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Publication Record


Probing the Virtual Proteome to Identify Novel Disease Biomarkers.
Mosley JD, Benson MD, Smith JG, Melander O, Ngo D, Shaffer CM, Ferguson JF, Herzig MS, McCarty CA, Chute CG, Jarvik GP, Gordon AS, Palmer MR, Crosslin DR, Larson EB, Carrell DS, Kullo IJ, Pacheco JA, Peissig PL, Brilliant MH, Kitchner TE, Linneman JG, Namjou B, Williams MS, Ritchie MD, Borthwick KM, Kiryluk K, Mentch FD, Sleiman PM, Karlson EW, Verma SS, Zhu Y, Vasan RS, Yang Q, Denny JC, Roden DM, Gerszten RE, Wang TJ
(2018) Circulation 138: 2469-2481
MeSH Terms: Adult, Aged, Aged, 80 and over, Biomarkers, Carotid Artery Diseases, Female, Genome-Wide Association Study, Genotype, Humans, Lectins, C-Type, Male, Middle Aged, Odds Ratio, Phenotype, Polymorphism, Single Nucleotide, Proteome, Proteomics, Receptor, Platelet-Derived Growth Factor beta
Show Abstract · Added April 2, 2019
BACKGROUND - Proteomic approaches allow measurement of thousands of proteins in a single specimen, which can accelerate biomarker discovery. However, applying these technologies to massive biobanks is not currently feasible because of the practical barriers and costs of implementing such assays at scale. To overcome these challenges, we used a "virtual proteomic" approach, linking genetically predicted protein levels to clinical diagnoses in >40 000 individuals.
METHODS - We used genome-wide association data from the Framingham Heart Study (n=759) to construct genetic predictors for 1129 plasma protein levels. We validated the genetic predictors for 268 proteins and used them to compute predicted protein levels in 41 288 genotyped individuals in the Electronic Medical Records and Genomics (eMERGE) cohort. We tested associations for each predicted protein with 1128 clinical phenotypes. Lead associations were validated with directly measured protein levels and either low-density lipoprotein cholesterol or subclinical atherosclerosis in the MDCS (Malmö Diet and Cancer Study; n=651).
RESULTS - In the virtual proteomic analysis in eMERGE, 55 proteins were associated with 89 distinct diagnoses at a false discovery rate q<0.1. Among these, 13 associations involved lipid (n=7) or atherosclerosis (n=6) phenotypes. We tested each association for validation in MDCS using directly measured protein levels. At Bonferroni-adjusted significance thresholds, levels of apolipoprotein E isoforms were associated with hyperlipidemia, and circulating C-type lectin domain family 1 member B and platelet-derived growth factor receptor-β predicted subclinical atherosclerosis. Odds ratios for carotid atherosclerosis were 1.31 (95% CI, 1.08-1.58; P=0.006) per 1-SD increment in C-type lectin domain family 1 member B and 0.79 (0.66-0.94; P=0.008) per 1-SD increment in platelet-derived growth factor receptor-β.
CONCLUSIONS - We demonstrate a biomarker discovery paradigm to identify candidate biomarkers of cardiovascular and other diseases.
0 Communities
1 Members
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18 MeSH Terms
Endogenous dendritic cells from the tumor microenvironment support T-ALL growth via IGF1R activation.
