Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 452

Publication Record

Connections

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.
0 Communities
1 Members
0 Resources
27 MeSH Terms
ARID1A Maintains Differentiation of Pancreatic Ductal Cells and Inhibits Development of Pancreatic Ductal Adenocarcinoma in Mice.
Kimura Y, Fukuda A, Ogawa S, Maruno T, Takada Y, Tsuda M, Hiramatsu Y, Araki O, Nagao M, Yoshikawa T, Ikuta K, Yoshioka T, Wang Z, Akiyama H, Wright CV, Takaori K, Uemoto S, Chiba T, Seno H
(2018) Gastroenterology 155: 194-209.e2
MeSH Terms: Adenocarcinoma in Situ, Animals, Carcinogenesis, Carcinoma, Pancreatic Ductal, Cell Culture Techniques, Cell Differentiation, DNA-Binding Proteins, Mice, Nuclear Proteins, Pancreatic Ducts, Pancreatic Neoplasms, Proto-Oncogene Proteins p21(ras), SOX9 Transcription Factor
Show Abstract · Added April 3, 2018
BACKGROUND & AIMS - The ARID1A gene encodes a protein that is part of the large adenosine triphosphate (ATP)-dependent chromatin remodeling complex SWI/SNF and is frequently mutated in human pancreatic ductal adenocarcinomas (PDACs). We investigated the functions of ARID1A during formation of PDACs in mice.
METHODS - We performed studies with Ptf1a-Cre;Kras mice, which express activated Kras in the pancreas and develop pancreatic intraepithelial neoplasias (PanINs), as well as those with disruption of Aird1a (Ptf1a-Cre;Kras;Arid1a mice) or disruption of Brg1 (encodes a catalytic ATPase of the SWI/SNF complex) (Ptf1a-Cre;Kras; Brg1mice). Pancreatic ductal cells (PDCs) were isolated from Arid1a mice and from Arid1a;SOX9OE mice, which overexpress human SOX9 upon infection with an adenovirus-expressing Cre recombinase. Pancreatic tissues were collected from all mice and analyzed by histology and immunohistochemistry; cells were isolated and grown in 2-dimensional and 3-dimensional cultures. We performed microarray analyses to compare gene expression patterns in intraductal papillary mucinous neoplasms (IPMNs) from the different strains of mice. We obtained 58 samples of IPMNs and 44 samples of PDACs from patients who underwent pancreatectomy in Japan and analyzed them by immunohistochemistry.
RESULTS - Ptf1a-Cre;Kras mice developed PanINs, whereas Ptf1a-Cre;Kras;Arid1a mice developed IPMNs and PDACs; IPMNs originated from PDCs. ARID1A-deficient IPMNs did not express SOX9. ARID1A-deficient PDCs had reduced expression of SOX9 and dedifferentiated in culture. Overexpression of SOX9 in these cells allowed them to differentiate and prevented dilation of ducts. Among mice with pancreatic expression of activated Kras, those with disruption of Arid1a developed fewer PDACs from IPMNs than mice with disruption of Brg1. ARID1A-deficient IPMNs had reduced activity of the mTOR pathway. Human IPMN and PDAC specimens had reduced levels of ARID1A, SOX9, and phosphorylated S6 (a marker of mTOR pathway activation). Levels of ARID1A correlated with levels of SOX9 and phosphorylated S6.
CONCLUSIONS - ARID1A regulates expression of SOX9, activation of the mTOR pathway, and differentiation of PDCs. ARID1A inhibits formation of PDACs from IPMNs in mice with pancreatic expression of activated KRAS and is down-regulated in IPMN and PDAC tissues from patients.
Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.
2 Communities
1 Members
0 Resources
13 MeSH Terms
Dynamic landscape and regulation of RNA editing in mammals.
