L Burton Nabors

Publications of L Burton Nabors

• A functional polymorphism in the pre-miR-146a gene is associated with risk and prognosis in adult glioma.

  Authors: Jennifer Permuth-Wey, Reid C Thompson, L Burton Nabors, Jeffrey J Olson, James E Browning, Melissa H Madden, Y Ann Chen, Kathleen M Egan

  Journal of neuro-oncology. 07/2011; 105(3):639-46.

  MicroRNAs (miRNAs) are non-coding RNAs that function as post-transcriptional regulators of tumor suppressors and oncogenes. Single nucleotide polymorphisms (SNPs) in miRNAs may contribute toMicroRNAs (miRNAs) are non-coding RNAs that function as post-transcriptional regulators of tumor suppressors and oncogenes. Single nucleotide polymorphisms (SNPs) in miRNAs may contribute to carcinogenesis by altering expression of miRNAs and their targets. A G>C polymorphism (rs2910164) in the miR-146a precursor sequence leads to a functional change associated with the risk for numerous malignancies. A role for this SNP in glioma pathogenesis has not yet been examined. We investigated whether rs2910164 genotypes influence glioma risk and prognosis in a multi-center case-control study comprised of 593 Caucasian glioma cases and 614 community-based controls. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for rs2910164 genotypes according to case status. Cox proportional hazards regression modeling was used to estimate hazards ratios (HR) and 95% CIs according to genotype among glioblastomas, the most lethal glioma subtype. An increased glioma risk was observed among rs2910164 minor allele (C) carriers (per allele OR (95% CI) = 1.22 (1.01-1.46, p (trend) = 0.039)). The association was stronger among older subjects carrying at least one copy of the C allele (OR (95% CI) = 1.38 (1.04-1.83, P = 0.026). Mortality was increased among minor allele carriers (HR (95% CI) = 1.33 (1.03-1.72, P = 0.029)), with the association largely restricted to females (HR (95% CI) = 2.02 (1.28-3.17, P = 0.002)). We provide novel data suggesting rs2910164 genotype may contribute to glioma susceptibility and outcome. Future studies are warranted to replicate these findings and characterize mechanisms underlying these associations.

• The ING4 Tumor Suppressor Attenuates NF-{kappa}B Activity at the Promoter of Target Genes.

  Authors: Susan Nozell, Travis Laver, Dorothy Moseley, Lisa Nowoslawski, Marijke Devos, George P. Atkinson, Keith Harrison, L Burton Nabors, Etty N Benveniste

  Molecular and cellular biology. 10/2008;

  The NF-kappaB family mediates immune and inflammatory responses. In many cancers, NF-kappaB is constitutively activated and induces the expression of genes that facilitate tumorigenesis. ING4 is aThe NF-kappaB family mediates immune and inflammatory responses. In many cancers, NF-kappaB is constitutively activated and induces the expression of genes that facilitate tumorigenesis. ING4 is a tumor suppressor that is absent or mutated in several cancers. Herein, we demonstrate that in human gliomas, NF-kappaB is constitutively activated, ING4 expression is negligible, and that NF-kappaB regulated gene expression is elevated. We demonstrate an ING4 and NF-kappaB interaction exists, but does not prevent NF-kappaB activation, nuclear translocation or DNA binding. Instead, ING4 and NF-kappaB bind simultaneously at NF-kappaB regulated promoters, and this correlates with reductions in p65 phosphorylation, p300, and the levels of acetylated histones and H3-Me3K4, while enhancing the levels of HDAC-1 at these promoters. Using a knockdown approach, we correlate reductions in ING4 protein levels with increased basal and inducible NF-kappaB target gene expression. Collectively, these data suggest that ING4 may specifically regulate the activity of NF-kappaB molecules that are bound to target gene promoters.

• Loss of protein inhibitors of activated STAT-3 expression in glioblastoma multiforme tumors: implications for STAT-3 activation and gene expression.

  Authors: Emily C Brantley, L Burton Nabors, G Yancey Gillespie, Youn-Hee Choi, Cheryl Ann Palmer, Keith Harrison, Kevin Roarty, Etty N Benveniste

  Clinical cancer research : an official journal of the American Association for Cancer Research. 09/2008; 14(15):4694-704.

