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Biomedical subjects

I King

Publications and source records attributed to I King.

At least 37 records · Page 2Linked to original sources
PubMed1998

Bis-S-acyl-2-thioethyl (SATE)-bearing monophosphate prodrug of beta-L-FD4C as potent anti-HBV agent.

The S-acyl-2-thioethyl (SATE)-bearing 5'-monophosphate prodrug of beta-L-FD4C (8) was synthesized and evaluated for its activity against HBV in the 2.2.15 cell line. This pronucleotide (8) exhibited an excellent inhibitory effect against HBV with an EC50 value that is more than eight fold lower than that of the parent nucleoside (4) under some assay conditions. It is also important to note that pronucleotide (8) was capable of inhibiting HBV replication by 90%; whereas its parent, beta-L-FD4C (4), could only inhibit virus replication no greater than 70% in the same assay. When evaluated in the standard cytotoxicity assay in CEM cell line, pronucleotide (8) exhibited an IC50 value of 52 microM, which was four times less toxic than parent beta-L-FD4C (4) (IC50 = 13 microM).

Antiviral Agents↗
PubMed1998

Board profile.

Explore the source record for details and available documents.

Ethics, Nursing↗
PubMed1998

Nursing informatics: a universal nursing language.

Knowledge is necessary to use information to make decisions in nursing situations. Nursing data must be grouped in a logical way so the interrelationship between the classification systems and specific concrete phenomena in individual nursing situations is useful. The processing and management of information for decision making is the focus in nursing and health care. The development and use of language that represents the domain of nursing is an essential dimension in an integrated and coordinated health care delivery system. The design and acceptance of a universal nursing language system is critical to collect appropriate data to document nursing's role, functions, and effectiveness in health care by the year 2000. This is an urgent message for nurses to be involved in the technology and nursing care documentation to demonstrate quality care that is cost effective. In the next century, nurses must speak a common nursing language that has the same meaning for all nurses.

Humans↗
PubMed1998

Interaction of beta-L-2',3'-dideoxy-2',3'-didehydro-5-fluoro-CTP with human immunodeficiency virus-1 reverse transcriptase and human DNA polymerases: implications for human immunodeficiency virus drug design.

The work reported in this article has evaluated the relative molecular activity of the 5'-triphosphate of a novel beta-L-nucleoside with an unsaturated ribose residue, beta-L-2', 3'-dideoxy-2',3'-didehydro-5-fluorocytidine (beta-L-Fd4CTP), with that of beta-L-2',3'-dideoxy-5-fluorocytidine (beta-L-FddCTP) and 2', 3'-dideoxycytidine (ddCTP), on DNA strand elongation by human immunodeficiency virus-1 reverse transcriptase (HIV RT) and human DNA polymerases alpha (pol alpha), beta (pol beta), gamma (pol gamma), and epsilon (pol epsilon). The concentrations of beta-L-Fd4CTP that inhibited the yield of products by 50% were 0.20 micro M, 1.8 micro M, and 4.0 micro M for HIV RT, pol gamma, and pol beta, respectively. The beta-L-Fd4CTP at a concentration as high as 40 micro M had no inhibitory effect on pol epsilon, but could inhibit pol alpha by 10-20% at 20 micro M. The Km and relative Vmax values of beta-L-Fd4CTP, beta-L-FddCTP, and ddCTP for incorporation into the standing start point of 5'-[32P]-oligonucleotide primer annealed with M13mp19 phage DNA by HIV RT and human DNA polymerases were evaluated. The efficiency of incorporation (Vmax/Km) of beta-L-Fd4CTP by HIV RT was about 4-fold and 12-fold higher than that of ddCTP and beta-L-FddCTP, respectively. In contrast, the Vmax/Km ratio of beta-L-Fd4CTP for pol gamma was 7-fold lower than that of ddCTP, but 4-fold higher than that of beta-L-FddCTP. Pol alpha could use beta-L-Fd4CTP as a substrate, but only at a high concentration (>20 micro M). Incorporation of beta-L-Fd4CTP by pol epsilon could not be detected. A hypothesis about the preferable recognition of the 2',3'-dideoxy-2',3'-didehydro- structure of beta-L-Fd4CTP to that of the 2',3'-dideoxy-structure of beta-L-FddCTP by HIV RT is discussed.

