William H Yong

University of California, Los Angeles, Los Ángeles, California, United States

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Publications (114)669.86 Total impact

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    ABSTRACT: Background: Temozolomide (TMZ) is an oral DNA-alkylating agent used for treating patients with glioblastoma. However, therapeutic benefits of TMZ can be compromised by the expression of O6-methylguanine methyltransferase (MGMT) in tumor tissue. Here we used MGMT-expressing glioblastoma stem cells (GSC) lines as a model for investigating the molecular mechanism underlying TMZ resistance, while aiming to explore a new treatment strategy designed to possibly overcome resistance to the clinically relevant dose of TMZ (35 μM). Methods: MGMT-expressing GSC cultures are resistant to TMZ, and IC50 (half maximal inhibitory concentration) is estimated at around 500 μM. Clonogenic GSC surviving 500 μM TMZ (GSC-500 μM TMZ), were isolated. Molecular signatures were identified via comparative analysis of expression microarray against parental GSC (GSC-parental). The recombinant protein of top downregulated signature was used as a single agent or in combination with TMZ, for evaluating therapeutic effects of treatment of GSC. Results: The molecular signatures characterized an activation of protective stress responses in GSC-500 μM TMZ, mainly including biotransformation/detoxification of xenobiotics, blocked endoplasmic reticulum stress-mediated apoptosis, epithelial-to-mesenchymal transition (EMT), and inhibited growth/differentiation. Bone morphogenetic protein 7 (BMP7) was identified as the top down-regulated gene in GSC-500 μM TMZ. Although augmenting BMP7 signaling in GSC by exogenous BMP7 treatment did not effectively stop GSC growth, it markedly sensitized both GSC-500 μM TMZ and GSC-parental to 35 μM TMZ treatment, leading to loss of self-renewal and migration capacity. BMP7 treatment induced senescence of GSC cultures and suppressed mRNA expression of CD133, MGMT, and ATP-binding cassette drug efflux transporters (ABCB1, ABCG2), as well as reconfigured transcriptional profiles in GSC by downregulating genes associated with EMT/migration/invasion, stemness, inflammation/immune response, and cell proliferation/tumorigenesis. BMP7 treatment significantly prolonged survival time of animals intracranially inoculated with GSC when compared to those untreated or treated with TMZ alone (p = 0.0017), whereas combination of two agents further extended animal survival compared to BMP7 alone (p = 0.0489). Conclusions: These data support the view that reduced endogenous BMP7 expression/signaling in GSC may contribute to maintained stemness, EMT, and chemoresistant phenotype, suggesting that BMP7 treatment may provide a novel strategy in combination with TMZ for an effective treatment of glioblastoma exhibiting unmethylated MGMT.
    Molecular Cancer 11/2015; 14(1):189. DOI:10.1186/s12943-015-0459-1 · 4.26 Impact Factor

  • Neuro-Oncology 11/2015; 17(suppl 5):v88-v88. DOI:10.1093/neuonc/nov214.11 · 5.56 Impact Factor
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    ABSTRACT: Glioblastoma stem cells (GSC) co-exhibiting a tumor-initiating capacity and a radio-chemoresistant phenotype, are a compelling cell model for explaining tumor recurrence. We have previously characterized patient-derived, treatment-resistant GSC clones (TRGC) that survived radiochemotherapy. Compared to glucose-dependent, treatment-sensitive GSC clones (TSGC), TRGC exhibited reduced glucose dependence that favor the fatty acid oxidation pathway as their energy source. Using comparative genome-wide transcriptome analysis, a series of defense signatures associated with TRGC survival were identified and verified by siRNA-based gene knockdown experiments that led to loss of cell integrity. In this study, we investigate the prognostic value of defense signatures in glioblastoma (GBM) patients using gene expression analysis with Probeset Analyzer (131 GBM) and The Cancer Genome Atlas (TCGA) data, and protein expression with a tissue microarray (50 GBM), yielding the first TRGC-derived prognostic biomarkers for GBM patients. Ribosomal protein S11 (RPS11), RPS20, individually and together, consistently predicted poor survival of newly diagnosed primary GBM tumors when overexpressed at the RNA or protein level [RPS11: Hazard Ratio (HR) = 11.5, p<0.001; RPS20: HR = 4.5, p = 0.03; RPS11+RPS20: HR = 17.99, p = 0.001]. The prognostic significance of RPS11 and RPS20 was further supported by whole tissue section RPS11 immunostaining (27 GBM; HR = 4.05, p = 0.01) and TCGA gene expression data (578 primary GBM; RPS11: HR = 1.19, p = 0.06; RPS20: HR = 1.25, p = 0.02; RPS11+RPS20: HR = 1.43, p = 0.01). Moreover, tumors that exhibited unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) or wild-type isocitrate dehydrogenase 1 (IDH1) were associated with higher RPS11 expression levels [corr (IDH1, RPS11) = 0.64, p = 0.03); [corr (MGMT, RPS11) = 0.52, p = 0.04]. These data indicate that increased expression of RPS11 and RPS20 predicts shorter patient survival. The study also suggests that TRGC are clinically relevant cells that represent resistant tumorigenic clones from patient tumors and that their properties, at least in part, are reflected in poor-prognosis GBM. The screening of TRGC signatures may represent a novel alternative strategy for identifying new prognostic biomarkers.
