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Biomedical subjects

Jun Liu

Publications and source records attributed to Jun Liu.

At least 55 records · Page 3Linked to original sources
PubMed2006

A model-based approach in the estimation of the maximum tolerated dose in phase I cancer clinical trials.

The primary aim of a phase I cancer clinical trial is to determine the maximum tolerated dose (MTD) of a new agent. The MTD is determined as the highest dose level of a potential therapeutic agent at which the patients have experienced an acceptable level of dose limiting toxicity. Although many other types of designs have been proposed in recent years, the traditional algorithm-based designs, especially the 3+3 designs, are still widely used due to their practical simplicity. Simulation studies have shown that the traditional algorithm-based designs cannot provide reasonable estimates of the MTD due to their intrinsic design limitations. In this paper, we propose a model-based approach in the estimation of the MTD following a traditional 3+3 design. Simulation results indicate that our model-based approach produces much less biased estimates of the MTD compared to the estimates obtained from the traditional 3+3 designs. Furthermore, our model-based approach can be easily extended to any traditional A+B design.

Algorithms↗
PubMed2006

Comparative analysis of tropism between canarypox (ALVAC) and vaccinia viruses reveals a more restricted and preferential tropism of ALVAC for human cells of the monocytic lineage.

The poxviruses including canarypox (ALVAC) and vaccinia viruses are promising vaccine vectors in humans, but little is known about their biology in human cells. Using recombinant enhanced green fluorescence protein (EGFP)-expressing ALVAC and vaccinia viruses, we have focused here on a side-by-side comparison of ALVAC and vaccinia virus tropism for cells from human peripheral blood and bone marrow. Both ALVAC and vaccinia viruses showed a strong bias towards monocyte infection. ALVAC minimally infected CD19+ B cells and was unable to infect ex vivo NK cells and T lymphocytes, whereas vaccinia virus could infect B lymphocytes and NK cell populations. Vaccinia virus was also able to infect T lymphocytes at low, but detectable levels that could be enhanced upon their activation. The observed preferential infection of ALVAC or vaccinia virus to monocytes was the result of preferential binding to this population, rather than lineage-specific differences in the expression of viral genes. Moreover, the level of CD14 expression on monocytes correlated with their preference to be infected with ALVAC or vaccinia virus. Both ALVAC and vaccinia viruses could infect immature monocyte derived dendritic cells (MDDCs), but only ALVAC infection induced their subsequent maturation. Vaccinia virus, however, showed greater tropism for mature MDDCs compared to ALVAC. Infection in human bone marrow cultures showed that ALVAC infection was restricted to a myelomonocytoid cell-specific CD33(+) cell population, while vaccinia virus showed a strong, but not exclusive, preference for these cells. These findings have implications in terms of choosing optimal pox virus derived vectors as vaccines in terms of reducing clinical reactogenicity and inducing dendritic cell (DC) maturation.

CD40 Ligand↗
PubMed2006

Ultrasonic model and system for measurement of corneal biomechanical properties and validation on phantoms.

Non-invasive measurement of biomechanical properties of corneas may provide important information for ocular disease management and therapeutic procedures. An ultrasonic non-destructive evaluation method with a wave propagation model was developed to determine corneal biomechanical properties in vivo. In this study, we tested the feasibility of the approach in differentiating the mechanical properties of soft contact lenses as corneal phantoms. Three material types of soft contact lenses (six samples in each group) were measured using a broadband ultrasound transducer. The ultrasonic reflections from the contact lenses were recorded by a 500MHz/8-bit digitizer, and displayed and processed by a PC. A reference signal was recorded to compute the normalized power spectra using Fast Fourier Transformation. An inverse algorithm based on least-squares minimization was used to reconstruct three parameters of the contact lenses: density, thickness, and elastic constants lambda+2micro. The thickness of each sample was verified using an electronic thickness gauge, and the averaged density for each type of lenses was verified using Archimedes' principle and manufacturer's report. Our results demonstrated that the ultrasonic system was able to differentiate the elastic properties of the three types of the soft contact lenses with statistical significance (P-value<0.001). The reconstructed thicknesses and densities agreed well with the independent measurements. Our studies on corneal phantoms indicated that the ultrasonic system was sensitive and accurate in measuring the material properties of cornea-like structures. It is important to optimize the system for in vivo measurements.

