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Biomedical subjects

J Wu

Publications and source records attributed to J Wu.

At least 19 recordsLinked to original sources
PubMed2006

Adeno-associated virus 2-mediated gene transfer: role of a cellular serine/threonine protein phosphatase in augmenting transduction efficiency.

We have documented that a cellular chaperone protein, FKBP52, when phosphorylated at tyrosine and/or serine/threonine (Ser/Thr) residues, interacts with the D-sequence in the inverted terminal repeats of the adeno-associated virus 2 (AAV) genome, inhibits the viral second-strand DNA synthesis, and leads to inefficient transgene expression from recombinant AAV vectors in certain cell types. We have also demonstrated that FKBP52 is dephosphorylated at tyrosine residues by T-cell protein tyrosine phosphatase (TC-PTP), and that deliberate overexpression of TC-PTP leads to more efficient viral second-strand DNA synthesis, and increased transgene expression. However, the identity of the putative Ser/Thr protein phosphatase that dephosphorylates FKBP52 at Ser/Thr residues has remained elusive. Using known inhibitors of Ser/Thr phosphatases, we have now identified protein phosphatase 5 (PP5) to be a candidate enzyme. Deliberate overexpression of PP5 in 293 cells, which does not influence cellular growth, leads to approximately 5-fold increase in the transduction efficiency of conventional single-stranded AAV vectors, but no significant enhancement in the transduction efficiency of self-complementary AAV vectors, suggesting that PP5 plays a role in AAV second-strand DNA synthesis. Electrophoretic mobility-shift assays show that in cells overexpressing PP5, the extent of the complex formation between FKBP52 and the AAV D-sequence is significantly reduced. These studies suggest that PP5-mediated dephosphorylation of FKBP52 at Ser/Thr residues augments viral second-strand DNA synthesis and enhances AAV transduction efficiency, which has implications in the optimal use of these vectors in human gene therapy.

Cell Line↗
PubMed2006

Evaluation of quality of life using ASQoL questionnaire in patients with ankylosing spondylitis in a Chinese population.

The purpose of this study was to evaluate the reliability of Chinese version of the ankylosing spondylitis quality of life questionnaire (ASQoL) for AS patients. All the enrolled AS patients should fulfill five questionnaires (BASDAI, BASFI, DFI, BAS-G and ASQoL) by himself, then the investigators did physical examination of the patients, fulfilling BASMI. Physical function has a strong correlation with QoL in patients with AS. In different disease activity groups, ASQoL had a correlation with BASFI, especially in the moderate activity group (gamma = 0.66, P < 0.0001). All four questionnaires in entanacept treatment group improved distinctly on week 6 and 12 comparing to baseline. There were significantly correlations of changing between ASQoL and BAS-G, BASDAI and BASFI after treatment with etanercept in AS patients. The Chinese ASQoL questionnaire is valuable to evaluate the activity of AS patients and effect of biologic agent treatment in patients with AS. It is a good generic instrument to measure QoL in patients with AS in China.

Activities of Daily Living↗
PubMed2006

Soliton polarization dynamics in fiber lasers passively mode-locked by the nonlinear polarization rotation technique.

By numerically solving the coupled laser Ginzburg-Landau equations and using the pulse tracing technique to incorporate the cavity effect in the simulation, we have explicitly calculated the soliton polarization ellipses throughout the cavity of a fiber-ring laser mode-locked by the nonlinear polarization rotation technique, and investigated the soliton polarization dynamics in laser cavities. It was found that in a conventional stable soliton operation state, although the soliton polarization varies as the pulse propagates, at a fixed position inside the laser cavity the soliton polarization is invariant with time. However, in the presence of laser dynamics, at a fixed location within the cavity the soliton could either have multiple alternating fixed polarization states or no fixed polarization state at all, depending on the soliton dynamics.

Journal Article↗
PubMed2006

Celecoxib reduces microvessel density in patients treated with nasopharyngeal carcinoma and induces changes in gene expression.

