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Unsupervised Trajectory Analysis of Single-Cell RNA-Seq and Imaging Data Reveals Alternative Tuft Cell Origins in the Gut.
Herring CA, Banerjee A, McKinley ET, Simmons AJ, Ping J, Roland JT, Franklin JL, Liu Q, Gerdes MJ, Coffey RJ, Lau KS
(2018) Cell Syst 6: 37-51.e9
MeSH Terms: Algorithms, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cell Lineage, Humans, Image Cytometry, Intestinal Mucosa, Intestine, Small, K562 Cells, Mice, Mice, Inbred C57BL, RNA, Sequence Analysis, RNA, Single-Cell Analysis
Show Abstract · Added April 3, 2018
Modern single-cell technologies allow multiplexed sampling of cellular states within a tissue. However, computational tools that can infer developmental cell-state transitions reproducibly from such single-cell data are lacking. Here, we introduce p-Creode, an unsupervised algorithm that produces multi-branching graphs from single-cell data, compares graphs with differing topologies, and infers a statistically robust hierarchy of cell-state transitions that define developmental trajectories. We have applied p-Creode to mass cytometry, multiplex immunofluorescence, and single-cell RNA-seq data. As a test case, we validate cell-state-transition trajectories predicted by p-Creode for intestinal tuft cells, a rare, chemosensory cell type. We clarify that tuft cells are specified outside of the Atoh1-dependent secretory lineage in the small intestine. However, p-Creode also predicts, and we confirm, that tuft cells arise from an alternative, Atoh1-driven developmental program in the colon. These studies introduce p-Creode as a reliable method for analyzing large datasets that depict branching transition trajectories.
Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
1 Communities
2 Members
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15 MeSH Terms
Evaluation and comparison of diffusion MR methods for measuring apparent transcytolemmal water exchange rate constant.
Tian X, Li H, Jiang X, Xie J, Gore JC, Xu J
(2017) J Magn Reson 275: 29-37
MeSH Terms: Algorithms, Cell Biology, Cell Membrane Permeability, Cell Size, Cells, Computer Simulation, Diffusion Magnetic Resonance Imaging, Electromagnetic Fields, Humans, K562 Cells, Kinetics, Saponins, Signal-To-Noise Ratio, Water
Show Abstract · Added April 10, 2017
Two diffusion-based approaches, CG (constant gradient) and FEXI (filtered exchange imaging) methods, have been previously proposed for measuring transcytolemmal water exchange rate constant k, but their accuracy and feasibility have not been comprehensively evaluated and compared. In this work, both computer simulations and cell experiments in vitro were performed to evaluate these two methods. Simulations were done with different cell diameters (5, 10, 20μm), a broad range of k values (0.02-30s) and different SNR's, and simulated k's were directly compared with the ground truth values. Human leukemia K562 cells were cultured and treated with saponin to selectively change cell transmembrane permeability. The agreement between measured k's of both methods was also evaluated. The results suggest that, without noise, the CG method provides reasonably accurate estimation of k especially when it is smaller than 10s, which is in the typical physiological range of many biological tissues. However, although the FEXI method overestimates k even with corrections for the effects of extracellular water fraction, it provides reasonable estimates with practical SNR's and more importantly, the fitted apparent exchange rate AXR showed approximately linear dependence on the ground truth k. In conclusion, either CG or FEXI method provides a sensitive means to characterize the variations in transcytolemmal water exchange rate constant k, although the accuracy and specificity is usually compromised. The non-imaging CG method provides more accurate estimation of k, but limited to large volume-of-interest. Although the accuracy of FEXI is compromised with extracellular volume fraction, it is capable of spatially mapping k in practice.
Copyright © 2016 Elsevier Inc. All rights reserved.
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14 MeSH Terms
Anti-proliferative effects of T cells expressing a ligand-based chimeric antigen receptor against CD116 on CD34(+) cells of juvenile myelomonocytic leukemia.