Biomechanical Phenomena↗
PubMed2006

An antagonistic role for the C. elegans Schnurri homolog SMA-9 in modulating TGFbeta signaling during mesodermal patterning.

In C. elegans, the Sma/Mab TGFbeta signaling pathway regulates body size and male tail patterning. SMA-9, the C. elegans homolog of Schnurri, has been shown to function as a downstream component to mediate the Sma/Mab TGFbeta signaling pathway in these processes. We have discovered a new role for SMA-9 in dorsoventral patterning of the C. elegans post-embryonic mesoderm, the M lineage. In addition to a small body size, sma-9 mutant animals exhibit a dorsal-to-ventral fate transformation within the M lineage. This M lineage defect of sma-9 mutants is unique in that animals carrying mutations in all other known components of the TGFbeta pathway exhibit no M lineage defects. Surprisingly, mutations in the core components of the Sma/Mab TGFbeta signaling pathway suppressed the M lineage defects of sma-9 mutants without suppressing their body size defects. We show that this suppression specifically happens within the M lineage. Our studies have uncovered an unexpected role of SMA-9 in antagonizing the TGFbeta signaling pathway during mesodermal patterning, suggesting a novel mode of function for the SMA-9/Schnurri family of proteins.

Animals↗
PubMed2006

Genetic variations in radiation and chemotherapy drug action pathways predict clinical outcomes in esophageal cancer.

PURPOSE: Understanding how specific genetic variants modify drug action pathways may provide informative blueprints for individualized chemotherapy. METHODS: We applied a pathway-based approach to examine the impact of a comprehensive panel of genetic polymorphisms on clinical outcomes in 210 esophageal cancer patients. RESULTS: In the Cox proportional hazards model, MTHFR Glu429Ala variant genotypes were associated with significantly improved survival (hazard ratio [HR] = 0.56; 95% CI, 0.35 to 0.89) in patients treated with fluorouracil (FU). The 3-year survival rates for patients with the variant genotypes and the wild genotypes were 65.26% and 46.43%, respectively. Joint analysis of five polymorphisms in three FU pathway genes showed a significant trend for reduced recurrence risk and longer recurrence-free survival as the number of adverse alleles decreased (P = .004). For patients receiving platinum drugs, the MDR1 C3435T variant allele was associated with significantly reduced recurrence risk (HR = 0.25; 95% CI, 0.10 to 0.64) and improved survival (HR = 0.44; 95% CI, 0.23 to 0.85). In nucleotide excision repair genes, there was a significant trend for a decreasing risk of death with a decreasing number of high-risk alleles (P for trend = .0008). In base excision repair genes, the variant alleles of XRCC1 Arg399Gln were significantly associated with the absence of pathologic complete response (odds ratio = 2.75; 95% CI, 1.14 to 6.12) and poor survival (HR = 1.92; 95% CI, 1.00 to 3.72). CONCLUSION: Several biologically plausible associations between individual single nucleotide polymorphisms and clinical outcomes were found. Our data also strongly suggest that combined pathway-based analysis may provide valuable prognostic markers of clinical outcomes.

Adenocarcinoma↗
PubMed2006

[Association of baseline cholesterol level and its 10-year change with carotid atherosclerosis in the population of Peking University community].

