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D Wu

Publications and source records attributed to D Wu.

At least 181 records · Page 10Linked to original sources
PubMed1999

Drug delivery of anticancer agents: water soluble 4-poly (ethylene glycol) derivatives of the lignan, podophyllotoxin.

This paper reports on the synthesis and in vivo oncolytic activity of a series of water-soluble acyl derivatives of polyethylene glycol (PEG) conjugated podophyllotoxin. Some analogs of the polymer conjugate showed significantly better activity in a murine leukemia model than native podophyllotoxin suspended in an intralipid emulsion. Additionally, when tested intravenously against a solid lung tumor (A549) model, some conjugated analogs were equivalent to the podophyllotoxin/intralipid emulsion, while those compounds demonstrating slower rates of plasma hydrolysis (in vitro) appeared to cause greater toxicity. There appeared to be an overall correlation between the in vivo antitumor activity of the conjugate and its rate of hydrolysis in vitro, with those showing faster release possessing greater antitumor activity. In conclusion, the solubilization and predictable release of podophyllotoxin from a PEG carrier was achieved and resulted in some derivatives demonstrating, at a minimum, equivalency with podophyllotoxin when administered on an equal molar basis. Further studies may be warranted to assess the PEG-conjugates pharmacokinetics and therapeutic indices in leukemic models.

Animals↗
PubMed1999

Genetic alteration of phospholipase C beta3 expression modulates behavioral and cellular responses to mu opioids.

Morphine and other micro opioids regulate a number of intracellular signaling pathways, including the one mediated by phospholipase C (PLC). By studying PLC beta3-deficient mice, we have established a strong link between PLC and mu opioid-mediated responses at both the behavioral and cellular levels. Mice lacking PLC beta3, when compared with the wild type, exhibited up to a 10-fold decrease in the ED(50) value for morphine in producing antinociception. The reduced ED(50) value was unlikely a result of changes in opioid receptor number or affinity because no differences were found in whole-brain B(max) and K(d) values for mu, kappa, and delta opioid receptors between wild-type and PLC beta3-null mice. We also found that opioid regulation of voltage-sensitive Ca(2+) channels in primary sensory neurons (dorsal root ganglion) was different between the two genotypes. Consistent with the behavioral findings, the specific mu agonist [D-Ala(2),(Me)Phe(4),Gly(ol)(5)]enkephalin (DAMGO) induced a greater whole-cell current reduction in a greater proportion of neurons isolated from the PLC beta3-null mice than from the wild type. In addition, reconstitution of recombinant PLC protein back into PLC beta3-deficient dorsal root ganglion neurons reduced DAMGO responses to those of wild-type neurons. In neurons of both genotypes, activation of protein kinase C with phorbol esters markedly reduced DAMGO-mediated Ca(2+) current reduction. These data demonstrate that PLC beta3 constitutes a significant pathway involved in negative modulation of mu opioid responses, perhaps via protein kinase C, and suggests the possibility that differences in opioid sensitivity among individuals could be, in part, because of genetic factors.

Animals↗
PubMed1999

Axin and Frat1 interact with dvl and GSK, bridging Dvl to GSK in Wnt-mediated regulation of LEF-1.

Wnt proteins transduce their signals through dishevelled (Dvl) proteins to inhibit glycogen synthase kinase 3beta (GSK), leading to the accumulation of cytosolic beta-catenin and activation of TCF/LEF-1 transcription factors. To understand the mechanism by which Dvl acts through GSK to regulate LEF-1, we investigated the roles of Axin and Frat1 in Wnt-mediated activation of LEF-1 in mammalian cells. We found that Dvl interacts with Axin and with Frat1, both of which interact with GSK. Similarly, the Frat1 homolog GBP binds Xenopus Dishevelled in an interaction that requires GSK. We also found that Dvl, Axin and GSK can form a ternary complex bridged by Axin, and that Frat1 can be recruited into this complex probably by Dvl. The observation that the Dvl-binding domain of either Frat1 or Axin was able to inhibit Wnt-1-induced LEF-1 activation suggests that the interactions between Dvl and Axin and between Dvl and Frat may be important for this signaling pathway. Furthermore, Wnt-1 appeared to promote the disintegration of the Frat1-Dvl-GSK-Axin complex, resulting in the dissociation of GSK from Axin. Thus, formation of the quaternary complex may be an important step in Wnt signaling, by which Dvl recruits Frat1, leading to Frat1-mediated dissociation of GSK from Axin.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Extracellular ATP-induced inward current in isolated epithelial cells of the endolymphatic sac.