Triplett TA, Cardenas KT, Lancaster JN, Hu Z, Selden HJ, Jasso GJ, Balasubramanyam S, Chan K, Li L, Chen X, Marcogliese AN, Davé UP, Love PE, Ehrlich LI
(2016) Proc Natl Acad Sci U S A 113: E1016-25
MeSH Terms: Animals, Cell Line, Tumor, Cell Survival, Dendritic Cells, Female, Humans, Male, Mice, Neoplasm Proteins, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Receptor, Platelet-Derived Growth Factor beta, Receptors, Somatomedin, Signal Transduction, Tumor Microenvironment
Show Abstract · Added February 22, 2016
Primary T-cell acute lymphoblastic leukemia (T-ALL) cells require stromal-derived signals to survive. Although many studies have identified cell-intrinsic alterations in signaling pathways that promote T-ALL growth, the identity of endogenous stromal cells and their associated signals in the tumor microenvironment that support T-ALL remains unknown. By examining the thymic tumor microenvironments in multiple murine T-ALL models and primary patient samples, we discovered the emergence of prominent epithelial-free regions, enriched for proliferating tumor cells and dendritic cells (DCs). Systematic evaluation of the functional capacity of tumor-associated stromal cells revealed that myeloid cells, primarily DCs, are necessary and sufficient to support T-ALL survival ex vivo. DCs support T-ALL growth both in primary thymic tumors and at secondary tumor sites. To identify a molecular mechanism by which DCs support T-ALL growth, we first performed gene expression profiling, which revealed up-regulation of platelet-derived growth factor receptor beta (Pdgfrb) and insulin-like growth factor I receptor (Igf1r) on T-ALL cells, with concomitant expression of their ligands by tumor-associated DCs. Both Pdgfrb and Igf1r were activated in ex vivo T-ALL cells, and coculture with tumor-associated, but not normal thymic DCs, sustained IGF1R activation. Furthermore, IGF1R signaling was necessary for DC-mediated T-ALL survival. Collectively, these studies provide the first evidence that endogenous tumor-associated DCs supply signals driving T-ALL growth, and implicate tumor-associated DCs and their mitogenic signals as auspicious therapeutic targets.
0 Communities
1 Members
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14 MeSH Terms
Renal fibrosis is not reduced by blocking transforming growth factor-β signaling in matrix-producing interstitial cells.
Neelisetty S, Alford C, Reynolds K, Woodbury L, Nlandu-Khodo S, Yang H, Fogo AB, Hao CM, Harris RC, Zent R, Gewin L
(2015) Kidney Int 88: 503-14
MeSH Terms: Actins, Animals, Aristolochic Acids, Cells, Cultured, Collagen Type I, Disease Models, Animal, Extracellular Matrix, Fibrosis, Kidney, Kidney Diseases, Mice, Inbred C57BL, Mice, Knockout, Protein-Serine-Threonine Kinases, Receptor, Platelet-Derived Growth Factor beta, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Signal Transduction, Time Factors, Transforming Growth Factor beta, Ureteral Obstruction
Show Abstract · Added August 3, 2015
Transforming growth factor-β (TGF-β) strongly promotes renal tubulointerstitial fibrosis, but the cellular target that mediates its profibrotic actions has not been clearly identified. While in vitro data suggest that TGF-β-induced matrix production is mediated by renal fibroblasts, the role of these cells in TGF-β-dependent tubulointerstitial fibrosis following renal injury is not well defined. To address this, we deleted the TGF-β type II receptor in matrix-producing interstitial cells using two different inducible Cre models: COL1A2-Cre with a mesenchymal enhancer element and tenascin-Cre that targets medullary interstitial cells, and either the mouse unilateral ureteral obstruction or the aristolochic acid renal injury model. Renal interstitial cells lacking the TGF-β receptor had significantly impaired collagen I production, but, unexpectedly, overall tissue fibrosis was unchanged in the conditional knockouts after renal injury. Thus, abrogating TGF-β signaling in matrix-producing interstitial cells is not sufficient to reduce fibrosis after renal injury.
1 Communities
3 Members
0 Resources
20 MeSH Terms
Stretching fibroblasts remodels fibronectin and alters cancer cell migration.
