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Biomedical subjects

M A Davis

Publications and source records attributed to M A Davis.

At least 127 records · Page 7Linked to original sources
PubMed1991

Fluorodeoxyuridine-mediated modulation of iododeoxyuridine incorporation and radiosensitization in human colon cancer cells in vitro and in vivo.

A study was conducted to assess the potential of 5-fluoro-2'-deoxyuridine (FdUrd) to increase the incorporation and radiosensitizing properties of 5-iodo-2'-deoxyuridine (IdUrd) using HT29 human colon cancer cells both in vitro and in nude mice bearing these tumors as xenografts. The purpose of this study was to assess (a) whether FdUrd could increase IdUrd efficacy using clinically achievable concentrations of drugs; (b) the relationships among radiosensitization, DNA damage and repair, and analogue incorporation; and (c) whether FdUrd improved the selectivity of IdUrd incorporation into tumor cells compared to normal tissues. It was found that FdUrd, at clinically achievable concentrations (1-100 nM), significantly increased IdUrd incorporation under all conditions but particularly when the IdUrd concentration was less than or equal to 10 microM. FdUrd increased IdUrd-mediated radiosensitization in proportion to the increase in IdUrd incorporation. FdUrd potentiated the ability of IdUrd to increase radiation-induced DNA double-strand breaks and to slow their repair. When IdUrd alone (100 and 200 mg/kg/day) was infused into nude mice bearing tumors, the extent of thymidine replaced in the tumor was 1.6 +/- 0.4 (mean +/- SE) and 2.5 +/- 0.4%, respectively. The combination of FdUrd (0.1 mg/kg/day) and IdUrd (100 mg/kg/day) increased the incorporation in the tumor to 5.3 +/- 0.9% with less toxicity than resulted from the use of 200 mg/kg/day of IdUrd alone. These data show that FdUrd is an effective biomodulator, because, for the same extent of normal tissue incorporation, the combination of IdUrd and FdUrd produces significantly greater incorporation into the tumor compared to the use of IdUrd alone. Furthermore, they suggest that the regional application of FdUrd with IdUrd, either through the use of regional infusions or in combination with focused irradiation, could potentially improve the outcome of treatment of localized gastrointestinal cancer.

Animals↗
PubMed1991

Gadolinium-labeled liposomes containing various amphiphilic Gd-DTPA derivatives: targeted MRI contrast enhancement agents for the liver.

Unique paramagnetic liposomal contrast agents were synthesized and utilized for selective augmentation of T1 MR imaging of the livers of normal Balb/c mice. A series of amphipathic gadolinium complexes, which mimic phospholipids, was incorporated into the lamella of small unilamellar liposomes such that they become an integral part of its surface. The amphipathic complexing agents consisted of DTPA reagents in which two stearyl chains are attached via amide, ester, and thioester linkages. The in vitro stability and the in vivo lifetimes of the new amphipathic agents were dependent on the method used to attach the long-chain alkyl groups.

Animals↗
PubMed1991

Gadolinium-labeled liposomes containing amphiphilic Gd-DTPA derivatives of varying chain length: targeted MRI contrast enhancement agents for the liver.

Paramagnetic liposomal contrast agents were synthesized and utilized for selective augmentation of T1 MR imaging of the livers of normal Balb/c mice. Amphiphilic gadolinium complexes, which mimic phospholipids, were incorporated into the lamella of small unilamellar liposomes (SUV) such that they become an integral part of its surface. The amphiphilic complexing agents consisted of DTPA reagents in which a pair of alkyl chains of varying lengths are attached via amide linkages. The in vivo lifetimes of the amphiphilic agents were found to be dependent on the chain length of the alkyl groups.

Animals↗
PubMed1991

Insulin-like growth factors in sheep uterine fluids: concentrations and relationship to ovine trophoblast protein-1 production during early pregnancy.

