Showing papers by "Bruce R. Southey published in 2011"
TL;DR: The identified biomarkers support the development of more accurate and personalized prognostic tools and gene-based therapies that improve the survival and quality of life of individuals afflicted by glioblastoma multiforme.
Abstract: Glioblastoma is a complex multifactorial disorder that has swift and devastating consequences. Few genes have been consistently identified as prognostic biomarkers of glioblastoma survival. The goal of this study was to identify general and clinical-dependent biomarker genes and biological processes of three complementary events: lifetime, overall and progression-free glioblastoma survival. A novel analytical strategy was developed to identify general associations between the biomarkers and glioblastoma, and associations that depend on cohort groups, such as race, gender, and therapy. Gene network inference, cross-validation and functional analyses further supported the identified biomarkers. A total of 61, 47 and 60 gene expression profiles were significantly associated with lifetime, overall, and progression-free survival, respectively. The vast majority of these genes have been previously reported to be associated with glioblastoma (35, 24, and 35 genes, respectively) or with other cancers (10, 19, and 15 genes, respectively) and the rest (16, 4, and 10 genes, respectively) are novel associations. Pik3r1, E2f3, Akr1c3, Csf1, Jag2, Plcg1, Rpl37a, Sod2, Topors, Hras, Mdm2, Camk2g, Fstl1, Il13ra1, Mtap and Tp53 were associated with multiple survival events. Most genes (from 90 to 96%) were associated with survival in a general or cohort-independent manner and thus the same trend is observed across all clinical levels studied. The most extreme associations between profiles and survival were observed for Syne1, Pdcd4, Ighg1, Tgfa, Pla2g7, and Paics. Several genes were found to have a cohort-dependent association with survival and these associations are the basis for individualized prognostic and gene-based therapies. C2, Egfr, Prkcb, Igf2bp3, and Gdf10 had gender-dependent associations; Sox10, Rps20, Rab31, and Vav3 had race-dependent associations; Chi3l1, Prkcb, Polr2d, and Apool had therapy-dependent associations. Biological processes associated glioblastoma survival included morphogenesis, cell cycle, aging, response to stimuli, and programmed cell death. Known biomarkers of glioblastoma survival were confirmed, and new general and clinical-dependent gene profiles were uncovered. The comparison of biomarkers across glioblastoma phases and functional analyses offered insights into the role of genes. These findings support the development of more accurate and personalized prognostic tools and gene-based therapies that improve the survival and quality of life of individuals afflicted by glioblastoma multiforme.
95 citations
TL;DR: Findings show that even late-onset exercise may attenuate age-related changes in gene expression and identifies possible pathways through which exercise may exert its beneficial effects.
Abstract: Normal aging alters expression of numerous genes within the brain. Some of these transcription changes likely contribute to age-associated cognitive decline, reduced neural plasticity, and the higher incidence of neuropathology. Identifying factors that modulate brain aging is crucial for improving quality of life. One promising intervention to counteract negative effects of aging is aerobic exercise. Aged subjects that exercise show enhanced cognitive performance and increased hippocampal neurogenesis and synaptic plasticity. Currently, the mechanisms behind the anti-aging effects of exercise are not understood. The present study conducted a microarray on whole hippocampal samples from adult (3.5-month-old) and aged (18-month-old) male BALB/c mice that were individually housed with or without running wheels for 8 weeks. Results showed that aging altered genes related to chromatin remodeling, cell growth, immune activity, and synapse organization compared to adult mice. Exercise was found to modulate many of the genes altered by aging, but in the opposite direction. For example, wheel running increased expression of genes related to cell growth and attenuated expression of genes involved in immune function and chromatin remodeling. Collectively, findings show that even late-onset exercise may attenuate age-related changes in gene expression and identifies possible pathways through which exercise may exert its beneficial effects.
68 citations
Journal Article•
TL;DR: Sensory perception and G protein-coupled receptor processes were enriched among microRNA gene targets also associated with survival and network visualization highlighted their relations, which can help to improve prognostic tools and personalized treatments.
Abstract: Aim—To identify and study targets of microRNA biomarkers of glioblastoma survival across events (death and recurrence) and phases (life expectancy or post-diagnostic) using functional and network analyses. Materials and Methods—microRNAs associated with glioblastoma survival within and across race, gender, recurrence, and therapy cohorts were identified using 253 individuals, 534 microRNAs, Cox survival model, cross-validation, discriminant analyses, and cross-study comparison. Results—All 45 microRNAs revealed were confirmed in independent cancer studies and 25 in glioblastoma studies. Thirty-nine and six microRNAs (including hsa-miR-222) were associated with one and multiple glioblastoma survival indicators, respectively. Nineteen and 26 microRNAs exhibited cohort-dependent (including hsa-miR-10b with therapy and hsa-miR-486 with race) and independent associations with glioblastoma, respectively. Conclusion—Sensory perception and G protein-coupled receptor processes were enriched among microRNA gene targets also associated with survival and network visualization highlighted their relations. These findings can help to improve prognostic tools and personalized treatments.