BACKGROUND: Celecoxib is a selective cyclooxygenase-2 inhibitor with antitumor and antiangiogenic activity. We sought to determine pharmacodynamic change in tumors of patients with nasopharyngeal carcinoma (NPC) treated with celecoxib. METHODS: Tumor biopsies were obtained before and after treatment with celecoxib 400 mg b.i.d. for 14 days in patients with newly diagnosed, untreated NPC. Tumor angiogenesis and cell proliferation were assessed by immunohistochemistry and gene expression by microarray analysis. Plasma celecoxib concentrations were obtained on days 8 and 14. RESULTS: Paired samples were analyzed in 15 patients. Microvessel density was reduced in post-treatment samples and mean celecoxib levels reached therapeutic levels. Thirty-five genes (27 down-regulated, eight up-regulated) were differentially expressed on microarray analysis (p < 0.001). Down-regulated genes included cell cycle regulation-related (cyclin-dependent kinase 2, YES1), transcription factor (TRIP-Br2), whereas the antigen processing and presentation-related gene HLA-DM B was up-regulated. CONCLUSION: Celecoxib reduced angiogenesis and induced tumor transcriptional changes. Further characterization of these transcriptional changes in vivo is needed to provide further insights into the effects of celecoxib in neoplastic tissue. Our findings provide a rationale for clinical studies aimed at assessing the efficacy of celecoxib in the treatment of NPC.

Adult↗
PubMed2006

Effect of endothelin-1 on erythropoietin production in a rat model under normoxia and functional carbon monoxide-induced hypoxia.

It has been hypothesized that autacoids, such as endothelin-1 (ET), may modulate erythropoietin (Epo) secretion. Therefore, we studied the effect of ET-1 infusion and of a nonselective ET(A/B) receptor antagonist on Epo secretion under carbon monoxide (CO) exposure. Anesthetized rats were supplied with room temperature air containing increasing concentrations of CO by an aerating cap. A CO-Epo dose-response curve over the range of 0.02-0.14 vol% CO was conducted. Subpressor doses of ET-1 (3 pmol/min/kg BW) and the ET(A/B) receptor antagonist LU302872 (LU; 30 mg/kg) were applied to anaesthetized rats under normoxia (controls CON, ET, LU) and following hypoxia (CO exposure; H-CON, H-ET, H-LU). Mean arterial blood pressure (MAP), glomerular filtration rate (GFR, inulin clearance), Epo and ET-1 serum concentrations (ELISA) and renal Epo mRNA (Light Cycler) were determined. The EC50 value for CO was 0.1 vol% with a 70-fold increase in Epo serum concentrations. CO exposure increased Epo serum and Epo mRNA concentrations in the expected range in all groups. None of the treatments with ET or LU influenced the effect of hypoxia on Epo serum concentrations and renal Epo mRNA content. Under hypoxia, administration of ET-1 as well as LU prevented the hypoxia-induced decrease in MAP (p<0.05). Under hypoxia, GFR was reduced by 50% except for H-LU with values comparable to normoxia. Taken together, the influence of hypoxia exceeds by far the effect of ET-1 on Epo production, irrespective of the presence or absence of exogenous ET-1. Thus, ET-1 does not appear to be a major modulator of Epo production.

Animals↗
PubMed2006

Gain-guided soliton in a positive group-dispersion fiber laser.

We report on the operation of a passively mode-locked fiber ring laser made of purely normal dispersive fibers. Self-started mode locking can still be achieved in the laser by use of the nonlinear polarization rotation technique, and the mode-locked pulse has large pulse energy, strong frequency chirp, and a mode-locked spectral width limited by the effective laser gain bandwidth. Furthermore, we show that the operation of the laser can be well described by an extended Ginzburg-Landau equation model that governs the soliton dynamics of fiber lasers.

Journal Article↗
PubMed2006

Classifying G protein-coupled receptors and nuclear receptors on the basis of protein power spectrum from fast Fourier transform.

As the potential drug targets, G-protein coupled receptors (GPCRs) and nuclear receptors (NRs) are the focuses in pharmaceutical research. It is of great practical significance to develop an automated and reliable method to facilitate the identification of novel receptors. In this study, a method of fast Fourier transform-based support vector machine was proposed to classify GPCRs and NRs from the hydrophobicity of proteins. The models for all the GPCR families and NR subfamilies were trained and validated using jackknife test and the results thus obtained are quite promising. Meanwhile, the performance of the method was evaluated on GPCR and NR independent datasets with good performance. The good results indicate the applicability of the method. Two web servers implementing the prediction are available at http://chem.scu.edu.cn/blast/Pred-GPCR and http://chem.scu.edu.cn/blast/Pred-NR.

Computer Simulation↗
PubMed2006

Iptakalim inhibits nicotinic acetylcholine receptor-mediated currents in dopamine neurons acutely dissociated from rat substantia nigra pars compacta.

