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Biomedical subjects

H Zhang

Publications and source records attributed to H Zhang.

At least 19 recordsLinked to original sources
PubMed2007

Degradation of supercoiled plasmid DNA within a capillary device.

Supercoiled plasmid DNA is susceptible to fluid stress in large-scale manufacturing processes. A capillary device was used to generate controlled shear conditions and the effects of different stresses on plasmid DNA structure were investigated. Computational fluid dynamics (CFD) analysis was employed to characterize the flow environment in the capillary device and different analytical techniques were used to quantify the DNA breakage. It was found that the degradation of plasmid DNA occurred at the entrance of the capillary and that the shear stress within the capillary did not affect the DNA structure. The degradation rate of plasmids was well correlated with the average elongational strain rate or the pressure drop at the entrance region. The conclusion may also be drawn that laminar shear stress does not play a significant role in plasmid DNA degradation.

Computer Simulation↗
PubMed2007

Variants of C1GALT1 gene are associated with the genetic susceptibility to IgA nephropathy.

IgA nephropathy (IgAN) is a polygenic disorder and the precise role of genetic factors remains elusive. Increasing evidences have implicated the aberrant galactosylation of IgA1 molecules in the pathogenesis of IgAN. The galactosyltransferase, core 1 beta3-Gal-T, and its chaperone, Cosmc, play important roles in beta1,3 glycosylation of IgA1 molecule. A case-control association study was performed to investigate the association between single-nucleotide polymorphisms (SNPs) of C1GALT1 and C1GALT1C1 genes and the susceptibility to IgAN. A total of 1164 subjects were enrolled, including 670 IgAN patients and 494 geographically matched healthy controls. Five SNPs, -734C/T, -465A/G, -330G/T, -292C/-, and 1365G/A in C1GALT1 were selected as tagging SNPs. The D allele and DD genotype of -292C/- in IgAN patients were significantly lower than in the controls (P<0.01). The frequency of haplotype YATIG (Y=C or T) was significantly lower in patients than in controls (0.0719 vs 0.1168, P=2.775 x 10(-4), odds ratio (OR)=0.70). The haplotype YAGDA (0.1236 vs 0.0791, P=3.815 x 10(-3), OR=1.77) and YATDG (0.0840 vs 0.0298, P=1.258 x 10(-5), OR=3.03) were significantly higher in patients than in controls. The present study suggested that the polymorphisms of C1GALT1 gene were associated with the genetic susceptibility to IgAN in Chinese population.

Adolescent↗
PubMed2007

Are radiogallium-labelled DOTA-conjugated somatostatin analogues superior to those labelled with other radiometals?

PURPOSE: Gallium-68 is a metallic positron emitter with a half-life of 68 min that is ideal for the in vivo use of small molecules, such as [68Ga-DOTA,Tyr3]octreotide, in the diagnostic imaging of somatostatin receptor-positive tumours. In preclinical studies it has shown a striking superiority over its 111In-labelled congener. The purpose of this study was to evaluate whether third-generation somatostatin-based, radiogallium-labelled peptides show the same superiority. METHODS: Peptides were synthesised on solid phase. The receptor affinity was determined by in vitro receptor autoradiography. The internalisation rate was studied in AR4-2J and hsst-HEK-transfected cell lines. The pharmacokinetics was studied in a rat xenograft tumour model, AR4-2J. RESULTS: All peptides showed high affinities on hsst2, with the highest affinity for the Ga(III)-complexed peptides. On hsst3 the situation was reversed, with a trend towards lower affinity of the Ga(III) peptides. A significantly increased internalisation rate was found in sst2-expressing cells for all 67Ga-labelled peptides. Internalisation into HEK-sst3 was usually faster for the 111In-labelled peptides. No internalisation was found into sst5. Biodistribution studies employing [67Ga-DOTA,1-Nal3]octreotide in comparison to [111In-DOTA,1-Nal3]octreotide and [67Ga-DOTA,Tyr3]octreotide showed a significantly higher and receptor-mediated uptake of the two 67Ga-labelled peptides in the tumour and somatostatin receptor-positive tissues. A patient study illustrated the potential advantage of a broad receptor subtype profile radiopeptide over a high-affinity sst2-selective radiopeptide. CONCLUSION: This study demonstrates that 67/68Ga-DOTA-octapeptides show distinctly better preclinical, pharmacological performances than the 111In-labelled peptides, especially on sst2-expressing cells and the corresponding animal models. They may be excellent candidates for further development for clinical studies.