  PURPOSE: STATs activate transcription in response to numerous cytokines, controlling proliferation, gene expression, and apoptosis. Aberrant activation of STAT proteins, particularly STAT-3, isPURPOSE: STATs activate transcription in response to numerous cytokines, controlling proliferation, gene expression, and apoptosis. Aberrant activation of STAT proteins, particularly STAT-3, is implicated in the pathogenesis of many cancers, including GBM, by promoting cell cycle progression, stimulating angiogenesis, and impairing tumor immune surveillance. Little is known about the endogenous STAT inhibitors, the PIAS proteins, in human malignancies. The objective of this study was to examine the expression of STAT-3 and its negative regulator, PIAS3, in human tissue samples from control and GBM brains. EXPERIMENTAL DESIGN: Control and GBM human tissues were analyzed by immunoblotting and immunohistochemistry to determine the activation status of STAT-3 and expression of the PIAS3 protein. The functional consequence of PIAS3 inhibition by small interfering RNA or PIAS3 overexpression in GBM cells was determined by examining cell proliferation, STAT-3 transcriptional activity, and STAT-3 target gene expression. This was accomplished using [(3)H]TdR incorporation, STAT-3 dominant-negative constructs, reverse transcription-PCR, and immunoblotting. Results and CONCLUSIONS: STAT-3 activation, as assessed by tyrosine and serine phosphorylation, was elevated in GBM tissue compared with control tissue. Interestingly, we observed expression of PIAS3 in control tissue, whereas PIAS3 protein expression in GBM tissue was greatly reduced. Inhibition of PIAS3 resulted in enhanced glioblastoma cellular proliferation. Conversely, PIAS3 overexpression inhibited STAT-3 transcriptional activity, expression of STAT-3-regulated genes, and cell proliferation. We propose that the loss of PIAS3 in GBM contributes to enhanced STAT-3 transcriptional activity and subsequent cell proliferation.

• ABT-510, a modified type 1 repeat peptide of thrombospondin, inhibits malignant glioma growth in vivo by inhibiting angiogenesis.

  Authors: Joshua C Anderson, J Robert Grammer, Wenquan Wang, L Burton Nabors, Jack Henkin, Jerry E Stewart, Candece L Gladson

  Cancer biology & therapy. 04/2007; 6(3):454-62.

  Anti-angiogenic therapies would be particularly beneficial in the treatment of malignant gliomas. Peptides derived from the second type 1 repeat (TSR) of thrombospondin-1 (TSP-1) have been shown toAnti-angiogenic therapies would be particularly beneficial in the treatment of malignant gliomas. Peptides derived from the second type 1 repeat (TSR) of thrombospondin-1 (TSP-1) have been shown to inhibit angiogenesis in non-glioma tumor models and a modified TSR peptide, ABT-510, has now entered into Phase II clinical trials of its efficacy in non-glioma tumors. As microvascular endothelial cells (MvEC) exhibit heterogeneity, we evaluated the ability of the modified TSR peptide (NAcSarGlyValDallolleThrNvalleArgProNHE, ABT-510) to inhibit malignant glioma growth in vivo and to induce apoptosis of brain microvessel endothelial cells (MvEC) propagated in vitro. We found that daily administration of ABT-510 until euthanasia (days 7 to 19), significantly inhibited the growth of human malignant astrocytoma tumors established in the brain of athymic nude mice. The microvessel density was significantly lower and the number of apoptotic MvEC was significantly higher (3-fold) in the tumors of the ABT-510-treated animals. Similar results were found using a model in which the established tumor is an intracerebral malignant glioma propagated in a syngeneic mouse model. ABT-510 treatment of primary human brain MvEC propagated as a monolayer resulted in induction of apoptosis in a dose- and time-dependent manner through a caspase-8-dependent mechanism. It also inhibited tubular morphogenesis of MvEC propagated in collagen gels in a dose- and caspase-8 dependent manner through a mechanism that requires the TSP-1 receptor (CD36) on the MvEC. These findings indicate that ABT-510 should be evaluated as a therapeutic option for patients with malignant glioma.

• Increased expression of thymidylate synthetase (TS), ubiquitin specific protease 10 (USP10) and survivin is associated with poor survival in glioblastoma multiforme (GBM).

  Authors: Jessica M Grunda, L Burton Nabors, Cheryl A Palmer, David C Chhieng, Adam Steg, Tom Mikkelsen, Robert B Diasio, Kui Zhang, David Allison, William E Grizzle, Wenquan Wang, G Yancey Gillespie, Martin R Johnson

  Journal of neuro-oncology. 12/2006; 80(3):261-74.