Iptakalim hydrochloride, a novel cardiovascular ATP-sensitive K(+) (K(ATP)) channel opener, has shown remarkable antihypertensive and neuroprotective effects in a variety of studies using in vivo and in vitro preparations. We recently found that iptakalim blocked human alpha4-containing nicotinic acetylcholine receptors (nAChRs) heterologously expressed in the human SH-EP1 cell line. In the present study, we examined the effects of iptakalim on several neurotransmitter-induced current responses in single DA neurons freshly dissociated from rat substantia nigra pars compacta (SNc), using perforated patch-clamp recordings combined with a U-tube rapid drug application. In identified DA neurons under voltage-clamp configuration, glutamate-, NMDA-, and GABA-induced currents were insensitive to co-application with iptakalim (100 microM), while whole-cell currents induced by ACh (1 mM+1 microM atropine) or an alpha4beta2 nicotinic acetylcholine receptors relatively selective agonist, RJR-2403 (300 microM), were eliminated by iptakalim. Iptakalim inhibited RJR-2403-induced current in a concentration-dependent manner, and reduced maximal RJR-2403-induced currents at the highest agonist concentration, suggesting a non-competitive block. In current-clamp mode, iptakalim failed to affect resting membrane potential and spontaneous action potential firing, but abolished RJR-2403-induced neuronal firing acceleration. Together, these results indicate that in dissociated SNc DA neurons, alpha4-containing nAChRs, rather than ionotropic glutamate receptors, GABA(A) receptors or perhaps K-ATP channels are the sensitive targets to mediate iptakalim's pharmacological roles.

Acetylcholine↗
PubMed2006

Inhibition of medulloblastoma cell invasion by Slit.

Invasion of brain tumor cells has made primary malignant brain neoplasms among the most recalcitrant to therapeutic strategies. We tested whether the secreted protein Slit2, which guides the projection of axons and developing neurons, could modulate brain tumor cell invasion. Slit2 inhibited the invasion of medulloblastoma cells in a variety of in vitro models. The effect of Slit2 was inhibited by the Robo ectodomain. Time-lapse videomicroscopy indicated that Slit2 reduced medulloblastoma invasion rate without affecting cell direction or proliferation. Both medulloblastoma and glioma tumors express Robo1 and Slit2, but only medulloblastoma invasion is inhibited by recombinant Slit2 protein. Downregulation of activated Cdc42 may contribute to this differential response. Our findings reinforce the concept that neurodevelopmental cues such as Slit2 may provide insights into brain tumor invasion.

Animals↗
PubMed2006

An approach of encoding for prediction of splice sites using SVM.

In splice sites prediction, the accuracy is lower than 90% though the sequences adjacent to the splice sites have a high conservation. In order to improve the prediction accuracy, much attention has been paid to the improvement of the performance of the algorithms used, and few used for solving the fundamental issues, namely, nucleotide encoding. In this paper, a predictor is constructed to predict the true and false splice sites for higher eukaryotes based on support vector machines (SVM). Four types of encoding, which were mono-nucleotide (MN) encoding, MN with frequency difference between the true sites and false sites (FDTF) encoding, Pair-wise nucleotides (PN) encoding and PN with FDTF encoding, were applied to generate the input for the SVM. The results showed that PN with FDTF encoding as input to SVM led to the most reliable recognition of splice sites and the accuracy for the prediction of true donor sites and false sites were 96.3%, 93.7%, respectively, and the accuracy for predicting of true acceptor sites and false sites were 94.0%, 93.2%, respectively.

Algorithms↗
PubMed2006

Quantitative analysis of amyloid plaques in a mouse model of Alzheimer's disease by phase-contrast X-ray computed tomography.

Densely aggregated beta-amyloid peptides are believed to play a key role in the pathogenesis of Alzheimer's disease. Amyloid plaques are a potential target for molecular imaging to determine the clinical status of Alzheimer's disease. Phase-contrast X-ray imaging combined with computed tomography is a promising technique that can be used to visualize the physical density of structures in biological tissues non-invasively, and without the use of imaging agents. Using brain tissue isolated from a mouse model of Alzheimer's disease, we show that beta-amyloid 40-positive/beta-amyloid 42-positive amyloid plaques, but not beta-amyloid 40-negative/beta-amyloid 42-positive amyloid plaques, exist as high-density aggregates that can be specifically detected by phase-contrast X-ray computed tomography. The phase-contrast X-ray computed tomography detected beta-amyloid 40-positive/beta-amyloid 42-positive amyloid plaques in three-dimensions with an extremely high sensitivity comparable to that of histological analysis, and also enabled the load of amyloid plaques to be quantified. Furthermore, the use of phase-contrast X-ray computed tomography reveals that the physical density of beta-amyloid 40-positive/beta-amyloid 42-positive amyloid plaques increases with age, and that the large volume, high-density, amyloid plaques that are specifically observed in aged Alzheimer's disease mice are closely associated with neuritic dystrophy. These results demonstrate that phase-contrast X-ray computed tomography is a highly sensitive imaging technique for analyzing dense-cored amyloid plaques in postmortem samples, and is beneficial in elucidating amyloid pathophysiology in Alzheimer's disease.

