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Molecular imaging metrics to evaluate response to preclinical therapeutic regimens.
Smith RA, Guleryuz S, Manning HC
(2011) Front Biosci (Landmark Ed) 16: 393-410
MeSH Terms: Diagnostic Imaging, Dideoxynucleosides, Fluorodeoxyglucose F18, Humans, Molecular Imaging, Neoplasms, Neovascularization, Pathologic, Positron-Emission Tomography, Thymidine Kinase
Show Abstract · Added March 5, 2014
Molecular imaging comprises a range of techniques, spanning not only several imaging modalities but also many disease states and organ sites. While advances in new technology platforms have enabled a deeper understanding of the cellular and molecular basis of malignancy, reliable non-invasive imaging metrics remain an important tool for both diagnostics and patient management. Furthermore, the non- invasive nature of molecular imaging can overcome shortcomings associated with traditional biological approaches and provide valuable information relevant to patient care. Integration of information from multiple imaging techniques has the potential to provide a more comprehensive understanding of specific tumor characteristics, tumor status, and treatment response.
0 Communities
1 Members
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9 MeSH Terms
POLG mutations cause decreased mitochondrial DNA repopulation rates following induced depletion in human fibroblasts.
Stewart JD, Schoeler S, Sitarz KS, Horvath R, Hallmann K, Pyle A, Yu-Wai-Man P, Taylor RW, Samuels DC, Kunz WS, Chinnery PF
(2011) Biochim Biophys Acta 1812: 321-5
MeSH Terms: Adult, Amino Acid Substitution, Case-Control Studies, DNA Polymerase gamma, DNA Replication, DNA, Mitochondrial, DNA-Directed DNA Polymerase, Diffuse Cerebral Sclerosis of Schilder, Enzyme Inhibitors, Epilepsy, Ethidium, Female, Fibroblasts, Heterozygote, Homozygote, Humans, Infant, Male, Mitochondria, Muscular Diseases, Mutation, Nucleic Acid Synthesis Inhibitors, Thymidine Kinase
Show Abstract · Added December 12, 2013
Disorders of mitochondrial DNA (mtDNA) maintenance have emerged as an important cause of human genetic disease, but demonstrating the functional consequences of de novo mutations remains a major challenge. We studied the rate of depletion and repopulation of mtDNA in human fibroblasts exposed to ethidium bromide in patients with heterozygous POLG mutations, POLG2 and TK2 mutations. Ethidium bromide induced mtDNA depletion occurred at the same rate in human fibroblasts from patients and healthy controls. By contrast, the restoration of mtDNA levels was markedly delayed in fibroblasts from patients with compound heterozygous POLG mutations. Specific POLG2 and TK2 mutations did not delay mtDNA repopulation rates. These observations are consistent with the hypothesis that mutations in POLG impair mtDNA repopulation within intact cells, and provide a potential method of demonstrating the functional consequences of putative pathogenic alleles causing a defect of mtDNA synthesis.
Copyright © 2010 Elsevier B.V. All rights reserved.
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23 MeSH Terms
A novel in vitro assay to assess phosphorylation of 3'-[(18)F]fluoro-3'-deoxythymidine.
Guo N, Xie J, Manning HC, Deane NG, Ansari MS, Coffey RJ, Gore J, Price RR, Baldwin RM, McIntyre JO
(2011) Mol Imaging Biol 13: 257-64
MeSH Terms: Biological Transport, Cell Extracts, Cell Line, Tumor, Cell Membrane, Dideoxynucleosides, Enzyme Assays, Enzyme Inhibitors, Humans, Kinetics, Nucleosides, Phosphorylation, Thymidine Kinase, Time Factors
Show Abstract · Added May 10, 2013
PURPOSE - 3'-[(18)F]fluoro-3'-deoxythymidine ([(18)F]FLT) is phosphorylated by thymidine kinase 1 (TK-1), a cell cycle regulated enzyme. Appropriate use of [(18)F]FLT tracer requires validation of the TK-1 activity. Here, we report development of a novel phosphoryl-transfer assay to assess phosphorylation of [(18)F]FLT both in tumor cell lysates and tumor cells.
PROCEDURES - The intrinsic F-18 radioactivity was used to quantify both substrate and phosphorylated products using a rapid thin layer chromatography method. Phosphorylation kinetics of [(18)F]FLT in SW480 and DiFi tumor cell lysates and cellular uptake were measured.
