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Abstract— Molecularly targeted ultrasound contrast agents provide for the potential to form an image responsive to early expression of molecular pathology in vivo and ex vivo. While 1D models are routinely employed to estimate the... more
Abstract— Molecularly targeted ultrasound contrast agents provide for the potential to form an image responsive to early expression of molecular pathology in vivo and ex vivo. While 1D models are routinely employed to estimate the dynamics of the microbubbles for imaging and therapeutic applications, these models are incapable of capturing asymmetric microbubble behavior or space-variant mechanical properties of microbubble’s shell.
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The authors describe a new technique for evaluating the quality of electrical insulation of power system apparatus while the apparatus is energized and in normal service.
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We are developing a 1 mm3 resolution breast-dedicated Positron Emission Tomography (PET) system with 4608 Position Sensitive Avalanche Photodiode (PSAPD) detectors. This paper focuses on three aspects of the system’s front-end... more
We are developing a 1 mm3 resolution breast-dedicated Positron Emission Tomography (PET) system with 4608 Position Sensitive Avalanche Photodiode (PSAPD) detectors. This paper focuses on three aspects of the system’s front-end electronics: multiplexing of the PSAPD analog output signals, scaling the dynamic range of the PSAPD output signals using charge attenuation, and positioning of individual interaction energy depositions that are
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The establishment of efficient gene delivery to target human tissue is a major obstacle for transition of gene therapy from the pre-clinical phases to the clinic. The poor long-term patency rates for coronary artery bypass grafting (CABG)... more
The establishment of efficient gene delivery to target human tissue is a major obstacle for transition of gene therapy from the pre-clinical phases to the clinic. The poor long-term patency rates for coronary artery bypass grafting (CABG) is a major clinical problem that lacks an effective and proven pharmacological intervention. Late vein graft failure occurs due to neointima formation and accelerated atherosclerosis. Since CABG allows a clinical window of opportunity to genetically modify vein ex vivo prior to grafting it represents an ideal opportunity to develop gene-based therapies. Adenoviral vectors have been frequently used for gene delivery to vein ex vivo and pre-clinical studies have shown effective blockade in neointima development by overexpression of candidate therapeutic genes. However, high titers of adenovirus are required to achieve sufficient gene delivery to provide therapeutic benefit. Improvement in the uptake of adenovirus into the vessel wall would therefore ...
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... 3 LYSO block was connected to a Hamamatsu H3164 Photo Multiplier Tube (PMT) using optical grease (BICRON BC 630) and Teflon tape. As depicted in Fig. 3, the 22 Na point source was positioned in between the LSO-PSAPD detector module... more
... 3 LYSO block was connected to a Hamamatsu H3164 Photo Multiplier Tube (PMT) using optical grease (BICRON BC 630) and Teflon tape. As depicted in Fig. 3, the 22 Na point source was positioned in between the LSO-PSAPD detector module and the LYSO-PMT detector. ...
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We are developing a 1 mm3 resolution breast-dedicated Positron Emission Tomography (PET) system in an effort to increase the role of PET in earlier stages of breast cancer management. The system consists of two 16 cm × 9 cm × 2 cm... more
We are developing a 1 mm3 resolution breast-dedicated Positron Emission Tomography (PET) system in an effort to increase the role of PET in earlier stages of breast cancer management. The system consists of two 16 cm × 9 cm × 2 cm detector panels constructed using stacked layers of 8×8 arrays of 1 mm3 LSO scintillation crystals coupled to Position
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Research Interests: Immunohistochemistry, Structural Stability, Cell Differentiation, Humans, Mutation, and 13 moreMice, Animals, Nicotinic Acetylcholine Receptors, Lung, Clinical Sciences, Spatial Pattern, Respiratory, Analysis of Variance, Transfection, Gestational Age, Organogenesis, binding sites, and Cardiovascular medicine and haematology
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Research Interests: Genetics, Human Genetics, Drosophila melanogaster, DNA damage, DNA repair, and 15 moreComparative Study, Gene expression, Multidisciplinary, Saccharomyces cerevisiae, Protein Structure and Function, Humans, Animals, Gene Structure, Enzyme, Genes, Molecular cloning, Schizosaccharomyces Pombe, Amino Acid Sequence, Base Sequence, and Molecular Sequence Data
Research Interests: Breast Cancer, Stem Cell, Gene expression, Multidisciplinary, Gene Silencing, and 12 moreEstrogen Receptor, Humans, DNA methylation, Epithelial cells, Transforming Growth Factor Beta, SERUM, CpG island, Epithelial to Mesenchymal Transition, Environmental Exposure, Tumor Progression, Cadherins, and Breast Neoplasms