Animals↗
PubMed2007

Bcl-2 family proteins are essential for platelet survival.

Platelets are relatively short-lived, anucleated cells that are essential for proper hemostasis. The regulation of platelet survival in the circulation remains poorly understood. The process of platelet activation and senescence in vivo is associated with processes similar to those observed during apoptosis in nucleated cells, including loss of mitochondrial membrane potential, caspase activation, phosphatidylserine (PS) externalization, and cell shrinkage. ABT-737, a potent antagonist of Bcl-2, Bcl-X(L), and Bcl-w, induces apoptosis in nucleated cells dependent on these proteins for survival. In vivo, ABT-737 induces a reduction of circulating platelets that is maintained during drug therapy, followed by recovery to normal levels within several days after treatment cessation. Whole body scintography utilizing ([111])Indium-labeled platelets in dogs shows that ABT-737-induced platelet clearance is primarily mediated by the liver. In vitro, ABT-737 treatment leads to activation of key apoptotic processes including cytochrome c release, caspase-3 activation, and PS externalization in isolated platelets. Despite these changes, ABT-737 is ineffective in promoting platelet activation as measured by granule release markers and platelet aggregation. Taken together, these data suggest that ABT-737 induces an apoptosis-like response in platelets that is distinct from platelet activation and results in enhanced clearance in vivo by the reticuloendothelial system.

Animals↗
PubMed2007

Revised statistical motor unit number estimation in the Celecoxib/ALS trial.

Techniques to estimate motor unit number (MUNE) measure the number of functioning motor units in a muscle. As amyotrophic lateral sclerosis (ALS) is characterized by progressive motor unit loss, this disease offers an ideal setting for the use of MUNE. Statistical MUNE was employed in a recent multicenter trial of creatine in ALS, and was shown to be reliable, reproducible, and to decline with disease progression. However, motor unit amplitude stayed constant over 7 months, a finding believed to reflect an artifact of the method. The statistical method was revised to reflect more accurately the presence of larger motor units and employed in a 12-month study of Celecoxib in ALS. MUNE declined by 49% in 12 months; however, motor unit amplitude again stayed constant over the same period. Statistical MUNE estimates motor unit number based on the variability of response to a repeated stimulus of constant strength, with an underlying assumption that this variability is due solely to the number of motor units responding in an intermittent manner. Based on studies showing that single motor units in ALS display excessive amplitude variability when stimulated repeatedly, we show that response variability in ALS patients is in large part due to single unit changes. Thus, we conclude that the statistical method is not an appropriate measure of motor unit number in any disease associated with motor unit instability.

Action Potentials↗
PubMed2007

Hepatitis B virus (HBV) antigen-pulsed monocyte-derived dendritic cells from HBV-associated hepatocellular carcinoma patients significantly enhance specific T cell responses in vitro.