Nakazawa Y, Matsuda K, Kurata T, Sueki A, Tanaka M, Sakashita K, Imai C, Wilson MH, Koike K
(2016) J Hematol Oncol 9: 27
MeSH Terms: Antigens, CD34, Cell Line, Tumor, Cell Proliferation, Cells, Cultured, Coculture Techniques, Flow Cytometry, Humans, Immunotherapy, Adoptive, K562 Cells, Leukemia, Myelomonocytic, Juvenile, Ligands, Mutation, Receptors, Antigen, T-Cell, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Recombinant Fusion Proteins, Stem Cell Factor, T-Lymphocytes, Thrombopoietin
Show Abstract · Added September 11, 2017
BACKGROUND - Juvenile myelomonocytic leukemia (JMML) is a fatal, myelodysplastic/myeloproliferative neoplasm of early childhood. Patients with JMML have mutually exclusive genetic abnormalities in granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor (GMR, CD116) signaling pathway. Allogeneic hematopoietic stem cell transplantation is currently the only curative treatment option for JMML; however, disease recurrence is a major cause of treatment failure. We investigated adoptive immunotherapy using GMR-targeted chimeric antigen receptor (CAR) for JMML.
METHODS - We constructed a novel CAR capable of binding to GMR via its ligand, GM-CSF, and generated piggyBac transposon-based GMR CAR-modified T cells from three healthy donors and two patients with JMML. We further evaluated the anti-proliferative potential of GMR CAR T cells on leukemic CD34(+) cells from six patients with JMML (two NRAS mutations, three PTPN11 mutations, and one monosomy 7), and normal CD34(+) cells.
RESULTS - GMR CAR T cells from healthy donors suppressed the cytokine-dependent growth of MO7e cells, but not the growth of K562 and Daudi cells. Co-culture of healthy GMR CAR T cells with CD34(+) cells of five patients with JMML at effector to target ratios of 1:1 and 1:4 for 2 days significantly decreased total colony growth, regardless of genetic abnormality. Furthermore, GMR CAR T cells from a non-transplanted patient and a transplanted patient inhibited the proliferation of respective JMML CD34(+) cells at onset to a degree comparable to healthy GMR CAR T cells. Seven-day co-culture of GMR CAR T cells resulted in a marked suppression of JMML CD34(+) cell proliferation, particularly CD34(+)CD38(-) cell proliferation stimulated with stem cell factor and thrombopoietin on AGM-S3 cells. Meanwhile, GMR CAR T cells exerted no effects on normal CD34(+) cell colony growth.
CONCLUSIONS - Ligand-based GMR CAR T cells may have anti-proliferative effects on stem and progenitor cells in JMML.
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18 MeSH Terms
Time-Dependent Influence of Cell Membrane Permeability on MR Diffusion Measurements.
Li H, Jiang X, Xie J, McIntyre JO, Gore JC, Xu J
(2016) Magn Reson Med 75: 1927-34
MeSH Terms: Algorithms, Cell Membrane Permeability, Computer Simulation, Diffusion Magnetic Resonance Imaging, Humans, Image Interpretation, Computer-Assisted, K562 Cells, Linear Models, Oscillometry, Permeability, Saponins, Signal Processing, Computer-Assisted, Water
Show Abstract · Added July 28, 2015
PURPOSE - To investigate the influence of cell membrane permeability on diffusion measurements over a broad range of diffusion times.
METHODS - Human myelogenous leukemia K562 cells were cultured and treated with saponin to selectively alter cell membrane permeability, resulting in a broad physiologically relevant range of 0.011-0.044 μm/ms. Apparent diffusion coefficient (ADC) values were acquired with the effective diffusion time (Δeff ) ranging from 0.42 to 3000 ms. Cosine-modulated oscillating gradient spin echo (OGSE) measurements were performed to achieve short Δeff from 0.42 to 5 ms, while stimulated echo acquisitions were used to achieve long Δeff from 11 to 2999 ms. Computer simulations were also performed to support the experimental results.
RESULTS - Both computer simulations and experiments in vitro showed that the influence of membrane permeability on diffusion MR measurements is highly dependent on the choice of diffusion time, and it is negligible only when the diffusion time is at least one order of magnitude smaller than the intracellular exchange lifetime.
CONCLUSION - The influence of cell membrane permeability on the measured ADCs is negligible in OGSE measurements at moderately high frequencies. By contrast, cell membrane permeability has a significant influence on ADC and quantitative diffusion measurements at low frequencies such as those sampled using conventional pulsed gradient methods.
© 2015 Wiley Periodicals, Inc.
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13 MeSH Terms
Discovery of tricyclic indoles that potently inhibit Mcl-1 using fragment-based methods and structure-based design.