Anti-HIV Agents↗
PubMed1997

Structure-activity relationship of 3-substituted N-(pyridinylacetyl)-4- (8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene )- piperidine inhibitors of farnesyl-protein transferase: design and synthesis of in vivo active antitumor compounds.

Novel tricyclic Ras farnesyl-protein transferase (FPT) inhibitors are described. A comprehensive structure-activity relationship (SAR) study of compounds arising from substitution at the 3-position of the tricyclic pyridine ring system has been explored. In the case of halogens, the chloro, bromo, and iodo analogues 19, 22, and 28 were found to be equipotent. However, the fluoro analogue 17 was an order of magnitude less active. Whereas a small alkyl substituent such as a methyl group resulted in a very potent FPT inhibitor (SCH 56580), introduction of bulky substituents such as tert-butyl, compound 33, or a phenyl group, compound 29, resulted in inactive FPT inhibitors. Polar groups at the 3-position such as amino 5, alkylamino 6, and hydroxyl 12 were less active. Whereas compound SCH 44342 did not show appreciable in vivo antitumor activity, the 3-bromo-substituted pyridyl N-oxide amide analogue 38 was a potent FPT inhibitor that reduced tumor growth by 81% when administered q.i.d. at 50 mpk and 52% at 10 mpk. These compounds are nonpeptidic and do not contain sulfhydryl groups. They selectively inhibit FPT and not geranylgeranyl-protein transferase-1 (GGPT-1). They also inhibit H-Ras processing in COS monkey kidney cells and soft agar growth of Ras-transformed cells.

3T3 Cells↗
PubMed1997

Plastid-localized acetyl-CoA carboxylase of bread wheat is encoded by a single gene on each of the three ancestral chromosome sets.

5'-End fragments of two genes encoding plastid-localized acetyl-CoA carboxylase (ACCase; EC 6.4.1.2) of wheat (Triticum aestivum) were cloned and sequenced. The sequences of the two genes, Acc-1,1 and Acc-1,2, are 89% identical. Their exon sequences are 98% identical. The amino acid sequence of the biotin carboxylase domain encoded by Acc-1,1 and Acc-1,2 is 93% identical with the maize plastid ACCase but only 80-84% identical with the cytosolic ACCases from other plants and from wheat. Four overlapping fragments of cDNA covering the entire coding region were cloned by PCR and sequenced. The wheat plastid ACCase ORF contains 2,311 amino acids with a predicted molecular mass of 255 kDa. A putative transit peptide is present at the N terminus. Comparison of the genomic and cDNA sequences revealed introns at conserved sites found in the genes of other plant multifunctional ACCases, including two introns absent from the wheat cytosolic ACCase genes. Transcription start sites of the plastid ACCase genes were estimated from the longest cDNA clones obtained by 5'-RACE (rapid amplification of cDNA ends). The untranslated leader sequence encoded by the Acc-1 genes is at least 130-170 nucleotides long and is interrupted by an intron. Southern analysis indicates the presence of only one copy of the gene in each ancestral chromosome set. The gene maps near the telomere on the short arm of chromosomes 2A, 2B, and 2D. Identification of three different cDNAs, two corresponding to genes Acc-1,1 and Acc-1,2, indicates that all three genes are transcriptionally active.

Acetyl-CoA Carboxylase↗
PubMed1997

Antitumor 8-chlorobenzocycloheptapyridines: a new class of selective, nonpeptidic, nonsulfhydryl inhibitors of ras farnesylation.

Ras farnesylation by farnesyl protein transferase (FPT) is an intracellular event that facilitates the membrane association of the ras protein and is involved in the signal transduction process. FPT inhibition could be a novel, noncytotoxic method of treating ras dependent tumor growth. We report here three structural classes of 8-chlorobenzocycloheptapyridines as novel, nonpeptidic, nonsulfhydryl FPT inhibitors having antitumor activity in mice when dosed orally. We discuss structural and conformational aspects of these compounds in relation to biological activities as well as a comparison to the conformation of a bound tetrapeptide FPT inhibitor.

Animals↗
PubMed1996

Interleukin-10 inhibits tumor metastasis through an NK cell-dependent mechanism.