Using whole-cell patch-clamp technique and Fura-2 fluorescence measurement, the presence of ATP-activated ion channels and its dependence on intracellular Ca2+ concentration ([Ca2+]i) in the epithelial cells of the endolymphatic sac were investigated. In zero current-clamp configuration, the average resting membrane potential was -66.8+/-1.3 mV (n=18). Application of 30 microM ATP to the bath induced a rapid membrane depolarization by 43.1+/-2.4 mV (n=18). In voltage-clamp configuration, ATP-induced inward current at holding potential (VH) of -60 mV was 169.7+/-6.3 pA (n=18). The amplitude of ATP-induced currents increased in sigmoidal fashion over the concentration range between 0.3 and 300 microM with a Hill coefficient (n) of 1.2 and a dissociation constant (Kd) of 11.7 microM. The potency order of purinergic analogues in ATP-induced current, which was 2MeSATP>ATPgammas>/=ATP>alpha, beta-ATP>ADP=AMP>/=adenosine=UTP, was consistent with the properties of the P2Y receptor. The independence of the reversal potential of the ATP-induced current from Cl- concentration suggests that the current is carried by a cation channel. The relative ionic permeability ratio of the channel modulated by ATP for cations was Ca2+>Na+>Li+>Ba2+>Cs+=K+. ATP (10 microM) increased [Ca2+]i in an external Ca2+-free solution to a lesser degree than that in the external solution containing 1.13 mM CaCl2. ATP-induced increase in [Ca2+]i can be mimicked by application of ionomycin in a Ca2+-free solution. These results indicate that ATP increases [Ca2+]i through the P2Y receptor with a subsequent activation of the non-selective cation channel, and that these effects of ATP are dependent on [Ca2+]i and extracellular Ca2+.

Adenosine Triphosphate↗
PubMed1999

Prognostic significance of anaplastic lymphoma kinase (ALK) protein expression in adults with anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL) is an aggressive lymphoma that is frequently associated with the t(2;5)(p23;q35), resulting in expression of a fusion protein, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), which can be detected by either monoclonal or polyclonal antibodies to the ALK protein. The clinical features of adults with ALCL are incompletely described, and the prognostic factors that are useful for predicting survival remain unclear. This report describes the clinical and laboratory findings in 70 adults with systemic ALCL who were treated with curative intent. We attempted to identify the clinical and pathological factors of prognostic importance, including the International Prognostic Index (IPI), immunophenotype, and expression of the ALK protein. The median age of the patients was 49 years (range, 15 to 75). There were 26 women and 44 men with a median follow-up of 50 months for living patients. Advanced stage was present in 56% and B symptoms were noted in 70% of the patients. Immunostains showed that 46% of the cases had a T-cell phenotype, 36% a null phenotype, and 18% a B-cell phenotype. The expression of ALK protein was found in 51% of the cases. The IPI factors were evenly distributed between the ALK+ and ALK- groups, except that the ALK+ patients were younger (median age, 30 v 61 years; P <.002). The ALK+ cohort included cases with null (44%), T-cell (42%), and B-cell (14%) phenotypes. All 10 cases with cytogenetic or molecular evidence of a t(2;5) were ALK+. The 5-year overall survival (OS) of the entire cohort was 65%. The 5-year OS of the ALK+ and ALK- cases was 79% and 46%, respectively (P <.0003). Analysis of only the T-cell/null cases (n = 57) showed a 5-year OS of 93% for the ALK+ cases and only 37% for the ALK- cases (P <.00001). Univariate analysis of the clinical features showed that age </=60 years (P <.007), a normal serum lactate dehydrogenase (LDH) (P <.00001), a good performance status (Eastern Cooperative Oncology Group [ECOG] <2) (P <.03), </=1 extranodal site of disease (P <.012), and an IPI score </=3 (P <.00001) were associated with improved OS. Although a younger age correlated with ALK positivity, multivariate analysis showed that only a normal serum LDH (P <. 00001), an IPI score of </=3 (P <.0005), and ALK protein expression (P <.005) predicted independently for an improved OS. We conclude that ALCL is a heterogeneous disorder. However, ALK protein expression is an independent predictor of survival and serves as a useful biologic marker of a specific disease entity within the spectrum of ALCL.