45 citations
TL;DR: The results indicate that distinct spatiotemporal foraging memories in honey bees are associated with distinct neurogenomic signatures, and the decomposition of these signatures into sets of genes that are also influenced by time or activity state hints at the modular composition of this complex neurogenomics phenotype.
Abstract: Honey bees can form distinct spatiotemporal memories that allow them to return repeatedly to different food sources at different times of day. Although it is becoming increasingly clear that different behavioral states are associated with different profiles of brain gene expression, it is not known whether this relationship extends to states that are as dynamic and specific as those associated with foraging-related spatiotemporal memories. We tested this hypothesis by training different groups of foragers from the same colony to collect sucrose solution from one of two artificial feeders; each feeder was in a different location and had sucrose available at a different time, either in the morning or afternoon. Bees from both training groups were collected at both the morning and afternoon training times to result in one set of bees that was undergoing stereotypical food anticipatory behavior and another that was inactive for each time of day. Between the two groups with the different spatiotemporal memories, microarray analysis revealed that 1329 genes were differentially expressed in the brains of honey bees. Many of these genes also varied with time of day, time of training or state of food anticipation. Some of these genes are known to be involved in a variety of biological processes, including metabolism and behavior. These results indicate that distinct spatiotemporal foraging memories in honey bees are associated with distinct neurogenomic signatures, and the decomposition of these signatures into sets of genes that are also influenced by time or activity state hints at the modular composition of this complex neurogenomic phenotype.
41 citations
TL;DR: The first evidence for the presence of a peptidyl-α-hydroxyglycine in vivo is provided, indicating that the reaction intermediate becomes free and is not handed directly from PHM to PAL in vertebrates.
Abstract: Amidated neuropeptides play essential roles throughout the nervous and endocrine systems. Mice lacking peptidylglycine α-amidating monooxygenase (PAM), the only enzyme capable of producing amidated peptides, are not viable. In the amidation reaction, the reactant (glycine-extended peptide) is converted into a reaction intermediate (hydroxyglycine-extended peptide) by the copper-dependent peptidylglycine-α-hydroxylating monooxygenase (PHM) domain of PAM. The hydroxyglycine-extended peptide is then converted into amidated product by the peptidyl-α-hydroxyglycine α-amidating lyase (PAL) domain of PAM. PHM and PAL are stitched together in vertebrates, but separated in some invertebrates such as Drosophila and Hydra. In addition to its luminal catalytic domains, PAM includes a cytosolic domain that can enter the nucleus following release from the membrane by γ-secretase. In this work, several glycine- and hydroxyglycine-extended peptides as well as amidated peptides were qualitatively and quantitatively assessed from pituitaries of wild-type mice and mice with a single copy of the Pam gene (PAM+/−) via liquid chromatography-mass spectrometry-based methods. We provide the first evidence for the presence of a peptidyl-α-hydroxyglycine in vivo, indicating that the reaction intermediate becomes free and is not handed directly from PHM to PAL in vertebrates. Wild-type mice fed a copper deficient diet and PAM+/− mice exhibit similar behavioral deficits. While glycine-extended reaction intermediates accumulated in the PAM+/− mice and reflected dietary copper availability, amidated products were far more prevalent under the conditions examined, suggesting that the behavioral deficits observed do not simply reflect a lack of amidated peptides.
23 citations
TL;DR: Four microarray experiments encompassing three developmental stages, two tissue sources, and two reproductive technologies were combined using two sets of meta-analyses that uncovered 434 genes differentially expressed between AI and NT (regardless of stage or source).
Abstract: Microarray gene expression experiments often consider specific developmental stages, tissue sources, or reproductive technologies. This focus hinders the understanding of the cattle embryo transcriptome. To address this, four microarray experiments encompassing three developmental stages (7, 25, 280 days), two tissue sources (embryonic or extra-embryonic), and two reproductive technologies (artificial insemination or AI and somatic cell nuclear transfer or NT) were combined using two sets of meta-analyses. The first set of meta-analyses uncovered 434 genes differentially expressed between AI and NT (regardless of stage or source) that were not detected by the individual-experiment analyses. The molecular function of transferase activity was enriched among these genes that included ECE2, SLC22A1, and a gene similar to CAMK2D. Gene POLG2 was over-expressed in AI versus NT 7-day embryos and was under-expressed in AI versus NT 25-day embryos. Gene HAND2 was over-expressed in AI versus NT extra-embryonic samples at 280 days yet under-expressed in AI versus NT embryonic samples at 7 days. The second set of meta-analyses uncovered enrichment of system, organ, and anatomical structure development among the genes differentially expressed between 7- and 25-day embryos from either reproductive technology. Genes PRDX1and SLC16A1 were over-expressed in 7- versus 25-day AI embryos and under-expressed in 7- versus 25-day NT embryos. Changes in stage were associated with high number of differentially expressed genes, followed by technology and source. Genes with transferase activity may hold a clue to the differences in efficiency between reproductive technologies.
