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PubMed1995

5-Ethoxy-2'-deoxyuridine, a novel substrate for thymidine phosphorylase, potentiates the antitumor activity of 5-fluorouracil when used in combination with interferon, an inducer of thymidine phosphorylase expression.

Clinical studies have demonstrated that the combination of 5-fluorouracil (FUra) and IFN-alpha has activity in the treatment of advanced colorectal cancer. Treatment of human colon carcinoma cells with IFN caused a 5-fold increase in the level of thymidine phosphorylase (TP) mRNA and an 8-fold increase in TP enzyme activity. Since TP catalyzes the first step in the direct conversion of FUra to deoxyribonucleotides, its induction by IFN is a potential biochemical mechanism for the modulation of the antitumor activity of FUra. In contrast to the activity measured in cell extracts, however, thymine utilization by intact cells was increased less than 2-fold by IFN, suggesting that the metabolic activation of FUra by TP in the IFN-treated cells was similarly suboptimal. This was likely due to a rate-limiting amount of cosubstrate for TP, and in this study, a series of 5-substituted 2'-deoxyuridine analogues were synthesized and tested as potential deoxyribose donors for TP. One of the compounds, the novel pyrimidine analogue 5-ethoxy-2'-deoxyuridine (EOdU), was found to be a substrate for the transferase reaction of TP, to have little or no direct cytotoxicity, to selectively increase the cellular levels of 5-fluoro-dUMP, to enhance the inhibitory effect of FUra on thymidylate synthase activity, and to potentiate the cytotoxicity of FUra and IFN in human colon carcinoma cells. EOdU was tested in vivo against HT-29 cells grown as xenografts in nude mice. The combination of EOdU+FUra+IFN-alpha 2a produced tumor regressions and a significantly greater delay in tumor growth when compared to FUra+IFN-alpha 2a, FUra+EOdU, or FUra or IFN used alone; tumors were 72% smaller in the EOdU+FUra+IFN-alpha 2a-treated animals compared to the saline control group. A comparable antitumor effect was also found when a related nucleoside analogue, 5-propynyloxy-2'-deoxyuridine, was used with FUra+IFN, and it also showed modulating activity when used with only FUra. The antitumor activity of the three agent combination (nucleoside+IFN+FUra) was comparable to that of a higher dose of FUra used alone, but it was substantially less toxic to the animals than the higher dose of FUra, indicating that the modulating agents improved the therapeutic index of FUra.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

[Preclinical diagnosis of metabolic osteopathy in feedlot bulls].

Diagnostic significance of some clinico-biochemical parameters was investigated in 221 fattened bulls. An evaluation of the results has shown that the determination of concentrations of calcium, inorganic phosphorus and alkaline phosphatase activity in blood plasma was not of essential importance for diagnostics. The values of these parameters were within the reference range (Tab. I). The parameters determined by chemical analyses of bioptates from the tuber coxae of the fattened bulls with various forms of alimentary osteopathy showed characteristics, statistically significant differences in comparison with the control animals (Tabs. II, III, IV). In the bulls of group B/1 (clinically healthy, phosphorus deficit in the feed ration, acidogenic nutrition in part of the animals, lowered performance, occurrence of clinical cases of osteopathy in fattening facilities), a significant decrease in the values of ash per 1 g fat-free dry matter and per 1 cm3 spongy substance of the t. coxae and a significantly wider index Ca/P were determined. In the bulls of group B/2 (clinically healthy, deficit of phosphorus, calcium, proteins and energy in the feed ration, decreased performance, occurrence of clinical osteopathy), a significant decrease of ash per 1 g fat-free dry matter and per 1 cm3 of spongy substance of the t. coxae was determined, the Ca/P index was significantly narrower. In the bulls of group C/1 (bulls with clinical symptoms of skeleton disorder, phosphorus deficit in the feed ration, acidogenic nutrition in part of the animals), a significant decrease of ash per 1 g far-free dry matter and per 1 cm3 spongy substance of the t. coxae was found out, the Ca/P index was wider.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

DNA synthesis and ploidy in non-Hodgkin's lymphomas demonstrate intrapatient variation depending on circadian stage of cell sampling.

