potential for both basic research and biotech applications.
doi:10.1093/nar/gkt1025
PMCID: PMC3965046  PMID: 24214964
3.  YM500: a small RNA sequencing (smRNA-seq) database for microRNA research 
Nucleic Acids Research  2012;41(Database issue):D285-D294.
MicroRNAs (miRNAs) are small RNAs ∼22 nt in length that are involved in the regulation of a variety of physiological and pathological processes. Advances in high-throughput small RNA sequencing (smRNA-seq), one of the next-generation sequencing applications, have reshaped the miRNA research landscape. In this study, we established an integrative database, the YM500 (http://ngs.ym.edu.tw/ym500/), containing analysis pipelines and analysis results for 609 human and mice smRNA-seq results, including public data from the Gene Expression Omnibus (GEO) and some private sources. YM500 collects analysis results for miRNA quantification, for isomiR identification (incl. RNA editing), for arm switching discovery, and, more importantly, for novel miRNA predictions. Wetlab validation on >100 miRNAs confirmed high correlation between miRNA profiling and RT-qPCR results (R = 0.84). This database allows researchers to search these four different types of analysis results via our interactive web interface. YM500 allows researchers to define the criteria of isomiRs, and also integrates the information of dbSNP to help researchers distinguish isomiRs from SNPs. A user-friendly interface is provided to integrate miRNA-related information and existing evidence from hundreds of sequencing datasets. The identified novel miRNAs and isomiRs hold the potential for both basic research and biotech applications.
doi:10.1093/nar/gks1238
PMCID: PMC3531161  PMID: 23203880
4.  Treating glioblastoma multiforme with selective high-dose liposomal doxorubicin chemotherapy induced by repeated focused ultrasound 
Background
High-dose tissue-specific delivery of therapeutic agents would be a valuable clinical strategy. We have previously shown that repeated transcranial focused ultrasound is able to increase the delivery of Evans blue significantly into brain tissue. The present study shows that repeated pulsed high-intensity focused ultrasound (HIFU) can be used to deliver high-dose atherosclerotic plaque-specific peptide-1 (AP-1)-conjugated liposomes selectively to brain tumors.
Methods
Firefly luciferase (Fluc)-labeled human GBM8401 glioma cells were implanted into NOD-scid mice. AP-1-conjugated liposomal doxorubicin or liposomal doxorubicin alone was administered followed by pulsed HIFU and the doxorubicin concentration in the treated brains quantified by fluorometer. Growth of the labeled glioma cells was monitored through noninvasive bioluminescence imaging and finally the brain tissue was histologically examined after sacrifice.
Results
Compared with the control group, the animals treated with 5 mg/kg injections of AP-1 liposomal doxorubicin or untargeted liposomal doxorubicin followed by repeated pulsed HIFU not only showed significantly enhanced accumulation of drug at the sonicated tumor site but also a significantly elevated tumor-to-normal brain drug ratio (P < 0.001). Combining repeated pulsed HIFU with AP-1 liposomal doxorubicin or untargeted liposomal doxorubicin has similar antitumor effects.
Conclusion
This study demonstrates that targeted or untargeted liposomal doxorubicin, followed by repeated pulsed HIFU, is a promising high-dose chemotherapy method that allows the desired brain tumor region to be targeted specifically.
doi:10.2147/IJN.S29229
PMCID: PMC3289450  PMID: 22393293
repeated focused ultrasound; interleukin-4 receptor; blood-brain barrier; brain tumor; target drug delivery
5.  Pharmacokinetic Analysis of 111In-Labeled Liposomal Doxorubicin in Murine Glioblastoma after Blood-Brain Barrier Disruption by Focused Ultrasound 
PLoS ONE  2012;7(9):e45468.
The goal of this study was to evaluate the pharmacokinetics of targeted and untargeted 111In-doxorubicin liposomes after these have been intravenously administrated to tumor-bearing mice in the presence of blood-brain barrier disruption (BBB-D) induced by focused ultrasound (FUS). An intracranial brain tumor model in NOD-scid mice using human brain glioblastoma multiforme (GBM) 8401 cells was developed in this study. 111In-labeled human atherosclerotic plaque-specific peptide-1 (AP-1)-conjugated liposomes containing doxorubicin (Lipo-Dox; AP-1 Lipo-Dox) were used as a microSPECT probe for radioactivity measurements in the GBM-bearing mice. Compared to the control tumors treated with an injection of 111In-AP-1 Lipo-Dox or 111In-Lipo-Dox, the animals receiving the drugs followed by FUS exhibited enhanced accumulation of the drug in the brain tumors (p<0.05). Combining sonication with drugs significantly increased the tumor-to-normal brain doxorubicin ratio of the target tumors compared to the control tumors. The tumor-to-normal brain ratio was highest after the injection of 111In-AP-1 Lipo-Dox with sonication. The 111In-liposomes micro-SPECT/CT should be able to provide important information about the optimum therapeutic window for the chemotherapy of brain tumors using sonication.
doi:10.1371/journal.pone.0045468
PMCID: PMC3445513  PMID: 23029030
6.  Evaluation of the increase in permeability of the blood–brain barrier during tumor progression after pulsed focused ultrasound 
Purpose
The purpose of this study was to evaluate the permeability of the blood–brain barrier after sonication by pulsed high-intensity focused ultrasound and to determine if such an approach increases the tumor:ipsilateral brain permeability ratio.
