William H Yong

Harbor-UCLA Medical Center, Torrance, California, United States

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Publications (103)593 Total impact

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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; DOI:10.1016/j.humpath.2014.12.003 · 2.81 Impact Factor
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    ABSTRACT: Purpose Diffusion magnetic resonance imaging (MRI) and 6-[18F]fluoro-l-dopa ([18F]FDOPA) positron emission tomography (PET) are used to interrogate malignant tumor microenvironment. It remains unclear whether there is a relationship between [18F]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 [18F]FDOPA PET prior to surgical resection. Qualitative associations were noted, and quantitative voxel-wise and median measurement correlations between [18F]FDOPA PET, ADC, and mitotic index were performed. Results Areas of high [18F]FDOPA uptake exhibited low ADC and areas of hyperintensity T2/fluid-attenuated inversion recovery (FLAIR) with low [18F]FDOPA uptake exhibited high ADC. There was a significant inverse voxel-wise correlation between [18F]FDOPA and ADC for all patients. Median [18F]FDOPA uptake and median ADC also showed a significant inverse correlation. Median [18F]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 [18F]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 · 2.87 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 · 1.25 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 · 2.08 Impact Factor
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    ABSTRACT: IntroductionPersistent 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 30minutes. Previous studies have shown that laser fluences between 100 and 500mJ/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 mu m) of titanium sandwiched between a 50 and 100 mu m thick layer of water glass and a 0.1mm 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. ResultsThe 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 Surg. Med. 46:620-627, 2014. (c) 2014 Wiley Periodicals, Inc.
    Lasers in Surgery and Medicine 10/2014; 46(8). DOI:10.1002/lsm.22278 · 2.61 Impact Factor
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    ABSTRACT: Purpose:IDH1/2 mutant gliomas harbor a distinct CpG island methylation profile (G-CIMP) that may promote the initiation and progression of secondary pathway gliomas by silencing tumor suppressive genes. The potential role of tumor suppressive miRNAs in this process is not understood. Experimental Design:To identify potential tumor suppressive microRNAs hypermethylated in glioma, the methylation profiles of IDH1/2WT gliomas (n=11) and IDH1MUT 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 IDH1WT and 72 IDH1/2MUT samples. The expression of selected miRNAs was determined by using TaqMan qPCR. Functional analyses of miRNA-148a were conducted and target genes were identified. Results:We identify miR-148a as a novel, G-CIMP associated miRNA whose methylation is tightly correlated with IDH1 mutation and associated with improved survival in malignant glioma patients. We confirm that down-regulation of miR-148a can occur via DNA methylation. We demonstrate that IDH1 mutation provides a mechanism of miR-148a methylation and downregulation, and that restoration of miR-148a reduced tumorigenic properties of glioma cells, possibly by targeting DNMT1. Conclusions:We identify miR-148a as a novel G-CIMP associated miRNA, and provide results suggesting that miR-148a restoration may have therapeutic implications.
    Clinical Cancer Research 09/2014; DOI:10.1158/1078-0432.CCR-14-0234 · 8.19 Impact Factor
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    ABSTRACT: 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.
    Neuro-Oncology 07/2014; DOI:10.1093/neuonc/nou139 · 5.29 Impact Factor
  • Brain Pathology 07/2014; 24(4):421-2. DOI:10.1111/bpa.12156 · 4.35 Impact Factor
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    ABSTRACT: Objectives To examine systemic and central nervous system (CNS) comorbidities of individuals with dementia evaluated during general autopsy.DesignRetrospective cohort study.SettingA large tertiary academic medical center in Los Angeles, California.ParticipantsIndividuals with clinically and neuropathologically diagnosed dementia who received complete autopsies (n = 86) and individuals with dementia who received partial (brain only) autopsies (n = 132).MeasurementsInformation on cause of death and systemic and CNS comorbidities was obtained from autopsy reports and clinical information as available from the medical records. Findings were tabulated with respect to type of dementia, semiquantitative assessment of the severity of cerebral amyloid angiopathy, semiquantitative assessment of the severity of cerebrovascular disease, and evidence of ischemic damage in the brain.ResultsOf 218 subjects with dementia, 175 (80.3%) had Alzheimer's disease alone or in combination with other lesions that might contribute to cognitive impairment, such as cerebrovascular disease and diffuse Lewy body disease (DLBD), 14 (6.4%) had frontotemporal dementia, and seven (3.2%) had isolated DLBD. The most common cause of death in participants with dementia was pneumonia (n = 57, 66.3%), followed by cardiovascular disease (n = 14, 16.3%). Eighteen subjects (20.9%) had lung disease, and 16 (18.6%) had evidence of an old or recent myocardial infarction. Clinically undiagnosed neoplasms included colonic adenocarcinoma, metastatic pulmonary neuroendocrine carcinoma, meningioma, and Schwannoma.Conclusion Significant comorbidities were discovered at autopsy in individuals with dementia. Understanding the causes of death and associated comorbidities in individuals with various subtypes of dementia is important in the assessment of end-of-life care in these individuals.