Tan MH, Li Q, Shanmugam R, Piskol R, Kohler J, Young AN, Liu KI, Zhang R, Ramaswami G, Ariyoshi K, Gupte A, Keegan LP, George CX, Ramu A, Huang N, Pollina EA, Leeman DS, Rustighi A, Goh YPS, GTEx Consortium, Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group, Statistical Methods groups—Analysis Working Group, Enhancing GTEx (eGTEx) groups, NIH Common Fund, NIH/NCI, NIH/NHGRI, NIH/NIMH, NIH/NIDA, Biospecimen Collection Source Site—NDRI, Biospecimen Collection Source Site—RPCI, Biospecimen Core Resource—VARI, Brain Bank Repository—University of Miami Brain Endowment Bank, Leidos Biomedical—Project Management, ELSI Study, Genome Browser Data Integration &Visualization—EBI, Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz, Chawla A, Del Sal G, Peltz G, Brunet A, Conrad DF, Samuel CE, O'Connell MA, Walkley CR, Nishikura K, Li JB
(2017) Nature 550: 249-254
MeSH Terms: Adenosine Deaminase, Animals, Female, Genotype, HEK293 Cells, Humans, Male, Mice, Muscles, Nuclear Proteins, Organ Specificity, Primates, Proteolysis, RNA Editing, RNA-Binding Proteins, Spatio-Temporal Analysis, Species Specificity, Transcriptome
Show Abstract · Added October 27, 2017
Adenosine-to-inosine (A-to-I) RNA editing is a conserved post-transcriptional mechanism mediated by ADAR enzymes that diversifies the transcriptome by altering selected nucleotides in RNA molecules. Although many editing sites have recently been discovered, the extent to which most sites are edited and how the editing is regulated in different biological contexts are not fully understood. Here we report dynamic spatiotemporal patterns and new regulators of RNA editing, discovered through an extensive profiling of A-to-I RNA editing in 8,551 human samples (representing 53 body sites from 552 individuals) from the Genotype-Tissue Expression (GTEx) project and in hundreds of other primate and mouse samples. We show that editing levels in non-repetitive coding regions vary more between tissues than editing levels in repetitive regions. Globally, ADAR1 is the primary editor of repetitive sites and ADAR2 is the primary editor of non-repetitive coding sites, whereas the catalytically inactive ADAR3 predominantly acts as an inhibitor of editing. Cross-species analysis of RNA editing in several tissues revealed that species, rather than tissue type, is the primary determinant of editing levels, suggesting stronger cis-directed regulation of RNA editing for most sites, although the small set of conserved coding sites is under stronger trans-regulation. In addition, we curated an extensive set of ADAR1 and ADAR2 targets and showed that many editing sites display distinct tissue-specific regulation by the ADAR enzymes in vivo. Further analysis of the GTEx data revealed several potential regulators of editing, such as AIMP2, which reduces editing in muscles by enhancing the degradation of the ADAR proteins. Collectively, our work provides insights into the complex cis- and trans-regulation of A-to-I editing.
0 Communities
1 Members
0 Resources
18 MeSH Terms
Chemosensitive Relapse in Small Cell Lung Cancer Proceeds through an EZH2-SLFN11 Axis.
Gardner EE, Lok BH, Schneeberger VE, Desmeules P, Miles LA, Arnold PK, Ni A, Khodos I, de Stanchina E, Nguyen T, Sage J, Campbell JE, Ribich S, Rekhtman N, Dowlati A, Massion PP, Rudin CM, Poirier JT
(2017) Cancer Cell 31: 286-299
MeSH Terms: Animals, Drug Resistance, Neoplasm, Enhancer of Zeste Homolog 2 Protein, Humans, Lung Neoplasms, Mice, Nuclear Proteins, Small Cell Lung Carcinoma, Twist-Related Protein 1
Show Abstract · Added January 29, 2018
Small cell lung cancer is initially highly responsive to cisplatin and etoposide but in almost every case becomes rapidly chemoresistant, leading to death within 1 year. We modeled acquired chemoresistance in vivo using a series of patient-derived xenografts to generate paired chemosensitive and chemoresistant cancers. Multiple chemoresistant models demonstrated suppression of SLFN11, a factor implicated in DNA-damage repair deficiency. In vivo silencing of SLFN11 was associated with marked deposition of H3K27me3, a histone modification placed by EZH2, within the gene body of SLFN11, inducing local chromatin condensation and gene silencing. Inclusion of an EZH2 inhibitor with standard cytotoxic therapies prevented emergence of acquired resistance and augmented chemotherapeutic efficacy in both chemosensitive and chemoresistant models of small cell lung cancer.
Copyright © 2017 Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
9 MeSH Terms
Hedgehog and TGFβ signaling converge on Gli2 to control bony invasion and bone destruction in oral squamous cell carcinoma.