RESULTS - The apparent Michaelis-Menten kinetic parameters for [(18)F]FLT are K(m) = 4.8 ± 0.3 μM and V(max) = 7.4 pmol min(-1) per 1 × 10(6) cells with ~2-fold higher TK-1 activity in DiFi versus SW480 lysates.
CONCLUSIONS - The apparent K (m) of [(18)F]FLT was comparable to the value reported with purified recombinant TK-1. The uptake of [(18)F]FLT by SW480 cells is inhibited by nitrobenzylthioinosine or dipyridamole indicating that uptake is mediated predominantly by the equilibrative nucleoside transporters in these tumor cells.
2 Communities
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13 MeSH Terms
The relationship between dNTP pool levels and mutagenesis in an Escherichia coli NDP kinase mutant.
Nordman J, Wright A
(2008) Proc Natl Acad Sci U S A 105: 10197-202
MeSH Terms: DNA Replication, Deoxyribonucleotides, Escherichia coli, Genes, Bacterial, Genetic Complementation Test, Humans, Mutagenesis, Mutation, NM23 Nucleoside Diphosphate Kinases, Nucleoside-Diphosphate Kinase, Phenotype, Recombinant Proteins, Species Specificity, Thymidine, Thymidine Kinase, Uracil
Show Abstract · Added March 3, 2020
Loss of nucleoside diphosphate kinase (Ndk) function in Escherichia coli results in an increased frequency of spontaneous mutation and an imbalance in dNTP pool levels. It is presumed that the imbalance in dNTP pool levels is responsible for the mutator phenotype of an E. coli ndk mutant. A human homologue of Ndk and potential suppressor of tumor metastasis, nm23-H2, can complement the mutagenic phenotype of an E. coli ndk mutant. Here, we show that the antimutagenic property of nm23-H2 in E. coli is independent of dNTP pool levels, indicating that dNTP pool imbalance is not responsible for the mutator phenotype associated with the loss of ndk function. We have identified multiple genetic interactions between ndk and genes involved in the metabolism of dUTP, a potentially mutagenic precursor of thymidine biosynthesis. We show that loss of ndk function is synergistic with a dut-1 mutation and synthetically lethal with the loss of thymidine kinase function. Our results suggest that Ndk prevents the accumulation of dUTP in vivo. Based on these results and biochemical studies of Ndk, we propose that the mutagenic phenotype of an ndk mutant is caused by excess misincorporation of uracil in place of thymidine combined with a defect in the uracil base excision pathway.
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MeSH Terms
Apoptosis of the thick ascending limb results in acute kidney injury.
Srichai MB, Hao C, Davis L, Golovin A, Zhao M, Moeckel G, Dunn S, Bulus N, Harris RC, Zent R, Breyer MD
(2008) J Am Soc Nephrol 19: 1538-46
MeSH Terms: Acute Kidney Injury, Animals, Antiviral Agents, Apoptosis, Disease Models, Animal, Epithelial Cells, Female, Ganciclovir, Gene Expression, Herpesvirus 1, Human, Loop of Henle, Male, Mice, Mice, Transgenic, Mucoproteins, Promoter Regions, Genetic, Thymidine Kinase, Uromodulin
Show Abstract · Added December 10, 2013
Ischemia- or toxin-induced acute kidney injury is generally thought to affect the cells of the proximal tubule, but it has been difficult to define the involvement of other tubular segments because of the widespread damage caused by ischemia/reperfusion or toxin-induced injury in experimental models. For evaluation of whether thick ascending limb (TAL)-specific epithelial injury results in acute kidney injury, a novel transgenic mouse model that expresses the herpes simplex virus 1 thymidine kinase gene under the direction of the TAL-specific Tamm-Horsfall protein promoter was generated. After administration of gancyclovir, these mice demonstrated apoptosis only in TAL cells, with little evidence of neutrophil infiltration. Compared with control mice, blood urea nitrogen and creatinine levels were at least five-fold higher in the transgenic mice, which also developed oliguria and impaired urinary concentrating ability. These findings suggest that acute injury targeted only to the TAL is sufficient to cause severe acute kidney injury in mice with features similar to those observed in humans.
2 Communities
2 Members
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18 MeSH Terms
Mitochondrial DNA copy number threshold in mtDNA depletion myopathy.
