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Laparoscopic nephron-sparing resection of synchronous Wilms tumors in a case of hyperplastic perilobar nephroblastomatosis.
Rauth TP, Slone J, Crane G, Correa H, Friedman DL, Lovvorn HN
(2011) J Pediatr Surg 46: 983-8
MeSH Terms: Antineoplastic Combined Chemotherapy Protocols, Combined Modality Therapy, Dactinomycin, Disease Progression, Doxorubicin, Female, Follow-Up Studies, Humans, Hyperplasia, Infant, Kidney Diseases, Kidney Neoplasms, Laparoscopy, Magnetic Resonance Imaging, Neoplasms, Multiple Primary, Nephrons, Precancerous Conditions, Vincristine, Wilms Tumor
Show Abstract · Added December 26, 2013
Diffuse hyperplastic perilobar nephroblastomatosis (DHPLN) is a rare precursor lesion of Wilms tumor (WT). Because of the increased risk to develop WT in either kidney, current management algorithms of DHPLN merit nephron-sparing strategies, beginning with chemotherapy and close radiographic monitoring into late childhood. After resolution of DHPLN, subsequent detection of a renal nodule mandates resection to exclude WT. Here, we report the case of a 4-year-old girl who developed 2 synchronous nodules in the right kidney more than 2 years after completion of therapy for DHPLN. Because of the early detection and peripheral location of these 2 nodules, laparoscopic nephron-sparing resection of each was performed using ultrasonic dissection. Both nodules were determined on pathology to be favorable histology WT with negative surgical margins. The child was placed on vincristine and actinomycin D therapy for 18 weeks.
Copyright © 2011 Elsevier Inc. All rights reserved.
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19 MeSH Terms
Reconstitution of Helicobacter pylori VacA toxin from purified components.
González-Rivera C, Gangwer KA, McClain MS, Eli IM, Chambers MG, Ohi MD, Lacy DB, Cover TL
(2010) Biochemistry 49: 5743-52
MeSH Terms: Antineoplastic Combined Chemotherapy Protocols, Cryoelectron Microscopy, Cyclophosphamide, Dactinomycin, Doxorubicin, HeLa Cells, Helicobacter pylori, Humans, Interleukin-2, Toxins, Biological, Vincristine, X-Rays
Show Abstract · Added May 7, 2013
Helicobacter pylori VacA is a pore-forming toxin that causes multiple alterations in human cells and contributes to the pathogenesis of peptic ulcer disease and gastric cancer. The toxin is secreted by H. pylori as an 88 kDa monomer (p88) consisting of two domains (p33 and p55). While an X-ray crystal structure for p55 exists and p88 oligomers have been visualized by cryo-electron microscopy, a detailed analysis of p33 has been hindered by an inability to purify this domain in an active form. In this study, we expressed and purified a recombinant form of p33 under denaturing conditions and optimized conditions for the refolding of the soluble protein. We show that refolded p33 can be added to purified p55 in trans to cause vacuolation of HeLa cells and inhibition of IL-2 production by Jurkat cells, effects identical to those produced by the p88 toxin from H. pylori. The p33 protein markedly enhances the cell binding properties of p55. Size exclusion chromatography experiments suggest that p33 and p55 assemble into a complex consistent with the size of a p88 monomer. Electron microscopy of these p33/p55 complexes reveals small rod-shaped structures that can convert to oligomeric flower-shaped structures in the presence of detergent. We propose that the oligomerization observed in these experiments mimics the process by which VacA oligomerizes when in contact with membranes of host cells.
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5 Members
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12 MeSH Terms
Functional analysis of neutralizing antibodies against Clostridium perfringens epsilon-toxin.
