Search PubMed⌕ Search

Biomedical subjects

R A Lawrence

Publications and source records attributed to R A Lawrence.

At least 37 records · Page 2Linked to original sources
PubMed1999

Activity of SCH 66336, a tricyclic farnesyltransferase inhibitor, against human tumor colony-forming units.

BACKGROUND: The ras gene product regulates transduction of growth-proliferative signals from the membrane to the nucleus. Mutationally-activated Ras is the oncogene most frequently found in human tumors. In order to perform its function in cell signaling, Ras must be farnesylated on the CAAX motif present on the carboxyl terminus of the ras protein. This reaction is catalysed by farnesyl protein transferase. In the present study, SCH 66336, an orally bioavailable nonpeptide tricyclic farnesyltransferase inhibitor, was tested against a large variety of human tumors to define its preclinical activity profile, utilizing the human tumor cloning assay. MATERIALS AND METHODS: A soft agar cloning assay was used to determine the in vitro effects of SCH 66336 against primary human tumor specimens taken directly from patients. A total of 70 evaluable specimens were exposed to SCH 66336 for 14-day continuous exposure at concentrations ranging from 0.1 to 2.5 microM. In vitro responses were defined as an inhibition > or = 50% of human tumor colony forming units at a given concentration. RESULTS: There was a positive relationship between concentration and response to SCH 66336. With the highest concentration (2.5 microM), response was demonstrated in 50% (three of six) of breast tumors, 40% (6 of 15) of ovarian tumors, and 38% (5 of 13) of non-small-cell lung tumor colony forming units. Among the 69 specimens tested at the concentration of 2.5 microM, SCH 66336 had activity in 27% of tumor specimens that were resistant to doxorubicin, 38% of tumor specimens resistant to cisplatin, 33% of tumor specimens resistant to paclitaxel, and 27% of tumor specimens resistant to etoposide. CONCLUSIONS: The broad spectrum of soft agar growth inhibition by SCH 66336 in the human tumor cloning assay, and its efficacy at physiologically relevant concentrations in animal models, suggest that SCH 66336 may deserve future clinical trials in patients with ovarian, breast and non-small-cell lung cancer.

Alkyl and Aryl Transferases↗
PubMed1999

Activity of MKT 077, a rhodacyanine dye, against human tumor colony-forming units.

MKT 077 is related to rhodamine 123 dye and demonstrates preferential accumulation in the mitochondria of cancer cells compared to normal cells. This difference in retention between cancer and normal cells led to the finding that MKT 077 selectively inhibits the growth of cancer cells in vitro. To define the preclinical activity profile of MKT 077, the compound was tested in vivo against a large variety of human tumors utilizing the human tumor-cloning assay. MKT 077 was studied using a sequential 2 h exposure separated by 24 h (2-24-2 h) and a 24 h exposure at final concentrations of 0.1, 0.2, 1.0, 2.0, 10.0 and 20.0 microg/ml. MKT 077 was also studied using continuous exposure at final concentrations of 0.1, 1.0 and 10 microg/ml. A decrease in tumor colony formation was considered significant if survival of colonies treated with MKT 077 was 50% or less compared to untreated controls. A total of 149 specimens was treated with MKT 077 with 51, 58 and 34 evaluable specimens with the 2-24-2 h, the 24 h and the continuous exposure, respectively. The results of the present study suggest a positive relationship between concentration and response. No relationship between exposure schedule and activity was observed. Inhibitory effects were obtained against multiple tumor types. High cytotoxic activity was obtained against breast, ovary, endometrial, colon and non-small cell lung cancer with concentrations of 2 microg/ml or above. In conclusion, the broad spectrum of cytotoxicity of MKT 077 in the human tumor-cloning assay and the unique mechanism of action of MKT 077 encourage additional preclinical and clinical studies with this compound and other rhodacyanine dyes.

Antineoplastic Agents↗
PubMed1999

Comparison of DX-8951f and topotecan effects on tumor colony formation from freshly explanted adult and pediatric human tumor cells.