To investigate whether hepatitis B virus (HBV) antigen-pulsed monocyte-derived dendritic cells (MoDC) could mount a T cell response in hepatocellular carcinoma (HCC) patients associated with chronic HBV infection, peripheral blood mononuclear cells (PBMCs) from 36 HBV-associated HCC patients were induced into MoDC and pulsed with hepatitis B core antigen (HBcAg) and hepatitis B surface antigen (HBsAg), alone and in combination. Co-stimulatory molecules CD80, CD86 and CD40, as well as human leucocyte antigens D-related (HLA-DR) were found to express at the highest level on MoDC pulsed with HBcAg or HBsAg + HBcAg, at a median level on MoDC pulsed with HBcAg or HBsAg alone, and at the lowest level on non-antigen-pulsed MoDC. Interleukin (IL)-10 and IL-12 cytokines were released by antigen-pulsed MoDC at increased levels in the order: no-antigen < HBsAg < HBcAg < HBcAg + HBsAg. MoDC pulsed with HBcAg or HBsAg + HBcAg also had the strongest ability to stimulate autologous T cell proliferation and intracellular interferon (IFN)-gamma production. HBcAg- or HBsAg + HBcAg-pulsed MoDC could also induce HBV core peptide-specific CD8(+) T cell proliferation determined by tetramer staining. In addition, the antigen-pulsed MoDC were found to have a stronger capacity to produce IL-12 and induce T cell response in vitro for patients with higher alanine transaminase (ALT) levels than those with lower ALT levels, indicating that antigen pulse could substantially reverse the impaired function of MoDC in primary HCC patients with active chronic hepatitis B. In conclusion, HBV antigen-pulsed MoDC from HCC patients with chronic hepatitis B could induce HBV-specific T cell response in vitro.

Adult↗
PubMed2006

Relativistic density functional calculations using two-spinor minimax finite-element method and linear combination of atomic orbitals for ZnO, CdO, HgO, UubO and Cu2, Ag2, Au2, Rg2.

In previous work the authors have presented a highly accurate two-spinor fully relativistic solution of the two-center Coulomb problem utilizing the finite-element method (FEM) and furthermore developed a relativistic minimax two-spinor linear combination of atomic orbitals (LCAO). In the present paper the authors present Dirac-Fock-Slater (DFS-) density functional calculations for two-atomic molecules up to super heavy systems using the fully nonlinear minimax FEM and the minimax LCAO in its linearized approximation (linear approximation to relativistic minimax). The FEM gives highly accurate benchmark results for the DFS functional. Especially considering molecules with up to super heavy atoms such as UubO and Rg2, the authors found that LCAO fails to give the correct systematic trends. The accurate FEM results shed a new light on the quality of the DFS-density functional.

Journal Article↗
PubMed2006

Protein tyrosine nitration in hydrophilic and hydrophobic environments.

In this review we address current concepts on the biological occurrence, levels and consequences of protein tyrosine nitration in biological systems. We focused on mechanistic aspects, emphasizing on the free radical mechanisms of protein 3-nitrotyrosine formation and critically analyzed the restrictions for obtaining large tyrosine nitration yields in vivo, mainly due to the presence of strong reducing systems (e.g. glutathione) that can potently inhibit at different levels the nitration process. Evidence is provided to show that the existence of metal-catalyzed processes, the assistance of nitric oxide-dependent nitration steps and the facilitation by hydrophobic environments, provide individually and/or in combination, feasible scenarios for nitration in complex biological milieux. Recent studies using hydrophobic tyrosine analogs and tyrosine-containing peptides have revealed that factors controlling nitration in hydrophobic environments such as biomembranes and lipoproteins can differ to those in aqueous compartments. In particular, exclusion of key soluble reductants from the lipid phase will more easily allow nitration and lipid-derived radicals are suggested as important mediators of the one-electron oxidation of tyrosine to tyrosyl radical in proteins associated to hydrophobic environments. Development and testing of hydrophilic and hydrophobic probes that can compete with endogenous constituents for the nitrating intermediates provide tools to unravel nitration mechanisms in vitro and in vivo; additionally, they could also serve to play cellular and tissue protective functions against the toxic effects of protein tyrosine nitration.

Cell Membrane↗
PubMed2006

Potential biomarker for early risk assessment of prostate cancer.