McClain MS, Cover TL
(2007) Infect Immun 75: 1785-93
MeSH Terms: Animals, Antibodies, Bacterial, Antibodies, Monoclonal, Bacterial Toxins, Cell Line, Cell Membrane Permeability, Clostridium perfringens, Dactinomycin, Dogs, Enzyme-Linked Immunosorbent Assay, Epitope Mapping, Mutation, Neutralization Tests, Peptides
Show Abstract · Added March 5, 2014
The Clostridium perfringens epsilon-toxin causes a severe, often fatal illness (enterotoxemia) characterized by cardiac, pulmonary, kidney, and brain edema. In this study, we examined the activities of two neutralizing monoclonal antibodies against the C. perfringens epsilon-toxin. Both antibodies inhibited epsilon-toxin cytotoxicity towards cultured MDCK cells and inhibited the ability of the toxin to form pores in the plasma membranes of cells, as shown by staining cells with the membrane-impermeant dye 7-aminoactinomycin D. Using an antibody competition enzyme-linked immunosorbent assay (ELISA), a peptide array, and analysis of mutant toxins, we mapped the epitope recognized by one of the neutralizing monoclonal antibodies to amino acids 134 to 145. The antibody competition ELISA and analysis of mutant toxins suggest that the second neutralizing monoclonal antibody also recognizes an epitope in close proximity to this region. The region comprised of amino acids 134 to 145 overlaps an amphipathic loop corresponding to the putative membrane insertion domain of the toxin. Identifying the epitopes recognized by these neutralizing antibodies constitutes an important first step in the development of therapeutic agents that could be used to counter the effects of the epsilon-toxin.
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2 Members
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14 MeSH Terms
Phosphorylation of the alpha subunit of eukaryotic initiation factor 2 is required for activation of NF-kappaB in response to diverse cellular stresses.
Jiang HY, Wek SA, McGrath BC, Scheuner D, Kaufman RJ, Cavener DR, Wek RC
(2003) Mol Cell Biol 23: 5651-63
MeSH Terms: Animals, Apoptosis, Cell Nucleus, Cells, Cultured, Cycloheximide, Dactinomycin, Dose-Response Relationship, Drug, Endoplasmic Reticulum, Enzyme Activation, Eukaryotic Initiation Factor-2, Heterozygote, Immunoblotting, Luciferases, Mice, Microscopy, Confocal, Microscopy, Fluorescence, NF-kappa B, Phosphorylation, Protein Biosynthesis, Protein Synthesis Inhibitors, Protein Transport, Thapsigargin, Transcription, Genetic, Transcriptional Activation
Show Abstract · Added August 13, 2010
Nuclear factor kappaB (NF-kappaB) serves to coordinate the transcription of genes in response to diverse environmental stresses. In this report we show that phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2) is fundamental to the process by which many stress signals activate NF-kappaB. Phosphorylation of this translation factor is carried out by a family of protein kinases that each respond to distinct stress conditions. During impaired protein folding and assembly in the endoplasmic reticulum (ER), phosphorylation of eIF2alpha by PEK (Perk or EIF2AK3) is essential for induction of NF-kappaB transcriptional activity. The mechanism by which NF-kappaB is activated during ER stress entails the release, but not the degradation, of the inhibitory protein IkappaB. During amino acid deprivation, phosphorylation of eIF2alpha by GCN2 (EIF2AK4) signals the activation of NF-kappaB. Furthermore, inhibition of general translation or transcription by cycloheximide and actinomycin D, respectively, elicits the eIF2alpha phosphorylation required for induction of NF-kappaB. Together, these studies suggest that eIF2alpha kinases monitor and are activated by a range of stress conditions that affect transcription and protein synthesis and assembly, and the resulting eIFalpha phosphorylation is central to activation of the NF-kappaB. The absence of NF-kappaB-mediated transcription and its antiapoptotic function provides an explanation for why eIF2alpha kinase deficiency in diseases such as Wolcott-Rallison syndrome leads to cellular apoptosis and disease.
1 Communities
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24 MeSH Terms
Cyclooxygenase-2 expression in cultured cortical thick ascending limb of Henle increases in response to decreased extracellular ionic content by both transcriptional and post-transcriptional mechanisms. Role of p38-mediated pathways.