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Research Interests: Immunohistochemistry, Signal Transduction, Humans, Oncogene, Male, and 15 morePromoter Analysis, Non small cell carcinoma, Transcription Factor, Clinical Sciences, Endothelial cell, DNA binding proteins, Binding Site, Response Elements, Nuclear Localization, Milk proteins, Interleukin, janus kinase, Signaling pathway, High density, and Protein tyrosine kinases
Research Interests: DNA repair, Transcription Factors, Biological Sciences, Saccharomyces cerevisiae, Environmental Sciences, and 11 moreHumans, Cell Viability, Nucleic Acids, Proteins, Schizosaccharomyces Pombe, Amino Acid Sequence, Base Sequence, DNA binding proteins, Molecular Sequence Data, Restriction Mapping, and Ultraviolet Rays
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Parathyroid hormone-related protein is a critical autocrine regulator of endochondral ossification in the growth plate, as demonstrated by the severe disruption of growth-plate structure and function in parathyroid hormone-related... more
Parathyroid hormone-related protein is a critical autocrine regulator of endochondral ossification in the growth plate, as demonstrated by the severe disruption of growth-plate structure and function in parathyroid hormone-related protein-deficient transgenic mice. In the present study, the effects of parathyroid hormone-related protein on the synthesis of collagen mRNA and protein were studied in short-term cultures of isolated chick growth-plate chondrocytes. Parathyroid hormone-related protein selectively inhibits type-X collagen protein synthesis with no significant effect on type-II collagen protein synthesis. These effects were present in all maturationally distinct populations of chondrocytes separated by countercurrent centrifugal elutriation. In cultures of resting chondrocytes, the onset of type-X collagen expression was inhibited, while the synthesis of type-X collagen was decreased in cultures of hypertrophic chondrocytes. Synthesis of type-II and type-X collagen mRNA was examined by nonradioactive in situ hybridization with synthetic oligonucleotide cDNA probes, and the level of expression was quantified using digital image analysis. Dose-dependent suppression of type-X collagen gene expression by parathyroid hormone-related protein was observed, with no significant effect on type-II collagen mRNA detected. The results were confirmed by analysis of Northern blots of total chondrocyte mRNA. These experiments demonstrated differential transcriptional regulation of type-II and type-X collagen, with selective suppression of type-X collagen expression, by parathyroid hormone-related protein in growth-plate chondrocytes. In addition, excellent agreement was found between traditional protein and mRNA analyses and microscopic digital image analysis techniques, supporting the use of this convenient and sensitive assay method. Parathyroid hormone-related protein inhibits chondrocyte maturation and is known to stimulate proliferation, suggesting that this autocrine factor may function to regulate premature hypertrophy in the growth plate.
Research Interests: Biomedical Engineering, Immunohistochemistry, Orthopaedic, In Situ Hybridization, Humans, and 10 moreCartilage, Collagen, Animals, Proteins, Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis, Parathyroid Hormone, Clinical Sciences, Parathyroid Hormone Related Protein, Chickens, and Growth Plate
Mutant BMP receptors were transfected into cultured embryonic upper sternal chrondrocytes using retroviral vectors to determine if BMP signaling is required for chondrocyte maturation and the expression of a key regulatory molecule,... more
Mutant BMP receptors were transfected into cultured embryonic upper sternal chrondrocytes using retroviral vectors to determine if BMP signaling is required for chondrocyte maturation and the expression of a key regulatory molecule, Indian hedgehog (Ihh). Chondrocytes infected with replication competent avian retroviruses (RCAS) viruses carrying constitutive active (CA) BMPR-IA and BMPR-IB had enhanced expression of type X collagen and Ihh mRNA. Addition of PTHrP, a known inhibitor of chondrocyte maturation, abolished the expression of type X collagen, BMP-6, and Ihh mRNAs in control cells. In contrast, PTHrP treated cultures infected with of CA BMPR-IA or CA BMPR-IB had low levels of BMP-6 and type X collagen, but high levels of Ihh expression. Although dominant negative (DN) BMPR-IA had no effect, DN BMPR-IB inhibited the expression of type X collagen and BMP-6, and decreased alkaline phosphatase activity, even in the presence of exogenously added BMP-2 and BMP-6. DN BMPR-IB also completely blocked Ihh expression. Overall, the effect of DN BMPR-IB mimicked the effects of PTHrP. To determine if there is an autocrine role for the BMPs in chondrocyte maturation, the cultures were treated with noggin and follistatin, molecules that bind BMP-2/-4 and BMP-6/-7, respectively. While noggin and follistatin inhibited the effects of recombinant BMP-2 and BMP-6, respectively, they had only minimal effects on the spontaneous maturation of chondrocytes in culture, suggesting that more than one subgroup of BMPs regulates chondrocyte maturation. The results demonstrate that: (i) BMP signaling stimulates chondrocyte maturation; (ii) BMP signaling increases Ihh expression independent of maturational effects; and (iii) BMP signaling can partially overcome the inhibitory effects of PTHrP on maturation.