Uterine luminal fluids (ULFs) from Days 10, 12, 14, and 16 cyclic (C) and pregnant (Px) ewes were analyzed for presence of insulin-like growth factors (IGF-I, IGF-II) and other mitogenic factor(s). IGF content and non-IGF mitogenic activity were measured by IGF RIAs after removal of IGF binding proteins and by stimulatory effects on DNA synthesis of density arrested AKR-2B cells, respectively. ULF IGF-I content was not different between days, but differences in IGF-I between C and Px groups at Day 16 (C greater than Px) were found (p less than 0.05). ULF IGF-II content was not different between C and Px ewes; however, differences among days (p less than 0.01) were apparent. In both C and Px ewes, Day 14 ULF had highest IGF-II content (C: 4.60 +/- 0.98 ng/ml, Px: 5.39 +/- 1.38 ng/ml). In Day 12 and Day 14 (C and Px) ULF, IGF-II concentration was about 10-fold greater than that of IGF-I. AKR-2B mitogenic activity in ULF differed among days (p less than 0.01), but not between C and Px ewes. Highest activity was observed for Day 14 and Px ULF, whereas lowest activity was for Day 10 C and Day 16 Px ULF. Sephadex G-200 gel-filtration chromatography of ULF from Day 14 Px ewes demonstrated mitogenic activity in the column void volume fractions and in the 30-kDa size range of eluted proteins. Day 13 conceptuses were cultured in serum-free medium to define the effect of exogenous IGFs on ovine trophoblast protein-1 (oTP-1) secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Age and sex differences in variation of nutrient intakes among U.S. adults.

Studies assessing associations of diet with health frequently use multi-day dietary records to estimate usual dietary intakes. We examined variation in intakes of 13 nutrients for 13,388 U.S. adults using 3 days of dietary data from the 1977-1978 Nationwide Food Consumption Survey. Ratios of within-person variability to between-person variability in intakes were large and would result in attenuated linear regression estimates of diet-health associations. For many nutrients, the magnitude of the attenuation decreased with age for both sexes but particularly for men, implying that fewer days of dietary intake per person would correctly assess diet-health associations among older adults than have been suggested for younger adults.

Adult↗
PubMed1991

Fine-structure analysis of the P1 plasmid partition site.

P1 plasmid partition requires two plasmid-encoded Par proteins and a cis-acting site. The site, parS, lies in a region consisting of a 13-bp palindrome and an adjacent AT-rich sequence. A series of point mutations were analyzed for their effects on partition site activity. The results indicated that only the left arm of the palindrome and some adjacent bases were needed. The limits of the functional site were further refined to a maximum of 22 bp, which includes binding sites for the P1 ParB protein. Mutations in the 22-bp site cause concomitant defects in partition and the ability to exert partition-mediated incompatibility. Like the region immediately to the left of the 22-bp region, the right arm of the palindrome is not essential for partition but does contain information that affects the specificity of incompatibility.

Bacterial Proteins↗
PubMed1991

Breast specimen microcalcifications: radiographic validation and pathologic-radiologic correlation.

A prospective analysis of specimens from location and biopsy of mammographically suspect microcalcifications in 108 patients was carried out to determine if microcalcifications were lost during histopathologic processing and the clinical relevance of such loss. Nine hundred sixty-eight paraffin blocks were prepared from 425 gross tissue slices containing calcifications identified at radiography of the specimens. Calcium was apparently lost both during preparation of the blocks (13.6%) and after slide preparation (12.6%), for a total possible loss of 26.2%. All specimens demonstrated calcification histologically. One pathology report was amended because of information obtained after recuts, but all cancers were detected on original slides whether or not calcifications were identified initially. The results indicate that, by following the suggestions offered to ensure adequate histopathologic sampling of calcification seen at mammography, most if not all of the calcification present can be detected on the original slide.

Breast↗
PubMed1991

Induction of megabase DNA fragments by 5-fluorodeoxyuridine in human colorectal tumor (HT29) cells.