Cannonier SA, Gonzales CB, Ely K, Guelcher SA, Sterling JA
(2016) Oncotarget 7: 76062-76075
MeSH Terms: Animals, Bone and Bones, Carcinoma, Squamous Cell, Cell Line, Tumor, Disease Models, Animal, Gene Expression, Hedgehog Proteins, Heterografts, Humans, Mice, Mouth Neoplasms, Neoplasm Invasiveness, Nuclear Proteins, Parathyroid Hormone-Related Protein, Signal Transduction, Transforming Growth Factor beta, Zinc Finger Protein Gli2
Show Abstract · Added April 26, 2017
Oral Squamous Cell Carcinoma (OSCC) is the sixth most common cancer worldwide. OSCC invasion into the lymph nodes and mandible correlates with increased rates of recurrence and lower overall survival. Tumors that infiltrate mandibular bone proliferate rapidly and induce bone destruction. While survival rates have increased 12% over the last 20 years, this improvement is attributed to general advances in prevention, earlier detection, and updated treatments. Additionally, despite decades of research, the molecular mechanisms of OSCC invasion into the mandible are not well understood. Parathyroid Hormone-related Protein (PTHrP), has been shown to be essential for mandibular invasion in OSCC animal models, and our previous studies demonstrate that the transcription factor Gli2 increases PTHrP expression in tumor metastasis to bone. In OSCC, we investigated regulators of Gli2, including Hedgehog, TGFβ, and Wnt signaling to elucidate how PTHrP expression is controlled. Here we show that canonical Hedgehog and TGFβ signaling cooperate to increase PTHrP expression and mandibular invasion in a Gli2-dependent manner. Additionally, in an orthotopic model of mandibular invasion, inhibition of Gli2 using shRNA resulted in a significant decrease of both PTHrP expression and bony invasion. Collectively, our findings demonstrate that multiple signaling pathways converge on Gli2 to mediate PTHrP expression and bony invasion, highlighting Gli2 as a therapeutic target to prevent bony invasion in OSCC.
0 Communities
2 Members
0 Resources
17 MeSH Terms
The MAPK Pathway Regulates Intrinsic Resistance to BET Inhibitors in Colorectal Cancer.
Ma Y, Wang L, Neitzel LR, Loganathan SN, Tang N, Qin L, Crispi EE, Guo Y, Knapp S, Beauchamp RD, Lee E, Wang J
(2017) Clin Cancer Res 23: 2027-2037
MeSH Terms: Animals, Antineoplastic Agents, Apoptosis, Cell Line, Tumor, Cell Proliferation, Colorectal Neoplasms, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Humans, MAP Kinase Signaling System, Mice, Mice, Nude, Nuclear Proteins, Real-Time Polymerase Chain Reaction, Transcription Factors, Xenograft Model Antitumor Assays
Show Abstract · Added November 19, 2016
The bromodomain and extra-terminal domain (BET) family proteins are epigenetic readers for acetylated histone marks. Emerging BET bromodomain inhibitors have exhibited antineoplastic activities in a wide range of human cancers through suppression of oncogenic transcription factors, including MYC. However, the preclinical activities of BET inhibitors in advanced solid cancers are moderate at best. To improve BET-targeted therapy, we interrogated mechanisms mediating resistance to BET inhibitors in colorectal cancer. Using a panel of molecularly defined colorectal cancer cell lines, we examined the impact of BET inhibition on cellular proliferation and survival as well as MYC activity. We further tested the ability of inhibitors targeting the RAF/MEK/ERK (MAPK) pathway to enhance MYC suppression and circumvent intrinsic resistance to BET inhibitors. Key findings were validated using genetic approaches. BET inhibitors as monotherapy moderately reduced colorectal cancer cell proliferation and MYC expression. Blockade of the MAPK pathway synergistically sensitized colorectal cancer cells to BET inhibitors, leading to potent apoptosis and MYC downregulation and A combination of JQ1 and trametinib, but neither agent alone, induced significant regression of subcutaneous colorectal cancer xenografts. Our findings suggest that the MAPK pathway confers intrinsic resistance to BET inhibitors in colorectal cancer and propose an effective combination strategy for the treatment of colorectal cancer. .
©2016 American Association for Cancer Research.
0 Communities
4 Members
0 Resources
17 MeSH Terms
Myeloid translocation genes differentially regulate colorectal cancer programs.
