Antitumour efficacy of VEGFR2 tyrosine kinase inhibitor correlates with expression of VEGF and its receptor VEGFR2 in tumour models.

During the development of indazolylpyrimidines as novel and potent inhibitors of vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2) tyrosine kinase, we observed that some human tumour xenografts are more sensitive to VEGFR2 kinase inhibitors than others. A better understanding of the basis for this differential response may help to identify a predictive marker that would greatly aid in the identification of a suitable patient population for treatment. One representative compound from the indazolylpyrimidine series is GW654652 that inhibited all three VEGFRs with similar potency.

Recombinant transferrin induces nitric oxide response in goldfish and murine macrophages.

We have previously demonstrated that the serum protein transferrin plays a key role in the activation of primary goldfish macrophages. The ability of this protein to activate goldfish macrophages was also shown to be dependent on enzymatic cleavage of the native (i.e.

Synthesis of antimicrofilament marine macrolides: synthesis and configurational assignment of a C5-C16 degradation fragment of reidispongiolide A.

Reidispongiolide A is a representative member of the sphinxolide/reidispongiolide group of cytotoxic 26-membered macrolides of marine origin. By interacting with actin in the cell cytoskeleton, the reidispongiolides and sphinxolides are potent microfilament destabilizing agents that represent a promising mechanism of action for developing novel anticancer drugs. An aldol-based synthesis of a library of diastereomers of C(8)-C(16) and C(5)-C(16) fragments and detailed NMR comparison with a reported degradation fragment enabled a configurational assignment for a major part of the reidispongiolide macrocyclic core, thus setting a solid foundation for ongoing synthetic efforts.

Development of a fluorescence polarization bead-based coupled assay to target different activity/conformation states of a protein kinase.

Most of the protein kinase inhibitors being developed are directed toward the adenosine triphosphate (ATP) binding site that is highly conserved in many kinases. A major issue with these inhibitors is the specificity for a given kinase. Structure determination of several kinases has shown that protein kinases adopt distinct conformations in their inactive state, in contrast to their strikingly similar conformations in their active states.

Granulocytic sarcoma of the breast antedating acute myelogenous leukemia.

We report a rare case of granulocytic sarcoma of the breast presenting as an isolated breast lump antedating bone marrow manifestation of acute myelogenous leukaemia.

Development of a fluorescence polarization AKT serine/threonine kinase assay using an immobilized metal ion affinity-based technology.

A bead-based FP assay methodology, termed IMAP trade mark, has been developed for the serine/threonine kinase, AKT, that allows for direct measurement of product formation. The assay design utilizes a fluoresceinated peptide substrate that, when phosphorylated by the kinase, binds to nanoparticles derivatized with trivalent metal cations through a metal-phospholigand interaction. The result of this bound fluoresceinated phosphorylated product is an increase in polarization signal caused by a decrease in the molecular mobility of the bound product.

Comparison of Haseman-Elston regression analyses using single, summary, and longitudinal measures of systolic blood pressure.

To compare different strategies for linkage analyses of longitudinal quantitative trait measures, we applied the "revisited" Haseman-Elston (RHE) regression model (the cross product of centered sib-pair trait values is regressed on expected identical-by-descent allele sharing) to cross-sectional, summary, and repeated measurements of systolic blood pressure (SBP) values in replicate 34, randomly selected from the Genetic Analysis Workshop 13 simulated data. RHE linkage scans were performed without knowledge of the generating model using the following phenotypes derived from untreated SBP measurements: the first, the last, the mean, the ratio of the change between the first and last over time, and the estimated linear regression slope coefficient. Estimates of allele sharing in sibling pairs were obtained from the complete genotype data of Cohorts 1 and 2, but linkage analyses were restricted to the five visits of Cohort 2 siblings.

Impact of managed care on the treatment, costs, and outcomes of fee-for-service Medicare patients with acute myocardial infarction.

Objective: To examine the effects of market-level managed care activity on the treatment, cost, and outcomes of care for Medicare fee-for-service acute myocardial infarction (AMI) patients.

Data Sources/study Setting: Patients from the Cooperative Cardiovascular Project (CCP), a sample of Medicare beneficiaries discharged from nonfederal acute-care hospitals with a primary discharge diagnosis of AMI from January 1994 to February 1996.

Study Design: We estimated models of patient treatment, costs, and outcomes using ordinary least squares and logistic regression.

High school drinking and its consequences.

The present study surveyed 930 high school students regarding self-reported alcohol use, their perceptions of parents and peers, and the negative consequences of drinking. Two-fifths of males and one-fifth of females reported frequent problem (binge) drinking. Problem drinkers reported more negative consequences associated with drinking.

A rare case of breast carcinoma co-existing with axillary mantle cell lymphoma.

ABSTRACT : BACKGROUND : Mantle cell lymphoma (MCL) is a rare variety of non-Hodgkin's lymphoma which originates from CD5+ B-cell population in the mantle zones of lymphoid follicles. Coexistence of such tumours in the axillary lymph nodes with invasive breast cancers without prior history of adjuvant chemotherapy or radiotherapy has not been previously reported in literature. CASE REPORT : We report a rare case of breast cancer co-existing with stage I mantle cell lymphoma of the ipsilateral axillary lymph node detected fortuitously by population screening.

Chlorpyrifos residue levels in avian food items following applications of a commercial EC formulation to alfalfa and citrus.

Two 10-day field residue studies were conducted to measure the amount of chlorpyrifos residue found in typical avian food following applications of a commercial 480 g liter(-1) EC (Lorsban 4E) at 1.1 kg AI ha(-1) (1 lb AI acre(-1)) to alfalfa and at 2.3 kg Al ha(-1) (2.

