Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.1.1.6 (CAD)
4,420 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous analyses by fluorescence in situ hybridization of structures present 20-30 cell generations after the primary events of mammalian gene amplification have shown that tens of megabases of DNA separate each copy of the selected gene in chromosomal arrays that contain up to 15 copies. Since these structures are very unstable, it is necessary to study amplified DNA as soon as possible after it has been formed to relate the structures observed to the primary mechanisms that generated them. Previously, new amplifications of the CAD gene were analyzed in colonies of 10(5) N-(phosphonoacetyl)-L-aspartate-resistant Syrian hamster BHK cells. CAD is on the p arm of chromosome B9 and the amplified genes were usually found in large extensions of B9p, with one copy in its normal position. We now report that dividing drug-resistant cells have been physically separated from static drug-sensitive cells, to allow the amplified structures to be observed only a few cell generations after they have been formed. The most informative results are that about one-third of the newly formed chromosomes carrying amplified CAD genes are dicentric and that about half of these carry two B9q arms. These observations reveal that recombination between the p telomeric regions of two B9 sister chromatids is an important primary event of amplification in this system. The resulting dicentric chromosomes can then enter bridge-breakage-fusion cycles that provide the means to increase the number of CAD genes per cell in successive generations by an asymmetric distribution at each cell division.
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PMID:Fusions near telomeres occur very early in the amplification of CAD genes in Syrian hamster cells. 135 82

On exercise testing after an episode of unstable coronary artery disease (CAD; unstable angina or non-Q-wave myocardial infarction), a proportion of patients show ST-segment depression, indicating myocardial ischaemia, but do not report concomitant symptoms of angina. Treatment of such "silent" ischaemia aims mainly to reduce the risk of subsequent cardiac events. We have studied the effect of low-dose aspirin in patients with myocardial ischaemia defined at the predischarge test as silent (though patients might have had symptomatic ischaemia at other times) or symptomatic. 740 men with unstable CAD aged 70 years or less underwent symptom-limited exercise testing before hospital discharge; 144 showed ST depression without pain and 230 ST depression with simultaneous chest pain. Of the silent ischaemia group, 67 were randomly assigned placebo and 77 aspirin (75 mg daily); the corresponding numbers in the symptomatic group were 125 and 105. Angina symptoms were less common in the silent than in the symptomatic ischaemia group both before inclusion and during follow-up, and a greater proportion of the silent ischaemia group were included because of myocardial infarction. In both ischaemia groups aspirin treatment reduced the risk of subsequent myocardial infarction or death by 3 months' follow-up (silent 4% of aspirin-treated vs 21% of placebo-treated patients, p = 0.004; symptomatic 9% vs 18%, p = 0.05); at 12 months' follow-up a significant benefit of aspirin was still apparent in the silent ischaemia group (9% vs 28%, p = 0.005) but not in the symptomatic group (13% vs 22%, p = 0.109). Low-dose aspirin reduced the risk of subsequent myocardial infarction at least as well in silent as in symptomatic myocardial ischaemia. Since improvement of outlook is the main treatment objective in symptom-free patients, aspirin should be a mainstay of their treatment.
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PMID:Prevention of serious cardiac events by low-dose aspirin in patients with silent myocardial ischaemia. The Research Group on Instability in Coronary Artery Disease in Southeast Sweden. 135 74

Recent investigations of SMI occurring during daily life have advanced our understanding of the pathophysiology of myocardial ischemia. These contributions have directed our attention away from "chest pain" alone and physical exertion as the central provoking factor toward transient myocardial ischemia and its broader triggers and consequences. Transient myocardial ischemic episodes, the majority of which are silent, are found in a subset of patients with any clinical manifestations of CAD (eg, stable angina, unstable angina, myocardial infarction, and sudden death), as well as in those patients with CAD who are and have been totally asymptomatic. These episodes are an independent predictor of increased risk for future cardiac events. Most medical therapy and revascularization therapies have the potential to prevent or relieve these silent episodes; however, we do not yet know which method is superior in reducing SMI episodes or preventing future cardiac events. Furthermore, the benefit of reducing SMI versus the cost and potential morbidity of these chosen therapies is not known. At least three trials are now underway to examine some of these concerns (Table 2). Focus on pain relief alone does not appear to be an adequate approach to alter outcome in patients with CAD and may prove insufficient to control SMI. Until these issues are resolved, we believe a conservative approach to the management of patients with CAD is warranted. Documentation of ischemia (painful or painless) is essential. Three general principles should be kept in mind. First, the presence of detectable ischemia is of central importance. This information should be used in the overall risk assessment of the patient. Second, the level of concern or aggressiveness of treatment should be based on the risk associated with the ischemic abnormalities documented (Table 3). The exercise stress test is the most useful to begin this process. The detection of ischemic-type ST-segment depression, either silent or painful, at a low workload (eg, less than or equal to 120 beats per minute or less than or equal to 6.5 metabolic equivalents [METS]) implies high risk for adverse outcome. Likewise, these ST-segment changes occurring in leads that reflect multiple coronary artery distribution, of greater than 2 mm in magnitude and persisting for greater than 6 minutes, are all markers for high risk. Thallium redistribution defects occurring at low work loads, in multiple areas, associated with increased lung uptake and enlargement of the cardiac pool all imply high risk.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Treatment strategies for daily life silent myocardial ischemia: a correlation with potential pathogenic mechanisms. 135 7