Aging↗
PubMed2006

Disease progression in recently diagnosed patients with inherited marrow failure syndromes: a Canadian Inherited Marrow Failure Registry (CIMFR) report.

BACKGROUND: Inherited bone marrow failure syndromes (IMFSs) are genetic disorders characterized by defective single-lineage or multi-lineage hematopoiesis. IMFS patients are at risk for severe cytopenias, development of marrow cytogenetic abnormalities (MCA), myelodysplasia (MDS), and malignancy. The rate of disease progression and proportion of patients at risk for these complications is currently unclear. We examined recently diagnosed IMFS patients to determine distribution of diagnoses, disease progression and development of significant outcomes. METHODS: The CIMFR is a prospective multi-center study established in 2001 to register all IMFS patients in Canada. Analysis was restricted to patients diagnosed after November 30, 1997. Summary statistics were used to depict the study population while survival was described using the Kaplan-Meier method. RESULTS: 74 CIMFR patients were considered recently diagnosed. Median age at diagnosis was 2.7 years (range, birth to 40.6). Annual follow-up data were available for 53 (72%) patients. The five most prevalent diagnoses were Fanconi anemia (FA), Shwachman-Diamond syndrome (SDS), Diamond-Blackfan anemia (DBA), dyskeratosis congenita (DKC), and Kostmann's neutropenia (KS). Eighteen (24%) patients were unclassifiable. Twenty-eight (53%) follow-up patients had disease progression as indicated by new or worsening cytopenias, new marrow changes, or initiation of transfusion support and/or medical therapy. Fourteen (19%) fulfilled minimal diagnostic criteria for myelodysplasia. Eleven patients had hematopoietic stem cell transplantation (HSCT) by first follow-up. Five patients have died. Survival at 36 months is 89.8 +/- 5.7%. CONCLUSIONS: IMFS patients are often diagnosed at a young age. The relative distribution of diagnoses is similar to previous reviews of published cases; however, 25% of patients are currently unclassifiable. Disease progression has occurred in approximately 50% of follow-up patients. Early mortality is noted. Continued prospective observation of these patients is warranted.

Adolescent↗
PubMed2006

Mitochondria and calpains mediate caspase-dependent apoptosis induced by doxycycline in HeLa cells.

Doxycycline (Dc) has been demonstrated to inhibit cell growth and induce apoptosis in tumor cells, although its mechanism of action is not fully understood. The present study demonstrates that apoptosis can be induced in HeLa cells. Western blot data demonstrated that cytochrome c (Cyt c), Smac (the second mitochondria-derived activator of caspase), calpain I, caspase-9, -3 and -8 were involved in the apoptotic process, while the pan caspase inhibitor zVAD-fmk almost completely inhibited Dc-induced apoptosis. We further demonstrated that the release of mitochondrial proteins and the activation of calpains occurred upstream of the caspase cascade, in which caspase-9 was activated in response to the release of Cyt c, that caspase-8 activation was caspase and calpain dependent, and that caspase-3 was activated mainly by caspase-8 and -9. Caspase-8 played important roles in the activation of caspase-3 and induction of apoptosis, whereas the role of the caspase-9 was limited.

Apoptosis↗
PubMed2006

Unscheduled CDK1 activity in G1 phase of the cell cycle triggers apoptosis in X-irradiated lymphocytic leukemia cells.

Cyclin-dependent kinase 1 (CDK1) is a major component of the cell cycle progression engine. Recently, several investigations provided evidence demonstrating that unscheduled CDK1 activation may also be involved in apoptosis in cancerous cells. In this article, we demonstrate that X-ray irradiation induced G1 arrest in MOLT-4 lymphocytic leukemia cells, the arrest being accompanied by reduction in the activity of CDK2, but increased CDK1 activity and cell apoptosis in the G1 phase. Interestingly, this increase in CDK1 and apoptosis by ionizing radiation was prevented by pretreatment with the CDK1 inhibitor, roscovitine, suggesting that CDK1 kinase activity is required for radiation-induced apoptotic cell death in this model system. Furthermore, cyclin B1 and CDK1 were detected co-localizing and associating in G1 phase MOLT-4 cells, with the cellular lysates from these cells revealing a genotoxic stress-induced increase in CDK1 phosphorylation (Thr-161) and dephosphorylation (Tyr-15), as analyzed by postsorting immunoprecipitation and immunoblotting. Finally, X-irradiation was found to increase Bcl-2 phosphorylation in G1 phase cells. Taken together, these novel findings suggest that CDK1 is activated by unscheduled accumulation of cyclin B1 in G1 phase cells exposed to X-ray, and that CDK1 activation, at the wrong time and in the wrong phase, may directly or indirectly trigger a Bcl-2-dependent signaling pathway leading to apoptotic cell death in MOLT-4 cells.