    Journal of the American Geriatrics Society 07/2014; 62(9). DOI:10.1111/jgs.12977 · 4.22 Impact Factor
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    ABSTRACT: The optimal timing to initiate bevacizumab (BV) therapy for recurrent glioblastoma (GBM) is currently unclear. To address this issue, we examined progression-free survival (PFS) and survival time (ST) in a large retrospective cohort of GBM patients treated with BV at different recurrences. We identified 468 primary GBM patients who underwent biopsy or surgery followed by radiation therapy and temozolomide (RT/TMZ), and then received BV. PFS and ST were compared between patients stratified by the recurrence that BV was initiated (upfront, first recurrence, second recurrence, or 3+ recurrences). We also examined the effect on PFS and ST of the addition of chemotherapy to BV. In a larger cohort of GBM patients, we determined overall treatment continuation rates at each recurrence and identified variables predictive of inability to continue treatment. BV PFS was similar for all 3 recurrence groups (median, 4.1 months). There were no differences in BV ST (median, 9.8 months). The addition of chemotherapy to BV improved PFS but not ST. Analysis of treatment continuation rates indicated that the number of patients unable to undergo further treatments is modest, and that patients unable to tolerate BV delay can be identified by age ≥60 years and low extent of resection. Deferred use of bevacizumab is not associated with diminished efficacy. Analysis of treatment continuation rates identified patients who may be unable to delay BV therapy. Our findings suggest that there is a fixed survival after BV initiation and that delayed BV treatment is preferable for most patients.
    Neuro-Oncology 03/2014; DOI:10.1093/neuonc/nou028 · 5.29 Impact Factor
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    ABSTRACT: Most patients with large pituitary tumors do not exhibit hyperprolactinemia as a result of pituitary lactotroph disinhibition (stalk effect). Studies have demonstrated that increased intrasellar pressure is associated with both "stalk effect" hyperprolactinemia and pituitary insufficiency. Our primary hypothesis was that, despite continued disinhibition, lactotroph failure is responsible for normoprolactinemia in patients with large macroadenomas. As a corollary, we proposed that the hyperprolactinemia phase, which presumably would precede the insufficiency/normoprolactinemic state, would more likely be discovered in premenopausal females and go unnoticed in males. Prospective, consecutive surgical series of 98 patients of clinically nonfunctional pituitary adenomas. Lactotroph insufficiency was inferred by the coexistence of insufficiency in another pituitary axis. The existence of pre-operative lactotroph disinhibition was inferred based on comparison of pre- versus post-operative prolactin levels. 87 % of patients with tumor size >20 mm and normoprolactinemia had pituitary insufficiency. Pre-operative prolactin in patients with pituitary insufficiency were lower than those with intact pituitary function. Prolactin levels dropped in nearly all patients, including patients with normoprolactinemia pre-operatively. Premenopausal women had smaller tumors and higher pre-operative prolactin levels compared to males. No premenopausal female exhibited evidence of pituitary insufficiency. Our study provides suggestive evidence that the "stalk effect" pathophysiology is the norm rather than the exception, and that the finding of normoprolactinemia in a patient with a large macroadenoma is likely a consequence of lactotroph insufficiency. In males, the hyperprolactinemia window is more likely to be missed clinically due to an absence of prolactin-related symptoms.
