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Molecular and epidemiologic characterization of Wilms tumor from Baghdad, Iraq.
Phelps HM, Al-Jadiry MF, Corbitt NM, Pierce JM, Li B, Wei Q, Flores RR, Correa H, Uccini S, Frangoul H, Alsaadawi AR, Al-Badri SAF, Al-Darraji AF, Al-Saeed RM, Al-Hadad SA, Lovvorn Iii HN
(2018) World J Pediatr 14: 585-593
MeSH Terms: Adaptor Proteins, Signal Transducing, Child, Preschool, DNA Topoisomerases, Type II, Female, Homeodomain Proteins, Humans, Immunohistochemistry, Infant, Insulin-Like Growth Factor II, Iraq, Kidney Neoplasms, Male, Multiplex Polymerase Chain Reaction, Mutation, N-Myc Proto-Oncogene Protein, Nerve Tissue Proteins, Neural Cell Adhesion Molecules, Nuclear Proteins, Poly-ADP-Ribose Binding Proteins, Receptors, Retinoic Acid, Sequence Analysis, DNA, Transcription Factors, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, WT1 Proteins, Wilms Tumor, beta Catenin
Show Abstract · Added January 28, 2019
BACKGROUND - Wilms tumor (WT) is the most common childhood kidney cancer worldwide, yet its incidence and clinical behavior vary according to race and access to adequate healthcare resources. To guide and streamline therapy in the war-torn and resource-constrained city of Baghdad, Iraq, we conducted a first-ever molecular analysis of 20 WT specimens to characterize the biological features of this lethal disease within this challenged population.
METHODS - Next-generation sequencing of ten target genes associated with WT development and treatment resistance (WT1, CTNNB1, WTX, IGF2, CITED1, SIX2, p53, N-MYC, CRABP2, and TOP2A) was completed. Immunohistochemistry was performed for 6 marker proteins of WT (WT1, CTNNB1, NCAM, CITED1, SIX2, and p53). Patient outcomes were compiled.
RESULTS - Mutations were detected in previously described WT "hot spots" (e.g., WT1 and CTNNB1) as well as novel loci that may be unique to the Iraqi population. Immunohistochemistry showed expression domains most typical of blastemal-predominant WT. Remarkably, despite the challenges facing families and care providers, only one child, with combined WT1 and CTNNB1 mutations, was confirmed dead from disease. Median clinical follow-up was 40.5 months (range 6-78 months).
CONCLUSIONS - These data suggest that WT biology within a population of Iraqi children manifests features both similar to and unique from disease variants in other regions of the world. These observations will help to risk stratify WT patients living in this difficult environment to more or less intensive therapies and to focus treatment on cell-specific targets.
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27 MeSH Terms
Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas.
Liu Y, Sethi NS, Hinoue T, Schneider BG, Cherniack AD, Sanchez-Vega F, Seoane JA, Farshidfar F, Bowlby R, Islam M, Kim J, Chatila W, Akbani R, Kanchi RS, Rabkin CS, Willis JE, Wang KK, McCall SJ, Mishra L, Ojesina AI, Bullman S, Pedamallu CS, Lazar AJ, Sakai R, Cancer Genome Atlas Research Network, Thorsson V, Bass AJ, Laird PW
(2018) Cancer Cell 33: 721-735.e8
MeSH Terms: Adenocarcinoma, Aneuploidy, Chromosomal Instability, DNA Methylation, DNA Polymerase II, Epigenesis, Genetic, Female, Gastrointestinal Neoplasms, Gene Regulatory Networks, Heterogeneous-Nuclear Ribonucleoproteins, Humans, Male, Microsatellite Instability, MutL Protein Homolog 1, Mutation, Poly-ADP-Ribose Binding Proteins, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins p21(ras), SOX9 Transcription Factor
Show Abstract · Added October 30, 2019
We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for insertions/deletions, representing microsatellite instability cases with epigenetic silencing of MLH1 in the context of CpG island methylator phenotype, plus tumors with elevated single-nucleotide variants associated with mutations in POLE. Tumors with chromosomal instability were diverse, with gastroesophageal adenocarcinomas harboring fragmented genomes associated with genomic doubling and distinct mutational signatures. We identified a group of tumors in the colon and rectum lacking hypermutation and aneuploidy termed genome stable and enriched in DNA hypermethylation and mutations in KRAS, SOX9, and PCBP1.
