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Biomedical subjects

K Cheng

Publications and source records attributed to K Cheng.

At least 19 recordsLinked to original sources
PubMed1998

Synthesis and biological activities of potent peptidomimetics selective for somatostatin receptor subtype 2.

A series of nonpeptide somatostatin agonists which bind selectively and with high affinity to somatostatin receptor subtype 2 (sst2) have been synthesized. One of these compounds, L-054,522, binds to human sst2 with an apparent dissociation constant of 0.01 nM and at least 3,000-fold selectivity when evaluated against the other somatostatin receptors. L-054,522 is a full agonist based on its inhibition of forskolin-stimulated adenylate cyclase activity in Chinese hamster ovary-K1 cells stably expressing sst2. L-054,522 has a potent inhibitory effect on growth hormone release from rat primary pituitary cells and glucagon release from isolated mouse pancreatic islets. Intravenous infusion of L-054,522 to rats at 50 microgram/kg per hr causes a rapid and sustained reduction in growth hormone to basal levels. The high potency and selectivity of L-054, 522 for sst2 will make it a useful tool to further characterize the physiological functions of this receptor subtype.

Animals↗
PubMed1998

Mutation of a Shc binding site tyrosine residue in ErbB3/HER3 blocks heregulin-dependent activation of mitogen-activated protein kinase.

The ErbB2 and ErbB3 proteins together constitute a functional coreceptor for heregulin (neuregulin). Heregulin stimulates the phosphorylation of both coreceptor constituents and initiates a variety of other signaling events, which include phosphorylation of the Shc protein. The role of Shc in heregulin-stimulated signal transduction through the ErbB2.ErbB3 coreceptor was investigated here. Heregulin was found to promote ErbB3/Shc association in NIH-3T3 cells expressing endogenous ErbB2 and recombinant ErbB3. A mutant ErbB3 protein was generated in which Tyr-1325 in a consensus Shc phosphotyrosine-binding domain recognition site was mutated to Phe (ErbB3-Y/F). This mutation abolished the association of Shc with ErbB3 and blocked the activation of mitogen-activated protein kinase by heregulin. Whereas heregulin induced mitogenesis in NIH-3T3 cells transfected with wild-type ErbB3 cDNA, this mitogenic response was markedly attenuated in NIH-3T3 cells transfected with the ErbB3-Y/F cDNA. These results showed a specific interaction of Shc with the ErbB3 receptor protein and demonstrated the importance of this interaction in the activation of mitogenic responses by the ErbB2. ErbB3 heregulin coreceptor complex.

3T3 Cells↗
PubMed1998

ErbB3 (HER3) interaction with the p85 regulatory subunit of phosphoinositide 3-kinase.

ErbB3 (HER3), a unique member of the ErbB receptor family, lacks intrinsic protein tyrosine kinase activity and contains six Tyr-Xaa-Xaa-Met (YXXM) consensus binding sites for the SH2 domains of the p85 regulatory subunit of phosphoinositide 3-kinase. ErbB3 also has a proline-rich sequence that forms a consensus binding site for the SH3 domain of p85. Here we have investigated the interacting domains of ErbB3 and p85 by a unique application of the yeast two-hybrid system. A chimaeric ErbB3 molecule containing the epidermal growth factor receptor protein tyrosine kinase domain was developed so that the C-terminal domain of ErbB3 could become phosphorylated in the yeast system. We also generated several ErbB3 deletion and Tyr-->Phe site-specific mutants, and observed that a single ErbB3 YXXM motif was necessary and sufficient for the association of ErbB3 with p85. The incorporation of multiple YXXM motifs into the ErbB3 C-terminus enabled a stronger ErbB3/p85 interaction. The proline-rich region of ErbB3 was not necessary for interaction with p85. However, either deletion or mutation of the p85 SH3 domain decreased the observed ErbB3/p85 association. Additionally an ErbB3/p85 SH3 domain interaction was detected by an assay in vitro. These results were consistent with a model in which pairs of phosphorylated ErbB3 YXXM motifs co-operate in binding to the tandem SH2 domains of p85. Although a contributing role for the p85 SH3 domain was suggested, the N- and C-terminal SH2 domains seemed to be primarily responsible for the high-affinity association of p85 and ErbB3.

Chimera↗
PubMed1998

Synthesis and biological activities of phenyl piperazine-based peptidomimetic growth hormone secretagogues.

A new class of potent, orally active phenyl piperazine-based GH secretagogues have been discovered from attempts to mimic the arrangement of the phenyl substituent in the spiroindanyl piperidine and spiroindoline sulfonamide privileged structures of 4 and 1, respectively. The best of these compounds, 18 (EC50 = 2.8 nM) is nearly as potent as MK-0677 for releasing GH from rat pituitary cells.

Animals↗
PubMed1998

A potent, orally bioavailable benzazepinone growth hormone secretagogue.