Cheng HF, Harris RC
(2002) J Biol Chem 277: 45638-43
MeSH Terms: Animals, Binding Sites, Cells, Cultured, Cyclooxygenase 2, Dactinomycin, Enzyme Inhibitors, Genes, Reporter, Humans, I-kappa B Kinase, Isoenzymes, Loop of Henle, Membrane Proteins, Mice, Mitogen-Activated Protein Kinases, Mutation, NF-kappa B, Nucleic Acid Synthesis Inhibitors, Promoter Regions, Genetic, Prostaglandin-Endoperoxide Synthases, Protein-Serine-Threonine Kinases, RNA Stability, Rabbits, Sodium Chloride, Transcription, Genetic, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added August 21, 2013
We showed previously that decreased extracellular salt or chloride up-regulates the cortical thick ascending limb of Henle (cTALH) COX-2 expression via a p38-dependent pathway. The present studies determined that low salt medium increased COX-2 mRNA expression 3.9-fold control by 6 h in cultured cTALH, which was blocked by actinomycin D pretreatment, suggesting transcriptional regulation. Luciferase activity (normalized to beta-galactosidase activity) of the full-length (-3400) COX-2 promoter in cTALH increased from 1.8 +/- 0.3 in control media to 5.8 +/- 0.7 in low salt (n = 9; p < 0.01). Low chloride medium had similar effects as low salt has on COX-2 promoter activity. Deletion constructs -815, -512, and -410 were similarly stimulated, but -385 could not be stimulated significantly by low salt (1.8 +/- 0.3 versus 2.4 +/- 0.5, n = 10). This suggested involvement of an NF-kappaB cis-element located in this region, which was confirmed by utilizing a construct with a point mutation of this NF-kappaB-binding site that was not stimulated by low salt medium. Co-incubation of the specific p38 inhibitor, SB203580 or PD169316, inhibited a low salt-induced increase in luciferase activity of the intact COX-2 promoter (5.8 +/- 0.7 versus 1.1 +/- 0.2, n = 8 and 1.4 +/- 0.4, n = 4 respectively, p < 0.01). Mobility shift assays indicated that the low salt medium stimulated NF-kappaB binding activity, and this stimulation was inhibited by p38 inhibitors. To test whether p38 also increased COX-2 expression by increasing mRNA stability, cTALH were incubated in low salt for 2 h, and actinomycin was then added with or without SB203580. p38 inhibition led to a decreased half-life of COX-2 mRNA (from 68 to 18 min, n = 4-7, p < 0.05). Therefore, these studies indicate that p38 stimulates COX-2 expression in cTALH and macula densa by transcriptional regulation predominantly via a NF-kappaB-dependent pathway and by post-transcriptional increases in mRNA stability.
1 Communities
2 Members
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25 MeSH Terms
Regulation of c-myc stability by selective stress conditions and by MEKK1 requires aa 127-189 of c-myc.
Alarcon-Vargas D, Tansey WP, Ronai Z
(2002) Oncogene 21: 4384-91
MeSH Terms: Antineoplastic Agents, Apoptosis, Calcium-Calmodulin-Dependent Protein Kinases, Cells, Cultured, Cycloheximide, Dactinomycin, Dose-Response Relationship, Drug, Electrophoresis, Polyacrylamide Gel, Enzyme Inhibitors, Fibroblasts, Flavonoids, Humans, Imidazoles, MAP Kinase Kinase Kinase 1, Oligopeptides, Peptide Fragments, Protein Synthesis Inhibitors, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-myc, Pyridines, Stress, Physiological, Tumor Necrosis Factor-alpha, Tyrphostins, Ultraviolet Rays
Show Abstract · Added March 10, 2014
C-myc availability is central for its ability to serve as a regulator of cell growth and death. Here we study the regulation of c-myc protein stability and identify domains of c-myc that are important for its stabilization in response to stress kinases activated following selective stress conditions. UV-irradiation elicited an increase in c-myc protein levels, which could be attenuated by inhibitors of stress kinases but also by actinomycin D-inhibitor of transcription. Inhibition of protein synthesis results in a noticeable decrease in c-myc levels, further pointing to the short half-life of the protein. However, in combination with tumor necrosis factor-alpha (TNF-alpha), cycloheximide efficiently increases steady-state levels of c-myc, suggesting that selective stress conditions are required to increase c-myc protein stability. Expression of MEKK1, an upstream regulator of protein kinases that has been implicated in mediating the response to diverse stress conditions, also results in an efficient increase in the half-life of c-myc protein. To map c-myc domains that are responsive to stress kinases, we monitored changes in the level of c-myc deletion mutants following MEKK1 expression. Of the seven c-myc deletion mutants analysed, the domain spanning amino acids 127-189 was found to be required for MEKK1-dependent increase in c-myc stability. In all, the present study identifies a novel domain that is important for the regulation of c-myc stability by stress kinases in response to selective stress conditions.
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1 Members
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25 MeSH Terms
Effects of DNA structure on oxopropenylation by the endogenous mutagens malondialdehyde and base propenal.