Copyright © 2018 Elsevier Inc. All rights reserved.
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MeSH Terms
Respiratory syncytial virus induces host RNA stress granules to facilitate viral replication.
Lindquist ME, Lifland AW, Utley TJ, Santangelo PJ, Crowe JE
(2010) J Virol 84: 12274-84
MeSH Terms: Antigens, Surface, Blotting, Western, Carrier Proteins, Cell Line, Cytoplasmic Granules, DNA Helicases, ELAV Proteins, ELAV-Like Protein 1, Epithelial Cells, Humans, Poly-ADP-Ribose Binding Proteins, RNA Helicases, RNA Interference, RNA Recognition Motif Proteins, RNA, Messenger, RNA-Binding Proteins, Respiratory Syncytial Virus Infections, Respiratory Syncytial Viruses, Reverse Transcriptase Polymerase Chain Reaction, Stress, Physiological, Virus Replication
Show Abstract · Added August 6, 2012
Mammalian cell cytoplasmic RNA stress granules are induced during various conditions of stress and are strongly associated with regulation of host mRNA translation. Several viruses induce stress granules during the course of infection, but the exact function of these structures during virus replication is not well understood. In this study, we showed that respiratory syncytial virus (RSV) induced host stress granules in epithelial cells during the course of infection. We also showed that stress granules are distinct from cytoplasmic viral inclusion bodies and that the RNA binding protein HuR, normally found in stress granules, also localized to viral inclusion bodies during infection. Interestingly, we demonstrated that infected cells containing stress granules also contained more RSV protein than infected cells that did not form inclusion bodies. To address the role of stress granule formation in RSV infection, we generated a stable epithelial cell line with reduced expression of the Ras-GAP SH3 domain-binding protein (G3BP) that displayed an inhibited stress granule response. Surprisingly, RSV replication was impaired in these cells compared to its replication in cells with intact G3BP expression. In contrast, knockdown of HuR by RNA interference did not affect stress granule formation or RSV replication. Finally, using RNA probes specific for RSV genomic RNA, we found that viral RNA predominantly localized to viral inclusion bodies but a small percentage also interacted with stress granules during infection. These results suggest that RSV induces a host stress granule response and preferentially replicates in host cells that have committed to a stress response.
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21 MeSH Terms
Epigenetic and genetic silencing of CHFR in esophageal adenocarcinomas.
Soutto M, Peng D, Razvi M, Ruemmele P, Hartmann A, Roessner A, Schneider-Stock R, El-Rifai W
(2010) Cancer 116: 4033-42
MeSH Terms: Adenocarcinoma, Cell Cycle Proteins, DNA Methylation, Down-Regulation, Esophageal Neoplasms, Gene Dosage, Gene Silencing, Genes, Tumor Suppressor, Genes, cdc, Humans, Immunohistochemistry, Neoplasm Proteins, Poly-ADP-Ribose Binding Proteins, Ubiquitin-Protein Ligases
Show Abstract · Added March 5, 2014
BACKGROUND - The checkpoint with forkhead-associated domain and RING-finger domain (CHFR) is a mitotic checkpoint protein with tumor-suppressor functions. In this study, the authors investigated the epigenetic and genetic mechanisms that regulate CHFR expression in esophageal adenocarcinomas (EACs).
METHODS - Quantitative reverse transcriptase polymerase chain reaction analysis demonstrated downregulation of CHFR transcript in 79% of EACs (44 of 56) compared with 41 normal samples (P < .001). Immunohistochemical analysis of CHFR protein expression showed absence or weak immunostaining for CHFR in 75% of EACs (56 of 75) compared with normal tissue samples. The authors next examined the promoter DNA hypermethylation of CHFR by using quantitative bisulfite pyrosequencing technology. They detected significant CHFR promoter DNA hypermethylation in 31% of tumor samples (18 of 58) compared with normal samples (P < .001). Treatment of OE33 cells with 5-Aza-deoxycytidine led to reduction in the promoter DNA methylation levels with restoration of the CHFR mRNA expression, which confirmed promoter DNA methylation as an epigenetic mechanism regulating CHFR expression. However, they identified several EACs where the CHFR mRNA expression was silenced in the absence of notable methylation. Therefore, the authors examined the relative DNA copy number level of CHFR compared with normal samples.