Current evidence suggests that DNA fragmentation plays an integral role in mediating cytotoxicity that results from thymidine nucleotide depletion ("thymineless death"). Recently, Ayusawa et al. [Mutat. Res. 200:221-230 (1988)] reported that dTMP starvation induces cellular processes that result in the release of 50-200-kilobase (kb) DNA fragments in FM3A cells, as detected by pulsed field gel electrophoresis (PFGE). The present study was undertaken to determine whether a similar DNA fragmentation process occurs in a human cell line in response to fluoropyrimidine treatment and, if so, to quantitate this process. When human colorectal tumor (HT29) cells were treated with 100 nm 5-fluorodeoxyuridine (FdUrd), this regimen induced the formation of high molecular weight DNA fragments, which were analyzed using three different PFGE protocols. Field inversion PFGE revealed that, in contrast to the discrete size range reported for FM3A cells, FdUrd-induced fragments in HT29 cells were broadly distributed from about 50 kb to sizes beyond the resolution of the field inversion mode (i.e., greater than 600 kb). Analysis of these same samples by contour-clamped homogeneous electric field PFGE showed that the bulk of these fragments migrated in the 1-5-megabase region. In contrast, fragments from DNA that was broken randomly by gamma-radiation appeared to be primarily in a zone corresponding to approximately 5-10 megabases. Equitoxic FdUrd and radiation treatments (100 nM FdUrd for 48 hr versus 10-Gy gamma-radiation) each increased the fraction of DNA entering the gel from about 0.07-0.09 (untreated cells) to about 0.22-0.25. To a first approximation, the time course and quantity of DNA fragmentation induced by 100 nM FdUrd appeared to correlate with the loss of clonogenicity within the 48-hr period analyzed. These findings suggest that the processes responsible for DNA fragmentation in response to a thymineless state may be different in FM3A and HT29 cells, that in both cases the breaks caused do not appear to be located randomly with respect to the entire genome, and that these processes may be related to the chain of events by which temporary dTMP starvation is made into a lethal insult.

Cell Survival↗
PubMed1991

Knee osteoarthritis and physical functioning: evidence from the NHANES I Epidemiologic Followup Study.

Although osteoarthritis (OA) is common among adults, little is known about its long-term impact on physical function. Therefore, in a cohort of 2,884 adults aged 45 years or older, [National Health and Nutrition Examination Survey I (NHANES I 1971-1975)] we examined the association of baseline radiographic knee OA and difficulty in physical functioning 10 years later (NHANES I Followup Study 1982-1984). In sex specific analyses, after controlling for age, race and length of followup, persons with radiographic knee OA were more likely than persons without knee OA to report difficulty with physical functioning, particularly for activities involving mobility, transfer and instrumental activities of daily living. However, the association of knee OA with physical functioning was influenced by the radiographic grade of OA and knee pain at NHANES I, suggesting that disease severity and pain are important in anticipating difficulties with physical functioning in persons with knee OA.

Adult↗
PubMed1990

Leuprolide with and without flutamide in advanced prostate cancer.

In a randomized, double-blind trial for metastatic prostate cancer (Stage D2), 603 men received leuprolide, a gonadotropin-releasing hormone analog that inhibits the release of gonadotropins, coupled with either placebo or flutamide, a nonsteroidal antiandrogen that inhibits the binding of androgens to the cell nucleus. The 303 men receiving androgen blockade with leuprolide and flutamide demonstrated a longer progression-free survival (16.9 vs. 13.9 months, P = 0.039) and an increased median length of survival (35.0 vs. 27.9 months, P = 0.035). In the subgroup of men with minimal disease and good performance status, the advantages of maximal androgen blockade were more pronounced. It is concluded that combined androgen blockade with leuprolide and flutamide was more effective than leuprolide alone for patients with metastatic cancer of the prostate. The therapeutic benefits, although greatest in patients with minimum disease, need to be evaluated in a prospective, randomized fashion in trials specifically designed for men with minimal disease and good performance status. Exploratory analyses using the black race as an explanatory variable were also performed. Black race is associated with shorter survival times and is also associated with other prognostic factors, including recent weight loss, anemia, elevated phosphatase levels, and pain. These findings suggest the need for future studies of the relationship of black race and response to prostate cancer therapy.

Adult↗
PubMed1990

Specificity switching of the P1 plasmid centromere-like site.

The P1 plasmid partition site acts like a centromere, promoting accurate segregation of copies to daughter cells. A 34 bp segment is essential for partition and binds the plasmid ParB protein. Additional sequences act as specificity elements that direct the choice of copies for partition. They include a second ParB binding site and a site for the host integration host factor protein. Sites lacking one or more of these additional elements are switched to a different specificity. Defined mutants were scored for partition specificity and protein binding. The results suggest that the wild-type site is folded in a specific DNA-protein complex. Disruption of the complex leads to an open configuration which, while still active in partition, has altered recognition specificity.

Base Sequence↗
PubMed1990

The influence of Na+,K(+)-pump blockade on doxorubicin-mediated cytotoxicity and DNA strand breakage in human tumor cells.