Ao M, Brewer BM, Yang L, Franco Coronel OE, Hayward SW, Webb DJ, Li D
(2015) Sci Rep 5: 8334
MeSH Terms: Cell Movement, Fibroblasts, Fibronectins, Humans, Male, Neoplasm Proteins, Prostatic Neoplasms, Receptor, Platelet-Derived Growth Factor beta, Signal Transduction, Tumor Cells, Cultured
Show Abstract · Added February 19, 2015
Most investigations of cancer-stroma interactions have focused on biochemical signaling effects, with much less attention being paid to biophysical factors. In this study, we investigated the role of mechanical stimuli on human prostatic fibroblasts using a microfluidic platform that was adapted for our experiments and further developed for both repeatable performance among multiple assays and for compatibility with high-resolution confocal microscopy. Results show that mechanical stretching of normal tissue-associated fibroblasts (NAFs) alters the structure of secreted fibronectin. Specifically, unstretched NAFs deposit and assemble fibronectin in a random, mesh-like arrangement, while stretched NAFs produce matrix with a more organized, linearly aligned structure. Moreover, the stretched NAFs exhibited an enhanced capability for directing co-cultured cancer cell migration in a persistent manner. Furthermore, we show that stretching NAFs triggers complex biochemical signaling events through the observation of increased expression of platelet derived growth factor receptor α (PDGFRα). A comparison of these behaviors with those of cancer-associated fibroblasts (CAFs) indicates that the observed phenotypes of stretched NAFs are similar to those associated with CAFs, suggesting that mechanical stress is a critical factor in NAF activation and CAF genesis.
0 Communities
2 Members
0 Resources
10 MeSH Terms
PDGFRB-rearranged T-lymphoblastic leukemia/lymphoma occurring with myeloid neoplasms: the missing link supporting a stem cell origin.
Ondrejka SL, Jegalian AG, Kim AS, Chabot-Richards DS, Giltnane J, Czuchlewski DR, Shetty S, Sekeres MA, Yenamandra A, Head D, Jagasia M, Hsi ED
(2014) Haematologica 99: e148-51
MeSH Terms: Adult, Bone Marrow, Gene Expression, Humans, Karyotype, Leukemia, Myeloid, Male, Middle Aged, Neoplastic Stem Cells, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Receptor, Platelet-Derived Growth Factor beta, Translocation, Genetic
Added January 20, 2015
0 Communities
1 Members
0 Resources
12 MeSH Terms
Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation.
Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee MK, Attar N, Sazegar H, Chodon T, Nelson SF, McArthur G, Sosman JA, Ribas A, Lo RS
(2010) Nature 468: 973-7
MeSH Terms: Base Sequence, Cell Line, Tumor, Drug Resistance, Neoplasm, Enzyme Activation, Gene Expression Regulation, Neoplastic, Genes, ras, Humans, Indoles, MAP Kinase Signaling System, Melanoma, Mitogen-Activated Protein Kinase Kinases, Mutation, Oligonucleotide Array Sequence Analysis, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Receptor Protein-Tyrosine Kinases, Receptor, Platelet-Derived Growth Factor beta, Sulfonamides, Up-Regulation, Vemurafenib
Show Abstract · Added March 20, 2014
Activating B-RAF(V600E) (also known as BRAF) kinase mutations occur in ∼7% of human malignancies and ∼60% of melanomas. Early clinical experience with a novel class I RAF-selective inhibitor, PLX4032, demonstrated an unprecedented 80% anti-tumour response rate among patients with B-RAF(V600E)-positive melanomas, but acquired drug resistance frequently develops after initial responses. Hypotheses for mechanisms of acquired resistance to B-RAF inhibition include secondary mutations in B-RAF(V600E), MAPK reactivation, and activation of alternative survival pathways. Here we show that acquired resistance to PLX4032 develops by mutually exclusive PDGFRβ (also known as PDGFRB) upregulation or N-RAS (also known as NRAS) mutations but not through secondary mutations in B-RAF(V600E). We used PLX4032-resistant sub-lines artificially derived from B-RAF(V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumours and tumour-matched, short-term cultures from clinical trial patients. Induction of PDGFRβ RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sub-lines, patient-derived biopsies and short-term cultures. PDGFRβ-upregulated tumour cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRβ or N-RAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRβ or N-RAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, MAPK reactivation predicts MEK inhibitor sensitivity. Thus, melanomas escape B-RAF(V600E) targeting not through secondary B-RAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.
0 Communities
1 Members
0 Resources
20 MeSH Terms
Mesothelium contributes to vascular smooth muscle and mesenchyme during lung development.