    PLoS ONE 10/2015; 10(10):e0141334. DOI:10.1371/journal.pone.0141334 · 3.23 Impact Factor
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    ABSTRACT: Epidermal growth factor receptor (EGFR) gene amplification and mutations are the most common oncogenic events in glioblastoma (GBM), but the mechanisms by which they promote aggressive tumor growth are not well understood. Here, through integrated epigenome and transcriptome analyses of cell lines, genotyped clinical samples, and TCGA data, we show that EGFR mutations remodel the activated enhancer landscape of GBM, promoting tumorigenesis through a SOX9 and FOXG1-dependent transcriptional regulatory network in vitro and in vivo. The most common EGFR mutation, EGFRvIII, sensitizes GBM cells to the BET-bromodomain inhibitor JQ1 in a SOX9, FOXG1-dependent manner. These results identify the role of transcriptional/epigenetic remodeling in EGFR-dependent pathogenesis and suggest a mechanistic basis for epigenetic therapy.
    Molecular cell 10/2015; 60(2). DOI:10.1016/j.molcel.2015.09.002 · 14.02 Impact Factor
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    ABSTRACT: Background: Immunotherapy is an ideal treatment modality to specifically target the diffusely infiltrative tumor cells of malignant gliomas while sparing the normal brain parenchyma. However, progress in the development of these therapies for glioblastoma has been slow due to the lack of immunogenic antigen targets that are expressed uniformly and selectively by gliomas. Methods: We utilized human glioblastoma cell cultures to induce expression of New York-esophageal squamous cell carcinoma (NY-ESO-1) following in vitro treatment with the demethylating agent decitabine. We then investigated the phenotype of lymphocytes specific for NY-ESO-1 using flow cytometry analysis and cytotoxicity against cells treated with decitabine using the xCelligence real-time cytotoxicity assay. Finally, we examined the in vivo application of this immune therapy using an intracranially implanted xenograft model for in situ T cell trafficking, survival, and tissue studies. Results: Our studies showed that treatment of intracranial glioma-bearing mice with decitabine reliably and consistently induced the expression of an immunogenic tumor-rejection antigen, NY-ESO-1, specifically in glioma cells and not in normal brain tissue. The upregulation of NY-ESO-1 by intracranial gliomas was associated with the migration of adoptively transferred NY-ESO-1-specific lymphocytes along white matter tracts to these tumors in the brain. Similarly, NY-ESO-1-specific adoptive T cell therapy demonstrated antitumor activity after decitabine treatment and conferred a highly significant survival benefit to mice bearing established intracranial human glioma xenografts. Transfer of NY-ESO-1-specific T cells systemically was superior to intracranial administration and resulted in significantly extended and long-term survival of animals. Conclusion: These results reveal an innovative, clinically feasible strategy for the treatment of glioblastoma.