Research Interests: Biomedical Engineering, Orthopaedic, Bone Morphogenetic Proteins, Collagen, Epidermal Growth Factor/ErbB receptors, and 10 moreAnimals, Proteins, Glycoproteins, Clinical Sciences, alkaline phosphatase activity (APA), Parathyroid Hormone Related Protein, Follistatin, Chondrocytes, Transforming Growth Factor Beta, and Chick embryo
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Research Interests: Computer Architecture, Distributed Computing, International Cooperation, Control Systems, Distributed Processing, and 9 moreInnovation Management, Personal, Intelligent Network, Software Systems, Service Architecture, Electrical And Electronic Engineering, Telecommunication Services, Mobile Communication System, and Intelligent Networks
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We used representational difference analysis to identify homozygous genomic deletions selected during tumor progression in the mouse NF2 and TP53 tumor model. We describe a deletion targeting DOCK4, a member of the CDM gene family... more
We used representational difference analysis to identify homozygous genomic deletions selected during tumor progression in the mouse NF2 and TP53 tumor model. We describe a deletion targeting DOCK4, a member of the CDM gene family encoding regulators of small GTPases. DOCK4 specifically activates Rap GTPase, enhancing the formation of adherens junctions. DOCK4 mutations are present in a subset of human cancer cell lines; a recurrent missense mutant identified in human prostate and ovarian cancers encodes a protein that is defective in Rap1 activation. The engulfment defect of C. elegans mutants lacking the CDM gene ced-5 is rescued by wild-type DOCK4, but not by the mutant allele. Expression of wild-type, but not mutant, DOCK4 in mouse osteosarcoma cells with a deletion of the endogenous gene suppresses growth in soft agar and tumor invasion in vivo. DOCK4 therefore encodes a CDM family member that regulates intercellular junctions and is disrupted during tumorigenesis.
Research Interests: Caenorhabditis elegans, Gene regulation, Cancer, Ovarian Cancer, Gene expression, and 15 moreGene Silencing, Biological Sciences, Cell line, Humans, Mutation, Mice, Animals, Osteosarcoma, Cell, Specific Activity, Eukaryotic Cells, Gene Family, Molecular Sequence Data, Adherens Junction, and Medical and Health Sciences
Desmoplastic small round cell tumor (DSRCT) is defined genetically by the chimeric fusion of the... more
Desmoplastic small round cell tumor (DSRCT) is defined genetically by the chimeric fusion of the Ewing's sarcoma and Wilms' tumor genes, generating a novel transcription factor, EWS-WT1. By using cells with inducible EWS-WT1 to screen high-density microarrays, we identified BAIAP3 as a transcriptional target of the chimera. The BAIAP3 promoter is specifically bound in vivo by the (-KTS) isoform of EWS-WT1, consistent with its activation in reporter assays. BAIAP3 encodes a protein implicated in regulated exocytosis, which is colocalized with a secreted growth factor within cytoplasmic organelles. Ectopic expression of BAIAP3 in tumor cells dramatically enhances growth in low serum and colony formation in soft agar. BAIAP3 therefore encodes a transcriptional target of an oncogenic fusion protein that implicates the regulated exocytotic pathway in cancer cell proliferation.