Materials and methods
F98 glioma-bearing Fischer 344 rats were injected intravenously with Evans blue with or without blood–tumor barrier disruption induced by transcranial pulsed high-intensity focused ultrasound. Sonication was applied at a frequency of 1 MHz with a 5% duty cycle and a repetition frequency of 1 Hz. The permeability of the blood–brain barrier was assessed by the extravasation of Evans blue. Contrast-enhanced magnetic resonance images were used to monitor the gadolinium deposition path associated with transcranial pulsed high-intensity focused ultrasound, and the influencing size and location was also investigated. In addition, whole brain histological analysis was performed. The results were compared by two-tailed unpaired t-test.
Results
The accumulation of Evans blue in brains and the tumor:ipsilateral brain permeability ratio of Evans blue were significantly increased after pulsed high-intensity focused ultrasound exposure. Evans blue injection followed by sonication showed an increase in the tumor:ipsilateral brain ratio of the target tumors (9.14:1) of about 2.23-fold compared with the control tumors (x4.09) on day 6 after tumor implantation. Magnetic resonance images showed that pulsed high-intensity focused ultrasound locally enhances the permeability of the blood–tumor barrier in the glioma-bearing rats.
Conclusion
This method could allow enhanced synergistic effects with respect to other brain tumor treatment regimens.
doi:10.2147/IJN.S28503
PMCID: PMC3282611  PMID: 22359451
focused ultrasound; blood-brain barrier; permeability; brain tumor; glioma
7.  Pediatric primary central nervous system germ cell tumors of different prognosis groups show characteristic miRNome traits and chromosome copy number variations 
BMC Genomics  2010;11:132.
Background
Intracranial pediatric germ cell tumors (GCTs) are rare and heterogeneous neoplasms and vary in histological differentiation, prognosis and clinical behavior. Germinoma and mature teratoma are GCTs that have a good prognosis, while other types of GCTs, termed nongerminomatous malignant germ cell tumors (NGMGCTs), are tumors with an intermediate or poor prognosis. The second group of tumors requires more extensive drug and irradiation treatment regimens. The mechanisms underlying the differences in incidence and prognosis of the various GCT subgroups are unclear.
Results
We identified a distinct mRNA profile correlating with GCT histological differentiation and prognosis, and also present in this study the first miRNA profile of pediatric primary intracranial GCTs. Most of the differentially expressed miRNAs were downregulated in germinomas, but miR-142-5p and miR-146a were upregulated. Genes responsible for self-renewal (such as POU5F1 (OCT4), NANOG and KLF4) and the immune response were abundant in germinomas, while genes associated with neuron differentiation, Wnt/β-catenin pathway, invasiveness and epithelial-mesenchymal transition (including SNAI2 (SLUG) and TWIST2) were abundant in NGMGCTs. Clear transcriptome segregation based on patient survival was observed, with malignant NGMGCTs being closest to embryonic stem cells. Chromosome copy number variations (CNVs) at cytobands 4q13.3-4q28.3 and 9p11.2-9q13 correlated with GCT malignancy and clinical risk. Six genes (BANK1, CXCL9, CXCL11, DDIT4L, ELOVL6 and HERC5) within 4q13.3-4q28.3 were more abundant in germinomas.
Conclusions
Our results integrate molecular profiles with clinical observations and provide insights into the underlying mechanisms causing GCT malignancy. The genes, pathways and microRNAs identified have the potential to be novel therapeutic targets.
doi:10.1186/1471-2164-11-132
PMCID: PMC2837036  PMID: 20178649
8.  Identification of CD133-Positive Radioresistant Cells in Atypical Teratoid/ Rhabdoid Tumor 
PLoS ONE  2008;3(5):e2090.
Atypical teratoid/rhabdoid tumor (AT/RT) is an extremely malignant neoplasm in the central nervous system (CNS) which occurs in infancy and childhood. Recent studies suggested that CD133 could be considered a marker for brain cancer stem-like cells (CSCs). However, the role of CD133 in AT/RT has never been investigated. Herein we report the isolation of CD133-positive cells (CD133+), found to have the potential to differentiate into three germ layer tissues, from tissues of nine AT/RT patients. The migration/invasion/malignancy and radioresistant capabilities of CD133+ were significantly augmented when compared to CD133−. The clinical data showed that the amount of CD133+ in AT/RTs correlated positively with the degree of resistance to radiation therapy. Using cDNA microarray analysis, the genotoxic–response profiles of CD133+ and CD133− irradiated with 10 Gy ionizing radiation (IR) were analyzed 0.5, 2, 6, 12 and 24 h post-IR. We then validated these microarray data and showed increased phosphorylation after IR of p-ATM, p-RAD17, and p-CHX2 as well as increased expression of BCL-2 protein in CD133+ compared to CD133−. Furthermore, we found that CD133+ can effectively resist IR with cisplatin- and/or TRAIL-induced apoptosis. Immunohistochemical analysis confirmed the up-regulated expression of p-ATM and BCL-2 proteins in IR-treated CD133+ xenotransgrafts in SCID mice but not in IR-treated CD133−. Importantly, the effect of IR in CD133+ transplanted mice can be significantly improved by a combination of BCL-2 siRNA with debromohymenialdisine, an inhibitor of checkpoint kinases. In sum, this is the first report indicating that CD133+ AT/RT cells demonstrate the characteristics of CSCs. The IR-resistant and anti-apoptotic properties in CD133+ may reflect the clinical refractory malignancy of AT/RTs and thus the activated p-ATM pathway and BCL-2 expression in CD133+ could be possible targets to improve future treatment of deadly diseases like AT/RT.
doi:10.1371/journal.pone.0002090
PMCID: PMC2396792  PMID: 18509505

Results 1-8 (8)