    Neuro-Oncology 09/2015; DOI:10.1093/neuonc/nov153 · 5.56 Impact Factor
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    ABSTRACT: Lymphocytic hypophysitis (LH) is a poorly understood autoimmune disorder of the pituitary gland. Symptoms include headache, pituitary dysfunction, visual disturbances and neurological deficits. The diagnosis can be made based on clinical and biochemical findings but for atypical presentations, no circulatory diagnostic biomarkers exist and pituitary biopsy is necessary for diagnosis. We used high-resolution human leukocyte antigen (HLA) screening assays to investigate for a relationship between specific HLA markers and lymphocytic hypophysitis. This was a retrospective analysis Setting: The study was conducted at a tertiary referral center. Fifteen patients with sporadic LH and 4 melanoma patients who developed hypophysitis following administration of CTLA4 antibodies and one patient with sarcoid-associated hypophysitis were evaluated. Clinical data including endocrine function, were assessed and HLA typing performed in all 20 patients with hypophysitis, 50 control patients with other sellar abnormalities and 4 CTLA4 antibody-treated patients without hypophysitis. Two major histocompatibility class II HLA markers, DQ8 and DR53, were found in 13/15 (87%) and 12/15 (80.0%) patients with sporadic lymphocytic hypophysitis respectively. In contrast, none of 4 patients who developed hypophysitis after administration of the CTLA4 antibodies exhibited the HLA-DQ8 marker and only 1/ 4(25%) exhibited the HLA-DR53 marker. In a parallel group of 50 control subjects with sellar masses and 4 CTLA4-Ab treated patients who did not develop evidence of pituitary failure, the candidate HLA subtypes were found in ∼20% for DQ8 and ∼48% for DR53 respectively. & Relevance: The HLA markers, DQ8 and DR53, were found to be commonly present in patients with LH. The odds ratio of a patient with LH expressing the HLA-DQ8 marker is 23.1-fold higher compared to a patient with another sellar mass. HLA-DQ8 testing may assist in diagnosis and avoid unnecessary biopsy in atypical LH cases.
    The Journal of Clinical Endocrinology and Metabolism 08/2015; DOI:10.1210/jc.2015-2702 · 6.21 Impact Factor

  • Journal of Neurological Surgery, Part B: Skull Base 08/2015; DOI:10.1055/s-0035-1554907 · 0.72 Impact Factor
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    ABSTRACT: Latino Americans are a rapidly growing ethnic group in the United States. The characteristics of glioblastoma in this population is poorly studied. We have evaluated the data of 47,540 glioblastoma patients from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute. This SEER data from 1973-2000 includes up to 13 cancer registries. For 2001 to 2011, the data has improved geographic coverage with 18 registries encompassing 28% of the U.S. population. Latinos have a lower incidence of GBM than non-Latino Whites. Gender distribution is similar. The total SEER data show that Latinos present slightly younger and have a higher incidence of giant cell glioblastoma and gliosarcoma than non-Latino Whites. Despite higher rates of radiation therapy, the one year survival rate (34.7%) for non-Latino White populations is less than for Latinos (39.0%, p <0.001). Subset analyses (2001-2011) of all the above parameters show similar results except for gliosarcoma incidence. A literature search does not identify MGMT or IDH1 data regarding Latino Americans. We have assessed 2 prognostic markers in 30 Latino glioblastoma patients. MGMT methylation is present in 24% and IDH1 mutation is found in 12.5%. Our preliminary data suggests that Latinos may have a greater incidence of MGMT unmethylated tumors. Younger age may possibly contribute to improved survival in Latinos but the underlying molecular basis is unresolved.