Plastaras JP, Dedon PC, Marnett LJ
(2002) Biochemistry 41: 5033-42
MeSH Terms: Acrolein, Aminacrine, Antineoplastic Agents, Base Pairing, Chromatography, Liquid, DNA, DNA Adducts, DNA Damage, Dactinomycin, Ethidium, Guanine, Kinetics, Malondialdehyde, Mass Spectrometry, Mutagens, Nucleic Acid Conformation, Protein Prenylation
Show Abstract · Added March 5, 2014
Malondialdehyde (MDA) and nucleobase propenals can transfer oxopropenyl groups to guanine residues of DNA to yield pyrimodopurinone (M(1)G) adducts. The DNA structural requirements for reaction with alpha,beta-unsaturated aldehydes were explored. We found that single-stranded DNA is more sensitive to oxopropenylation than double-stranded DNA, and supercoiled plasmid DNA is more sensitive than linearized plasmid DNA. Increasing ionic strength inhibits oxopropenylation, especially by adenine propenal. The intercalating agents ethidium bromide and 9-aminoacridine enhanced oxopropenylation by severalfold. In contrast, actinomycin D, which both intercalates and binds in the minor groove, inhibited oxopropenylation. The anthracycline drugs daunorubicin and doxorubicin enhanced oxopropenylation by MDA up to 3-fold and by adenine propenal up to 7-fold in a concentration-dependent manner. The minor groove binders netropsin and distamycin inhibited oxopropenylation, but methyl green, a major groove binder, had little effect. These data suggest that steric access to the target nucleophile located in the minor groove of DNA is critical for adduct formation by the endogenous mutagens MDA and base propenals.
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1 Members
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17 MeSH Terms
Near-precise interchromosomal recombination and functional DNA topoisomerase II cleavage sites at MLL and AF-4 genomic breakpoints in treatment-related acute lymphoblastic leukemia with t(4;11) translocation.
Lovett BD, Lo Nigro L, Rappaport EF, Blair IA, Osheroff N, Zheng N, Megonigal MD, Williams WR, Nowell PC, Felix CA
(2001) Proc Natl Acad Sci U S A 98: 9802-7
MeSH Terms: Antigens, Neoplasm, Antineoplastic Combined Chemotherapy Protocols, Catechols, Child, Chromosome Breakage, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 4, Combined Modality Therapy, Cyclophosphamide, DNA Topoisomerases, Type II, DNA, Neoplasm, DNA-Binding Proteins, Dactinomycin, Etoposide, Female, Histone-Lysine N-Methyltransferase, Humans, Ifosfamide, Isoenzymes, Models, Genetic, Molecular Sequence Data, Myeloid-Lymphoid Leukemia Protein, Neoplasm Proteins, Neoplasms, Second Primary, Nuclear Proteins, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Proto-Oncogenes, Radiotherapy, Adjuvant, Recombination, Genetic, Rhabdomyosarcoma, Alveolar, Soft Tissue Neoplasms, Transcription Factors, Transcriptional Elongation Factors, Translocation, Genetic, Vincristine
Show Abstract · Added March 5, 2014
We analyzed the der(11) and der(4) genomic breakpoint junctions of a t(4;11) in the leukemia of a patient previously administered etoposide and dactinomycin by molecular and biochemical approaches to gain insights about the translocation mechanism and the relevant drug exposure. The genomic breakpoint junctions were amplified by PCR. Cleavage of DNA substrates containing the normal homologues of the MLL and AF-4 translocation breakpoints was examined in vitro upon incubation with human DNA topoisomerase IIalpha and etoposide, etoposide catechol, etoposide quinone, or dactinomycin. The der(11) and der(4) genomic breakpoint junctions both involved MLL intron 6 and AF-4 intron 3. Recombination was precise at the sequence level except for the overall gain of a single templated nucleotide. The translocation breakpoints in MLL and AF-4 were DNA topoisomerase II cleavage sites. Etoposide and its metabolites, but not dactinomycin, enhanced cleavage at these sites. Assuming that DNA topoisomerase II was the mediator of the breakage, processing of the staggered nicks induced by DNA topoisomerase II, including exonucleolytic deletion and template-directed polymerization, would have been required before ligation of the ends to generate the observed genomic breakpoint junctions. These data are inconsistent with a translocation mechanism involving interchromosomal recombination by simple exchange of DNA topoisomerase II subunits and DNA-strand transfer; however, consistent with reciprocal DNA topoisomerase II cleavage events in MLL and AF-4 in which both breaks became stable, the DNA ends were processed and underwent ligation. Etoposide and/or its metabolites, but not dactinomycin, likely were the relevant exposures in this patient.
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35 MeSH Terms
B-Myc, a proximal caput epididymal protein, is dependent on androgens and testicular factors for expression.