    Journal of Neuro-Oncology 02/2014; DOI:10.1007/s11060-014-1386-5 · 2.79 Impact Factor
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    ABSTRACT: Malignant gliomas are the most common human primary brain tumors. Point mutation of amino acid arginine 132 to histidine (R132H) in the IDH1 protein leads to an enzymatic gain-of-function and is thought to promote gliomagenesis. Little is known about the downstream effects of the IDH1 mutation on protein expression and how and whether changes in protein expression are involved in tumor formation or propagation. In the current study, we used 2D DIGE (difference gel electrophoresis) and mass spectrometry to analyze differences in protein expression between IDH1(R132H) mutant and wild type anaplastic (grade III) astrocytoma from human brain cancer tissues. We show that expression levels of many proteins are altered in IDH1(R132H) mutant anaplastic astrocytoma. Some of the most over-expressed proteins in the mutants include several forms of αB-crystallin, a small heat-shock and anti-apoptotic protein. αB-crystallin proteins are elevated up to 22-fold in IDH1(R132H) mutant tumors, and αB-crystallin expression appears to be controlled at the post-translational level. We identified the most abundant form of αB-crystallin as a low molecular weight species that is C-terminally truncated. We also found that overexpression of αB-crystallin can be induced by transfecting U251 human glioblastoma cell lines with the IDH1(R132H) mutation. In conclusion, the association of a C-terminally truncated form of αB-crystallin protein with the IDH1(R132H) mutation is a novel finding that could impact apoptosis and stress response in IDH1 mutant glioma.
    Journal of Neuro-Oncology 01/2014; DOI:10.1007/s11060-014-1371-z · 2.79 Impact Factor
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    ABSTRACT: Well preserved frozen biospecimens are ideal for evaluating the genome, transcriptome, and proteome. While papers reviewing individual aspects of frozen biospecimens are available, we present a current overview of experimental data regarding procurement, storage, and quality assurance that can inform the handling of frozen biospecimens. Frozen biospecimen degradation can be influenced by factors independent of the collection methodology including tissue type, premortem agonal changes, and warm ischemia time during surgery. Rapid stabilization of tissues by snap freezing immediately can mitigate artifactually altered gene expression and, less appreciated, protein phosphorylation profiles. Collection protocols may be adjusted for specific tissue types as cellular ischemia tolerance varies widely. If data is not available for a particular tissue type, a practical goal is snap freezing within 20 minutes. Tolerance for freeze-thaw events is also tissue type dependent. Tissue storage at -80°C can preserve DNA and protein for years but RNA can show degradation at 5 years. For -80°C freezers, aliquots frozen in RNAlater or similar RNA stabilizing solutions is a consideration. It remains unresolved as to whether storage at -150°C provides significant advantages relative to -80°C. Histologic quality assurance of tissue biospecimens is typically performed at the time of surgery but should also be conducted on the aliquot to be distributed because of tissue heterogeneity. Biobanking protocols for blood and its components are highly dependent on intended use and multiple collection tube types may be needed. Additional quality assurance testing should be dictated by the anticipated downstream applications.
    Clinical biochemistry 01/2014; 47(4-5). DOI:10.1016/j.clinbiochem.2014.01.002 · 2.23 Impact Factor
  • The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 01/2014; 41(1):112-4. DOI:10.1017/S0317167100016401 · 1.60 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.) 01/2014; 1180:137-62. DOI:10.1007/978-1-4939-1050-2_8 · 1.29 Impact Factor
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    ABSTRACT: Frozen biospecimens are crucial for translational research and contain well preserved nucleic acids and protein. However, the risk for catastrophic freezer failure as well as space, cost, and environmental concerns argue for evaluating long-term room temperature storage alternatives. Formalin-fixed paraffin embedded (FFPE) tissues have great value but their use is limited by cross-linking and fragmentation of nucleic acids, as well as loss of enzymatic activity. Stabilization solutions can now robustly preserve fresh tissue for up to 7days at room temperature. For longer term storage, commercial vendors of chemical matrices claim real time stability of nucleic acids of over 2years and their accelerated aging studies to date suggest stability for 12years for RNA and 60years for DNA. However, anatomic pathology biorepositories store mostly frozen tissue rather than nucleic acids. Small quantities of tissue can be directly placed on some chemical matrices to stabilize DNA, however RNA and proteins are not preserved. Current lyophilization approaches can preserve histomorphology, DNA, RNA, and proteins though RNA shows moderate degradation after 1-2years. Formalin free fixatives show improved but varying abilities to preserve nucleic acids and face validation as well as cost barriers in replacing FFPE specimens. The paraffin embedding process can degrade RNA. Development of robust long-term room temperature biospecimen tissue storage technology can potentially reduce costs for the biomedical community in the face of growing targeted therapy needs and decreasing budgets.