  BACKGROUND: The limited success of empirically designed treatment paradigms for patients diagnosed with glioblastoma multiforme (GBM) emphasizes the need for rationally designed treatment strategiesBACKGROUND: The limited success of empirically designed treatment paradigms for patients diagnosed with glioblastoma multiforme (GBM) emphasizes the need for rationally designed treatment strategies based on the molecular profile of tumor samples and their correlation to clinical parameters. METHODS: In the current study, we utilize a novel real-time quantitative low density array (RTQ-LDA) to identify differentially expressed genes in de novo GBM tissues obtained from patients with distinctly different clinical outcomes. Total RNA was isolated from a cohort of 21 GBM specimens obtained from patients with either good (long-term survival (LTS) >36 months post surgery, n = 8) or poor (died of the disease (DOD) <24 months post surgery, n = 13) prognosis. Non-neoplastic brain tissue (n = 5) was obtained from patients who underwent surgery for refractory epilepsy. Demographic data was assessed for correlation with survival using Cox proportional hazards models. Sufficient RNA was available to use RTQ-LDA to quantify the expression of 93 independent genes in 5 LTS, 4 DOD, and 5 non-neoplastic brain samples. The eight differentially expressed genes identified by RTQ-LDA in LTS versus DOD (P <or= 0.050) were subsequently quantified in all 21 GBM samples by real-time quantitative PCR (RTQ). RESULTS: A correlation between younger patients and good prognosis was demonstrated (P <or= 0.05). The combination of RTQ-LDA and RTQ identified thymidylate synthetase (TS), ubiquitin specific protease 10 (USP10), and survivin as significantly over-expressed (P <or= 0.050) in DOD compared to LTS patients. Ribonucleotide reductase subunit M2 (RRM2) was identified as tumor-specific, but not associated with survival. CONCLUSIONS: Taken collectively, TS, USP10, survivin and RRM2 may be useful as prognostic indicators and/or in the development of rationally designed treatment protocols.

• 1p/19q chromosome deletions in metastatic oligodendroglioma.

  Authors: Ryan Merrell, L Burton Nabors, Arie Perry, Cheryl Ann Palmer

  Journal of neuro-oncology. 12/2006; 80(2):203-7.

  Extracranial metastasis of primary brain tumors is a rare phenomenon. Of the few cases reported of metastatic oligodendroglioma, only two have evaluated genetic alterations, specifically deletions ofExtracranial metastasis of primary brain tumors is a rare phenomenon. Of the few cases reported of metastatic oligodendroglioma, only two have evaluated genetic alterations, specifically deletions of chromosomes 1p and 19q. Herein, we report two additional patients with metastatic anaplastic oligodendroglioma to bone, both followed until death. All available pathology specimens were reviewed and genetic analysis was performed in one of the cases. Although the bone metastasis was non-informative, the primary intracranial tumor revealed codeletions of the 1p and 19q chromosomal arms, commonly recognized as the genetically favorable profile of oligodendrogliomas. Both patients died of complications related to their systemic disease and did not have any radiologic evidence of intracranial progression at the time of their last MRI studies. Along with the reported literature, our data suggest that despite their generally favorable behavioral profiles, oligodendroglial tumors with 1p/19q deletions may be more prone to metastasis as they progress. Genetic analysis serves a valuable ancillary role in the diagnostic workup of such cases.

• A novel technique to quantify glioma tumor invasion using serial microscopy sections.

  Authors: N Shastry Akella, Qiang Ding, Ingrid Menegazzo, Wenquan Wang, G Yancey Gillespie, J Robert Grammer, Candece L Gladson, L Burton Nabors

  Journal of neuroscience methods. 07/2006; 153(2):183-9.

  Here we present a new technique to quantitatively characterize malignant glioma invasion in a syngeneic mouse model. The GL261 mouse malignant glioma cell line was injected intracerebrally into theHere we present a new technique to quantitatively characterize malignant glioma invasion in a syngeneic mouse model. The GL261 mouse malignant glioma cell line was injected intracerebrally into the C57B1/6 black mouse and allowed to propagate for 10 or 17 days, followed by euthanasia of the animal, harvesting of the brain, fixation, and serial sectioning. Histologic examination was performed and the primary tumor mass and discontinuous sites of tumor invasion were traced on digital images of serial microscopy sections, followed by analysis of the invasion characteristics using a custom-written MATLAB program. We found a significant increase in the number of discontinuous tumor invasion sites and in the distance of these sites from the tumor centroid in mice that were euthanized at 17 days post-tumor cell injection, as compared to mice euthanized at 10 days. Furthermore, a scatter plot analyses indicated that the invasion site data could be grouped based on the characteristics of area and distance from the tumor centroid to reveal significant differences between the two experimental groups of mice. This quantitative method will allow a future in vivo analysis of invasion characteristics in glioma cells expressing altered levels or function of invasion genes, and of new therapy targeting invading glioma cells.