BACKGROUND: Catechol estrogen quinones (CEQ) derived from 4-hydroxyestrone (4-OHE1) and 4-hydroxyestradiol (4-OHE2) react with DNA to form depurinating--N7Gua and--N3Ade adducts. This damage leads to mutations that can initiate breast and prostate cancer. To determine whether this damage occurs in humans, urine samples from men with prostate cancer and benign urological conditions, and healthy controls were analyzed. The objective was determining whether any of the cancer patients had formed the depurinating 4-OHE1(E2)-1-N3Ade adducts. METHODS: The adducts were extracted from samples by using affinity columns equipped with a monoclonal antibody developed for detecting 4-OHE1(E2)-1-N3Ade adducts. Eluted extracts were separated by capillary electrophoresis with field-amplified sample stacking and/or ultraperformance liquid chromatography. Absorption/luminescence spectroscopies and mass spectrometry were used to identify the adducts. RESULTS: 4-OHE1-1-N3Ade was detected at higher levels in samples from subjects with prostate cancer (n = 7) and benign urological conditions (n = 4) compared to healthy males (n = 5). CONCLUSION: This is the first demonstration that CEQ-derived DNA adducts are present in urine samples from subjects with prostate cancer.

Antibodies, Monoclonal↗
PubMed2006

Granzyme K cleaves the nucleosome assembly protein SET to induce single-stranded DNA nicks of target cells.

Although granzymes (Gzms) A- and B-induced cell death pathways have been defined, little is known about how other orphan Gzms function in CTL-mediated cytotoxicity. GzmK and A are tryptases among all the Gzms of humans and they are closely linked on the same chromosome. In this study, we showed that GzmK can be efficiently delivered into target cells with a cationic lipid protein transfection reagent Pro-Ject. We found human GzmK triggers rapid cell death independently of caspase activation. The features of death are characterized by rapid externalization of phosphatidylserine, nuclear morphological changes and single-stranded DNA nicks. GzmK hydrolyzes the nucleosome assembly protein SET in its recombinant and native forms or in intact cells. Cleavage of SET by GzmK abrogates its nucleosome assembly activity. After GzmK loading, SET and DNase NM23H1 rapidly translocate into the nucleus and SET is cleaved, where the nuclease activity of NM23H1 is activated to nick chromosomal DNA.

Caspases↗
PubMed2006

Theoretical comparison of how soil processes affect uptake of metals by diffusive gradients in thinfilms and plants.

The theoretical basis for using measurements of metal uptake by the technique of diffusive gradients in thinfilms (DGT) to mimic processes in soils that affect uptake of metals by plants is examined. The uptake of metals by plants and DGT were compared conceptually and quantitatively by using the classic Barber model of plant uptake and the DIFS (DGT-induced fluxes in soils) model of uptake by DGT. For most metals and plants considered, uptake fluxes were similar to those induced by DGT using the most common gel layer thicknesses of 0.2 to 2 mm. Consequently DGT perturbs the chemical equilibrium of metals in the soil solution and between soil solution and solid phase, to a similar extent to plants, and therefore induces a similar balance in supply by diffusion and by release from the solid phase. DIFS was used to show that desorption kinetics, which are not considered by the plant uptake model, are likely important for uptake when the capacity of the soil solid phase is large. Model calculations showed that mass flow into a plant root would only contribute appreciably to the total flux of metal under circumstances when the solid phase reservoir of metal was very low. Generally, however, DGT is likely to emulate supply processes from the soil that govern uptake of metal by plants. Exceptions are likely to be found in poorly buffered soils (typically sandy and/or low pH), and at very high concentrations of metals in soil solution, such that the soil solution concentration at the plant root interface is higher than the Michaelis-Menten constant (Km).

Diffusion↗
PubMed2006

Expression of aromatase and 17beta-hydroxysteroid dehydrogenase types 1, 7 and 12 in breast cancer. An immunocytochemical study.