    Clinical biochemistry 12/2013; 47(4-5). DOI:10.1016/j.clinbiochem.2013.12.011 · 2.23 Impact Factor
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    ABSTRACT: Glioblastoma stem cells (GSC) are a significant cell model for explaining brain tumor recurrence. However, mechanisms underlying their radiochemoresistance remain obscure. Here we show that most clonogenic cells in GSC cultures are sensitive to radiation treatment (RT) with or without temozolomide (TMZ). Only a few single cells survive treatment and regain their self-repopulating capacity. Cells re-populated from treatment-resistant GSC clones contain more clonogenic cells compared to those grown from treatment-sensitive GSC clones, and repeated treatment cycles rapidly enriched clonogenic survival. When compared to sensitive clones, resistant clones exhibited slower tumor development in animals. Upregulated genes identified in resistant clones via comparative expression microarray analysis characterized cells under metabolic stress, including blocked glucose uptake, impaired insulin/Akt signaling, enhanced lipid catabolism and oxidative stress, and suppressed growth and inflammation. Moreover, many upregulated genes highlighted maintenance and repair activities, including detoxifying lipid peroxidation products, activating lysosomal autophagy/ubiquitin-proteasome pathways, and enhancing telomere maintenance and DNA repair, closely resembling the anti-aging effects of caloric/glucose restriction (CR/GR), a nutritional intervention that is known to increase lifespan and stress resistance in model organisms. Although treatment-introduced genetic mutations were detected in resistant clones, all resistant and sensitive clones were subclassified to either proneural (PN) or mesenchymal (MES) glioblastoma subtype based on their expression profiles. Functional assays demonstrated the association of treatment resistance with energy stress, including reduced glucose uptake, fatty acid oxidation (FAO)-dependent ATP maintenance, elevated reactive oxygen species (ROS) production and autophagic activity, and increased AMPK activity and NAD(+) levels accompanied by upregulated mRNA levels of SIRT1/PGC-1α axis and DNA repair genes. These data support the view that treatment resistance may arise from quiescent GSC exhibiting a GR-like phenotype, and suggest that targeting stress response pathways of resistant GSC may provide a novel strategy in combination with standard treatment for glioblastoma.
    PLoS ONE 11/2013; 8(11):e80397. DOI:10.1371/journal.pone.0080397 · 3.53 Impact Factor
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    ABSTRACT: Brain metastases are frequently treated with radiation. It is critical to distinguish recurrent or progressive brain metastases (RPBM) from late or delayed radiation injury (LDRI). The purpose of this study was to examine the diagnostic accuracy as well as the prognostic power of 6-(18)F-fluoro-l-dopa ((18)F-FDOPA) PET for differentiating RPBM from LDRI. Thirty-two patients who had 83 previously irradiated brain metastases and who underwent (18)F-FDOPA PET because of an MR imaging-based suggestion of RPBM were studied retrospectively. PET studies were analyzed semiquantitatively (lesion-to-striatum and lesion-to-normal brain tissue ratios based on both maximum and mean standardized uptake values) and visually (4-point scale). The diagnostic accuracy of PET was verified by histopathologic analysis (n = 9) or clinical follow-up (n = 74) on a lesion-by-lesion basis. Receiver operating characteristic curve analysis was used to identify the best diagnostic indices. The power of (18)F-FDOPA PET to predict disease progression was evaluated with the Kaplan-Meier and Cox regression methods. The best overall accuracy was achieved by visual scoring, with which a score of 2 or more (lesion uptake greater than or equal to striatum uptake) resulted in a sensitivity of 81.3% and a specificity of 84.3%. Semiquantitative (18)F-FDOPA PET uptake indices based on lesion-to-normal brain tissue ratios were significantly higher for RPBM than for LDRI. Among the various predictors tested, (18)F-FDOPA PET was the strongest predictor of tumor progression (hazard ratio, 6.26; P < 0.001), and the lesion-to-normal brain tissue ratio or visual score was the best discriminator. The mean time to progression was 4.6 times longer for lesions with negative (18)F-FDOPA PET results than for lesions with positive (18)F-FDOPA PET results (76.5 vs. 16.7 mo; P < 0.001). (18)F-FDOPA PET findings tended to predict overall survival. Metabolic imaging with (18)F-FDOPA PET was useful for differentiating RPBM from LDRI. Semiquantitative indices, particularly lesion-to-normal uptake ratios, could be used. A visual score comparing tumor (18)F-FDOPA uptake and striatum (18)F-FDOPA uptake provided the highest sensitivity and specificity and was predictive of disease progression.