The identification of L-739,943 (8b), a potent, orally bioavailable benzolactam growth hormone secretagogue, is obtained from zwitterionic L-692,429 through modification of its amino acid side chain and replacement of the acidic 2'-tetrazole with the neutral and potency enhancing 2'-(N-methylaminocarbonylamino)methyl substituent. L-739,943 is orally active for the release of growth hormone in beagle dogs at doses as low as 0.5 mg/kg. Oral bioavailability in dogs of 8b is 24% at a dose of 2 mg/kg with a mean drug Cmax of 145 +/- 46 ng/mL. L-739,943 represents a significant breakthrough in terms of both potency and oral bioavailability as compared to the prototype benzolactam L-692,429.

Administration, Oral↗
PubMed1998

Tripeptide growth hormone secretagogues.

A series of C-terminus capped dipeptides and tripeptides was synthesized as growth hormone (GH) secretagogues. Among them, tripeptide Aib-D-Trp-D-homoPhe-OEt showed low nanomolar activity in the rat pituitary assay. Thus, we have demonstrated that the GH secretagogue activity of the hexa-hepta-GH releasing peptides can be mimicked at the tripeptide level.

Amino Acid Sequence↗
PubMed1998

Nucleotide-binding properties of kinase-deficient epidermal-growth-factor-receptor mutants.

The nucleotide-binding properties of wild-type epidermal- growth-factor (EGF)-receptor protein tyrosine kinase (PTK) and EGF-receptor mutants with site-specific amino acid substitutions known to attenuate protein kinase activity were analysed by a fluorescence competition assay employing the nucleotide analogue 2'(3')-O-(2,4,6-trinitrophenyl)adenosine 5'-triphosphate. Binding affinities for ATP and Mn.ATP complex were determined for the PTK domains of the wild-type and two mutant proteins. Surprisingly, mutation of the highly conserved Lys-721 residue in the nucleotide-binding site of the EGF- receptor PTK domain did not abolish ATP and Mn.ATP binding, although the binding affinity for the Mn.ATP complex was significantly reduced. A second kinase-inactivating mutation that targeted the highly conserved Asp-813 residue had little effect on the nucleotide-binding properties of the EGF-receptor PTK domain. These results indicated that the principle effect of these two kinase-inactivating amino acid substitutions is not to block nucleotide binding, but is instead an inhibition of the phospho-transfer reaction.

Adenosine Triphosphate↗
PubMed1998

Potent 3-spiropiperidine growth hormone secretagogues.

Systematic SAR studies of the different regioisomers and homologues of the spiro(indane-1,4-piperidine) moiety in the growth hormone secretagogue L-162,752 are presented. Among them, spiro(3H-1-benzopyran-2,3-piperidine) was found to afford secretagogues with low nanomolar in vitro activity.

Animals↗
PubMed1998

Time to publication as full reports of abstracts of randomized controlled trials in cystic fibrosis.

OBJECTIVES: To determine 1) what proportion of abstracts of randomized controlled trials (RCTs) presented at international conferences on cystic fibrosis (CF) are published as full reports, 2) time to publication, and 3) factors that might delay or prevent publication. METHODS: At the end of 1995, the Cochrane CF Group's register of RCTs contained 199 abstracts describing 180 RCTs. Abstracts were identified by handsearching 44 abstract books of three international CF conferences over a 30-year period. We searched the register for subsequent full reports of these RCTs and used survival analysis to investigate time to publication. Using the log-rank test, we examined 1) whether there is a difference in time to publication between reports where the investigators concluded that the test treatment was as effective as or better than the control treatment, and reports where it was not, and 2) whether there is a difference in time to publication according to sample size. RESULTS: Thirty-two percent of the 178 abstracts analyzed were subsequently published in full. Survival analysis indicated that the proportions published before 12 months, 2 years, and 5 years were 8.1%, 29%, and 40% respectively. No difference in time to publication was identified when the abstracts were stratified according to conclusions or sample size; no significant association (P > 0.05) existed between time to publication and both sample size and conclusions together. CONCLUSION: Only a small proportion of abstracts of RCTs presented at international conferences on CF are followed by full publication, and usually only after several years. Therefore, many potentially valuable studies do not reach a wide audience. However, we found no consistent factors which might delay or prevent publication.

Abstracting and Indexing↗
PubMed1998

Electric fields and proliferation in a dermal wound model: cell cycle kinetics.

In a dermal wound model, consisting of human skin fibroblasts in collagen matrix, continuous sinusoidal electrical current stimulation elicited a maximum increase of [3H]thymidine relative to control at 41 mV/m amplitude, 10 Hz. In this paper we elaborate cell cycle kinetics, using the same parameters. Labeling occurred over 4-h intervals beginning at 12 to 20 h after onset of electric exposure. The results suggest a significant increase in [3H]thymidine incorporation over an 8-h period extending from 16-24 hours after stimulus initiation.

Cell Cycle↗
PubMed1997

Organization of corticostriatal and corticoamygdalar projections arising from the anterior inferotemporal area TE of the macaque monkey: a Phaseolus vulgaris leucoagglutinin study.