Significant circadian cell cycle variations with a maximal number of cells in S-phase during the night have been found in a series of 24 patients (18 men and 6 women) with histologically established non-Hodgkin's lymphomas. Pathological lymph nodes of a total of 26 patients were punctured and aspirated by fine needle technique every 4 h during a single 24-h time span. Twenty-four patients (92.3%) had Stage III or IV disease. Twelve patients (46.1%) had low grade, 10 patients (38.5%) had intermediate grade, and 4 patients (15.4%) had high grade lymphomas according to the Working Formulation. The samples were analyzed by flow cytometry, and DNA synthesis (S-phase) and ploidy were determined according to circadian stage. The individual mean 24-h S-phase varied from 2.2 +/- 1.2% (mean +/- SD) to 24.0 +/- 3.3%. Within the group of patients with low grade lymphomas, a wide range in mean S-phase from 2.4 +/- 1.2% to 9.2 +/- 2.8% was observed. The percentage variation within each patient between the lowest and highest S-phase as compared to the lowest value (range of change) during the 24-h time span varied from 21 to 353%, with a mean range of change of 128 +/- 19%. When each individual S-phase series was converted to percent of mean and combined for analysis by one-way analysis of variance to test for time-effect across 2 12-h time spans (8 p.m.-8 a.m. versus 8 a.m.-8 p.m.), S-phase variation according to circadian stage was found to be statistically significant (P < 0.004), with higher values found in the 8 p.m.-8 a.m. time span. By single cosinor analysis, S-phase yielded a near significant P value of 0.069 for the least-squares fit of a 24-h cosine to all data as percent of mean, with the acrophase found to be near midnight (0.05 h). For those patients with low and intermediate grade lymphomas and with mean S-phase values < 10.0%, we found that mean S-phase was higher during winter (5.8 +/- 0.4%) than during spring (3.8 +/- 0.3%) or during fall (3.6 +/- 0.3%) (P < 0.001, analysis of variance). Twenty-one of the 26 patients (80.8%) had an aneuploid, hypodiploid, or near diploid population in one or several of the repeated samples. For the whole series, the DNA indices for the aneuploid populations varied from 1.09 to 1.96, the median DNA index being 1.20.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1964

THE CDC-CDCR DOCUMENTATION PROJECT.

A progress report on an experiment in mechanized methods for the storage and retrieval of communicable diseases information. The project, supported by National Institutes of Health grants and begun in 1958, is being conducted by the Center for Documentation and Communication Research (CDCR), School of Library Science, Western Reserve University, Cleveland, Ohio, in cooperation with the Communicable Disease Center (CDC), United States Public Health Service, Atlanta, Georgia. Initial phases have been completed. Seventy-seven questions submitted by the CDC Documentation Committee have been searched by CDCR on their GE-225 computer. For seventy-three of the seventy-seven questions, the system responded with at least one appropriate answer. The combined pertinent and peripheral responses totaled 94.7 percent. The file of abstracted literature is being increased preparatory to large-scale testing. Further investigation and evaluation are necessary before the project can be fairly appraised.

Abstracting and Indexing↗
PubMed1965

COMPUTERIZED BIBLIOGRAPHIC SERVICES FOR BIOMEDICINE.

By its development of improved media for dissemination of information, the National Library of Medicine is fostering a greater awareness and a better understanding of research and development efforts in behalf of public health and clinical medicine, and a more rapid translation of research into clinical application. The library's transformation from a passive repository of information to an active ally of the researcher, teacher, and clinician has led to increased use of medical library facilities and has stimulated thinking through better communication of published information. The library's success in using automation for bibliographic control of medical literature suggests that other disciplines that have not already developed automated techniques of literature-reference retrieval might profitably do so.

Abstracting and Indexing↗
PubMed1992

Effects of policy manual reorganization on user proficiency.

This study compared the proficiency of nurses who located policies in a traditional, alphabetically arranged policy manual vs. a reorganized, indexed manual. Nurses were asked to locate policy statements that would resolve issues presented in three vignettes that were typical of the decisions nurses must regularly make. Answers were scored as correct or incorrect; time to respond and search strategies were also recorded. Data analyses show the overall superiority of the reorganized, indexed manual.

Abstracting and Indexing↗