    The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 08/2015; 42(S2):S2. DOI:10.1017/cjn.2015.251 · 1.53 Impact Factor
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    ABSTRACT: Management of intracranial chordomas remains challenging, despite improvements in microsurgical techniques and radiotherapy. Here, we analyzed the prognostic factors associated with improved rates of tumor control in patients with intracranial chordomas, who received either gross (GTR) or subtotal resections (STR). A retrospective review was performed to identify all patients who were undergoing resection of their intracranial chordomas at the Ronald Reagan University of California Los Angeles Medical Center from 1990 to 2011. In total, 57 patients undergoing 81 resections were included. There were 24 females and 33 males with a mean age of 44.6years, and the mean tumor diameter was 3.36cm. The extent of resection was not associated with recurrence. For all 81 operations, the 1 and 5year progression free survival (PFS) was 87.5 and 40.4%, and 88.0 and 33.6% for STR and GTR, respectively (p=0.90). Adjuvant radiotherapy was associated with improved rates of PFS (hazard ratio [HR] 0.20; p=0.009). Additionally, age >45years (HR 5.88; p=0.01) and the presence of visual deficits (HR 7.59; p=0.03) were associated with worse rates of tumor control. Tumor size, sex, tumor histology, and recurrent tumors were not predictors of recurrence. Younger age, lack of visual symptoms on presentation and adjuvant radiotherapy were associated with improved rates of tumor control following surgery. However, GTR and STR produced comparable rates of tumor control. The surgical management of intracranial chordomas should take a conservative approach, with the aim of maximal but safe cytoreductive resection with adjuvant radiation therapy, and a major focus on quality of life. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Journal of Clinical Neuroscience 07/2015; 22(11). DOI:10.1016/j.jocn.2015.05.024 · 1.38 Impact Factor
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    ABSTRACT: Cancer cells adapt their signaling in response to nutrient availability. To uncover the mechanisms regulating this process and its functional consequences, we interrogated cell lines, mouse tumor models, and clinical samples of glioblastoma (GBM), the highly lethal brain cancer. We discovered that glucose or acetate is required for epidermal growth factor receptor vIII (EGFRvIII), the most common growth factor receptor mutation in GBM, to activate mechanistic target of rapamycin complex 2 (mTORC2) and promote tumor growth. Glucose or acetate promoted growth factor receptor signaling through acetyl-CoA-dependent acetylation of Rictor, a core component of the mTORC2 signaling complex. Remarkably, in the presence of elevated glucose levels, Rictor acetylation is maintained to form an autoactivation loop of mTORC2 even when the upstream components of the growth factor receptor signaling pathway are no longer active, thus rendering GBMs resistant to EGFR-, PI3K (phosphoinositide 3-kinase)-, or AKT (v-akt murine thymoma viral oncogene homolog)-targeted therapies. These results demonstrate that elevated nutrient levels can drive resistance to targeted cancer treatments and nominate mTORC2 as a central node for integrating growth factor signaling with nutrient availability in GBM.
    Proceedings of the National Academy of Sciences 07/2015; 112(30):201511759. DOI:10.1073/pnas.1511759112 · 9.67 Impact Factor
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    ABSTRACT: Interstitial tissue acidosis resulting from abnormal perfusion and metabolism is a hallmark of cancer. The current study demonstrates that chemical exchange saturation transfer (CEST) MRI can be used as a noninvasive pH-weighted molecular imaging technique by targeting the chemical exchange between amine protons and protons in extracellular bulk water. First, the sensitivity of amine CEST was validated in phantoms under a variety of conditions, including different magnetic field strengths, amino acid concentrations, and pH values. Amine CEST was compared with histology in both a preclinical GL261 intracranial glioma model at 7T and human patients at 3T. The association between physiologic and pH-weighted MRI was explored, along with the ability to predict time to progression to radiochemotherapy in 20 glioblastoma patients. z-Spectral asymmetry increased at 3 ppm (amine range) on CEST MRI with decreasing pH within the range observed in tumors for both 3T and 7T scanners. Lesions with acidic signatures showed active tumor and pseudopalisading tumor on histology and showed elevated FDOPA PET uptake, lactate on MR spectroscopy, and perfusion abnormalities. Patients with acidic lesions after surgery or stable/growing acidic lesions had a shorter time to progression following radiochemotherapy compared with patients with lesions demonstrating relatively low acidity (P < .001). Results suggest pH-weighted MRI may provide new insight into brain tumor physiology beyond traditional imaging technologies. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
    Neuro-Oncology 06/2015; DOI:10.1093/neuonc/nov106 · 5.56 Impact Factor
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    ABSTRACT: Brain biopsies have an uncertain role in the diagnosis of patients with dementia or neurologic decline of unknown etiology. They are often performed only after an exhaustive panel of less invasive tests and procedures have failed to provide a definitive diagnosis. The objective of this study was to evaluate the sensitivity of brain biopsies in this patient group through the retrospective analysis of 53 brain biopsies performed for neurologic disease of unknown etiology at a single tertiary care institution between December 2001 and December 2011. Patients with known nonlymphomatous neoplasms thought to be associated with the neurologic symptoms or with immunodeficiency were excluded from the study. Furthermore, the clinical presentation, imaging and laboratory tests were compared between diagnostic groups to identify factors more likely to yield a diagnosis. Sixty percent of the biopsies were diagnostic (32 of 53), with the most common histologic diagnosis of central nervous system lymphoma in 14 of 53 patients (26% of total) followed by infarct in four subjects (7.5%). A few patients were found to have rare and unsuspected diseases such as lymphomatosis cerebri, neurosarcoidosis and neuroaxonal leukodystrophy. Complications from biopsy were uncommon and included hemorrhage and infection with abscess formation at the biopsy site. These results suggest that brain biopsies may be useful in difficult cases in which less invasive measures have been unable to yield a definitive diagnosis. Copyright © 2015 Elsevier Inc. All rights reserved.