DX-8951f, which shows great therapeutic potential, was tested in the human tumor cloning system in adult and pediatric tumor types against which topotecan has been active. In 47 tumors from adults, DX-8951f had definite cytotoxic activity in a concentration-dependent manner with both 1 h and continuous exposures. Topotecan was minimally effective using a 1 h exposure and showed concentration-dependent inhibition with continuous exposure. In head-to-head comparisons at 1 h exposure against adult tumors, DX-8951f was significantly more effective at 0.1 and 1.0 microg/ml than topotecan. In head-to-head comparisons (continuous exposure), 1.0 microg/ml DX-8951f was more effective than topotecan at 1.0 microg/ml in adult tumors, including three of four head and neck, one of two kidney, two of five liver, six of 10 non-small cell lung, five of eight ovarian, four of eight prostate tumors, and in single specimens of breast, mesothelioma, colon and small cell lung tumors. With continuous exposure, DX-8951f and topotecan were equally effective at equimolar concentrations. The maximum tolerated dose for DX-8951f is 3 times that of topotecan, so higher doses of DX-8951f could be administered to patients. DX-8951f is a promising new antineoplastic agent with significant activity against tumors taken directly from patients.

Adult↗
PubMed1999

Storage of human milk and the influence of procedures on immunological components of human milk.

The storage of human milk for use later by the mother's own infant or an unrelated recipient has an impact on its constituents. These effects involve the storage container, heating, cooling and freezing the milk. Overall, glass is the least destructive container. Milk can be safely refrigerated for 72 h with little change. Freezing destroys cellular activity and reduces vitamins B6 and C. Boiling, in addition, destroys lipase and reduces the effect of immunoglobulin A and secretory immunoglobulin A. The nutrient value of human milk is essentially unchanged, but the immunological properties are reduced by various storage techniques.

Female↗
PubMed1999

The effects of early pacifier use on breastfeeding duration.

OBJECTIVE: To evaluate the effects of pacifier use and the timing of pacifier introduction on breastfeeding duration, problems, and frequency. METHODS: A cohort of 265 breastfeeding mother-infant dyads was followed prospectively. Maternal interviews were conducted at delivery, 2, 6, 12, and 24 weeks, and thereafter every 90 days until breastfeeding ended. Information was obtained regarding pacifier use, infant feeding, use of supplemental foods and breastfeeding frequency, duration, and problems. The effect of pacifier introduction by 6 weeks of age on breastfeeding duration was evaluated with Kaplan-Meier and Cox proportional hazards models. The effect of the timing of pacifier introduction (</=2 weeks and </=6 weeks) on breastfeeding duration at 2 and 3 months was evaluated using logistic regression modeling. RESULTS: A total of 181 mothers (68%) introduced a pacifier before 6 weeks. In adjusted analyses, pacifier introduction by 6 weeks was associated with a significantly increased risk for shortened duration of full (hazard ratio, 1.53; 95% confidence interval: 1.15, 2.05) and overall (hazard ratio, 1.61; 95% confidence interval: 1.19,2.19) breastfeeding. Women who introduced pacifiers tended to breastfeed their infants fewer times per day, with significant differences noted at 2 (8.1 +/- 2.6 vs 9.0 +/- 2.3) and 12 weeks' (6.3 +/- 2.0 vs 7.4 +/- 1.6) postpartum. At 12 weeks postpartum, women who introduced pacifiers also were more likely to report that breastfeeding was inconvenient and that they had insufficient milk supplies. Pacifier use begun either before 2 weeks or before 6 weeks' postpartum was not significantly associated with breastfeeding duration at 2 and 3 months. CONCLUSIONS: Pacifier use was independently associated with significant declines in the duration of full and overall breastfeeding. Breastfeeding duration in the first 3 months' postpartum, however, was unaffected by pacifier use. Women who introduced pacifiers tended to breastfeed their infants less frequently and experienced breastfeeding problems consistent with infrequent feeding. Findings from this study suggest that the decreases in breastfeeding duration associated with pacifier use may be a consequence of less frequent breastfeeding among women who introduce pacifiers to their infants.

Breast Feeding↗
PubMed1999

Pediatricians' practices and attitudes regarding breastfeeding promotion.