OBJECTIVE: To explore the association of baseline cholesterol level in 1992 and its 10-year change from 1992 to 2002 with the prevalence of carotid atherosclerosis. METHODS: In 1992, 1985 subjects of the community of Peking University, aged 35 - 64, underwent physical examination and blood-lipid test to study the cardio-vascular disease (CVD) risk factors. In 2002, the second survey on CVD risk factors was conducted among the existing 1932 subjects, now aged 45 - 74. In addition, B-mode ultrasonography of the carotid artery was performed too. The complete data of 1331 subjects were analyzed. RESULTS: (1) In 2002, the prevalence rates of intimal medial thickening (IMT) and carotid plaque in the study population were 47.8% and 29.9% respectively. (2) The post-10-year prevalence rate of carotid plaque was 19.7% in the subjects with the baseline cholesterol < 3.64 mmol/L, and was 46.8% in those with the baseline cholesterol 6.24 mmol/L, with a thickening rate 3.1 times that of the subjects with the baseline cholesterol < 3.64 mmol/L. The higher the baseline TV level, the higher the prevalence rates of carotid plaque and IMT. (3) The prevalence rate of carotid plaque was 32.0% in the subjects with normal TC in both 1992 and 2002, and 50.0% in those with hypercholesterolemia in both 1992 and 2002. CONCLUSION: Carotid atherosclerosis is a prevalent disorder in the people aged 45 - 74 in Beijing. The prevalence rates of carotid plaque and IMT increase with the elevation of baseline cholesterol level.

Adult↗
PubMed2006

Phytophthora nicotianae PnPMA1 encodes an atypical plasma membrane H+ -ATPase that is functional in yeast and developmentally regulated.

PnPMA1, a gene encoding a putative P-type plasma membrane H(+)-ATPase, has been isolated by differential screening of a Phytophthora nicotianae germinated cyst cDNA library. PnPMA1 is differentially expressed during pathogen asexual development with a more than 10-fold increase in expression in germinated cysts, the stage at which plant infection is initiated, compared to vegetative or sporulating hyphae or motile zoospores. PnPMA1 proteins are encoded by two closely linked genes that have no introns and encode identical proteins having 1,068 amino acid residues and a molecular mass of 116.3kDa. PnPMA1 shows moderate identity (30-50%) to plant and fungal plasma membrane H(+)-ATPases and weak identity to other P-type cation-transporting ATPases. PnPMA1 contains all the catalytic domains characteristic of H(+)-ATPases but also has a distinct domain of approximately 155 amino acids that forms a putative cytoplasmic loop between transmembrane domains 8 and 9, a feature that is not present in PMA1 proteins from other organisms. Polyclonal antibodies raised against the 155 residue domain were shown by immunogold labelling to react with a protein in the plasma membrane of P. nicotianae germinated cysts but not with the plasma membrane of motile zoospores. Genetic complementation experiments demonstrated that the P. nicotianae PnPMA1 is functional in yeast, Saccharomyces cerevisiae.

Algal Proteins↗
PubMed2006

Plasmodium falciparum ensures its amino acid supply with multiple acquisition pathways and redundant proteolytic enzyme systems.

Degradation of host hemoglobin by the human malaria parasite Plasmodium falciparum is a massive metabolic process. What role this degradation plays and whether it is essential for parasite survival have not been established, nor have the roles of the various degradative enzymes been clearly defined. We report that P. falciparum can grow in medium containing a single amino acid (isoleucine, the only amino acid missing from human hemoglobin). In this medium, growth of hemoglobin-degrading enzyme gene knockout lines (missing falcipain-2 and plasmepsins alone or in combination) is impaired. Blockade of plasmepsins with the potent inhibitor pepstatin A has a minimal effect on WT parasite growth but kills falcipain-2 knockout parasites at low concentrations and is even more potent on falcipain-2, plasmepsin I and IV triple knockout parasites. We conclude that: (i) hemoglobin degradation is necessary for parasite survival; (ii) hemoglobin degradation is sufficient to supply most of the parasite's amino acid requirements; (iii) external amino acid acquisition and hemoglobin digestion are partially redundant nutrient pathways; (iv) hemoglobin degradation uses dual protease families with overlapping function; and (v) hemoglobin-degrading plasmepsins are not promising drug targets.

Amino Acids↗
PubMed2006

Distribution and three-dimensional structure of AIDS virus envelope spikes.