Corticostriatal and corticoamygdalar projections arising from area TE of the macaque monkey were studied by focal injections of the anterograde tracer Phaseolus vulgaris leucoagglutinin into the dorsolateral and ventromedial subdivisions of the anterior TE (TEad and TEav, respectively). This approach yielded several new results. First, the global distributions of labeled terminals revealed that both TEad and TEav projected to the ventrocaudal striatum, including the tail of the caudate nucleus and the adjacent ventral putamen, and the dorsolateral aspect of the deep amygdaloid nuclei. TEav also projected to the medial basal nucleus of the amygdala and the ventral striatum. Second, the reconstructed single axons (n = 18) demonstrated that some axons originating from TEav or TEad projected simultaneously to the ventrocaudal striatum and the dorsolateral aspect of the deep amygdaloid nuclei by giving off collaterals. TEav axons projected to the medial basal nucleus of the amygdala also had collaterals projecting to the perirhinal cortex or area TG. And third, it was revealed that the axons originating from a focal TEav or TEad projected to a restricted territory (3.4-3.6 mm rostrocaudally) in the ventrocaudal striatum with four to six dispersed, rostrocaudally elongated, rod-like modules. Individual axons with multiple arbors innervated many of these modules. These findings add the evidence that the anterior part of TE is anatomically heterogeneous and suggest that the deep amygdaloid nuclei may be functionally dissociated, with the dorsolateral aspect more closely related to the ventrocaudal striatum and the medial basal nucleus more closely related to the perirhinal cortex.

Amygdala↗
PubMed1997

Changes in Acidity of Fe-Pillared/Delaminated Smectites on Heat Treatment

Hydroxy-iron smectites were prepared using solutions with a OH/Fe content of about 1.2 and 2.5. To study thermal stability, the samples were heated in air at temperatures between 473 and 873 K. Changes in surface chemistry imposed by heat treatment were evaluated using potentiometric titration. The pKa distributions revealed peaks characteristic for iron complexes (FeIII) deposited on the surface of smectite. Heat treatment resulted in significant changes in the chemistry of the material and creation new species; however, the sorbents textural properties did not alter significantly. Data obtained from X-ray diffraction and sorption of nitrogen demonstrate that iron species are adsorbed mainly on the external surface of smectite and that the properties of the final products depend upon the OH/Fe ratio of hydroxy-iron solutions used in their preparation.

Journal Article↗
PubMed1997

Biochemical characterization of the protein tyrosine kinase homology domain of the ErbB3 (HER3) receptor protein.

The putative protein tyrosine kinase domain (TKD) of the ErbB3 (HER3) receptor protein was generated as a histidine-tagged recombinant protein (hisTKD-B3) and characterized enzymologically. CD spectroscopy indicated that the hisTKD-B3 protein assumed a native conformation with a secondary structure similar to that of the epidermal growth factor (EGF) receptor TKD. However, when compared with the EGF receptor-derived protein, hisTKD-B3 exhibited negligible intrinsic protein tyrosine kinase activity. Immune complex kinase assays of full-length ErbB3 proteins also yielded no evidence of catalytic activity. A fluorescence assay previously used to characterize the nucleotide-binding properties of the EGF receptor indicated that the ErbB3 protein was unable to bind nucleotide. The hisTKD-B3 protein was subsequently found to be an excellent substrate for the EGF receptor protein tyrosine kinase, which suggested that in vivo phosphorylation of ErbB3 in response to EGF could be attributed to a direct cross-phosphorylation by the EGF receptor protein tyrosine kinase.

Animals↗
PubMed1997

Growth hormone releasing peptides: a comparison of the growth hormone releasing activities of GHRP-2 and GHRP-6 in rat primary pituitary cells.

In the present study, the effect of GHRP-2 on GH release was evaluated in rat primary pituitary cells, and the results were compared with those elicited by GHRP-6. In the rat system, GHRP-2, like GHRP-6, acts synergistically with GRF to release GH. Co-administration of GHRP-2 and GHRP-6 at maximal concentrations had no further effect on GH release than either one alone. The GHRP's were able to desensitize cells to each other, but not to GRF. The effect of GHRP-2 was inhibited by Peptide Antagonist, but was not affected by a GRF antagonist. In conclusion, GHRP-2 was found to stimulate GH release from rat pituitary cells via the same receptor and mechanism as GHRP-6, despite the structural difference between the peptides.

Animals↗
PubMed1997

Identification of an oligodeoxynucleotide sequence motif that specifically inhibits phosphorylation by protein tyrosine kinases.

Protein tyrosine kinases (PTKs) have central roles in cellular signal transduction. We have identified a sequence motif (CGT[C]GA) in phosphorothioate-modified oligodeoxynucleotides (ODNs) that specifically inhibits the enzymatic activity of recombinant or immunoprecipitated PTK in vitro. Hexamer ODNs containing this motif block both substrate and autophosphorylation of at least four different PTKs but have no apparent effect on the enzymatic activity of a serine/threonine protein kinase. These data suggest possible new applications for ODNs and have implications for the design and interpretation of experiments using antisense or triplex ODNs.

Cell Line↗