Five restriction fragment length polymorphisms (RFLP) of the apo B gene and their association with serum lipids and apolipoprotein levels have been studied in 139 Chinese patients with angiographically confirmed CAD (mean age 56.2 +/- 0.8 years) and 154 healthy Chinese subjects (mean 44.0 +/- 1.0 years) of both sexes. The patient group had significantly higher levels of serum total and LDL cholesterol; and apo B (P < 0.001) and lower HDL cholesterol and apo A-I (P < 0.001 and < 0.01, respectively). The frequencies of the rarer alleles of the ins/del, XbaI and EcoRI (but not the PvuII and MspI) polymorphisms were significantly lower in the Chinese compared to those reported in Caucasians. There was no significant difference in allelic frequencies of the signal peptide region (Ins/Del), XbaI, MspI and EcoRI sites of the apo B gene between the patient and control groups. The frequency of the rarer allele of the PvuII RFLP was significantly lower in the CAD patients (P < 0.05) compared to that in the control group (0.05 vs 0.10). None of the DNA polymorphisms was associated with a significant influence on serum lipid and apolipoprotein levels in the patients with coronary artery disease.
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PMID:DNA polymorphisms of the apolipoprotein B gene in Chinese coronary artery disease patients. 135 87

The mammalian CAD gene codes for a 240-kDa multifunctional protein that catalyzes the first three steps of de novo pyrimidine biosynthesis. Previously, the longest cDNA construct available was missing approximately 500 bp of coding sequence at the 5' end, thereby lacking the sequence to encode the entire carbamylphosphate synthetase (CPSase) domain. Here, a complete CAD hamster cDNA is constructed, placed into a mammalian expression vector, and transfected into hamster cells deficient in CAD. Transfectants show coordinately restored levels of all three enzyme activities and the presence of full-length CAD protein. A derivative construct of the CAD cDNA was generated that should encode only the CPSase domain. When transfected into mammalian cells, a protein was synthesized that had significant CPSase activity both in vivo and in vitro. The two constructs generated in this study will facilitate the study of CAD structure, function, and allosteric regulation.
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PMID:Complete hamster CAD protein and the carbamylphosphate synthetase domain of CAD complement mammalian cell mutants defective in de novo pyrimidine biosynthesis. 135 54

The multienzyme polypeptide CAD is phosphorylated at two sites by cyclic AMP (cAMP)-dependent protein kinase. Site 2 has two interesting features: it is located in a 'linking region' between two discretely folded enzyme domains, and a histidine, instead of the more usual arginine, is found three positions N-terminal to the phosphorylated serine. A synthetic peptide corresponding to the sequence around site 2 has an extended or random structure in solution, and the proton n.m.r. chemical shift of the histidine residues can be titrated against pH in the range 6.0-8.0. The peptide is phosphorylated more rapidly by cAMP-dependent protein kinase at lower pH values, indicating that the protonated histidine side chain corresponds to the arginine in the consensus recognition sequence for the kinase. Kemptide, a specific synthetic substrate for the kinase, was phosphorylated with a higher affinity and at a similar rate at all pH values. CAD was a better substrate than the synthetic peptide, and labelling was not affected by the pH of the incubation conditions. The results indicate that the phosphorylation site in the interdomain linker is sufficiently exposed to the solvent to ensure accessibility to the kinase, but that secondary or tertiary structure in the intact protein allows the histidine residue to remain protonated at physiological pH and enhances recognition of the phosphorylatable serine residue.
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PMID:A protonated histidine residue in a phosphorylation site for cyclic AMP-dependent protein kinase. Comparison of a synthetic peptide with the exposed linking region in the multienzyme polypeptide CAD. 135 77