    Human pathology 12/2014; 46(4). DOI:10.1016/j.humpath.2014.12.003 · 2.77 Impact Factor
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    ABSTRACT: Purpose: Diffusion magnetic resonance imaging (MRI) and 6-[(18)F]fluoro-L-dopa ([(18)F]FDOPA) positron emission tomography (PET) are used to interrogate malignant tumor microenvironment. It remains unclear whether there is a relationship between [(18)F]FDOPA uptake, diffusion MRI estimates of apparent diffusion coefficient (ADC), and mitotic activity in the context of recurrent malignant gliomas, where the tumor may be confounded by the effects of therapy. The purpose of the current study is to determine whether there is a correlation between these imaging techniques and mitotic activity in malignant gliomas. Procedures: We retrospectively examined 29 patients with recurrent malignant gliomas who underwent structural MRI, diffusion MRI, and [(18)F]FDOPA PET prior to surgical resection. Qualitative associations were noted, and quantitative voxel-wise and median measurement correlations between [(18)F]FDOPA PET, ADC, and mitotic index were performed. Results: Areas of high [(18)F]FDOPA uptake exhibited low ADC and areas of hyperintensity T2/fluid-attenuated inversion recovery (FLAIR) with low [(18)F]FDOPA uptake exhibited high ADC. There was a significant inverse voxel-wise correlation between [(18)F]FDOPA and ADC for all patients. Median [(18)F]FDOPA uptake and median ADC also showed a significant inverse correlation. Median [(18)F]FDOPA uptake was positively correlated, and median ADC was inversely correlated with mitotic index from resected tumor tissue. Conclusions: A significant association may exist between [(18)F]FDOPA uptake, diffusion MRI, and mitotic activity in recurrent malignant gliomas.
    Molecular Imaging & Biology 12/2014; 17(3). DOI:10.1007/s11307-014-0807-3 · 2.77 Impact Factor
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    ABSTRACT: Background Ventriculoperitoneal shunt obstruction remains a major problem in pediatric neurosurgery. We analyzed the tissue reaction to ventriculoperitoneal shunts and compared the histology versus time elapsed to shunt failure. Methods 85 ventricular catheter tissues samples obtained from 71 patients were reviewed along with time elapsed to shunt revision. Pathology reports of all tissue samples were divided into three categories: inflammatory based on the presence of lymphocytes, macrophages, and microglial cells; reactive based on the presence of fibro-connective tissue, reactive astrocytes, and Rosenthal fibers; and normal brain tissue based on presence of choroid plexus. These categories were then grouped according to time elapsed to shunt revision. Group I had those shunts revised < 6 months, group II included shunts revised between 6 months to 3 years, while group III had shunts revised after more than 3 years. Results The incidence of inflammatory type of histology was 44% (16/36) in group I, 22% (6/27) in group II, and 18% (4/22) in group III. The reactive histology was 42% (15/36) in group I, 67% (18/27) in group II, and 77% (17/22) in group III. There was a clear noted difference of incidence between inflammatory versus reactive histology between early shunt failure compared to late shunt failure. Incidence of normal brain tissue remained high in group I with 8%, 11% in group II, and none in group III. Conclusion Early shunt obstruction arises from pathologies different from those causing late shunt obstructions.