Research Interests: Genetics, In Situ Hybridization, Humans, Animals, Osteosarcoma, and 15 moreProteins, Non small cell carcinoma, Transcription Factor, Cancer Cell, Exocytosis, High Density Concrete, Cell Proliferation, Base Sequence, Mosaicism, Growth Factor, Fusion Protein, Neurosciences, Molecular Sequence Data, Angiogenesis inhibitors, and High density
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Research Interests: Medical Microbiology, Western blotting, Estrogen Receptor, Biological Sciences, Humans, and 13 moreEndothelial Cells, Physical sciences, NF-kappa B, Transcription Factor, Endothelial cell, Receptor for Advanced Glycation End Products, Site-directed Mutagenesis, Estradiol, Biochemistry and cell biology, Gene Expression Regulation, Estrogen receptor alpha, reverse transcriptase polymerase chain reaction, and Estrogen Receptor beta
Research Interests: Immunology, Proteomics, Juvenile Idiopathic Arthritis, Adolescent, Humans, and 12 moreChild, Female, Male, Arthritis, Clinical Sciences, Public health systems and services research, Two-Dimensional Gel Electrophoresis, Two dimensional Gel Electrophoresis, Proteome, Synovial-fluid, Child preschool, and reverse transcriptase polymerase chain reaction
Patients with acute lung injury almost always require supplemental oxygen during treatment; however, elevated oxygen itself is toxic. Receptors for advanced glycation end-products (RAGE) are multi-ligand cell surface receptors... more
Patients with acute lung injury almost always require supplemental oxygen during treatment; however, elevated oxygen itself is toxic. Receptors for advanced glycation end-products (RAGE) are multi-ligand cell surface receptors predominantly localized to alveolar type I cells that influence development and cigarette smoke-induced inflammation, but studies that address the role of RAGE in acute lung injury are insufficient. In the present investigation, we test the hypothesis that RAGE signaling functions in hyperoxia-induced inflammation. RAGE-null mice exposed to hyperoxia survived 3 days longer than age-matched wild-type mice. After 4 days in hyperoxia, RAGE-null mice had less total cell infiltration into the airway, decreased total protein leak, diminished alveolar damage in hematoxylin and eosin-stained lung sections, and a lower lung wet-to-dry weight ratio. An inflammatory cytokine antibody array revealed decreased secretion of several proinflammatory molecules in lavage fluid obtained from RAGE knockout mice when compared with wild-type control animals. Real-time RT-PCR and immunoblotting revealed that hyperoxia induced RAGE expression in primary alveolar epithelial cells, and immunohistochemistry identified increased RAGE expression in the lungs of mice after exposure to hyperoxia. These data reveal that RAGE targeting leads to a diminished hyperoxia-induced pulmonary inflammatory response. Further research into the role of RAGE signaling in the lung should identify novel targets likely to be important in the therapeutic alleviation of lung injury and associated persistent inflammation.
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Previous analysis of lung injury and repair has provided evidence for region-specific stem cells that maintain proximal and distal epithelial compartments. However, redundant expression of lineage markers by cells at several levels of the... more
Previous analysis of lung injury and repair has provided evidence for region-specific stem cells that maintain proximal and distal epithelial compartments. However, redundant expression of lineage markers by cells at several levels of the stem cell hierarchy has complicated phenotypic and functional characterization of clonogenic airway cells. Based on the demonstration that rapid efflux of the DNA dye Hoechst 33342 can be used to prospectively purify long-term repopulating hematopoietic stem cells, we hypothesized that lung cells with similar biochemical properties would be enriched for clonogenic progenitors. We demonstrate that Hoechst-dim side population (SP) cells isolated from proximal and distal compartments of the mouse lung were relatively small and agranular, exhibited low red and green autofluorescence, and that the SP fraction was highly enriched in clonogenic cells. Quantitative RT-PCR indicated that vimentin mRNA was enriched and that epithelial markers were depleted i...