Adolescent↗
PubMed1999

[Effects of alcohol on membrane lipid fluidity of astrocytes and oligodendrocytes].

To explore the mechanism of neuron development retardation and myelination abnormality caused by alcohol, the membrane lipid fluidity of astrocytes and oligodendrocytes which is related to neuron and myelin development were measured by using DPH fluorescence probe. The results showed that 5 mmol/L alcohol could lead to decrease the polarization of fluorescence (Pr) and increase the lipid fluidity unit of membrane in both cells. The alteration was in obvious dose-response relationship. The effect of alcohol on astrocytes was stronger than that of oligodendrocytes. It indicated that alcohol could change lipid fluidity of cell membrane. Alcohol probably plays major role in the dysfunction of astrocytes and oligodendrocytes.

Animals↗
PubMed1999

Adsorption of Dimers at Surfaces.

A model for the adsorption of dimers at a surface is presented. The model is based on a generalization of the Ono-Kondo lattice theory. The densities of dimer molecules that are parallel to the surface, x parallel, and perpendicular to the surface, x perpendicular, are calculated. It is shown that symmetric dimer molecules adsorb preferentially parallel to the surface at all densities. The model also predicts that the Gibbs adsorption is negative for small interaction energies between dimers and the surface. Copyright 1999 Academic Press.

Journal Article↗
PubMed1999

[Loss of heterozygosity and microsatellite instability in laryngeal carcinoma near p16 gene]

OBJECTIVE: To search for the minimal overlap region of tumor suppressor gene in laryngeal carcinoma and discuss the correlation of p16 gene with laryngeal carcinogenesis. METHODS: Five microsatellite polymorphism markers near p16 gene were selected to detect loss of heterozygosity (LOH) and microsatellite instability (MI) in 60 cases of laryngeal squamous cell carcinoma. RESULTS: The frequencies of LOH in 5 markers were less than 23.1%, while the frequencies of MI in 2 markers were higher, with the highest frequency (46.1%) in D9S1752. CONCLUSION: The results suggest that the deletion of p16 gene does not play an important role in the laryngeal carcinogenesis and there may exist a gene around D9S1752 participating in the development of laryngeal carcinoma, which correlates with the mutation of repair gene.

Journal Article↗
PubMed1999

Bone morphogenetic proteins regulate the developmental program of human hematopoietic stem cells.

The identification of molecules that regulate human hematopoietic stem cells has focused mainly on cytokines, of which very few are known to act directly on stem cells. Recent studies in lower organisms and the mouse have suggested that bone morphogenetic proteins (BMPs) may play a critical role in the specification of hematopoietic tissue from the mesodermal germ layer. Here we report that BMPs regulate the proliferation and differentiation of highly purified primitive human hematopoietic cells from adult and neonatal sources. Populations of rare CD34(+)CD38(-)Lin- stem cells were isolated from human hematopoietic tissue and were found to express the BMP type I receptors activin-like kinase (ALK)-3 and ALK-6, and their downstream transducers SMAD-1, -4, and -5. Treatment of isolated stem cell populations with soluble BMP-2, -4, and -7 induced dose-dependent changes in proliferation, clonogenicity, cell surface phenotype, and multilineage repopulation capacity after transplantation in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Similar to transforming growth factor beta, treatment of purified cells with BMP-2 or -7 at high concentrations inhibited proliferation yet maintained the primitive CD34(+)CD38(-) phenotype and repopulation capacity. In contrast, low concentrations of BMP-4 induced proliferation and differentiation of CD34(+) CD38(-)Lin- cells, whereas at higher concentrations BMP-4 extended the length of time that repopulation capacity could be maintained in ex vivo culture, indicating a direct effect on stem cell survival. The discovery that BMPs are capable of regulating repopulating cells provides a new pathway for controlling human stem cell development and a powerful model system for studying the biological mechanism of BMP action using primary human cells.