Que J, Wilm B, Hasegawa H, Wang F, Bader D, Hogan BL
(2008) Proc Natl Acad Sci U S A 105: 16626-30
MeSH Terms: Animals, Blood Vessels, Cell Lineage, Embryo, Mammalian, Epithelium, Fluorescent Dyes, Genes, Reporter, Lung, Mesoderm, Mice, Muscle, Smooth, Vascular, Organogenesis, Receptor, Platelet-Derived Growth Factor beta
Show Abstract · Added September 28, 2015
During mouse development, the sophisticated vascular network of the lung is established from embryonic day (E) approximately 10.5 and continues to develop postnatally. This network is composed of endothelial cells enclosed by vascular smooth muscle, pericytes, and other mesenchymal cells. Recent in vivo lineage labeling studies in the developing heart and intestine suggest that some of the vascular smooth muscle cells arise from the surface mesothelium. In the developing lung, the Wilm's tumor 1 gene (Wt1) is expressed only in the mesothelial cells. Therefore, we lineage-labeled the mesothelium in vivo by using a Wt1-Cre transgene in combination with either Rosa26R(lacZ), Rosa26R(CAG-hPLAP), or Rosa26R(EYFP) reporter alleles. In all three cases, cells derived from lineage-labeled mesothelium are found inside the lung and as smooth muscle actin (SMA) and PDGF receptor-beta positive cells in the walls of pulmonary blood vessels. To corroborate this finding, we used 5-(and-6)-carboxy-2',7'-dichlorofluorescein diacetate, succinimidyl ester "mixed isomers" (CCFSE) dye to label mesothelial cells on the surface of the embryonic lung. Over the course of 72-h culture, dye-labeled cells also appear within the lung mesenchyme. Together, our data provide evidence that mesothelial cells serve as a source of vascular smooth muscle cells in the developing lung and suggest that a conserved mechanism applies to the development of blood vessels in all coelomic organs.
1 Communities
1 Members
0 Resources
13 MeSH Terms
PDGFR-beta expression in small cell lung cancer patients.
Shinohara ET, Gonzalez A, Massion PP, Olson SJ, Albert JM, Shyr Y, Carbone DP, Johnson DH, Hallahan DE, Lu B
(2007) Int J Radiat Oncol Biol Phys 67: 431-7
MeSH Terms: Adult, Aged, Aged, 80 and over, Carcinoma, Small Cell, Chi-Square Distribution, Humans, Lung Neoplasms, Middle Aged, Multivariate Analysis, Neoplasm Proteins, Prognosis, Receptor, Platelet-Derived Growth Factor beta, Statistics, Nonparametric, Survival Analysis
Show Abstract · Added March 10, 2014
BACKGROUND - Platelet derived growth factor (PDGF) and PDGFR-beta are expressed and have been found to have prognostic value in several human cancers. Data in non-small-cell cancer cell lines have suggested that PDGFR is a therapeutic target for drug development. In the current study PDGFR-beta expression and prognostic value in small cell lung cancer (SCLC) was investigated.
METHODS AND MATERIALS - Paraffin-embedded tissue blocks from 53 patients with limited and extensive stage SCLC were obtained for immunohistochemical staining. Tumors from each patient were sampled 3 times and stained with PDGFR-beta specific antibody. Patients were divided into low and high staining groups based on intensity.
RESULTS - There was high intensity PDGFR-beta staining in 20 patients with SCLC. Another 29 expressed low intensity PDGFR-beta staining, with only 4 patients showing no PDGFR-beta staining. There was no statistically significant difference in 5 year overall survival between patients with low levels of PDGFR-beta staining vs. those with high level staining SCLC tumors (p = 0.538).
CONCLUSIONS - The present study found that the majority of SCLC patients express, at least, a low level of PDGF-beta. However, the level of PDGFR-beta expression was not a statistically significant predictor of 5 year overall survival in SCLC.
0 Communities
1 Members
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14 MeSH Terms
Requirement of Nck adaptors for actin dynamics and cell migration stimulated by platelet-derived growth factor B.