We have previously shown that blockade of the Na+,K(+)-pump by the cardiac glycoside ouabain produces doxorubicin resistance and decreases topoisomerase II-mediated DNA strand breakage in hamster cells. To determine if this were a general phenomenon, the effect of pump blockade on doxorubicin resistance was assessed in three human tumor cell lines: A549 lung and HT29 colon adenocarcinomas and U1 melanoma. When cells were exposed to 1 microM ouabain prior to and during incubation with doxorubicin, cytotoxicity was markedly reduced. Ouabain had no effect on either the influx or the efflux of doxorubicin. However, all cell lines showed a ouabain-induced decrease in doxorubicin-induced topoisomerase-mediated DNA strand breakage (SSB). These data suggest that blockade of the Na+,K+ pump decreases doxorubicin cytotoxicity in human tumor cells by inhibiting topoisomerase-mediated SSB. Furthermore, they indicate that altered ionic gradients are a potential cause of resistance to drugs that use topoisomerase II as a target.

Adenocarcinoma↗
PubMed1990

Obesity and osteoarthritis of the knee: evidence from the National Health and Nutrition Examination Survey (NHANES I).

The importance of systemic/metabolic factors in the association of obesity with radiographic knee osteoarthritis (OA) was examined for 3,905 adults aged 45 to 74 from the United States National Health and Nutrition Examination Survey, 1971 to 1975 (NHANES I). Obesity was associated with both bilateral and unilateral OA, but more strongly with bilateral OA. Obesity was also associated with both symptomatic and nonsymptomatic knee OA. Controlling for age, sex, serum cholesterol, serum uric acid, diabetes, body fat distribution, bone density, and blood pressure did not significantly reduce the association between obesity and knee OA. Findings from these data are not supportive of a metabolic link between obesity and knee OA.

Adult↗
PubMed1990

The dependence of halogenated pyrimidine incorporation and radiosensitization on the duration of drug exposure.

The influence of the duration of exposure to the halogenated pyrimidines iododeoxyuridine (IdUrd) and bromodeoxyuridine (BrdUrd) on incorporation into DNA and the resulting radiosensitization was studied in cultured human colon cancer cells. Cells were incubated with either 10 microM BrdUrd or IdUrd for periods up to 7 days. They were also assessed for up to 4 days after removal of drug from the medium. Replacement of thymidine by fraudulent bases was measured using a sensitive gas chromatographic, mass spectrometric (GC/MS) assay. Incorporation of BrdUrd and IdUrd plateaued at 35% and 30%, respectively, after 4 days of exposure. Prolonging the time of exposure to 7 days increased cytotoxicity without affecting either incorporation or radiosensitization. Incorporation remained constant for 1-2 days after removal of drug from the medium. Radiosensitization was linearly related to incorporation throughout the range of conditions assessed. These data suggest that it may be possible to develop a predictive assay for radiosensitization based on measurements of halogenated pyrimidine incorporation in a tumor biopsy specimen. They also suggest that a clinical approach based on repeated short exposures to halogenated pyrimidines may present certain advantages over the current practice of prolonged continuous exposure. A Phase I/II trial using IdUrd and external beam irradiation for the treatment of patients with poor prognosis soft tissue sarcomas has been initiated based on this concept.

Bromodeoxyuridine↗
PubMed1990

Body fat distribution and osteoarthritis.

The association of body fat distribution with single and combined site osteoarthritis was investigated using data from the US Health Examination Survey I, 1960-1962 (HES I) and the first National Health and Nutrition Examination Survey I, 1971-1975 (NHANES I). The study included 1,636 adults aged 35-79 years from HES I with hands and feet radiographs and four anthropometric fat distribution measures--subscapular and triceps skinfolds, waist girth, and seat breadth--and 3,885 adults aged 45-74 from NHANES I with knee radiographs and subscapular and triceps skinfold measures. Sex-specific data, adjusted for age, race, and body mass index, were analyzed using polychotomous logistic regression. There was a positive association of body mass index with knee osteoarthritis and with combined hands and feet osteoarthritis. A peripheral body girth pattern was associated with combined site osteoarthritis of the hands and feet; however, there was no consistent pattern of association of body fat distribution with knee osteoarthritis nor with osteoarthritis of the hands or feet only. These findings suggest that the central body fat pattern observed in previous studies to be associated with cardiovascular and gallbladder disease, and with diabetes, is not associated with osteoarthritis of the hands, feet, or knees.

Adipose Tissue↗