OBJECTIVE: Public awareness of the benefits of breastfeeding is expected to increase during and after the national, federally funded Best Start Breastfeeding Promotion Campaign. It is anticipated that this will result in more breastfeeding-based interactions between families and pediatricians. The American Academy of Pediatrics conducted a survey of its members to identify their educational needs regarding breastfeeding to assist in the design of appropriate information programs. METHOD: An eight-page, self-administered questionnaire was sent to 1602 active Fellows of the American Academy of Pediatrics. RESULTS: The response rate was 71%. Breastfeeding, as the exclusive feeding practice for the first month after birth, was recommended by only 65% of responding pediatricians; only 37% recommended breastfeeding for 1 year. A majority of pediatricians agreed with or had a neutral opinion about the statement that breastfeeding and formula-feeding are equally acceptable methods for feeding infants. Reasons given for not recommending breastfeeding included medical conditions with known treatments that did not preclude breastfeeding. The majority of pediatricians (72%) were unfamiliar with the contents of the Baby-Friendly Hospital Initiative. The majority of pediatricians had not attended a presentation on breastfeeding management in the previous 3 years; most said they wanted more education on breastfeeding management. CONCLUSION: Pediatricians have significant educational needs in the area of breastfeeding management.

Adult↗
PubMed1999

Drugs and breastfeeding.

Breastfeeding provides important benefits to mother and infant and should be strongly encouraged as the optimal infant feeding choice for most infants. In assessing the impact of maternal medication on breastfeeding, the clinician must always weigh the many benefits of breastfeeding for the mother and infant against the risk of exposing the infant to the drug as it appears in breast milk. With regard to the vast majority of medications, continued breastfeeding is advantageous to both mother and infant.

Breast Feeding↗
PubMed1999

Given the benefits of breastfeeding, are there any contraindications?

There are many benefits to the infant to be breastfed and to the mother to breastfeed. There are, however, a few conditions where the tremendous benefit may be outweighed by maternal infection, disease, drugs, or contaminants as these are rare. HIV is the only infection that is an absolute contraindication in developed countries. Galactosemia is the only infant disease and there are a few medications that are contraindicated.

Breast Feeding↗
PubMed1999

Physiologic stability of newborns during cup- and bottle-feeding.

BACKGROUND: To prevent breastfeeding problems, cup-feeding has been recommended as a method of providing medically necessary supplemental feedings to breastfed infants. OBJECTIVES: To compare amounts ingested, administration time, and infant physiologic stability during cup-, bottle-, and breastfeeding. DESIGN/METHODS: A total of 98 term, healthy newborns were randomized to either cup-feeding (n = 51) or bottle-feeding (n = 47). The heart (HR), respiratory (RR), and oxygen (O(2)) saturation rates were monitored on these infants and 25 breastfed newborns during 1 feeding. Differences in amounts ingested and administration times were evaluated with t tests and physiologic data with repeat measures analysis of variance. RESULTS: There were no significant differences in administration time, amounts ingested or overall HR, RR, and (O(2)) saturation rates, between cup and bottle groups. Breastfed infants had longer administration times and lower overall HR, RR, and higher O(2) saturation as compared with cup- and bottle-fed infants. CONCLUSIONS: Administration times, amounts ingested, and infant physiologic stability do not differ with cup- and bottle-feeding. Breastfeeding takes longer than cup- or bottle-feeding, but infants experience less physiologic variability. These data support cup-feeding as an alternative to bottle-feeding for supplying supplements to breastfed infants.

Bottle Feeding↗
PubMed1999

Should home ipecac-induced emesis be routinely recommended in the management of toxic berry ingestions?

Poison center (PC) management of toxic berry ingestions may include recommendations to administer syrup of ipecac (SI) regardless of the number of berries ingested. We investigated whether the routine use of SI in the home management of asymptomatic single or few (< 6) berry ingestions may be unnecessary. A prospective, randomized clinical trial compared SI + home observation (HO) to HO alone for management of pediatric toxic berry ingestions. Subjects were children 9 mo to 5 y who ingested a small number (< 6) of Taxus sp (yew), Solanum americanus (nightshade), Ilex sp (holly) or unknown potentially toxic berries. Exclusions were symptomatic subjects, ingestion of more than 1 type of berry or other plant part, or contraindication to SI. Outcome variables consisting of symptom assessment and disposition were assessed 24 h following the ingestion. Over a 27-mo period 103 subjects were entered into the study; 45 received SI/HO and 51 received only HO. While 100% of the SI/HO group experienced vomiting, none of the HO group vomited. Diarrhea and sedation were more common in the SI/HO group. Use of SI in the home management of young children who ingest fewer than 6 toxic berries (yew, nightshade, holly or unknown) and who are asymptomatic when the PC is contacted may be responsible for the majority of symptoms. Ingestion of small amounts of berries may require no intervention beyond observation. Methodological limitations of this study included the lack of confirmed identification of the berries and the inability to confirm ingestion and absorption.