Interleukin-10 (IL-10) is a recently described pleiotropic cytokine secreted mainly by type 2 helper T cells. Previous studies have shown that IL-10 suppresses cytokine expression by natural killer (NK) and type 1 T cells, thus down-regulating cell-mediated immunity and stimulating humoral responses. We here report that injected IL-10 protein is an efficient inhibitor of tumor metastasis in experimental (B16-F10) and spontaneous (M27 and Lox human melanoma) metastasis models in vivo at doses that do not have toxic effects on normal or cancer cells. Histological characterization after IL-10 treatment confirmed the absence of CD8+ and CD4+ T cells and macrophages at the sites of tumor growth, but abundant NK cells were localized at these sites. This unexpected finding was confirmed by showing that IL-10 inhibits most B16-F10 and Lox metastases in mice deficient in T or B cells (SCID and nu/nu mice), but not in those deficient in NK cells (beige mice or NK cell-depleted mice). However, IL-10 downregulation of pro-inflammatory cytokine production and/or recruitment of additional effector cells may also be involved in the anti-tumor effect at higher local concentrations of IL-10, since transfected B16 tumor cells expressing high amounts of IL-10 were rejected by normal, nu/nu, or SCID mice at the primary tumor stage, and there was still a 33% inhibition of tumor metastasis in beige mice.

Animals↗
PubMed1995

Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest.

OBJECTIVE: To assess whether the dietary intake of long-chain n-3 polyunsaturated fatty acids from seafood, assessed both directly and indirectly through a biomarker, is associated with a reduced risk of primary cardiac arrest. DESIGN: Population-based case-control study. SETTING: Seattle and suburban King County, Washington. PARTICIPANTS: A total of 334 case patients with primary cardiac arrest, aged 25 to 74 years, attended by paramedics during 1988 to 1994 and 493 population-based control cases and controls, matched for age and sex, randomly identified from the community. All cases and controls were free of prior clinical heart disease, major comorbidity, and use of fish oil supplements. MEASURES OF EXPOSURE: Spouses of case patients and control subjects were interviewed to quantify dietary n-3 polyunsaturated fatty acid intake from seafood during the prior month and other clinical characteristics. Blood specimens from 82 cases (collected in the field) and 108 controls were analyzed to determine red blood cell membrane fatty acid composition, a biomarker of dietary n-3 polyunsaturated fatty acid intake. RESULTS: Compared with no dietary intake of eicosapentaenoic acid (C20:5n-3) and docosahexaenoic acid (C22:6n-3), an intake of 5.5 g of n-3 fatty acids per month (the mean of the third quartile and the equivalent of one fatty fish meal per week) was associated with a 50% reduction in the risk of primary cardiac arrest (odds ratio [OR], 0.5; 95% confidence interval [CI], 0.4 to 0.8), after adjustment for potential confounding factors. Compared with a red blood cell membrane n-3 polyunsaturated fatty acid level of 3.3% of total fatty acids (the mean of the lowest quartile), a red blood cell n-3 polyunsaturated fatty acid level of 5.0% of total fatty acids (the mean of the third quartile) was associated with a 70% reduction in the risk of primary cardiac arrest (OR, 0.3; 95% CI, 0.2 to 0.6). CONCLUSION: Dietary intake of n-3 polyunsaturated fatty acids from seafood is associated with a reduced risk of primary cardiac arrest.

Adult↗
PubMed1995

Antitumor effect of keto-diepoxides isolated from the fungus Nattrassia mangiferae.

A novel keto-diepoxide Sch 49209 and its derivative Sch 50672, produced by the fungus Nattrassia mangiferae, inhibited tumor cell invasion through an artificial basement membrane. These compounds, at nontoxic concentrations, inhibited invasion of HT-1080 cells in a dose-dependent manner. The IC50 values for Sch 49209 and Sch 50672 were 0.75 and 8 microM, respectively, when cells were incubated with drugs for 5 h. Sch 49209 inhibited both tumor cell invasion and cell motility to the same extent under conditions that did not cause any apparent cytotoxicity. Sch 4209 and Sch 50672, however, inhibited the growth of ras-transformed cells in a semisolid medium in a 5-day culture with IC50 values of 0.6 and 2.4 microM, respectively. They also inhibited the anchorage-dependent growth of pT24 cells in vitro with IC50 values of 0.5 and 0.9 microM for Sch 40209 and Sch 50672, respectively. Using the murine lung epidermoid carcinoma M27 cells implanted SC in mice as a model, we found both Sch 49209 and Sch 50672 inhibited the growth of this tumor at doses ranging from 2 to 10 mg/kg. These compounds also decreased the formation of spontaneous lung metastasis in this model. Sch 50672 inhibited the growth of human tumor xenografts, SW620 and A431, in athymic mode mice. Our data suggest that keto-diepoxides inhibit tumor growth and metastasis and that this activity may be due, in part, to anti-invasive activity.