Durham SE, Bonilla E, Samuels DC, DiMauro S, Chinnery PF
(2005) Neurology 65: 453-5
MeSH Terms: Adult, DNA, Mitochondrial, Electron Transport Complex IV, Energy Metabolism, Female, Gene Dosage, Humans, Infant, Mitochondrial Myopathies, Muscle Fibers, Skeletal, Muscle, Skeletal, Predictive Value of Tests, Reference Values, Succinate Dehydrogenase, Thymidine Kinase
Show Abstract · Added December 12, 2013
The authors measured the absolute amount of mitochondrial DNA (mtDNA) within single muscle fibers from two patients with thymidine kinase 2 (TK2) deficiency and two healthy controls. TK2 deficient fibers containing more than 0.01 mtDNA/microm3 had residual cytochrome c oxidase (COX) activity. This defines the minimum amount of wild-type mtDNA molecules required to maintain COX activity in skeletal muscle and provides an explanation for the mosaic histochemical pattern seen in patients with mtDNA depletion syndrome.
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15 MeSH Terms
A computational model of mitochondrial deoxynucleotide metabolism and DNA replication.
Bradshaw PC, Samuels DC
(2005) Am J Physiol Cell Physiol 288: C989-1002
MeSH Terms: Animals, Biological Transport, Cell Division, Cytoplasm, DNA Replication, DNA, Mitochondrial, Humans, Mitochondria, Models, Biological, Neoplasms, Nucleoside-Diphosphate Kinase, Nucleotides, Phosphorylation, Thymidine Kinase
Show Abstract · Added December 12, 2013
We present a computational model of mitochondrial deoxynucleotide metabolism and mitochondrial DNA (mtDNA) synthesis. The model includes the transport of deoxynucleosides and deoxynucleotides into the mitochondrial matrix space, as well as their phosphorylation and polymerization into mtDNA. Different simulated cell types (cancer, rapidly dividing, slowly dividing, and postmitotic cells) are represented in this model by different cytoplasmic deoxynucleotide concentrations. We calculated the changes in deoxynucleotide concentrations within the mitochondrion during the course of a mtDNA replication event and the time required for mtDNA replication in the different cell types. On the basis of the model, we define three steady states of mitochondrial deoxynucleotide metabolism: the phosphorylating state (the net import of deoxynucleosides and export of phosphorylated deoxynucleotides), the desphosphorylating state (the reverse of the phosphorylating state), and the efficient state (the net import of both deoxynucleosides and deoxynucleotides). We present five testable hypotheses based on this simulation. First, the deoxynucleotide pools within a mitochondrion are sufficient to support only a small fraction of even a single mtDNA replication event. Second, the mtDNA replication time in postmitotic cells is much longer than that in rapidly dividing cells. Third, mitochondria in dividing cells are net sinks of cytoplasmic deoxynucleotides, while mitochondria in postmitotic cells are net sources. Fourth, the deoxynucleotide carrier exerts the most control over the mtDNA replication rate in rapidly dividing cells, but in postmitotic cells, the NDPK and TK2 enzymes have the most control. Fifth, following from the previous hypothesis, rapidly dividing cells derive almost all of their mtDNA precursors from the cytoplasmic deoxynucleotides, not from phosphorylation within the mitochondrion.
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14 MeSH Terms
The gatekeeper effect of epithelial-mesenchymal transition regulates the frequency of breast cancer metastasis.