Child, Preschool↗
PubMed1999

Telomere-interactive agents affect proliferation rates and induce chromosomal destabilization in sea urchin embryos.

Cationic porphyrins, which interact with guanine quadruplex (G4) telomeric folds, inhibit telomerase activity in human tumor cells. In this study, we have further examined effects of porphyrins and other telomere- and telomerase-interactive agents on proliferation rates and chromosome stability in a novel in vivo model, developing sea urchin embryos. We studied two porphyrins: (i) TMPyP4, a potent telomerase inhibitor; and (ii) TMPyP2, an isomer of TMPyP4 and an inefficient telomerase inhibitor, azidothymine (AZT), the reverse transcriptase inhibitor, antisense phosphorothioate oligonucleotide to telomerase RNA (TAG6) and a control scrambled sequence (ODN). TMPyP4, AZT and TAG6 (but not TMPyP2 or ODN) decreased the rates of cell proliferation and increased the percentage of cells trapped in mitosis. Nuclear localization of TAG6, but not of ODN, was demonstrated with 5'-fluoresceinated analogs of TAG6 and ODN. Formation of elongated chromosomes incapable of separating in anaphase, induced by TMPyP4, AZT and TAG6, closely resembled phenotypes resulting from telomerase template mutation or dominant negative TRF2 allele. Our data suggest that G4-interactive agents exert their antiproliferative effects via chromosomal destabilization and warrant their further development as valuable anticancer tools.

Animals↗
PubMed1998

Requirement for in vivo production of IL-4, but not IL-10, in the induction of proliferative suppression by filarial parasites.

Loss of T lymphocyte proliferation and the emergence of a host response that is dominated by a Th2-type profile are well-established features of human filariasis. We have previously reported that adherent peritoneal exudate cells (PEC) from mice transplanted with adult Brugia malayi parasites suppress the proliferation of lymphocytes without blocking Ag-cytokine production in vitro. We now show that infection of mice with the infective larval (L3) stage of B. malayi generates a similar population of PEC. Suppressive cells are generated within 7 days of infection and mediate their effects through a nitric oxide-independent pathway. Both L3 and adult infection elicit high levels of host IL-4 whereas the microfilarial stage of the parasite induces IFN-gamma production and does not generate a similar form of suppression. Production of host IL-4 was necessary to allow the generation of suppressive PEC, given that IL-4-deficient mice implanted with adult parasites failed to induce proliferative block. However, IL-10-deficient mice implanted with adult parasites resulted in T cell suppression, indicating that IL-10 is not essential for the induction of hyporesponsiveness. Neither IL-4 nor IL-10 were directly responsible for ablating cellular proliferation in vitro, as the addition of neutralizing Ab to either cytokine did not reverse the proliferative block. Thus, IL-4 produced in vivo in response to filarial L3 and adult parasites is essential for the induction of proliferative suppression but is not itself the suppressive factor.

Animals↗
PubMed1998

Requirement for in vivo production of IL-4, but not IL-10, in the induction of proliferative suppression by filarial parasites.

Loss of T lymphocyte proliferation and the emergence of a host response that is dominated by a Th2-type profile are well-established features of human filariasis. We have previously reported that adherent peritoneal exudate cells (PEC) from mice transplanted with adult Brugia malayi parasites suppress the proliferation of lymphocytes without blocking Ag-cytokine production in vitro. We now show that infection of mice with the infective larval (L3) stage of B. malayi generates a similar population of PEC. Suppressive cells are generated within 7 days of infection and mediate their effects through a nitric oxide-independent pathway. Both L3 and adult infection elicit high levels of host IL-4 whereas the microfilarial stage of the parasite induces IFN-gamma production and does not generate a similar form of suppression. Production of host IL-4 was necessary to allow the generation of suppressive PEC, given that IL-4-deficient mice implanted with adult parasites failed to induce proliferative block. However, IL-10-deficient mice implanted with adult parasites resulted in T cell suppression, indicating that IL-10 is not essential for the induction of hyporesponsiveness. Neither IL-4 nor IL-10 were directly responsible for ablating cellular proliferation in vitro, as the addition of neutralizing Ab to either cytokine did not reverse the proliferative block. Thus, IL-4 produced in vivo in response to filarial L3 and adult parasites is essential for the induction of proliferative suppression but is not itself the suppressive factor.