Burke JP, Bian Z, Shaw S, Zhao B, Goodwin CM, Belmar J, Browning CF, Vigil D, Friberg A, Camper DV, Rossanese OW, Lee T, Olejniczak ET, Fesik SW
(2015) J Med Chem 58: 3794-805
MeSH Terms: Crystallography, X-Ray, Heterocyclic Compounds, 3-Ring, Humans, Indoles, K562 Cells, Models, Molecular, Molecular Conformation, Myeloid Cell Leukemia Sequence 1 Protein, Protein Binding, Structure-Activity Relationship, bcl-X Protein
Show Abstract · Added February 11, 2016
Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family of proteins that is overexpressed and amplified in many cancers. Overexpression of Mcl-1 allows cancer cells to evade apoptosis and contributes to the resistance of cancer cells to be effectively treated with various chemotherapies. From an NMR-based screen of a large fragment library, several distinct chemical scaffolds that bind to Mcl-1 were discovered. Here, we describe the discovery of potent tricyclic 2-indole carboxylic acid inhibitors that exhibit single digit nanomolar binding affinity to Mcl-1 and greater than 1700-fold selectivity over Bcl-xL and greater than 100-fold selectivity over Bcl-2. X-ray structures of these compounds when complexed to Mcl-1 provide detailed information on how these small-molecules bind to the target, which was used to guide compound optimization.
1 Communities
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11 MeSH Terms
Dengue virus envelope protein domain I/II hinge determines long-lived serotype-specific dengue immunity.
Messer WB, de Alwis R, Yount BL, Royal SR, Huynh JP, Smith SA, Crowe JE, Doranz BJ, Kahle KM, Pfaff JM, White LJ, Sariol CA, de Silva AM, Baric RS
(2014) Proc Natl Acad Sci U S A 111: 1939-44
MeSH Terms: Amino Acid Sequence, Animals, Antibodies, Neutralizing, Antibodies, Viral, Dengue, Dengue Virus, HEK293 Cells, Humans, Immunity, K562 Cells, Macaca mulatta, Molecular Sequence Data, Neutralization Tests, Protein Multimerization, Protein Structure, Tertiary, Recombinant Proteins, Serotyping, Species Specificity, Structure-Activity Relationship, Time Factors, Viral Envelope Proteins, Viremia
Show Abstract · Added January 26, 2016
The four dengue virus (DENV) serotypes, DENV-1, -2, -3, and -4, are endemic throughout tropical and subtropical regions of the world, with an estimated 390 million acute infections annually. Infection confers long-term protective immunity against the infecting serotype, but secondary infection with a different serotype carries a greater risk of potentially fatal severe dengue disease, including dengue hemorrhagic fever and dengue shock syndrome. The single most effective measure to control this threat to global health is a tetravalent DENV vaccine. To date, attempts to develop a protective vaccine have progressed slowly, partly because the targets of type-specific human neutralizing antibodies (NAbs), which are critical for long-term protection, remain poorly defined, impeding our understanding of natural immunity and hindering effective vaccine development. Here, we show that the envelope glycoprotein domain I/II hinge of DENV-3 and DENV-4 is the primary target of the long-term type-specific NAb response in humans. Transplantation of a DENV-4 hinge into a recombinant DENV-3 virus showed that the hinge determines the serotype-specific neutralizing potency of primary human and nonhuman primate DENV immune sera and that the hinge region both induces NAbs and is targeted by protective NAbs in rhesus macaques. These results suggest that the success of live dengue vaccines may depend on their ability to stimulate NAbs that target the envelope glycoprotein domain I/II hinge region. More broadly, this study shows that complex conformational antibody epitopes can be transplanted between live viruses, opening up similar possibilities for improving the breadth and specificity of vaccines for influenza, HIV, hepatitis C virus, and other clinically important viral pathogens.
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1 Members
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22 MeSH Terms
Genomic organization of human transcription initiation complexes.