Activin Receptors↗
PubMed1999

[Effect of lead on the expression of immediate early genes in different regions of rat brain].

In order to study the role of immediate early genes (IEG) in the neurotoxic mechanism of lead, expression of c-fos and c-jun genes in different regions of rat brain treated with lead (13 and 130 mg/kg) were observed by using immuno-histochemical method. The observation and image analysis showed that after rats treated by lead for 2 hours, the c-fos and c-jun expression in cortex, CA3 area of hippocampus and cerebellum of rats were higher than those of control rats significantly (P < 0.05). The results indicated that IEG, as a transcription regular factor, may participate in the neurological toxicity damaging the learning and memory ability induced by lead. The study provided experimental basis for revealing the molecular neurotoxic mechanism of lead.

Animals↗
PubMed1999

[Study on the correlation of silicosis with antioxidant and antioxidase].

Plasma vitamin C(P-VC), vitamin E(P-VE) and beta-carotene(P-beta-CAR) contents and the activities of superoxide dismutase(E-SOD), catalase(E-CAT) and glutathione peroxidase (E-GSH-Px) in erythrocyte in 73 silicosis patients and 60 healthy control subjects were measured. The average levels of P-VC, P-VE, P-beta-CAR, E-SOD, E-CAT and E-GSH-Px of patients were significantly lower than those of the controls (P < 0.001). All indexes were correlated to the course, condition and pulmonary function of silicosis patients. The results analyzed by stepwise regression showed that the correlation between course, condition and pulmonary function of patients and P-VE and E-SOD was close. The balance between oxidation and the antioxidation in silicosis patients may be disturbed, and oxygen free radical reaction may be pathologically exacerbated.

Adult↗
PubMed1999

[The toxicity of combination of selenium, fluoride and arsenic on rat embryos].

Whole embryo rotated culture technique was used to investigate the toxicity of combination of selenium, fluoride and arsenic on rat embryos at day 9.5 of gestation. The result of factorial analysis (3 x 3 x 3) showed that the main effect of combination of selenium, fluoride and arsenic on the developmental toxicity was synergistic. The mixtures with different level of these three chemicals in combination could result in different developmental toxicity. The low level combinations mainly caused teratogenic effect, and the high level combinations(selenium 2.0 micrograms + fluoride 10 micrograms + arsenic 1.0 microgram/ml culture media) caused lethal effect. The results suggested that the disorders of yolk-sac placenta in structure and function were one of teratogenic mechanisms for the combination of selenium, fluoride and arsenic.

Animals↗
PubMed1999

Neuroprotection with noninvasive neurotrophin delivery to the brain.

Brain-derived neurotrophic factor (BDNF) is neuroprotective in the ischemic hippocampus if the neurotrophin is injected directly into the brain. However, the efficacy of BDNF via peripheral (i.v.) administration is limited by the lack of transport of the neurotrophin through the brain capillary wall, which makes up the blood-brain barrier (BBB) in vivo. The present studies describe a molecular reformulation of BDNF that incorporates polyethylene glycol (PEG) moieties at surface carboxyl residues, to optimize plasma pharmacokinetics, and links pegylated BDNF to the OX26 mAb, which undergoes receptor-mediated transport through the BBB via the brain capillary endothelial transferrin receptor. The BDNF-PEG 2000-biotin conjugated to OX26/streptavidin was administered i.v. daily to rats for 1 week after a 12-min period of transient forebrain ischemia. The neuronal density in the CA1 sector of the hippocampus was decreased 68 +/- 10% at 1 week after the ischemia. There was no neuroprotective effect of the unconjugated BDNF or unconjugated OX26 mAb. However, the hippocampal CA1 neuronal density was normalized by i.v. administration of the BDNF-PEG 2000-biotin conjugated to OX26/streptavidin. These studies demonstrate that peripherally administered BDNF may have neuroprotective effects in brain, if the neurotrophin is reformulated to (i) optimize plasma pharmacokinetics with carboxyl-directed pegylation, and (ii) enable transport through the BBB by coupling to brain transport vectors.