Rivera GM, Antoku S, Gelkop S, Shin NY, Hanks SK, Pawson T, Mayer BJ
(2006) Proc Natl Acad Sci U S A 103: 9536-41
MeSH Terms: Actins, Adaptor Proteins, Signal Transducing, Animals, Cell Membrane, Cell Movement, Cells, Cultured, Crk-Associated Substrate Protein, Cytoskeleton, Gene Expression Regulation, Mice, Oncogene Proteins, Phosphotyrosine, Protein Binding, Proto-Oncogene Proteins c-sis, Receptor, Platelet-Derived Growth Factor beta
Show Abstract · Added January 20, 2015
The Nck family of Src homology (SH) 2/SH3 domain adaptors functions to link tyrosine phosphorylation induced by extracellular signals with downstream regulators of actin dynamics. We investigated the role of mammalian Nck adaptors in signaling from the activated platelet-derived growth factor (PDGF) receptor (PDGFbetaR) to the actin cytoskeleton. We report here that Nck adaptors are required for cytoskeletal reorganization and chemotaxis stimulated by PDGF-B. Analysis of tyrosine-phosphorylated proteins demonstrated that Crk-associated substrate (p130(Cas)), not the activated PDGFbetaR itself, is the major Nck SH2 domain-binding protein in PDGF-B-stimulated cells. Both Nck- and p130(Cas)-deficient cells fail to display cytoskeletal rearrangements, including the formation of membrane ruffles and the disassembly of actin bundles, typically shown by their WT counterparts in response to PDGF-B. Furthermore, Nck and p130(Cas) colocalize in phosphotyrosine-enriched membrane ruffles induced by PDGF-B in NIH 3T3 cells. These results suggest that Nck adaptors play an essential role in linking the activated PDGFbetaR with actin dynamics through a pathway that involves p130(Cas).
0 Communities
1 Members
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15 MeSH Terms
Multicenter Phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy.
Wyman K, Atkins MB, Prieto V, Eton O, McDermott DF, Hubbard F, Byrnes C, Sanders K, Sosman JA
(2006) Cancer 106: 2005-11
MeSH Terms: Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Benzamides, Female, Humans, Imatinib Mesylate, Immunohistochemistry, Male, Melanoma, Middle Aged, Piperazines, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-kit, Pyrimidines, Receptor, Platelet-Derived Growth Factor alpha, Receptor, Platelet-Derived Growth Factor beta
Show Abstract · Added March 5, 2014
BACKGROUND - Systemic treatment of metastatic melanoma is largely ineffective and alternative approaches are needed. Imatinib mesylate is an oral tyrosine kinase inhibitor that targets bcr-Abl, c-kit, platelet-derived growth factor receptor (PDGFR)-alpha, and PDGFR-beta, leading to remarkable clinical responses in several cancers. Signal transduction via c-kit, PDGFR-alpha, and PDGFR-beta has been demonstrated in malignant melanoma.
METHODS - The primary objective of this Phase II study was to determine the response rate, response duration, and the frequency of 6-month progression-free survival in patients who could receive up to 2 prior therapeutic regimens. Initially, patients received imatinib at at dose of 400 mg twice orally each day. Based on Simon's optimal design, the study allowed entry of 21 patients; if there were > or = 2 objective responses, accrual would then continue to a total of 41 patients.
RESULTS - Twenty-six patients were enrolled. Patients experienced 29 episodes of Grade 3 and 2 episodes of Grade 4 toxicity (according to National Cancer Institute common toxicity criteria). No objective clinical responses were noted among the 25 evaluable patients. The median time to progression was 54 days and the median overall survival was 200 days. No patient was free of disease progression at 6 months. Paraffin-embedded tumor specimens from 15 patients were tested for expression of imatinib responsive kinases by immunohistochemistry. Three tumors had moderate and 5 tumors had weak staining for c-kit. Five tumor samples had weak staining for PDGFR-alpha and -beta.
CONCLUSIONS - Imatinib is an inactive single agent in metastatic melanoma in a population of predominantely pretreated patients. The levels of c-kit and/or PDGFR-alpha, -beta expression in the current study were lower than previously reported. Alternative treatment strategies remain a priority for patients with advanced melanoma.
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18 MeSH Terms