Envelope glycoprotein (Env) spikes on AIDS retroviruses initiate infection of host cells and are therefore targets for vaccine development. Though crystal structures for partial Env subunits are known, the structure and distribution of native Env spikes on virions is obscure. We applied cryoelectron microscopy tomography to define ultrastructural details of spikes. Virions of wild-type human immunodeficiency virus 1 (HIV-1) and a mutant simian immunodeficiency virus (SIV) had approximately 14 and approximately 73 spikes per particle, respectively, with some clustering of HIV-1 spikes. Three-dimensional averaging showed that the surface glycoprotein (gp120) 'head' of each subunit of the trimeric SIV spike contains a primary mass, with two secondary lobes. The transmembrane glycoprotein 'stalk' of each trimer is composed of three independent legs that project obliquely from the trimer head, tripod-like. Reconciling available atomic structures with the three-dimensional whole spike density map yields insights into the orientation of Env spike structural elements and possible structural bases of their functions.

Acquired Immunodeficiency Syndrome↗
PubMed2006

The relation between D-galactose injection and mitochondrial DNA 4834 bp deletion mutation.

Since,D-galactose (D-gal) overload model has been used as a premature aging model, we hypothesized that it may also lead to accelerated aging in the inner ear. Furthermore, though the mitochondrial DNA (mtDNA) 4834 bp deletion mutation has been considered as the marker of aging, there is no information available in the literature concerning the mtDNA 4834 bp deletion mutation condition of the D-gal induced premature aging model. We investigate the changes in inner ear enzymatic activity, the occurring of mtDNA 4834 bp deletion in inner ear and other tissues and the relating hearing thresholds after the administration of high dosage (150 mg/kg per day) and low dosage (50 mg/kg per day) of D-gal to rats. Furthermore, the incidence of the mtDNA 4834 bp deletion in different tissues as well as in blood sample was compared. The results showed that daily subcutaneous injections of D-gal into rats for 8 weeks could lead to the biochemical defects and mtDNA 4834 bp deletion in the inner ear tissue and other tissues, which represent the typical aging animals, but the relating hearing threshold shifts (TS) were nearly identical in the three groups. This study also indicates that using of blood samples to detect mtDNA 4834 bp deletion in clinical research might lead to a 'false negative' result. A higher sensitive result could be gained using tissue biopsy to examine mtDNA 4834 bp deletion.

Aging↗
PubMed2006

A new class of silica cross-linked micellar core-shell nanoparticles.

Micellar nanoparticles made of surfactants and polymers have attracted wide attention in the materials and biomedical community for controlled drug delivery, molecular imaging, and sensing; however, their long-term stability remains a topic of intense study. Here we report a new class of robust, ultrafine silica core-shell nanoparticles formed from silica cross-linked, individual block copolymer micelles. Compared with pure polymeric micelles, the main advantage of the new core-shell nanoparticles is that they have significantly improved stability and do not break down during dilution. We also studied the drug loading and release properties of the silica cross-linked micellar particles, and we found that the new core-shell nanoparticles have a slower release rate which allows the entrapped molecules to be slowly released over a much longer period of time under the same experimental conditions. A range of functional groups can be easily incorporated through co-condensation with the silica matrix. The potential to deliver hydrophobic agents into cancer cells has been demonstrated. Because of their unique structures and properties, these novel core-shell nanoparticles could potentially provide a new nanomedicine platform for imaging, detection, and treatment, as well as novel colloidal particles and building blocks for mutlifunctional materials.

Antineoplastic Agents↗
PubMed2006

Distance-based clustering of CGH data.