RESULTS - The results confirmed a decrease or absence of the relative CHFR DNA copy number levels in 59% of tumor samples. Nine tumors that showed loss of CHFR mRNA expression, in absence of promoter DNA hypermethylation, demonstrated a significant loss of relative CHFR DNA copy numbers.
CONCLUSIONS - Taken together, their findings demonstrated that both epigenetic and genetic mechanisms were involved in silencing CHFR expression in EACs.
Cancer 2010. (c) 2010 American Cancer Society.
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14 MeSH Terms
Microtubule-dependent association of AKAP350A and CCAR1 with RNA stress granules.
Kolobova E, Efimov A, Kaverina I, Rishi AK, Schrader JW, Ham AJ, Larocca MC, Goldenring JR
(2009) Exp Cell Res 315: 542-55
MeSH Terms: A Kinase Anchor Proteins, Apoptosis Regulatory Proteins, Arsenites, Carrier Proteins, Cell Cycle Proteins, Cytoplasmic Granules, Cytoskeletal Proteins, Cytosol, DNA Helicases, Golgi Apparatus, HeLa Cells, Humans, Microtubules, Nocodazole, Poly-ADP-Ribose Binding Proteins, Protein Transport, RNA Helicases, RNA Recognition Motif Proteins, RNA Stability, RNA, Messenger
Show Abstract · Added December 10, 2013
Recent investigations have highlighted the importance of subcellular localization of mRNAs to cell function. While AKAP350A, a multifunctional scaffolding protein, localizes to the Golgi apparatus and centrosomes, we have now identified a cytosolic pool of AKAP350A. Analysis of AKAP350A scaffolded complexes revealed two novel interacting proteins, CCAR1 and caprin-1. CCAR1, caprin-1 and AKAP350A along with G3BP, a stress granule marker, relocate to RNA stress granules after arsenite treatment. Stress also caused loss of AKAP350 from the Golgi and fragmentation of the Golgi apparatus. Disruption of microtubules with nocodazole altered stress granule formation and changed their morphology by preventing fusion of stress granules. In the presence of nocodazole, arsenite induced smaller granules with the vast majority of AKAP350A and CCAR1 separated from G3BP-containing granules. Similar to nocodazole treatment, reduction of AKAP350A or CCAR1 expression also altered the size and number of G3BP-containing stress granules induced by arsenite treatment. A limited set of 69 mRNA transcripts was immunoisolated with AKAP350A even in the absence of stress, suggesting the association of AKAP350A with mRNA transcripts. These results provide the first evidence for the microtubule dependent association of AKAP350A and CCAR1 with RNA stress granules.
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20 MeSH Terms
Modulation of DNA fragmentation factor 40 nuclease activity by poly(ADP-ribose) polymerase-1.