Parang B, Bradley AM, Mittal MK, Short SP, Thompson JJ, Barrett CW, Naik RD, Bilotta AJ, Washington MK, Revetta FL, Smith JJ, Chen X, Wilson KT, Hiebert SW, Williams CS
(2016) Oncogene 35: 6341-6349
MeSH Terms: Animals, Colorectal Neoplasms, Female, Humans, Male, Mice, Mice, Inbred C57BL, Nuclear Proteins, Repressor Proteins, Signal Transduction, Transcription Factors, Translocation, Genetic, Tumor Suppressor Proteins
Show Abstract · Added June 23, 2016
Myeloid translocation genes (MTGs), originally identified as chromosomal translocations in acute myelogenous leukemia, are transcriptional corepressors that regulate hematopoietic stem cell programs. Analysis of The Cancer Genome Atlas (TCGA) database revealed that MTGs were mutated in epithelial malignancy and suggested that loss of function might promote tumorigenesis. Genetic deletion of MTGR1 and MTG16 in the mouse has revealed unexpected and unique roles within the intestinal epithelium. Mtgr1 mice have progressive depletion of all intestinal secretory cells, and Mtg16 mice have a decrease in goblet cells. Furthermore, both Mtgr1 and Mtg16 mice have increased intestinal epithelial cell proliferation. We thus hypothesized that loss of MTGR1 or MTG16 would modify Apc-dependent intestinal tumorigenesis. Mtgr1 mice, but not Mtg16 mice, had a 10-fold increase in tumor multiplicity. This was associated with more advanced dysplasia, including progression to invasive adenocarcinoma, and augmented intratumoral proliferation. Analysis of chromatin immunoprecipitation sequencing data sets for MTGR1 and MTG16 targets indicated that MTGR1 can regulate Wnt and Notch signaling. In support of this, immunohistochemistry and gene expression analysis revealed that both Wnt and Notch signaling pathways were hyperactive in Mtgr1 tumors. Furthermore, in human colorectal cancer (CRC) samples MTGR1 was downregulated at both the transcript and protein level. Overall our data indicates that MTGR1 has a context-dependent effect on intestinal tumorigenesis.
0 Communities
3 Members
0 Resources
13 MeSH Terms
An In Vivo Gain-of-Function Screen Identifies the Williams-Beuren Syndrome Gene GTF2IRD1 as a Mammary Tumor Promoter.
Huo Y, Su T, Cai Q, Macara IG
(2016) Cell Rep 15: 2089-2096
MeSH Terms: Animals, Bone Morphogenetic Protein Receptors, Type I, Breast Neoplasms, Carcinogenesis, Female, Gene Expression Regulation, Neoplastic, Genetic Testing, Humans, Mammary Neoplasms, Animal, Mice, Transgenic, Muscle Proteins, Nuclear Proteins, Protein-Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Trans-Activators, Williams Syndrome
Show Abstract · Added April 3, 2018
The broad implementation of precision medicine in cancer is impeded by the lack of a complete inventory of the genes involved in tumorigenesis. We performed in vivo screening of ∼1,000 genes that are associated with signaling for positive roles in breast cancer, using lentiviral expression vectors in primary MMTV-ErbB2 mammary tissue. Gain of function of five genes, including RET, GTF2IRD1, ADORA1, LARS2, and DPP8, significantly promoted mammary tumor growth. We further studied one tumor-promoting gene, the transcription factor GTF2IRD1. The mis-regulation of genes downstream of GTF2IRD1, including TβR2 and BMPR1b, also individually promoted mammary cancer development, and silencing of TβR2 suppressed GTF2IRD1-driven tumor promotion. In addition, GTF2IRD1 is highly expressed in human breast tumors, correlating with high tumor grades and poor prognosis. Our in vivo approach is readily expandable to whole-genome annotation of tumor-promoting genes.
Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
0 Communities
2 Members
0 Resources
17 MeSH Terms
BET Inhibition Attenuates Helicobacter pylori-Induced Inflammatory Response by Suppressing Inflammatory Gene Transcription and Enhancer Activation.