    Clinical Neurology and Neurosurgery 12/2014; 127. DOI:10.1016/j.clineuro.2014.09.029 · 1.13 Impact Factor
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    ABSTRACT: Ornithine transcarbamylase deficiency (OTCD, OMIM 311250), the most common urea cycle disorder, results in impaired synthesis of citrulline from carbamoyl phosphate and ornithine. Individuals have been identified with OTCD due to a contiguous gene deletion at Xp11.4-p21.1 and unique clinical features, described as the "extended OTCD phenotype". We present a male with neonatal-lethal OTCD due to a 1.87Mb microdeletion at Xp11.4-p21.1 (37126841-38998991 hg18). Autopsy revealed a novel histological finding of hepatocyte globular and granular inclusions. Such inclusions have not been described in OTCD or other metabolic disorders and are not an associated finding in neonatal liver failure due to other causes. The deleted region includes the gene SYTL5, potentially involved in RAB27A-dependent membrane trafficking in the liver and placenta. We propose that the contiguous gene deletion could contribute to the severity of the clinical presentation here and hypothesize that deletion of SYTL5 could contribute to the liver findings. Copyright © 2014. Published by Elsevier B.V.
    Gene 11/2014; 556(2). DOI:10.1016/j.gene.2014.11.057 · 2.14 Impact Factor
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    ABSTRACT: Introduction: Persistent bacterial infection prolongs hospitalizations, leading to increased healthcare costs. Treatment of these infections costs several billion dollars annually. Biofilm production is one mechanism by which bacteria become resistant. With the help of biofilms, bacteria withstand the host immune response and are much less susceptible to antibiotics. Currently, there is interest in the use of laser-generated shockwaves (LGS) to delaminate biofilm from infected wound surfaces; however, the safety of such an approach has not yet been established. Of particular concern are the thermal and mechanical effects of the shockwave treatment on the epidermis and the underlying collagen structure of the dermis. The present study is a preliminary investigation of the effect of LGS on freshly harvested ex vivo porcine skin tissue samples. Materials and methods: Tissue samples for investigation were harvested immediately post-mortem and treated with LGS within 30 minutes. Previous studies have shown that laser fluences between 100 and 500 mJ/pulse are capable of delaminating biofilms off a variety of surfaces, thus our preliminary investigation focused on this range of laser energy. For each sample, LGS were produced via laser irradiation of a thin layer (0.5 µm) of titanium sandwiched between a 50 and 100 µm thick layer of water glass and a 0.1 mm thick sheet of Mylar. The rapid thermal expansion of the irradiated titanium film generates a transient compressive wave that is coupled through a liquid layer to the surface of the ex vivo pigskin sample. Shocked samples were immediately fixed in formalin and prepared for histological analysis. A blinded pathologist evaluated and scored each section on the basis of its overall appearance (O) and presence of linear/slit-like spaces roughly parallel to the surface of the skin (S). The scores were given on a scale of 0-3. Results: The present investigation revealed no visible difference between the tissue sections of the control sample and those that were subjected to laser-generated shockwaves. There was no relationship between the scores received by the samples and the energy with which they were shocked. Conclusion: Preliminary investigation into the safety of the LGS treatment for biofilm delamination appears promising. Additional investigation will continue on ex vivo porcine samples, followed by an in vivo animal trial to better understand the physiological response to LGS treatment.
    Lasers in Surgery and Medicine 10/2014; 46(8). DOI:10.1002/lsm.22278 · 2.62 Impact Factor
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    ABSTRACT: Purpose: IDH1/2-mutant gliomas harbor a distinct glioma-CpG island methylation phenotype (G-CIMP) that may promote the initiation and progression of secondary pathway gliomas by silencing tumor-suppressive genes. The potential role of tumor-suppressive microRNAs (miRNA; miR) in this process is not understood. Experimental design: To identify potential tumor-suppressive miRNA hypermethylated in glioma, the methylation profiles of IDH1/2(WT) gliomas (n = 11) and IDH1(MUT) glioma (n = 20) were compared by using massively parallel reduced representation bisulfite sequencing (RRBS). The methylation status of selected miRNA was validated by using targeted bisulfite sequencing (BiSEQ) in a large cohort of glioma tissue samples including 219 IDH1(WT) and 72 IDH1/2(MUT) samples. The expression of selected miRNAs was determined by using the TaqMan qPCR. Functional analyses of miR148a were conducted and target genes were identified. Results: We identify miR148a as a novel, G-CIMP-associated miRNA whose methylation is tightly correlated with IDH1 mutation and associated with improved survival in patients with malignant glioma. We confirm that downregulation of miR148a can occur via DNA methylation. We demonstrate that IDH1 mutation provides a mechanism of miR148a methylation and downregulation, and that restoration of miR148a reduced tumorigenic properties of glioma cells, possibly by targeting DNMT1. Conclusions: We identify miR148a as a novel G-CIMP-associated miRNA, and provide results suggesting that miR148a restoration may have therapeutic implications.