Resistance to phosphonacetyl-L-aspartate (PALA) is caused by CAD gene amplification. The marker chromosome of a PALA-resistant cell line containing a homogeneously staining region with amplified CAD gene was introduced into PALA-sensitive Chinese hamster cells by microcell-mediated chromosome transfer. Two monochromosomal hybrids containing the marker chromosome in addition to the normal chromosome complement of sensitive cells and 1 tetraploid hybrid containing the complete genomes of donor (resistant) and recipient (sensitive) cells were studied in detail. It was shown that (i) the presence of the marker chromosome was both a necessary and a sufficient condition for the expression of the PALA-resistant phenotype; (ii) the marker chromosome underwent rearrangements in the monochromosomal hybrids, with preferential loss of non-amplified chromosomal regions, while it was not rearranged in the tetraploid hybrid; (iii) unlike the original PALA-resistant cells obtained after long-term selection in the presence of PALA, the PALA-resistant hybrids did not show chromosomal aberrations of other than the marker chromosome. This result indicates that chromosomal aberrations may be due to the selective procedure and is not an inherent property of cells containing amplified genes.
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PMID:Chromosome rearrangements associated with CAD gene amplification. Experiments with cell hybrids. 137 Feb 46

Analysis of chromosomal alterations during stepwise development of mdr1, dhfr, or CAD gene amplifications in a large number of independently selected Djungarian hamster DM-15 and murine P388 sublines revealed typical patterns of karyotypic evolution, specific for multiplication of each of these genes in each cell type. Some principal similarities of karyotypic evolution were noted in at least two different systems. They include: (i) appearance at the first selection step of a new chromosomal arm bearing the resident gene copy followed at the next selection steps by the formation in these specific chromosomal arms of amplified DNA tandem arrays; (ii) translocations of amplified DNA from its initial site to other, also non-random, chromosomal sites; and (iii) emergence in the cell variants with high degrees of gene amplification of multiple extra-chromosomal elements. The most prominent distinctions among the systems were as follows: (i) different structures, evidently containing amplified DNAs, appeared at the initial steps of amplification of different genes--additional heterogeneously staining regions in specific chromosomal segments in the case of amplification of dhfr or CAD genes in DM-15 cells, and mini-chromosomes in the case of mdr1 gene amplification in both DM-15 and P380 cells; (ii) distinct patterns of location of the amplified mdr1 gene copies are characteristic of Djungarian hamster DM-15 and murine P388 cell derivatives after subsequent steps of selection--at the site of resident gene localization or in some other, also non-random, chromosomal sites in DM-15 sublines, and predominantly extra-chromosomal in P388 sublines. We propose that different mechanisms are responsible for the initial steps of amplification of dhfr and CAD genes on the one hand and the mdr1 gene on the other: non-equal sister-chromatid exchanges and autonomous replication of the extra-chromosomal elements. It seems, however, that both mechanisms may be involved in further rounds of amplification of each of these three genes.
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PMID:Regularities of karyotypic evolution during stepwise amplification of genes determining drug resistance. 137 12

Use of a CAD program to design the shape of a crown, restoration of 6 molar was studied. Stone models of 5 to 7 molars with 6 prepared die for crown and a complete 6 crown which was applied for restoration were measured. The 6 crown data were adapted on the 6 die, and adjusted with 5 and 7 proximal teeth. The coordinates of the data of 6 were then transferred to that of the 6 die. The ends of the adapted crown data were linked with the margin of 6 die. Further the occlusal condition with antagonistic tooth was adjusted by applying the FGP (functionally generated path) technique. FGP was recorded on bite wax and measured. Comparing FGP record and adapted crown, modulation of the occlusal surface was accomplished.
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PMID:Three dimensional shape measurement of teeth (2). CAD to produce crown considering occlusion. 139 85

There has been much interest in the in-office fabrication of ceramic posterior restorations using computer-aided design and computer-aided manufacture (CAD-CAM) units. One concern that practitioners have concerning the use of one of these systems is the initial expense of the CAD-CAM unit for the office. This article deals with the financial implications involved when considering the purchase or lease of a CEREC (CAD-CAM) unit.
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PMID:Financial considerations regarding acquisition of the Siemens Cerec computer reconstruction system. 141 18


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