It is known that there is a local biosynthesis of estradiol (E2) in breast carcinoma. The steroidogenic enzymes involved in E2 formation are aromatase which transforms testosterone into E2 and androstenedione into estrone (E1) and reductive 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) which convert E1 into E2. Using immunocytochemistry, we have studied the expression of aromatase and the three reductive 17beta-HSDs 17beta-HSD types 1, 7 and 12 in 41 specimens of female human breast carcinoma and adjacent non-malignant tissues. These results were correlated with the estrogen receptor alpha (ERalpha) and beta (ERbeta), progesterone receptor, androgen receptor, CDC47 and c-erb B-2 expressions and with the tumor stages. Aromatase was found in 58%, 17beta-HSD type 7 in 47% and 17beta-HSD type 12 in 83% of the breast cancer specimens. The 17beta-HSD type 1 could be detected in only one tumor. A significant correlation was observed between the aromatase, 17beta-HSD type 7 and 17beta-HSD type 12 expression, as well as between each of the two enzymes 17beta-types 7 and 12 and the ERbeta expression. The expression of 17beta-HSD type 12 was significantly higher in breast carcinoma specimens than in normal tissue. There was also a significant association of CDC 47 expression with ERbeta, AR and 17beta-HSD type 12. The results indicate that aromatase, 17beta-HSD type 7 and 17beta-HSD type 12, but not 17beta-HSD type 1, are commonly expressed in human breast cancer. Moreover, the high expression of both 17beta-HSD type 12 and ERbeta in breast carcinoma cells may play a role in the development and/or progression of breast cancer.

17-Hydroxysteroid Dehydrogenases↗
PubMed2006

A modified Zeeman model for producing HRV signals and its application to ECG signal generation.

Developing a mathematical model for the artificial generation of electrocardiogram (ECG) signals is a subject that has been widely investigated. One of the challenges is to generate ECG signals with a wide range of waveforms, power spectra and variations in heart rate variability (HRV)--all of which are important indexes of human heart functions. In this paper we present a comprehensive model for generating such artificial ECG signals. We incorporate into our model the effects of respiratory sinus arrhythmia, Mayer waves and the important very low-frequency component in the power spectrum of HRV. We use a new modified Zeeman model for generating the time series for HRV, and a single cycle of ECG is produced by using a simple neural network. The importance of the work is the model's ability to produce artificial ECG signals that resemble experimental recordings under various physiological conditions. As such the model provides a useful tool to simulate and analyse the main characteristics of ECG, such as its power spectrum and HRV under different conditions. Potential applications of this model include using the generated ECG as a flexible signal source to assess the effectiveness of a diagnostic ECG signal-processing device.

Arrhythmia, Sinus↗
PubMed2006

Computational evaluation of the roles of Na+ current, iNa, and cell death in cardiac pacemaking and driving.

Voltage-dependent sodium (Na(+)) channels are heterogeneously distributed through the pacemaker of the heart, the sinoatrial node (SA node). The measured sodium channel current (i(Na)) density is higher in the periphery but low or zero in the center of the SA node. The functional roles of i(Na) in initiation and conduction of cardiac pacemaker activity remain uncertain. We evaluated the functional roles of i(Na) by computer modeling. A gradient model of the intact SA node and atrium of the rabbit heart was developed that incorporates both heterogeneities of the SA node electrophysiology and histological structure. Our computations show that a large i(Na) in the periphery helps the SA node to drive the atrial muscle. Removal i(Na) from the SA node slows down the pacemaking rate and increases the sinoatrial node-atrium conduction time. In some cases, reduction of the SA node i(Na) results in impairment of impulse initiation and conduction that leads to the SA node-atrium conduction exit block. Decrease in active SA node cell population has similar effects. Combined actions of reduced cell population and removal of i(Na) from the SA node have greater impacts on weakening the ability of the SA node to pace and drive the atrium.

Action Potentials↗
PubMed2006

AHNP-streptavidin: a tetrameric bacterially produced antibody surrogate fusion protein against p185her2/neu.