    Clinical Cancer Research 09/2014; 20(22). DOI:10.1158/1078-0432.CCR-14-0234 · 8.72 Impact Factor
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    ABSTRACT: Background: Nitroxoline is an FDA-approved antibiotic with potential antitumor activity. Here we evaluated whether nitroxoline has antiproliferative properties on glioma cell growth in vitro and in vivo using glioma cell lines and a genetically engineered PTEN/KRAS mouse glioma model. Methods: The effect of nitroxoline treatment on U87 and/or U251 glioma cell proliferation, cell-cycle arrest, invasion, and ability to induce an apoptotic cascade was determined in vitro. Magnetic resonance imaging was used to measure glioma volumes in genetically engineered PTEN/KRAS mice prior to and after nitroxoline therapy. Induction of apoptosis by nitroxoline was evaluated at the end of treatment using terminal deoxyribonucleotidyl transferase (TDT)-mediated dUTP-digoxigenin nick end labeling (TUNEL). Results: Nitroxoline inhibited the proliferation and invasion of glioblastoma cells in a time- and dose-dependent manner in vitro. Growth inhibition was associated with cell-cycle arrest in G1/G0 phase and induction of apoptosis via caspase 3 and cleaved poly(ADP-ribose) polymerase. In vivo, nitroxoline-treated mice had no increase in tumor volume after 14 days of treatment, whereas tumor volumes doubled in control mice. Histological examination revealed 15%-20% TUNEL-positive cells in nitroxoline-treated mice, compared with ∼5% in the control group. Conclusion: Nitroxoline induces apoptosis and inhibits glioma growth in vivo and in vitro. As an already FDA-approved treatment for urinary tract infections with a known safety profile, nitroxoline could move quickly into clinical trials pending confirmatory studies.
    Neuro-Oncology 07/2014; 17(1). DOI:10.1093/neuonc/nou139 · 5.56 Impact Factor
  • William H Yong · Sarah M Dry · Maryam Shabihkhani ·
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    ABSTRACT: Powerful technologies critical to personalized medicine and targeted therapeutics require the analysis of carefully validated, procured, stored, and managed biospecimens. Reflecting advancements in biospecimen science, the National Cancer Institute and the International Society for Biological and Environmental Repositories are periodically publishing best practices that can guide the biobanker. The modern biobank will operate more like a clinical laboratory with formal accreditation, standard operating procedures, and quality assurance protocols. This chapter highlights practical issues of consent, procurement, storage, quality assurance, disbursement, funding, and space. Common topics of concern are discussed including the differences between clinical and research biospecimens, stabilization of biospecimens during procurement, optimal storage temperatures, and technical validation of biospecimen content and quality. With quickly expanding biospecimen needs and limited healthcare budgets, biobanks may need to be selective as to what is stored. Furthermore, a shift to room-temperature storage modalities where possible can reduce long-term space and fiscal requirements.
    Methods in molecular biology (Clifton, N.J.) 07/2014; 1180:137-62. DOI:10.1007/978-1-4939-1050-2_8 · 1.29 Impact Factor

  • Brain Pathology 07/2014; 24(4):421-2. DOI:10.1111/bpa.12156 · 3.84 Impact Factor

Publication Stats

4k Citations
669.86 Total Impact Points


  • 2006-2015
    • University of California, Los Angeles
      • Department of Pathology and Laboratory Medicine
      Los Ángeles, California, United States
  • 2014
    • Harbor-UCLA Medical Center
      Torrance, California, United States
  • 2009
    • Laureate Institute for Brain Research
      Tulsa, Oklahoma, United States
  • 2008
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      • Department of Medicine
      Torrance, California, United States
  • 2005
    • University of Southern California
      • Department of Biomedical Engineering
      Los Angeles, CA, United States
  • 2000-2004
    • Cedars-Sinai Medical Center
      • Cedars Sinai Medical Center
      Los Ángeles, California, United States
  • 2001
    • Los Angeles Neurosurgical Institute
      Los Angeles, California, United States