Venters BJ, Pugh BF
(2013) Nature 502: 53-8
MeSH Terms: Chromatin, Genome, Human, HeLa Cells, Hep G2 Cells, Humans, K562 Cells, MCF-7 Cells, Nucleotide Motifs, Polyadenylation, Promoter Regions, Genetic, RNA, Messenger, RNA, Transfer, TATA Box, Transcription Factors, Transcription Initiation, Genetic
Show Abstract · Added March 25, 2014
The human genome is pervasively transcribed, yet only a small fraction is coding. Here we address whether this non-coding transcription arises at promoters, and detail the interactions of initiation factors TATA box binding protein (TBP), transcription factor IIB (TFIIB) and RNA polymerase (Pol) II. Using ChIP-exo (chromatin immunoprecipitation with lambda exonuclease digestion followed by high-throughput sequencing), we identify approximately 160,000 transcription initiation complexes across the human K562 genome, and more in other cancer genomes. Only about 5% associate with messenger RNA genes. The remainder associates with non-polyadenylated non-coding transcription. Regardless, Pol II moves into a transcriptionally paused state, and TBP and TFIIB remain at the promoter. Remarkably, the vast majority of locations contain the four core promoter elements- upstream TFIIB recognition element (BREu), TATA, downstream TFIIB recognition element (BREd), and initiator element (INR)-in constrained positions. All but the INR also reside at Pol III promoters, where TBP makes similar contacts. This comprehensive and high-resolution genome-wide detection of the initiation machinery produces a consolidated view of transcription initiation events from yeast to humans at Pol II/III TATA-containing/TATA-less coding and non-coding genes.
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15 MeSH Terms
Kaiso directs the transcriptional corepressor MTG16 to the Kaiso binding site in target promoters.
Barrett CW, Smith JJ, Lu LC, Markham N, Stengel KR, Short SP, Zhang B, Hunt AA, Fingleton BM, Carnahan RH, Engel ME, Chen X, Beauchamp RD, Wilson KT, Hiebert SW, Reynolds AB, Williams CS
(2012) PLoS One 7: e51205
MeSH Terms: Binding Sites, Chromatin Immunoprecipitation, Fluorescent Antibody Technique, Gene Knockdown Techniques, HEK293 Cells, HT29 Cells, Humans, K562 Cells, Matrix Metalloproteinase 7, Oligonucleotide Array Sequence Analysis, Promoter Regions, Genetic, Repressor Proteins, Transcription Factors, Transcription, Genetic, Tumor Suppressor Proteins
Show Abstract · Added December 12, 2013
Myeloid translocation genes (MTGs) are transcriptional corepressors originally identified in acute myelogenous leukemia that have recently been linked to epithelial malignancy with non-synonymous mutations identified in both MTG8 and MTG16 in colon, breast, and lung carcinoma in addition to functioning as negative regulators of WNT and Notch signaling. A yeast two-hybrid approach was used to discover novel MTG binding partners. This screen identified the Zinc fingers, C2H2 and BTB domain containing (ZBTB) family members ZBTB4 and ZBTB38 as MTG16 interacting proteins. ZBTB4 is downregulated in breast cancer and modulates p53 responses. Because ZBTB33 (Kaiso), like MTG16, modulates Wnt signaling at the level of TCF4, and its deletion suppresses intestinal tumorigenesis in the Apc(Min) mouse, we determined that Kaiso also interacted with MTG16 to modulate transcription. The zinc finger domains of Kaiso as well as ZBTB4 and ZBTB38 bound MTG16 and the association with Kaiso was confirmed using co-immunoprecipitation. MTG family members were required to efficiently repress both a heterologous reporter construct containing Kaiso binding sites (4×KBS) and the known Kaiso target, Matrix metalloproteinase-7 (MMP-7/Matrilysin). Moreover, chromatin immunoprecipitation studies placed MTG16 in a complex occupying the Kaiso binding site on the MMP-7 promoter. The presence of MTG16 in this complex, and its contributions to transcriptional repression both required Kaiso binding to its binding site on DNA, establishing MTG16-Kaiso binding as functionally relevant in Kaiso-dependent transcriptional repression. Examination of a large multi-stage CRC expression array dataset revealed patterns of Kaiso, MTG16, and MMP-7 expression supporting the hypothesis that loss of either Kaiso or MTG16 can de-regulate a target promoter such as that of MMP-7. These findings provide new insights into the mechanisms of transcriptional control by ZBTB family members and broaden the scope of co-repressor functions for the MTG family, suggesting coordinate regulation of transcription by Kaiso/MTG complexes in cancer.