Xue C, Plieth D, Venkov C, Xu C, Neilson EG
(2003) Cancer Res 63: 3386-94
MeSH Terms: Adoptive Transfer, Alleles, Animals, Calcium-Binding Proteins, Carcinoma, Caseins, Cell Differentiation, Cell Movement, Epithelial Cells, Female, Fibroblasts, Gene Expression Regulation, Neoplastic, Genes, Reporter, Green Fluorescent Proteins, Luminescent Proteins, Lung Neoplasms, Mammary Neoplasms, Experimental, Mesoderm, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, Neoplasm Metastasis, Neoplasm Transplantation, Phenotype, S100 Calcium-Binding Protein A4, S100 Proteins, Stromal Cells, Thymidine Kinase, Tumor Suppressor Protein p53
Show Abstract · Added August 13, 2010
When carcinoma cells metastasize, they change their phenotype to enhance motility. Cells making this switch selectively express S100A4, a p53-associated, calcium-binding protein known in the fibroblast literature as fibroblast-specific protein-1 (FSP1). FSP1 normally acts as a conversion signal for the local formation of tissue fibroblasts by epithelial-mesenchymal transition. We describe here a novel connection between the process of fibroblast development and the acquisition of a metastatic phenotype in genetically engineered mice with mammary carcinoma. More frequent lung metastases were observed in naïve recipients given purified populations of green fluorescent protein (GFP)(+) tumor cells harvested from PyV-mT x FSP1(+/+.GFP) F1 mice compared with GFP(-) tumor cells (P < or = 0.01), where GFP expression is under the control of the FSP1 promoter. The expression of GFP in these metastases reversibly attenuates with the establishment of secondary tumor nodules. Reduced numbers of metastases were also observed in PyV-mT x FSP1(GFP/GFP) F1 mice carrying null alleles for FSP1 (P < or = 0.04) and in PyV-mT x FSP1.Delta TK(+) F1 mice rescued with nucleoside analogues while expressing thymidine kinase under the control of the FSP1 promoter (P < or = 0.01). We propose that epithelial-mesenchymal transition associated with the expression of FSP1 in tumor cells has a functional role in determining the latency of tumor dispersion and may be a convenient therapeutic target for controlling a key initiating event in metastatic progression.
1 Communities
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31 MeSH Terms
Alternate replication in B cells and epithelial cells switches tropism of Epstein-Barr virus.
Borza CM, Hutt-Fletcher LM
(2002) Nat Med 8: 594-9
MeSH Terms: Animals, B-Lymphocytes, Cell Line, DNA, Viral, Epithelial Cells, Gene Deletion, Herpesvirus 4, Human, Histocompatibility Antigens Class II, Lymphocyte Activation, Thymidine Kinase, Virus Replication, Virus Shedding
Show Abstract · Added August 22, 2013
Epstein-Barr virus is ubiquitous and is causally implicated in lymphoid and epithelial malignancies. Virus invades oropharyngeal mucosa and establishes latency in B lymphocytes. Reactivating lymphocytes shed virus into saliva for spread to new hosts. A complex of three virus glycoproteins, gH, gL and gp42, is essential for entry. B-cell entry requires binding of gp42 to human leukocyte antigen (HLA) class II whereas entry into epithelial cells lacking HLA class II requires complexes without gp42. To accommodate infection of each, the virus carries both three-part and two-part complexes. We show here that HLA class II in the virus-producing cell alters the ratio of three-part to two-part complexes. As a consequence, virus originating in epithelial cells efficiently infects B cells whereas B-cell derived virus better infects epithelial cells. This molecular switch is a novel strategy that could alter tropism of virus from epithelium to B cells and then back to epithelium in a new host.
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12 MeSH Terms
Inclusion of the herpes simplex thymidine kinase gene in a replicating adenovirus does not augment antitumor efficacy.
Lambright ES, Amin K, Wiewrodt R, Force SD, Lanuti M, Propert KJ, Litzky L, Kaiser LR, Albelda SM
(2001) Gene Ther 8: 946-53
MeSH Terms: Adenoviridae, Analysis of Variance, Animals, Antiviral Agents, Female, Ganciclovir, Genetic Therapy, Genetic Vectors, Injections, Intralesional, Lung Neoplasms, Male, Mice, Mice, Nude, Mice, SCID, Neoplasm Transplantation, Neoplasms, Experimental, Simplexvirus, Thymidine Kinase, Transduction, Genetic, Virus Replication
Show Abstract · Added March 5, 2014
Replication-incompetent adenoviruses (Ad) carrying the herpes simplex thymidine kinase (HSVtk) gene have been used in a number of human cancer gene therapy trials, however transduction has generally been limited to a small minority of tumor cells. To solve this problem, replication-competent adenoviral vectors carrying transgenes such as HSVtk have been developed. However, contradictory evidence exists regarding the efficacy of these new vectors. Accordingly, we constructed and tested a replication-competent E3-deleted adenoviral vector containing the HSVtk suicide gene driven by the endogenous E3 promoter (Ad.wt.tk). This virus showed high level production of the HSVtk transgene and was more efficacious than a non-replicating virus in vitro, after injection into flank tumors, and against established intraperitoneal tumors. However, addition of ganciclovir (GCV) therapy to cells or tumor-bearing animals treated with the replicating vector containing the HSVtk suicide gene did not result in increased cell killing. Our results indicate that addition of HSVtk to a replicating Ad virus will not likely be useful in augmenting antitumor effects.
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20 MeSH Terms