    Journal of Nuclear Medicine 10/2013; 55(1). DOI:10.2967/jnumed.113.121418 · 5.56 Impact Factor
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    ABSTRACT: Aerobic glycolysis (the Warburg effect) is a core hallmark of cancer, but the molecular mechanisms underlying it remain unclear. Here, we identify an unexpected central role for mTORC2 in cancer metabolic reprogramming where it controls glycolytic metabolism by ultimately regulating the cellular level of c-Myc. We show that mTORC2 promotes inactivating phosphorylation of class IIa histone deacetylases, which leads to the acetylation of FoxO1 and FoxO3, and this in turn releases c-Myc from a suppressive miR-34c-dependent network. These central features of activated mTORC2 signaling, acetylated FoxO, and c-Myc levels are highly intercorrelated in clinical samples and with shorter survival of GBM patients. These results identify a specific, Akt-independent role for mTORC2 in regulating glycolytic metabolism in cancer.
    Cell metabolism 10/2013; 18(5). DOI:10.1016/j.cmet.2013.09.013 · 16.75 Impact Factor
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    ABSTRACT: Although the immune system may provide early protection against cancer, tumors may exploit the healing arm of the immune system to enhance their growth and metastasis. For example, myeloid derived suppressor cells (MDSCs) are thought to promote tumor growth by several mechanisms, including the suppression of T cell activity. It has been suggested that STAT3 activation in myeloid cells modulates multiple aspects of MDSC physiology, including their expansion and activity. Whereas most animal studies investigating tumor immunology have used tumor implants, we used transgenic mice (Smo*) that spontaneously develop medulloblastoma brain tumors to investigate the temporal accumulation of MDSCs within tumors and how myeloid STAT3 disruption affects MDSC and other immune cell types. We found distinct populations of MDSC in medulloblastoma tumors, with a high prevalence of CD11b(+)Ly6G(+)Ly6C(low/-) cells, described previously by others as G-MDSCs. These were found early in tumor development, in premalignant lesions located on the surface of the cerebellum of 28-day-old mice. In fully developed tumors, pSTAT3 was found in the majority of these cells. Conditional STAT3 gene disruption in myeloid cells resulted in an enhanced proinflammatory phenotype of macrophages in Smo* mice. Moreover, a significant reduction in the abundance of G-MDSCs and Tregs was observed within tumors along with an increased presence of CD4(+) and CD8(+) cells. Despite these alterations in immune cells induced by myeloid STAT3 disruption, we found no effect on tumor incidence in Smo* mice with this deletion mice was observed.
    Journal of leukocyte biology 09/2013; 95(2). DOI:10.1189/jlb.1012531 · 4.99 Impact Factor

Publication Stats

3k Citations
593.00 Total Impact Points

Institutions

  • 2014
    • Harbor-UCLA Medical Center
      Torrance, California, United States
  • 2006–2014
    • University of California, Los Angeles
      • Department of Pathology and Laboratory Medicine
      Los Ángeles, California, United States
  • 2013
    • Tongji Hospital
      Wu-han-shih, Hubei, China
  • 2012
    • CSU Mentor
      Long Beach, California, United States
  • 2009
    • Laureate Institute for Brain Research
      Tulsa, Oklahoma, United States
  • 2008
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      Torrance, California, United States
  • 2005–2007
    • 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