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Pulmonary host defense employs a combination of biochemical and biophysical activities to recognize, inactivate, and mediate clearance of environmental agents as well as modulate the overall response to such challenge. Dysregulation of... more
Pulmonary host defense employs a combination of biochemical and biophysical activities to recognize, inactivate, and mediate clearance of environmental agents as well as modulate the overall response to such challenge. Dysregulation of the inflammatory arm of this response is associated with chronic lung diseases (CLD) including cystic fibrosis and chronic obstructive lung disease. Although mechanisms mediating immunoregulation are incompletely characterized, decrements in levels of the nonciliated secretory cell product Clara cell secretory protein (CCSP) in numerous CLD and identification of proinflammatory state in mice homozygous for a null allele of the CCSP gene (CCSP−/−) suggest a central role for the nonciliated secretory cell in this process. In an effort to determine the molecular basis for immunoregulatory defects associated with CCSP deficiency, we utilized difference gel electrophoresis in combination with matrix-assisted laser desorption ionization time-of-flight to co...
Research Interests: Physiology, Macrophages, Mice, Animals, Cell Polarity, and 11 moreAmerican, Medical Physiology, Lung, Epithelium, Protein isoforms, Two-Dimensional Gel Electrophoresis, Amino Acid Sequence, Two dimensional Gel Electrophoresis, Protein Transport, Gene Expression Regulation, and Molecular Sequence Data
The receptor for advanced glycation end-products (RAGE) is a member of the immunoglobin superfamily of multiligand receptors. Following ligand binding, mechanisms associated with host defense, tissue remodeling, and inflammation are... more
The receptor for advanced glycation end-products (RAGE) is a member of the immunoglobin superfamily of multiligand receptors. Following ligand binding, mechanisms associated with host defense, tissue remodeling, and inflammation are activated. RAGE is highly expressed in pulmonary epithelium transitioning from alveolar type (AT) II to ATI cells and is upregulated in the presence of ligand; however, the regulation and function of RAGE during development are less clear. Herein, immunohistochemistry demonstrated a temporal-spatial pattern of RAGE expression in pulmonary epithelial cells from embryonic day 17.5 to postnatal day 10. Cotransfection experiments revealed that the mouse RAGE promoter was activated by early growth response gene 1 (Egr-1) and inhibited by thyroid transcription factor-1 (TTF-1) via interaction with specific regulatory elements. A rat ATI cell line (R3/1) with endogenous RAGE expression also differentially regulated RAGE when transfected with TTF-1 or Egr-1. Bec...
Research Interests: Physiology, Transcription Factors, Growth, Cell line, Smoking, and 10 moreMice, Animals, American, Gene, Medical Physiology, Lung, Exposure, Positive Feedback, Gen, and Rats
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Chronic obstructive pulmonary disease (COPD) is associated with inflammation of airway epithelium, including an increase in the number of intraepithelial T cells. Increased apoptosis of these T cells has been reported in the airways in... more
Chronic obstructive pulmonary disease (COPD) is associated with inflammation of airway epithelium, including an increase in the number of intraepithelial T cells. Increased apoptosis of these T cells has been reported in the airways in COPD, and although this process is critical for clearing excess activated T cells, excessive rates of apoptosis may result in unbalanced cellular homeostasis, defective clearance of apoptotic material by monocytes/macrophages, secondary necrosis, and prolongation of the inflammatory response. Lymphocytes are known to traffic between the airway and the peripheral circulation, thus we hypothesized that in COPD, circulating T cells may show an increased propensity to undergo apoptosis. We analyzed phytohemagglutinin (PHA)-stimulated peripheral blood T cells from COPD patients and controls for apoptosis using flow cytometry and staining with annexin V and 7-aminoactinomycin D. As several pathways are involved in induction of apoptosis of T cells, including transforming growth factor (TGF)-β/TGF receptor (TGFR), TNF-α/TNFR1, and Fas/Fas ligand, these mediators were also investigated in peripheral blood samples from these subject groups. Significantly increased apoptosis of PHA-stimulated T cells was observed in COPD (annexin positive 75.0 ± 14.7% SD vs. control 50.2 ± 21.8% SD, P = 0.006), along with upregulation of TNF-α/TNFR1, Fas, and TGFR. Monocyte production of TGF-β was also increased. In conclusion we have demonstrated the novel finding of increased apoptosis of stimulated T cells in COPD and have also shown that the increased T-cell death may be associated with upregulation of apoptotic pathways, TGF-β, TNF-α, and Fas in the peripheral blood in COPD.