West JD, Ji C, Marnett LJ
(2005) J Biol Chem 280: 15141-7
MeSH Terms: Animals, Apoptosis, Blotting, Western, Caspase 3, Caspase 7, Caspases, Cell Line, Cell Line, Tumor, DNA Fragmentation, DNA Repair, Deoxyribonucleases, Enzyme Activation, Epitopes, Genetic Vectors, Glycoside Hydrolases, Humans, Immunoprecipitation, Lipid Peroxidation, Mice, Models, Biological, Models, Molecular, Plasmids, Poly Adenosine Diphosphate Ribose, Poly(ADP-ribose) Polymerases, Poly-ADP-Ribose Binding Proteins, Protein Binding, Time Factors, Transcription, Genetic, Transfection
Show Abstract · Added March 5, 2014
Poly(ADP-ribose) polymerase-1 (PARP-1) influences numerous cellular processes, including DNA repair, transcriptional regulation, and caspase-independent cell death, by utilizing NAD(+) to synthesize long chains of poly(ADP-ribose) (PAR) on target proteins, including itself. During the apoptotic response, caspases-3 and -7 cleave PARP-1, thereby inhibiting its activity. Here, we have examined the role of PARP-1 activation and cleavage in the latter stages of apoptosis in response to DNA fragmentation. PARP-1 poly(ADP-ribosyl)ation correlated directly with induction of apoptosis by the lipid peroxidation product, 4-hydroxy-2-nonenal. A significant decrease in PAR accumulation was observed upon caspase or DNA fragmentation factor 40 (DFF40) inhibition. Because DNA fragmentation mediated by DFF40 augmented PARP-1 modification status in apoptotic cells, we hypothesized that PARP-1 alters DFF40 function following PAR accumulation. Indeed, PARP-1, in the presence of NAD(+), significantly decreased DFF40 activity on plasmid substrates. Conversely, PARP-1 enhanced the DNase activity of DFF40 in the absence of NAD(+). The inhibition of DFF40 activity in the presence of NAD(+) was reduced by co-incubation with poly(ADP-ribose) glycohydrolase and a PARP inhibitor. Additionally, caspase-cleaved PARP-1, in the presence of NAD(+), did not inhibit DFF40 activity significantly. Our results suggest that PARP-1 poly(ADP-ribosyl)ation is a terminal event in the apoptotic response that occurs in response to DNA fragmentation and directly influences DFF40 activity.
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29 MeSH Terms
Coamplified and overexpressed genes at ERBB2 locus in gastric cancer.
Varis A, Zaika A, Puolakkainen P, Nagy B, Madrigal I, Kokkola A, Väyrynen A, Kärkkäinen P, Moskaluk C, El-Rifai W, Knuutila S
(2004) Int J Cancer 109: 548-53
MeSH Terms: Adenocarcinoma, Antigens, Neoplasm, Case-Control Studies, Chromosomes, Human, Pair 17, DNA Topoisomerases, Type II, DNA, Neoplasm, DNA-Binding Proteins, Dopamine and cAMP-Regulated Phosphoprotein 32, Gastric Mucosa, Gastrointestinal Neoplasms, Gene Amplification, Gene Dosage, Gene Expression Regulation, Neoplastic, Humans, In Situ Hybridization, Fluorescence, Nerve Tissue Proteins, Phosphoproteins, Poly-ADP-Ribose Binding Proteins, RNA, Messenger, RNA, Neoplasm, Receptor, ErbB-2, Reverse Transcriptase Polymerase Chain Reaction
Show Abstract · Added March 5, 2014
DNA copy number amplification at the chromosomal region of 17q is frequent in gastric cancer. Recently 17q21 was identified as the critical region for the amplicon formation because this region harbors the ERBB2 oncogene and several other targets, such as TOP2A and DARPP32. In our study, we characterized the amplification (52 cases) and expression (29 cases) levels of ERBB2, TOP2A and DARPP32 in gastric cancer samples. These 3 genes were concomitantly amplified in 17% of the intestinal type of gastric adenocarcinoma. However, the expression levels were independent, showing overexpression of DARPP32 (48%), TOP2A (17%) and ERBB2 (3%) studied by quantitative real-time PCR. The most frequently overexpressed gene, DARPP32, exhibited strong protein overexpression in 45% (30/66) of the cases in immunohistochemical study of gastric cancer tumor tissue array. Additional studies are required to thoroughly understand the biological significance of these genes in gastric cancer.
Copyright 2004 Wiley-Liss, Inc.
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22 MeSH Terms
Conducting the mitotic symphony.
Cortez D, Elledge SJ
(2000) Nature 406: 354-6
MeSH Terms: Animals, Cell Cycle Proteins, Chromosome Segregation, Genes, cdc, Humans, Mitosis, Neoplasm Proteins, Poly-ADP-Ribose Binding Proteins, Spindle Apparatus, Tumor Cells, Cultured, Ubiquitin-Protein Ligases
Added March 11, 2014
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11 MeSH Terms