The anti-p185(her2/neu) peptidomimetic (AHNP) is a small exo-cyclic peptide derived from the anti-p185(her2/neu) rhumAb 4D5 (h4D5). AHNP mimics many but not all of the antitumor characteristics exhibited by h4D5. However, the pharmacokinetic profiles of AHNP are less than optimal for therapeutic or diagnostic purposes. To improve the binding affinity to p185(her2/neu) and the antitumor efficacy, we have engineered a fusion protein containing AHNP and a nonimmunoglobulin protein scaffold, streptavidin (SA). The recombinant protein, AHNP-SA (ASA) bound to p185(her2/neu) with high affinity, inhibited the proliferation of p185(her2/neu)-overexpressing cells, and reduced tumor growth induced by p185(her2/neu)-transformed cells. These data suggest that the bacterially produced tetrameric ASA can be used as an antibody-surrogate molecule. This class of molecule will play a role in the diagnosis and treatment of p185(her2/neu)-related tumors. Our studies establish a general principle by which a small biologically active synthetic exo-cyclic peptide can be engineered to enhance functional aspects by structured oligomerization and can be produced recombinantly using bacterial expression.

Animals↗
PubMed2006

Role of lymphangiogenesis in epithelial ovarian cancer.

We investigated the significance of lymphatic count, vascular count and angiogenic growth factors using immunohistochemistry in 108 tumour specimens of epithelial ovarian cancer with antibodies to lymphatic vessel endothelial hyaluronan receptor (LYVE-1), platelet endothelial cell adhesion molecule CD31, vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP) in epithelial ovarian cancer to understand the pathogenesis of metastasis in ovarian cancer. The effect of prognostic variables on progression-free and overall survival was assessed. On multivariate analysis, bulky residual disease after surgery was the best prognostic indicator (P<0.001) for progression-free and overall survival (P<0.001). Lymphatic count was statistically significant as a prognostic factor for progression-free (P=0.05) and overall survival (P=0.04). However, lymphatic count did not impact on survival curves. No correlation was found between lymphatic count and age, histological subtype, FIGO stage or residual disease. Vascular count, VEGF or TP expressions were not significant in either analysis. Lymphatic spread may be significant in aiding metastases in ovarian cancer but requires other biological factors to act in conjunction, as it does not have clearcut prognostic significance. Dissemination of ovarian cancer does not occur primarily through vascular or lymphatic routes but may occur through direct intraperitoneal spread of disease.

Adult↗
PubMed2006

PAK1 hyperactivation is sufficient for mammary gland tumor formation.

Emerging data suggest that p21-activated kinase 1 (Pak1), a downstream signaling molecule of the small GTPases, growth factors, and lipid signaling, is upregulated or hyperactivated in human breast cancer. Until now, however, no direct causative role had been found for Pak1 in mammary tumor formation. We therefore sought to identify the role that Pak1 plays in mammary gland tumorigenesis. Our results showed that in a transgenic mouse model, overexpression of catalytically active Pak1 leads to the development of malignant mammary tumors and to a variety of other breast lesions, including focal solid nodules, ductal hyperplasia, and mini-intraductal neoplasm and adenoma. We also found that Pak1 hyperactivation increases the stimulation of downstream proliferative signaling effectors MEK1/2 and p38-MAPK in mammary tumor epithelial cells. Moreover, in our study, we detected expression of estrogen receptor-alpha expression and progesterone receptor expression during early stages of the lesions, but their expression was lost during the cells' transition to malignant invasive tumors. Finally, we found that consistent with a role in breast tumor progression, Pak1 expression and its nuclear accumulation was increased progressively during the transition from ductal hyperplasia to ductal carcinoma in situ to adenocarcinoma in widely used multistep polyoma-middle T-antigen transgenic mice. Together, these findings provide the first direct evidence that Pak1 deregulation may be sufficient for the formation of mammary gland tumors.

Animals↗