Animals↗
PubMed1999

Dishevelled proteins lead to two signaling pathways. Regulation of LEF-1 and c-Jun N-terminal kinase in mammalian cells.

Dishevelled (Dsh/Dvl) proteins are known to mediate Wnt signaling by up-regulating beta-catenin levels and stimulating T cell factor (TCF)/LEF-1-dependent transcription. We have identified a new Dvl-mediated signaling pathway in that mouse Dvl proteins, when expressed in COS-7 cells, stimulate c-Jun-dependent transcription activity and the kinase activity of the c-Jun N-terminal kinase (JNK). The DEP domain of Dvl1 is essential for JNK activation. By contrast, all three conserved domains of Dvl, including DIX, PDZ, and DEP, are required for up-regulation of beta-catenin and for stimulation of LEF-1-mediated transcription in mammalian cells. Thus, Dvl can lead to two different signaling pathways. Furthermore, the small G proteins of Cdc42 or Rac1, which are involved in JNK activation by many stimuli, do not appear to play a major role in Dvl-mediated JNK activation, because the dominant negative mutants of Cdc42 and Rac1 could not inhibit Dvl-induced JNK activation. This suggests that Dvl may activate JNK via novel pathways.

3T3 Cells↗
PubMed1999

Serum bound forms of PSP94 (prostate secretory protein of 94 amino acids) in prostate cancer patients.

PSP94 (prostate secretory protein of 94 amino acids) was regarded as a possible prostate cancer marker, however, it has been controversial. All prior studies were designed to test the free form in serum using antibodies to PSP94. Results presented here demonstrate that PSP94 exists in prostate cancer patients in two forms, free and bound, and that the majority is present as serum bound complexes. This result was demonstrated by using both native and SDS-PAGE analyses of serum proteins from prostate cancer patients. Chromatographic separation of serum total proteins by a molecular sieve column generated two peaks (peak I and II), which were reactive with rabbit antiserum to human PSP94 in Western blot experiments. Peak I was eluted before the IgG fraction at a molecular weight larger than 150 kDa, and peak II appeared after serum albumin ( approximately 67 kDa) was eluted. By using a biotinylated PSP94 as an indicator of the free form of PSP94, we demonstrate that peak I contains serum PSP94-bound complexes and peak II is likely the free form of serum PSP94. Since the molecular weight of serum PSP94-bound complexes is close to IgG during molecular sieve separation, serum PSP94 complexes were further purified through two rounds of protein A column separation, followed by DEAE-ion exchange column chromatography. In vitro dissociation tests of the purified PSP94-bound complexes showed that the binding of serum PSP94-complexes is probably via disulfide bonds and is chemically stable. The results presented here indicate that serum PSP94-bound complexes must be considered in evaluating the clinical utility of PSP94 as a prostate cancer marker.

Antibodies↗
PubMed1999

String-plucking as a mechanism of chordal rupture during balloon mitral valvuloplasty using inoue balloon catheter.

Percutaneous transvenous mitral commissurotomy using the Inoue technique was performed in a 59-year-old female with mitral stenosis and a severely calcified mitral leaflets. Although not entrapped in the subvalvular apparatus, the balloon catheter was deviated away from the mitral orifice-apex axis of the left ventricle during the inflation of the proximal balloon, which plucked and severed the chordae tendineae of the posterior mitral leaflet and resulted in severe mitral regurgitation.

Calcinosis↗