Chen J, Wang Z, Hu X, Chen R, Romero-Gallo J, Peek RM, Chen LF
(2016) J Immunol 196: 4132-42
MeSH Terms: Azepines, Cell Line, Tumor, Enhancer Elements, Genetic, Gastritis, Gene Expression Regulation, Helicobacter Infections, Helicobacter pylori, Humans, Inflammation Mediators, NF-kappa B, Nuclear Proteins, Promoter Regions, Genetic, Protein Binding, RNA Polymerase II, RNA, Messenger, Transcription Factors, Triazoles
Show Abstract · Added April 6, 2017
Helicobacter pylori infection causes chronic gastritis and peptic ulceration. H. pylori-initiated chronic gastritis is characterized by enhanced expression of many NF-κB-regulated inflammatory cytokines. Brd4 has emerged as an important NF-κB regulator and regulates the expression of many NF-κB-dependent inflammatory genes. In this study, we demonstrated that Brd4 was not only actively involved in H. pylori-induced inflammatory gene mRNA transcription but also H. pylori-induced inflammatory gene enhancer RNA (eRNA) synthesis. Suppression of H. pylori-induced eRNA synthesis impaired H. pylori-induced mRNA synthesis. Furthermore, H. pylori stimulated NF-κB-dependent recruitment of Brd4 to the promoters and enhancers of inflammatory genes to facilitate the RNA polymerase II-mediated eRNA and mRNA synthesis. Inhibition of Brd4 by JQ1 attenuated H. pylori-induced eRNA and mRNA synthesis for a subset of NF-κB-dependent inflammatory genes. JQ1 also inhibited H. pylori-induced interaction between Brd4 and RelA and the recruitment of Brd4 and RNA polymerase II to the promoters and enhancers of inflammatory genes. Finally, we demonstrated that JQ1 suppressed inflammatory gene expression, inflammation, and cell proliferation in H. pylori-infected mice. These studies highlight the importance of Brd4 in H. pylori-induced inflammatory gene expression and suggest that Brd4 could be a potential therapeutic target for the treatment of H. pylori-triggered inflammatory diseases and cancer.
Copyright © 2016 by The American Association of Immunologists, Inc.
0 Communities
1 Members
0 Resources
17 MeSH Terms
Effects of Twelve Germline Missense Variations on DNA Lesion and G-Quadruplex Bypass Activities of Human DNA Polymerase REV1.
Yeom M, Kim IH, Kim JK, Kang K, Eoff RL, Guengerich FP, Choi JY
(2016) Chem Res Toxicol 29: 367-79
MeSH Terms: DNA, DNA Adducts, DNA Damage, G-Quadruplexes, Germ-Line Mutation, Humans, Models, Molecular, Mutation, Missense, Nuclear Proteins, Nucleotidyltransferases
Show Abstract · Added March 14, 2018
The Y-family DNA polymerase REV1 is involved in replicative bypass of damaged DNA and G-quadruplex (G4) DNA. In addition to a scaffolding role in the replicative bypass, REV1 acts in a catalytic role as a deoxycytidyl transferase opposite some replication stall sites, e.g., apurinic/apyrimidinic (AP) sites, N(2)-guanyl lesions, and G4 sites. We characterized the biochemical properties of 12 reported germline missense variants of human REV1, including the N373S variant associated with high risk of cervical cancer, using the recombinant REV1 (residues 330-833) proteins and DNA templates containing a G, AP site, N(2)-CH2(2-naphthyl)G (N(2)-NaphG), or G4. In steady-state kinetic analyses, the F427L, R434Q, M656V, D700N, R704Q, and P831L variants displayed 2- to 8-fold decreases in kcat/Km for dCTP insertion opposite all four templates, compared to that of wild-type, while the N373S, M407L, and N497S showed 2- to 3-fold increases with all four and the former three or two templates, respectively. The F427L, R434Q, M656V, and R704Q variants also had 2- to 3-fold lower binding affinities to DNA substrates containing G, an AP site, and/or N(2)-NaphG than wild-type. Distinctively, the N373S variant had a 3-fold higher binding affinity to G4 DNA than the wild-type, as well as a 2-fold higher catalytic activity opposite the first tetrad G, suggesting a facilitating effect of this variation on replication of G4 DNA sequences in certain human papillomavirus genomes. Our results suggest that the catalytic function of REV1 is moderately or slightly altered by at least nine genetic variations, and the G4 DNA processing function of REV1 is slightly enhanced by the N373S variation, which might provide the possibility that certain germline missense REV1 variations affect the individual susceptibility to carcinogenesis by modifying the capability of REV1 for replicative bypass past DNA lesions and G4 motifs derived from chemical and viral carcinogens.
0 Communities
1 Members
0 Resources
10 MeSH Terms