Cornwall GA, Collis R, Xiao Q, Hsia N, Hann SR
(2001) Biol Reprod 64: 1600-7
MeSH Terms: Androgens, Animals, Blotting, Northern, Cell Line, Dactinomycin, Drug Stability, Epididymis, Female, Gene Expression, Immunohistochemistry, In Situ Hybridization, Male, Mice, Mice, Inbred ICR, Nucleic Acid Synthesis Inhibitors, Proto-Oncogene Proteins c-myc, RNA, Messenger, Testis
Show Abstract · Added March 5, 2014
The myc family of transcriptional regulators carries out critical roles in the control of cellular proliferation, differentiation, apoptosis, and tumorigenesis. The B-myc gene is a recently identified myc family member that has not been well characterized. Previously, we have shown that B-Myc inhibits the ability of c-Myc to transform cells and can inhibit cellular proliferation. Because B-myc is primarily expressed in hormonally regulated tissues with predominant expression in the epididymis, we examined in greater detail B-myc expression in the epididymis to ultimately understand potential roles B-myc may play in this and other hormonally regulated tissues. Herein we demonstrate that, in contrast to c-myc, B-myc mRNA and protein expression are highly regionalized with expression predominantly in the proximal caput epididymal region. Furthermore, in situ and immunohistochemical analyses show that within the epididymis B-myc mRNA and protein are specifically expressed by the epithelial cells and that B-Myc protein is localized to both the nuclear and cytosolic compartments. Castration and hormone replacement studies further show that expression of the B-myc mRNA is highly dependent on the presence of androgens and testicular factors. Finally, mRNA turnover studies demonstrate that the B-myc mRNA is relatively unstable with a half-life of 3.5 h. Taken together, the highly restricted and regulated expression of the B-myc gene suggests it may play important regulatory roles in the epididymis and perhaps other hormonally regulated tissues.
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18 MeSH Terms
Differential induction of rat hepatic cytochromes P450 3A1, 3A2, 2B1, 2B2, and 2E1 in response to pyridine treatment.
Kim H, Putt DA, Zangar RC, Wolf CR, Guengerich FP, Edwards RJ, Hollenberg PF, Novak RF
(2001) Drug Metab Dispos 29: 353-60
MeSH Terms: Animals, Aryl Hydrocarbon Hydroxylases, Base Sequence, Blotting, Western, Clofibrate, Cycloheximide, Cytochrome P-450 CYP3A, Cytochrome P-450 Enzyme System, Dactinomycin, Deoxyadenosines, Dexamethasone, Dose-Response Relationship, Drug, Enzyme Induction, Isoenzymes, Liver, Male, Methylcholanthrene, Microsomes, Liver, Oxidoreductases, N-Demethylating, Phenobarbital, Pyridines, RNA, Messenger, Rats, Rats, Sprague-Dawley, Sequence Alignment, Transcription, Genetic
Show Abstract · Added May 26, 2014
Pyridine (PY) effects on rat hepatic cytochromes P450 (CYP) 3A1 and 3A2 expression were examined at the levels of metabolic activity, protein, and mRNA and were compared with those of CYP2B1/2 and CYP2E1. CYP3A metabolic activity as well as CYP3A protein and mRNA levels increased following treatment of rats with PY. CYP3A1 and CYP3A2 were differentially affected by PY treatment in terms of induction levels, dose dependence, and stability of mRNA. CYP3A1 mRNA levels maximally increased ~42-fold after PY treatment, whereas CYP3A2 mRNA level increased ~4-fold. Moreover, CYP3A1 mRNA levels decreased more rapidly than those of CYP3A2 as determined following inhibition of transcription with actinomycin D or cordycepin. Treatment of rats with PY resulted in a dose-dependent increase in CYP3A1, CYP3A2, and CYP2B1/2B2 protein levels. In contrast to the effects of PY treatment on CYP3A1 and 2B, CYP2E1 protein levels increased in the absence of a concomitant increase in CYP2E1 mRNA levels. Treatment of rats with PY at 200 mg/kg/day for 3 days increased both protein and mRNA levels of CYP3A2, whereas treatment with higher than 200 mg/kg/day for 3 days increased CYP3A2 protein levels without an increase in CYP3A2 mRNA levels. These data demonstrated that PY regulates the various CYPs examined in this study at different levels of expression and that PY regulates CYP3A1 expression through transcriptional activation and CYP3A2 expression through transcriptional and post-transcriptional activation at a low- and high-dose PY treatment, respectively.
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26 MeSH Terms