9 citations
12 Nov 2011
TL;DR: An all-encompassing model that describes tandem mass spectra intensity and can offer insights into the factors that influence ion intensity was developed and applied to 61,543 mouse peptides and supported the precise prediction and realistic simulation ofmass spectra and augment the understanding of the factors influencing ion intensity in mass spectrometry experiments.
Abstract: In tandem mass spectrometry experiments, the spectra relating peak intensity to the mass-to-charge of the ions is used to identify the peptides in a sample. However, multiple factors influence the spectra profile. An all-encompassing model that describes tandem mass spectra intensity and can offer insights into the factors that influence ion intensity was developed and applied to 61,543 mouse peptides. Several factors had a significant association with the intensity of ions formed. Among these factors are: the type of ions formed after the fragmentation of peptides, the residue content of the fragmenting peptide, proton mobility, neutral mass loss and peptide-ion charge combination. The results from our model support the precise prediction and realistic simulation of mass spectra and augment the understanding of the factors influencing ion intensity in mass spectrometry experiments.
2 citations
27 Dec 2011
TL;DR: The expression of exons corresponding to 25,403 genes was related to the survival of 328 patients diagnosed with Glioblastoma multiforme (GBM), and among the multiple-exon genes exhibiting AEU were epidermal growth factor and nidogen2 that have known association with GBM.
Abstract: Exon expression platforms have allowed the detection of associations between alternative exon usage (AEU) and the proliferation of malignant cells in cancer. However, due to inadequate number of studies performed on AEU and the approaches utilized to detect AEU events, well established biomarkers for GBM are not available. The expression of exons corresponding to 25,403 genes was related to the survival of 328 patients diagnosed with Glioblastoma multiforme (GBM). An approach that takes exon expression into account was adopted to detect the association between exon expression and survival. Association between expression and survival were identified in 22 single-exon genes 248 genes with 2–25 exons, 1430 genes with >24 and 50 exons. Among the multiple-exon genes exhibiting AEU were epidermal growth factor (EGF) and nidogen2 (NID2) that have known association with GBM. These results are consistent with reports that these genes have 12 and 10 transcripts, respectively.
1 citations
1 citations
12 Nov 2011
TL;DR: The results suggest that methods optimized to detect neuropeptides are required and OMSSA, X!Tandem and Crux were applied to identify simulated mass spectra on a database of 7857 mouse neuropePTides from 92 prohormones.
Abstract: Tools to identify proteins in tandem mass spectrometry experiments are not optimized to identify neuropeptides due to complex processing, post-translational modifications and neuropeptide size. The complementary strengths of three widely-used protein identification tools to identify neuropeptides were assessed. OMSSA, X!Tandem and Crux were applied to identify simulated mass spectra on a database of 7857 mouse neuropeptides from 92 prohormones. For each peptide, spectra was simulated with either +1, +2 and +3 precursor charge states, +1 charged b and y product ions having single water and/or ammonia loss depending on amino acid composition. OMSSA and X!Tandem identified 83% of the peptides with an E-value or P-value < 10−9, while Crux detected 81% and 11% of the peptides with a P-value < 10−1 and < 10−2, respectively. Precursor charge states have minor effect on the detection of neuropeptides. The sensitivity of either tool to detect small neuropeptides (< 10 amino acids in length) was limited. Our results suggest that methods optimized to detect neuropeptides are required.
12 Nov 2011
TL;DR: The genomic characterization allows the use of the pig as an effective animal model to gain a deeper understanding of neuropeptides and to obtain an in silico library of pig prohormone and convertase genes and to functionally annotate these genes based on a large number of complementary gene expression microarray experiments.
Abstract: Neuropeptides support inter-cell communication and have a role in many diverse biological processes. For pig, a biomedical model, few prohormones from which neuropeptides result after convertase processing are listed in the UniProt database. Therefore, our goals are to obtain an in silico library of pig prohormone and convertase genes and to functionally annotate these genes based on a large number of complementary gene expression microarray experiments. Using a bioinformatics pipeline, 101 prohormone genes and 8 convertase genes known in human, rat, mouse, chicken, and cow were located in the pig genome. Frequently (P-value < 0.005) differentially expressed prohormone genes included adrenomedullin (ADML), augurin (AUGN), neuropeptide Y (NPY), proenkephalin-A (PENK), parathyroid hormone-related protein (PTHR), and vascular endothelial growth factor C (VEGFC) and convertases (PCSK1 and PCSK7). Embryo and placental tissues displayed the most differentially expressed genes. Our genomic characterization allows the use of the pig as an effective animal model to gain a deeper understanding of neuropeptides.