Animals↗
PubMed1994

Differentiation of WEHI-3B D+ myelomonocytic leukemia cells induced by ectopic expression of the protooncogene c-jun.

The product of the protooncogene c-jun is one of the components of the AP-1 transcription factor complex, which is involved in the control of cell proliferation and differentiation. To study the role of c-jun in leukemia cell growth and maturation, a plasmid (pMTJ11) was constructed that contained the rat c-jun complementary DNA under the control of the human metallothionein promoter and the neo gene. Murine myelomonocytic WEHI-3B D+ cells were transfected by electroporation with the linearized pMTJ11 plasmid and subsequently cloned in the presence of G-418. Exposure of these clones to cadmium resulted in a high level of expression of c-jun mRNA and protein, as demonstrated by Northern hybridization and Western blotting. When these clones were examined immediately after their establishment, expression of c-jun was accompanied by the appearance of a mature phenotype in many clones, as measured by the reduction of nitroblue tetrazolium and by the expression of Mac-1 (CD11b), a cell surface marker on differentiated cells. Morphological changes indicative of the differentiated state were also observed by staining. These findings indicate that expression of c-jun is capable of initiating the differentiation of WEHI-3B D+ cells in the absence of an external inducer of maturation. Furthermore, the expression of c-jun led to an enhancement of the induction of the differentiation of WEHI-3B D+ cells by retinoic acid, suggesting an involvement of c-jun in the retinoic acid signal transduction pathway.

Animals↗
PubMed1991

Long-term storage of red blood cells and correlations between red cell and dietary fatty acids: results from a pilot study.

Levels of red blood cell (RBC) fatty acids were determined at baseline and 12 months after storage at -70 degrees C in 15 postmenopausal women to determine whether storage had a detrimental effect on the stability of fatty acids. Four-day diet records were also completed at baseline, allowing comparisons between RBC fatty acid levels and fatty acid levels computed from recent dietary intake. The major fatty acid composition of RBCs did not change substantially during 12 months of storage, and, in particular, for n-6 and n-3 fatty acids most correlations between baseline and 12-month values were greater than 0.90. We also found strong positive correlations between RBC and dietary fatty acids, including oleic, linoleic (18:2n-6), total n-6, and the polyunsaturated-to-saturated fat ratio. We concluded that frozen RBCs may be a useful measure of recent dietary intake for epidemiological studies.

Blood Preservation↗
PubMed1990

Role of lipocortin I in the glucocorticoid induction of the terminal differentiation of a human squamous carcinoma.

The human squamous cell carcinoma SqCC/Y1 undergoes spontaneous terminal differentiation in the confluent state. The degree of maturation was markedly increased by glucocorticoids and by both human recombinant and placental lipocortin I. Western analyses demonstrated cellular secretion of lipocortin into the medium. Glucocorticoid-induced maturation was antagonized by a lipocortin I-specific monoclonal antibody, by phospholipase A2 (PLA2), and by arachidonic acid. Induction of the differentiation of SqCC/Y1 cells by lipocortin I was prevented by arachidonic acid. The PLA2 inhibitor, dibromoacetophenone, caused an increase in envelope-competent cells indicating that inhibition of PLA2 results in induction of differentiation. Epidermal growth factor prevented the induction of differentiation by both lipocortin I and by glucocorticoids. The nonsteroidal lipoxygenase/cyclo-oxygenase inhibitor, phenidone, also increased SqCC/Y1 differentiation, suggesting that leukotrienes, thromboxanes, and/or prostaglandins may be involved in lipocortin-mediated regulation of SqCC/Y1 maturation. The findings support a role for lipocortin I in mediating the effects of glucocorticoids on epidermal cell differentiation.

Annexins↗
PubMed1990

Shellfish: proximate composition, minerals, fatty acids, and sterols.