Animals↗
PubMed1998

Breast-feeding and drug exposure.

Breast-feeding provides important benefits to mother and infant and should be strongly encouraged as the optimal feeding choice for most infants. In the mother with an ongoing illicit drug abuse problem, the risks posed to the infant are substantial and outweigh the benefits of breast-feeding in most cases. Moderate use of alcohol, cigarettes, or caffeine is compatible with breast-feeding.

Breast Feeding↗
PubMed1998

Effects of selenium deficiency on diaphragmatic function after resistive loading.

Diaphragmatic fatigue has been associated with increased production of reactive oxygen species. Among the defenses against reactive oxygen species is the glutathione redox system. The selenium-dependent enzyme glutathione peroxidase is an important component of this system. Thus, we hypothesized that selenium deficiency would lower glutathione peroxidase activity and render the diaphragm more susceptible to a mild exertional protocol. Sprague-Dawley rats were fed a selenium-deficient or control diet for 12 weeks then divided into four experimental groups: (1) unloaded, basic diet with selenium supplementation (control); (2) unloaded, selenium-deficient diet; (3) loaded, basic diet with selenium supplementation; and (4) loaded, selenium-deficient diet. Diaphragmatic in vitro contractile properties, glutathione peroxidase activity and glutathione content were measured. During inspiratory resistive loading, the animals breathed against an inspiratory resistor at 70% of maximal airway pressure until the target pressure was not achieved for five consecutive breaths. Selenium deficiency resulted in a significant decrease in diaphragmatic glutathione peroxidase activity, without changes in total glutathione content. Neither selenium deficiency nor inspiratory resistive loading alone impaired diaphragmatic contractility. Selenium deficiency in conjunction with inspiratory resistive loading resulted in a significant decrease in diaphragmatic twitch and tetanic force, with a downward shift in the force/frequency curve. These data suggest that selenium deficiency lowers diaphragmatic glutathione peroxidase activity, and when these animals are subjected to the oxidative stress of resistive loading, there is an impairment in muscle function. We conclude that a functional glutathione peroxidase is necessary to protect the diaphragm against the effects of resistive loading.

Animals↗
PubMed1997

Identification of the FP-receptor as a discrete entity by radioligand binding in biosystems that exhibit different functional rank orders of potency in response to prostanoids.

The definition of the FP-receptor is currently based on the functional potency of agonists. Functional studies suggest that the FP-receptor has particular sensitivity to PGF2 alpha and certain PGF2 alpha analogs but is also stimulated by PGD2 and PGE2. In order to examine the concept that these responses involve a single (FP) receptor, we compared functional responses with radioligand binding competition studies. In Swiss 3T3 cells, an identical potency rank order was obtained for Ca2+ transient signals and competition at binding sites for 3H-PGF2 alpha and 3H-17-phenyl PGF2 alpha (i.e., 17-phenyl PGF2 alpha > PGF2 alpha > PGD2 > PGE2), suggesting interaction at a single receptor. This conclusion was further supported by successive addition studies where cells pretreated with a maximally effective dose of PGF2 alpha were refractory to subsequent addition of PGF2 alpha, PGD2, or PGE2 but not PDGF. We also performed competition binding studies in the rat colon and uterus as representative tissues where the functional potency rank order is inconsistent with an FP receptor or any other prostanoid receptor subtype. Radioligand binding studies involving 3H-17-phenyl PGF2 alpha and 3H-PGE2 in the rat colon and uterus indicated the co-existence of both FP and EP3 receptors according to the competition afforded by natural PGs and selective analogs for FP and EP3 receptors. Thus, the FP-receptor can be identified in a mixed population of prostanoid receptors and this lends further support to the FP-receptor as a discrete entity.

3T3 Cells↗