6 Communities
9 Members
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15 MeSH Terms
CUX1 is a haploinsufficient tumor suppressor gene on chromosome 7 frequently inactivated in acute myeloid leukemia.
McNerney ME, Brown CD, Wang X, Bartom ET, Karmakar S, Bandlamudi C, Yu S, Ko J, Sandall BP, Stricker T, Anastasi J, Grossman RL, Cunningham JM, Le Beau MM, White KP
(2013) Blood 121: 975-83
MeSH Terms: Acute Disease, Animals, Blotting, Western, Cell Line, Tumor, Chromosome Deletion, Chromosomes, Human, Pair 7, Drosophila melanogaster, Gene Expression Profiling, Haploinsufficiency, HeLa Cells, Homeodomain Proteins, Humans, Interleukin Receptor Common gamma Subunit, K562 Cells, Leukemia, Myeloid, Mice, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Nuclear Proteins, RNA Interference, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors, Translocation, Genetic, Tumor Suppressor Proteins, U937 Cells, Xenograft Model Antitumor Assays
Show Abstract · Added March 28, 2014
Loss of chromosome 7 and del(7q) [-7/del(7q)] are recurring cytogenetic abnormalities in hematologic malignancies, including acute myeloid leukemia and therapy-related myeloid neoplasms, and associated with an adverse prognosis. Despite intensive effort by many laboratories, the putative myeloid tumor suppressor(s) on chromosome 7 has not yet been identified.We performed transcriptome sequencing and SNP array analysis on de novo and therapy-related myeloid neoplasms, half with -7/del(7q). We identified a 2.17-Mb commonly deleted segment on chromosome band 7q22.1 containing CUX1, a gene encoding a homeodomain-containing transcription factor. In 1 case, CUX1 was disrupted by a translocation, resulting in a loss-of-function RNA fusion transcript. CUX1 was the most significantly differentially expressed gene within the commonly deleted segment and was expressed at haploinsufficient levels in -7/del(7q) leukemias. Haploinsufficiency of the highly conserved ortholog, cut, led to hemocyte overgrowth and tumor formation in Drosophila melanogaster. Similarly, haploinsufficiency of CUX1 gave human hematopoietic cells a significant engraftment advantage on transplantation into immunodeficient mice. Within the RNA-sequencing data, we identified a CUX1-associated cell cycle transcriptional gene signature, suggesting that CUX1 exerts tumor suppressor activity by regulating proliferative genes. These data identify CUX1 as a conserved, haploinsufficient tumor suppressor frequently deleted in myeloid neoplasms.
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28 MeSH Terms
Systematic screen for tyrosine kinase rearrangements identifies a novel C6orf204-PDGFRB fusion in a patient with recurrent T-ALL and an associated myeloproliferative neoplasm.
Chmielecki J, Peifer M, Viale A, Hutchinson K, Giltnane J, Socci ND, Hollis CJ, Dean RS, Yenamandra A, Jagasia M, Kim AS, Davé UP, Thomas RK, Pao W
(2012) Genes Chromosomes Cancer 51: 54-65
MeSH Terms: Adult, Algorithms, Amino Acid Sequence, Base Sequence, Cell Line, Tumor, Computational Biology, Cytoskeletal Proteins, Gene Order, HEK293 Cells, Humans, K562 Cells, Karyotyping, Male, Molecular Sequence Data, Myeloproliferative Disorders, Oncogene Proteins, Fusion, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Protein-Tyrosine Kinases, Sequence Alignment, Sequence Analysis, DNA, Translocation, Genetic
Show Abstract · Added September 3, 2013
Gene fusions involving the catalytic domain of tyrosine kinases (TKs) are found in a variety of hematological and solid tumor malignancies. Clinically, TK fusions have emerged as prime targets for therapy with small molecule kinase inhibitors. Unfortunately, identification of TK fusions has been hampered by experimental limitations. Here, we developed version 2.0 of a genomically based systematic kinase fusion screen and used it to detect a novel imatinib-sensitive C6orf204-PDGFRB fusion in a patient with precursor T lymphoblastic lymphoma (T-ALL) and an associated myeloproliferative neoplasm with eosinophilia. These data validate the ability of this targeted capture-sequencing approach to detect TK fusion events in small amounts of DNA extracted directly from patient samples.
Copyright © 2011 Wiley Periodicals, Inc.
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21 MeSH Terms