MOTIVATION: We consider the problem of clustering a population of Comparative Genomic Hybridization (CGH) data samples. The goal is to develop a systematic way of placing patients with similar CGH imbalance profiles into the same cluster. Our expectation is that patients with the same cancer types will generally belong to the same cluster as their underlying CGH profiles will be similar. RESULTS: We focus on distance-based clustering strategies. We do this in two steps. (1) Distances of all pairs of CGH samples are computed. (2) CGH samples are clustered based on this distance. We develop three pairwise distance/similarity measures, namely raw, cosine and sim. Raw measure disregards correlation between contiguous genomic intervals. It compares the aberrations in each genomic interval separately. The remaining measures assume that consecutive genomic intervals may be correlated. Cosine maps pairs of CGH samples into vectors in a high-dimensional space and measures the angle between them. Sim measures the number of independent common aberrations. We test our distance/similarity measures on three well known clustering algorithms, bottom-up, top-down and k-means with and without centroid shrinking. Our results show that sim consistently performs better than the remaining measures. This indicates that the correlation of neighboring genomic intervals should be considered in the structural analysis of CGH datasets. The combination of sim with top-down clustering emerged as the best approach. AVAILABILITY: All software developed in this article and all the datasets are available from the authors upon request. CONTACT: juliu@cise.ufl.edu.

Algorithms↗
PubMed2006

[Experimental research on establishing chronic ischemic heart failure model of minipig with intracoronary perfusion of plastic microspheres by catheterization].

OBJECTIVE: To establish a stable chronic ischemic heart failure (CIHF) model of minipig caused by gradual myocardial ischemia and necrosis that was achieved with repetitive microspheres perfusion in left anterior descending artery (LAD). METHODS: A total of fifteen Wuzhishan minipigs original in Hainan China (8 to 11 months old with body weight of 20 to 30 kg) were used. The 4F angiographic catheter was superselectively engaged in LAD, and 1 ml of suspending plastic microspheres fluid were given repeatedly at ten-minute intervals, which include microspheres 1.0 x 10(5)/ml, until LVEDP raising and maintaining from 15 mm Hg to 18 mm Hg and TIMI flow was less than or equal to grade 2. Electrocardiography, hemodynamic parameters, CK-MB and cTnT were monitored during the procedure. LVEF was repeatedly measured with ultracardiography at 10 d, 20 d, 30 d, 40 d, 50 d, 60 d after establishing chronic ischemic heart failure model. Meanwhile, hemodynamic indices including mRAP, mRVP, mPAP, PCWP and CO (thermo-dilution method) were measured before and two months after procedure. The success rate, stability and repetition of chronic ischemic heart failure model were identified and evaluated. Finally, myocardial infarcted area was measured and myocardial pathologic examination was investigated. RESULTS: Eleven minipigs survived two months after procedure. There were ten minipigs accorded with the criteria (LVEDP > 18 mm Hg CO reduced by 30%) of the CIHF model and the success rate was 66.7% with a mean of 3.2 +/- 0.9 times of microspheres injections and total doses of (3.2 +/- 0.9) x 10(5) microspheres. This resulted in 38.5% reduction in LVEF, 197.8% elevation in LVEDP and 46.8% declining in CO from baseline values (P < 0.01), while mRAP, mRVP, mPAP and PCWP increased significantly as compared with those before procedure. Cross myocardium pathology showed the ratio of necrosis area to left ventricle (LV) area was 25.4% - 34.9% (mean 28.6%) and light microscopy examination of LV myocardium revealed that intravascular semitransparent plastic microspheres distributed throughout subendocardium of left ventricular anterior and apical parts, with more numerous focal myofiber necrosis, which characterized by pathologic founding of ischemic necrosis of myocardium with fibre proliferation. CONCLUSION: A stable CIHF model could be established in Chinese Wuzhishan minipigs with intra-coronary microspheres perfusion via superselectively engaging in LAD, which was prior to those of drug-induced, tachycardia-pacing induced or coronary artery ligation-induced, and had the advantages of stability, closed chest, mild trauma higher success rate and easy for repetition. It might be suitable for using the research of CIHF as large reliable experimental animal model.

Animals↗
PubMed2006

Three-dimensional structure of the myosin V inhibited state by cryoelectron tomography.