Proximate composition, minerals, fatty acids, and sterols were determined for eight species of shellfish commonly marketed in the Northwest. Moisture and total lipid content varied with the size of the species, with more variation in mollusca than in crustacea; total lipid content ranged from 0.7% in sea scallops to 3.1% in blue mussels but only from 1.2% in Dungeness crab to 1.3% in pink shrimp. The mineral content was highly variable; the mineral content of Northwest samples tended to be lower than that reported in other studies. Generally, shellfish are good sources of zinc, and Pacific oysters, blue mussels, and Manila clams are also good sources of iron. Five fatty acids (16:0, 16:1, 18:1, 20:5n-3, and 22:6n-3) represented from 60% to 84% of the fatty acid content. Palmitic acid ranged from 13% to 32% of the total fatty acids. Long-chain n-3 polyunsaturated fatty acids were predominant (37.6% to 54.3%), with sea scallops containing more than 50%; n-6 polyunsaturated fatty acids ranged from 1.5% to 6.5%. In crustacea, cholesterol was the primary sterol, and brassicasterol was the only other measurable sterol. In all mollusca except California squid, cholesterol averaged 37 mg/100 gm and ranged from 23% to 39% of the total sterols. In squid, cholesterol, at 231 mg/100 gm, was the only measurable sterol. We conclude that shellfish vary widely in their nutrient content but, in general, are valuable additions to the diet.

Chromatography, Gas↗
PubMed1989

Epidermal growth factor receptor gene expression, protein kinase activity, and terminal differentiation of human malignant epidermal cells.

A number of epidermal growth factor (EGF)-resistant clones have been isolated from human epidermoid carcinoma A431 cells (I. King and A. C. Sartorelli, Biochem. Biophys. Res. Commun., 140: 837, 1986). These cells had a higher capacity to enter a pathway of terminal differentiation, as determined by their ability to form cornified envelopes. Thus, after 6 days in culture, 10% of parental A431 cells expressed a differentiated phenotype, while more than 50% of each of the EGF-resistant variants (M1, A5, and A7) formed cornified envelopes. These EGF-resistant clones expressed fewer EGF receptors and had a lower capacity for EGF receptor autophosphorylation than parental A431 cells. Clone M1 had the highest capacity to form cornified cell envelopes and expressed about 10% of the EGF receptor autophosphorylation activity of parental cells. The decrease in the level of EGF receptor autophosphorylation appeared to be due to a decrease in EGF receptor number rather than to a lowering of enzyme activity per se. Southern analysis demonstrated that all of the EGF-resistant variants contained fewer copies of the EGF receptor gene and no apparent gene rearrangement was detected in these variant cells. A corresponding decrease in EGF receptor mRNA was also observed in M1, A5, and A7 cells, with a ratio of 18:1:10:5 for A431, M1, A5, and A7 cells, respectively. In addition, two other malignant epithelial cell lines, SqCC/Y1 and FaDu, contained relatively few copies of EGF receptor genes, had low EGF receptor kinase activity and showed a relatively high capacity to form cornified envelopes. These findings suggest that the level of the EGF receptor was critical to the regulation of the degree of maturation of malignant epidermal cells.

Blotting, Northern↗
PubMed1989

Induction of the terminal differentiation of a human squamous cell carcinoma by steroids with glucocorticoid activity.

SqCC/Y1, a human malignant squamous cell carcinoma, spontaneously differentiates when grown to confluence in delipidized serum-containing medium, as measured by the capacity to form detergent-insoluble cornified cell envelopes. Thus, 30% of SqCC/Y1 cells spontaneously attained the differentiated state after 6 days in culture. Exposure of SqCC/Y1 cells to 30, 100, or 300 nM hydrocortisone increased the number of mature cells, producing a 25, 100, and 225%, respective, increase in the number of differentiated cells over the spontaneous rate of maturation. Retinoic acid at levels of 3-300 nM was inhibitory, causing a 24-85% decrease in the number of differentiated cells. Simultaneous treatment with hydrocortisone and retinoic acid indicated mutual antagonism of the effects of these agents on the formation of cornified envelopes. Since hydrocortisone possesses antiangiogenic (AG), mineralocorticoid (MC) and glucocorticoid (GC) activities, steroids with different degrees of GC, MC, and AG potency were examined for their capacities to induce terminal differentiation. Only steroids with GC activity, such as dexamethasone, hydrocortisone, and RU-28362, were capable of increasing the degree of SqCC/Y1 differentiation and antagonizing the inhibitory effects of retinoic acid on the maturation process. In addition, the GC antagonist, RU-38486, reversed the stimulation of cellular differentiation produced by the glucocorticoids. The findings indicate that GC activity is required for the steroid-induced terminal differentiation of SqCC/Y1 cells.

17-alpha-Hydroxyprogesterone↗