Apoptosis↗
PubMed2006

Prolongation of renal allograft survival in rats by replication-defective recombinant adenovirus-mediated coexpression of CD40L and CTLA4Ig.

BACKGROUND: Blockade of costimulatory signals has been shown to prolong allograft survival. The aim of the present study was to investigate the effect of simultaneous blockade of CD40/CD40L and CD28/B7 costimulatory pathways by replication-defective adenovirus-mediated expression of secretable extracellular domain of human CD40L (shCD40L) and CTLA4Ig to prolong rats renal allograft survival. METHODS: We constructed Adv-shCD40L-IRES2-CTLA4Ig, a replication-defective adenovirus carrying genes encoding human CD40L and CTLA4Ig. Coexpression of shCD40L and CTLA4Ig was evaluated by confocal laser scanning microscopy. The function of these two molecules was examined in human mixed lymphocyte reactions (MLRs) in vitro and in experimental BN-to-LEWIS rat renal transplantation in vivo. RESULTS: Successful construction of Adv-shCD40L-IRES2-CTLA4Ig was confirmed by polymerase chain reaction. Coexpression of shCD40L and CTLA4Ig on human kidney cell line HK-2 cells after transfection was detected by direct immunofluorescence staining. Human MLR was inhibited to 52.2%+/-0.6% and 42.1%+/-0.2% of the vehicle control by Adv-shCD40L and Adv-CTLA4Ig, respectively. Adv-shCD40L-IRES2-CTLA4Ig resulted in further inhibition of MLR to 22.0%+/-0.2% of vehicle control. Transfection with Adv-shCD40L or Adv-CTLA4Ig alone prolonged renal graft survival to 24.8+/-2.5 days and 27.3+/-3.6 days, respectively, as compared to vehicle-treated controls (7.8+/-0.3 days). Cotransfection of both genes extended graft survival to 41.8+/-3.7 days. CONCLUSIONS: Adv-shCD40L-IRES2-CTLA4Ig, a replication-defective adenovirus carrying genes encoding human CD40L and CTLA4Ig, achieved simultaneous blockade of CD40/CD40L and CD28/B7 costimulatory pathways, Adv-shCD40L-IRES2-CTLA4 by Ig synergistically inhibited human T-cell proliferation in MLR, and prolonged rats renal allograft survival.

Abatacept↗
PubMed2006

Survival analysis of liver transplant patients in Canada 1997-2002.

UNLABELLED: Liver transplantation is an important health care issue for Canadians. Very few studies have assessed survival and determinants of survival in liver transplant patients in Canada. METHODS: We carried out an epidemiological analysis of 1 year survival and determinants of 1 year survival in liver transplant patients, using Canadian Organ Replacement Registry data (1997-2002). Survival curves were plotted by the Kaplan-Meier method. Cox proportional hazards analysis was applied to evaluate hazard ratios with different age groups, gender, ethnicity, blood groups, donor type, pretransplantation medical status, and HBV infection status. RESULTS: A total of 1164 liver transplant patients were included in the analysis. One-year survival rate was 84.7%. Male recipients had a 21% higher risk of developing organ failure than females. Recipients over 60 years of age had a 5% lower survival probability in comparison with recipients below 20 years of age. Pacific Islanders and Aboriginals had 32% and 9% lower survival probabilities, respectively, in comparison with Caucasians. Type B blood recipients had a 12% higher survival probability, whereas type AB blood recipients had a 7% lower survival probability compared with type O blood recipients. Twenty-six live organ recipients had 40% higher survival probabilities than 1138 cadaveric organ recipients. Patients with fulminant hepatitis (status 3F) had the highest survival, while patients with fulminant failure in ICU with intubation/ventilation (status 4F) had the lowest survival. One hundred sixty-seven recipients with positive HBsAg antigen showed 10% lower survival probability than 997 cases with negative HBsAg antigen. CONCLUSION: In Canada, the first year survival rate is about 85%, which is comparable with other industrialized countries. Type of donor organs and recipient gender, ethnicity, ABO blood group, pretransplantation medical status, and HBV infection status had significant affects on the recipient survival.

Canada↗