Unconventional myosin V (myoV) is an actin-based molecular motor that has a key function in organelle and mRNA transport, as well as in membrane trafficking. MyoV was the first member of the myosin superfamily shown to be processive, meaning that a single motor protein can 'walk' hand-over-hand along an actin filament for many steps before detaching. Full-length myoV has a low actin-activated MgATPase activity at low [Ca2+], whereas expressed constructs lacking the cargo-binding domain have a high activity regardless of [Ca2+] (refs 5-7). Hydrodynamic data and electron micrographs indicate that the active state is extended, whereas the inactive state is compact. Here we show the first three-dimensional structure of the myoV inactive state. Each myoV molecule consists of two heads that contain an amino-terminal motor domain followed by a lever arm that binds six calmodulins. The heads are followed by a coiled-coil dimerization domain (S2) and a carboxy-terminal globular cargo-binding domain. In the inactive structure, bending of myoV at the head-S2 junction places the cargo-binding domain near the motor domain's ATP-binding pocket, indicating that ATPase inhibition might occur through decreased rates of nucleotide exchange. The actin-binding interfaces are unobstructed, and the lever arm is oriented in a position typical of strong actin-binding states. This structure indicates that motor recycling after cargo delivery might occur through transport on actively treadmilling actin filaments rather than by diffusion.

Actins↗
PubMed2006

Proteomic analysis of microglial contribution to mouse strain-dependent dopaminergic neurotoxicity.

Although the pathogenesis of Parkinson's disease (PD) remains unknown, it appears that microglial activation is associated with enhanced neurodegeneration in animal models of PD as well as in PD patients. Experimentally, C57BL/6 and SWR/J mice demonstrate striking differences in the extent of dopaminergic (DAergic) neurodegeneration induced by a parkinsonian toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The purpose of this study was to determine whether differences in microglial activation between these two strains of mice could provide insight into the variability seen in toxicant induced neuronal death, and subsequently to use a high-throughput proteomic method, combining stable isotope labeling with amino acids in cell culture (SILAC) with liquid chromatography and tandem mass spectrometry, to compare the microglial proteomes of C57BL/6 and SWR/J mice after stimulation with a classical microglial activator, lipopolysaccharide (LPS). We found that DAergic neurotoxicity induced by LPS in a primary neuron-microglia coculture was twofold greater with microglia isolated from the brains of C57BL/6 mice compared with that of SWR/J mice. Upon proteomic analysis we found that, out of over 1,000 proteins identified and quantified, 400 displayed a significant difference in their relative abundance between these two murine strains. Several proteins, which had relatively higher levels in C57BL/6 mice, have previously been implicated in LPS-mediated microglial activation, including those involved in the COX-2 pathway and in prostaglandin E-2 (PGE(2)) production. To validate our proteomic results we confirmed the increased expression level of iNOS in C57BL/6 vs. SWR/J microglia with semiquantitative Western blot. Further analysis of our proteomic discovery data will likely reveal numerous novel proteins involved in inflammation-mediated neurotoxicity in PD.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2006

Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration.

Liver mass depends on one or more unidentified humoral signals that drive regeneration when liver functional capacity is diminished. Bile acids are important liver products, and their levels are tightly regulated. Here, we identify a role for nuclear receptor-dependent bile acid signaling in normal liver regeneration. Elevated bile acid levels accelerate regeneration, and decreased levels inhibit liver regrowth, as does the absence of the primary nuclear bile acid receptor FXR. We propose that FXR activation by increased bile acid flux is a signal of decreased functional capacity of the liver. FXR, and possibly other nuclear receptors, may promote homeostasis not only by regulating expression of appropriate metabolic target genes but also by driving homeotrophic liver growth.

Animals↗
PubMed2006

Stereoselective nucleophilic monofluoromethylation of N-(tert-butanesulfinyl)imines with fluoromethyl phenyl sulfone.

[reaction: see text] Highly stereoselective nucleophilic monofluoromethylation of (R)-(tert-butanesulfinyl)imines with fluoromethyl phenyl sulfone was achieved to afford alpha-monofluoromethylamines with a nonchelation-controlled stereoselectivity mode. By using the same chemistry, (R)-(tert-butanesulfinyl)imines bearing a terminal tosylate (OTs) group can be converted to alpha-monofluoromethylated cyclic secondary amines with high stereoselectivity.

Journal Article↗