• Lyn kinase activity is the predominant cellular SRC kinase activity in glioblastoma tumor cells.

  Authors: Michelle R Stettner, Wenquan Wang, L Burton Nabors, Suman Bharara, Daniel C Flynn, J Robert Grammer, G Yancey Gillespie, Candece L Gladson

  Cancer research. 07/2005; 65(13):5535-43.

  Cellular Src activity modulates cell migration, proliferation, and differentiation, and recent reports suggest that individual members of the Src family may play specific roles in these processes. AsCellular Src activity modulates cell migration, proliferation, and differentiation, and recent reports suggest that individual members of the Src family may play specific roles in these processes. As we have found that Lyn, but not Fyn, activity promotes migration of glioblastoma cells in response to the cooperative signal generated by platelet-derived growth factor receptor beta and integrin alpha(v)beta3, we compared the activity and expression of Lyn and Fyn in glioblastoma (grade IV) tumor biopsy samples with that in anaplastic astrocytoma (grade III) tumors, nonneoplastic brain, and normal autopsy brain samples. Lyn kinase activity was significantly elevated in glioblastoma tumor samples. Notably, the Lyn kinase activity accounted for >90% of pan-Src kinase activity in glioblastoma samples but only approximately 30% of pan-Src kinase activity in the other groups. The levels of phosphorylation of the autophosphorylation site were consistent with significantly higher Lyn activity in glioblastoma tumor tissue than nonneoplastic brain. Although the normalized levels of Lyn protein and the relative levels of Lyn message were significantly higher in glioblastoma samples than nonneoplastic brain, the normalized levels of Lyn protein did not correlate with Lyn activity in the glioblastoma samples. There was no significant difference in the normalized levels of c-Src and Fyn protein and message in the glioblastoma and nonneoplastic brain. Immunostaining revealed that Lyn is located primarily in the glioblastoma cells in the tumor biopsies. These data indicate that Lyn kinase activity is significantly elevated in glioblastoma tumors and suggest that it is the Lyn activity that promotes the malignant phenotype in these tumors.

• Prognostic value of 1p, 19q, 9p, 10q, and EGFR-FISH analyses in recurrent oligodendrogliomas.

  Authors: Kenneth B Fallon, Cheryl A Palmer, Kevin A Roth, L Burton Nabors, Wenquan Wang, Mark Carpenter, Ruma Banerjee, Peter Forsyth, Keith Rich, Arie Perry

  Journal of neuropathology and experimental neurology. 04/2004; 63(4):314-22.

  Although 1p/19q codeletions define "genetically favorable" oligodendrogliomas, eventual tumor progression and patient death remain constant. Genetic testing is often performed at the time ofAlthough 1p/19q codeletions define "genetically favorable" oligodendrogliomas, eventual tumor progression and patient death remain constant. Genetic testing is often performed at the time of recurrence, though it is unclear whether these or other genetic alterations provide useful prognostic information. We characterized 138 of 189 (73%) available primary and recurrent oligodendroglial neoplasms from 80 patients, utilizing paired FISH probes for 1p32/1q42, 19p13/19q13, CEP7/EGFR, CEP9/p16, and PTEN/DMBT1. Patients were followed until death (49%), or a median follow-up of 8.9 years. Patients with 1p/19q codeleted tumors (71%) had an estimated overall median survival of 14.9 years with an estimated 3.9 years from first recurrence. In contrast, those lacking deletions had significantly lower estimated overall median survivals of 4.7 years and 1.0 year after first recurrence (both p < 0.001). This increased survival in patients with 1p/19q codeleted tumors remained significant when adjustments were made for age, tumor grade, type of surgical procedure, and treatment with radiation or chemotherapy. Only 1 recurrence showed focal EGFR amplification, while 5 developed 10q deletions, mostly in high-grade mixed oligoastrocytomas lacking 1p/19q deletions. In contrast, p16 (9p21) deletions were common and associated with both high grade (p < 0.001) and recurrence (p = 0.002). Our data suggest that in classic oligodendrogliomas: 1) 1p/19q tumor status is a powerful predictor of patient survival, even after recurrence; 2) p16 deletions are common progression-associated alterations; and 3) 10q deletions and EGFR amplifications are sufficiently rare to suggest the possibility of alternate diagnoses.