Structure elucidation of Sch 538415, a novel acyl carrier protein synthase inhibitor from a microorganism.

A novel acyl carrier protein synthase inhibitor, Sch 538415 (1), was isolated from an unidentified bacterial microbe. Structure elucidation of 1 was accomplished based on analysis of spectroscopic data including UV, MS and 2D-NMR spectra. Compound 1 exhibited inhibitory activity in the acyl carrier protein synthase (AcpS) assay with an IC(50) value of 4.

A toll-like receptor (TLR) gene that is up-regulated in activated goldfish macrophages.

An expressed sequence tag screen of a macrophage activation factor and lipopolysaccharide (LPS) stimulated goldfish macrophage subtractive library generated several transcripts of a putative teleost homologue of the toll-like receptor (TLR) family. The full-length TLR cDNA was sequenced and is predicted to encode a type I transmembrane protein with an extracellular domain containing leucine rich repeats and a cytoplasmic tail encoding a toll/interleukin-1 receptor domain. These findings indicate that the gene identified is the first teleost homologue of the TLR family reported.

Plasma membrane depolarization reduces nitric oxide (NO) production in P388D.1 macrophage-like cells during Leishmania major infection.

In the present study, we compare changes in host cell plasma membrane potential (V(m)), K(+) fluxes, and NO production during K(+) channel blockade with those changes that occur during infection with Leishmania major. Infection of P388D.1 cells with L.

Avian food selection with application to pesticide risk assessment: are dead and desiccated insects a desirable food source?

Past evaluations of pesticide exposure have been conducted with substantial uncertainty regarding avian consumption of contaminated food items. One question is whether birds consume invertebrates that are killed by a chemical application and that may present an increasing chemical concentration as they desiccate. We addressed the research question in two phases.

Research interests in the field of behavioral, psychosocial, and policy cancer research.

The growth of research in behavioral, psychosocial, and policy aspects of cancer is quite evident through examination of the literature. Although it is necessary to recognize the importance of past achievements in these areas, it is equally essential to identify the current interests and future areas that will form a new research agenda. The present study is the first attempt to shed light on these issues by surveying a group of behavioral, psychosocial and policy researchers from 1997 (n=714) and 2002 (n=1102).

Efficient and regioselective synthesis of 2-alkyl-2H-indazoles.

An efficient and regioselective synthesis of 2-methyl-2H-indazoles and 2-ethyl-2H-indazoles using trimethyloxonium tetrafluoroborate or triethyloxonium hexafluorophosphate is reported.

Transferrin and the innate immune response of fish: identification of a novel mechanism of macrophage activation.

We have previously demonstrated that a non-cytokine serum protein called transferrin was a primary activating molecule of the goldfish (Carassius auratus) macrophage antimicrobial response. The ability of the enzymatically cleaved forms of this protein to modulate fish macrophage function is novel and may represent a primitive and evolutionary conserved mechanism for the induction of NO response of macrophages. In the present study we confirm our earlier findings using immunoaffinity purified goldfish transferrin from mitogen-stimulated leukocyte supernatants.

2,5-dialkylresorcinol biosynthesis in Pseudomonas aurantiaca: novel head-to-head condensation of two fatty acid-derived precursors.

2-Hexyl-5-propylresorcinol is the predominant analog of several dialkylresorcinols produced by Pseudomonas aurantiaca (Pseudomonas fluorescens BL915). We isolated and characterized three biosynthetic genes that encode an acyl carrier protein, a beta-ketoacyl-acyl carrier protein synthase III, and a protein of unknown function, all of which collectively allow heterologous production of 2-hexyl-5-propylresorcinol in Escherichia coli. Two regulatory genes exhibiting similarity to members of the AraC family of transcriptional regulators are also present in the identified gene cluster.

Macrophage-mediated innate host defense against protozoan parasites.

Macrophages are immune cells that play a pivotal role in the detection and elimination of pathogenic microorganisms. Macrophages possess a variety of surface receptors devoted to the recognition of non-self by discriminating between host and pathogen-derived structures. Recognition of foreign microorganisms by the macrophage ultimately results in phagocytosis and the eventual destruction of microorganisms by lysosomal enzymes, toxic reactive oxygen and nitrogen intermediates, and/or nutrient deprivational mechanisms.

Relating the structure, activity, and physical properties of ultrashort-acting benzodiazepine receptor agonists.

The ultrashort-acting benzodiazepine (USA BZD) agonists reported previously have been structurally modified to improve aqueous solubility. Lactam-to-amidine modifications, replacement of the C5-haloaryl ring, and annulation of heterocycles are presented. These analogues retain BZD receptor potency and full agonism profiles.

Identification and structure-activity studies of novel ultrashort-acting benzodiazepine receptor agonists.

The synthesis and evaluation of novel ultrashort-acting benzodiazepine (USA BZD) agonists is described. A BZD scaffold was modified by incorporation of amino acids and derivatives. The propionate side chain of glutamic acid tethers an enzymatically labile functionality where the metabolite carboxylic acid displays markedly reduced BZD receptor affinity.

Assessment of contemporary stent deployment using intravascular ultrasound.

Four second- and third-generation coronary stents were evaluated using QCA and intravascular ultrasound for adequacy of stent expansion, the influence of disease burden on adequacy of deployment, and postdeployment structural effects on the artery. Despite satisfactory stent deployment rates on angiography of 92 %, adequate stent deployment by IVUS ranged from 38% to 55%. There was no significant difference in deployment success across the four stent types.