Http Dx Doi Org 10 1080 02678290802245468, Jul 1, 2008
To improve the morphological and electro‐optical properties of a polymer‐dispersed liquid crystal... more To improve the morphological and electro‐optical properties of a polymer‐dispersed liquid crystal (PDLC) grating, a type of highly fluorine‐substituted acrylate monomer was added to the prepolymer mixture. The morphologies of the PDLC gratings were investigated using ...
An integral part of drug discovery and development is the identification of drug metabolites that... more An integral part of drug discovery and development is the identification of drug metabolites that indicate intrinsic pharmacokinetic mechanism, pharmacological activity or specific toxicity. We describe the use of MSM, which utilizes multiple collision cells, dissociation methods, scan modes, mass analyzers and detectors to perform intelligent metabolite identification experiments. A modified LTQ Orbitrap XL with an HCD (Higher-energy Collisional Dissociation) collision cell was used. An isolation mass window up to 600 amu for HCD scans was enabled. In this experiment, a high resolution full scan was acquired followed by a high resolution HCD MS/MS of all incoming ions within that 600amu window. In parallel, the linear ion trap (LIT) acquired data dependent MSn spectra. Accela UPLC and Hypersil Gold C18 column(1x100mm, 1.9m) with a 20-minute gradient was used. 10M and 1M of rat and human hepatocytes incubation samples from verapamil and haloperidol were analyzed. The performance of ...
Abstract: Cell migration plays the essential role in embryogenesis, wound healing, immunization, ... more Abstract: Cell migration plays the essential role in embryogenesis, wound healing, immunization, infection, and cancer metastasis. To study actions of cell migration-associated genes in liver regeneration, these genes were obtained by seaching for the related ...
Transforming growth factor (TGF)beta is implicated in the pathogenesis of cyclosporine A (CsA) ne... more Transforming growth factor (TGF)beta is implicated in the pathogenesis of cyclosporine A (CsA) nephrotoxicity. We examined the efficacy of TGF beta receptor (R)II/immunoglobulin (Ig)G Fc, a soluble chimeric protein consisting of the extracellular domain of human TGF beta RII and IgG1 Fc, on CsA nephrotoxicity in mice. Subcutaneous injection of CsA (25 mg/kg/d) was given daily to mice maintained on a low-sodium diet. On days 1 and 7, an expression vector carrying cDNA for either TGF beta RII/IgG Fc or beta-galactosidase was transfected into the skeletal muscles by electroporation. At 2 or 3 weeks of CsA administration, plasma and renal TGF beta 1 levels, and tubulointerstitial injury and fibrosis were evaluated. After 2 weeks of CsA administration, plasma and renal TGF beta 1 levels increased to the maximum and then declined toward the baseline levels. Renal TGF beta 1 mRNA remained elevated until 3 weeks. Tubulointerstitial alterations became appreciable in 2 weeks and intensified b...
Chemical communications (Cambridge, England), Jan 21, 2004
Bioassay-guided fractionation of an extract prepared from Alangium javanicum using an assay to mo... more Bioassay-guided fractionation of an extract prepared from Alangium javanicum using an assay to monitor Cu(2+)-dependent DNA strand scission led to the isolation of javaniside, a new type of oxindole glycoside.
Bioassay-guided fractionation of an active organic extract of Piper caninum, using a sensitive ye... more Bioassay-guided fractionation of an active organic extract of Piper caninum, using a sensitive yeast assay to monitor putative double-strand DNA-damaging activity, resulted in the isolation of the 4,5-dioxoaporphine alkaloid cepharadione A (1). Compound 1 exhibited potent inhibitory activity in a yeast cytotoxicity assay with IC(50) values of 50.2 nM toward RS321NpRAD52 grown on glucose versus 293 nM toward the same yeast strain grown on galactose.
A crude extract prepared from roots of Mallotus resinosus exhibited significant Cu(2+)-dependent ... more A crude extract prepared from roots of Mallotus resinosus exhibited significant Cu(2+)-dependent DNA strand scission activity and was thus selected for bioassay-guided fractionation. Scopoletin (1), a simple coumarin, was identified as the active principle responsible for DNA cleavage activity of the crude extract. The DNA strand scission activity of 1, as well as that of three structural analogues, is reported.
Medical oncology (Northwood, London, England), 2012
Over-expression of RhoA in esophageal squamous cell carcinoma (ESCC) indicates a poor prognosis a... more Over-expression of RhoA in esophageal squamous cell carcinoma (ESCC) indicates a poor prognosis and is correlated with the tumor-node-metastasis (TNM) clinical classification. However, until now RhoA function in the ESCC progression remains to be established. We employed adenovirus-mediated small hairpin RNA (shRNA) against human RhoA (Ad-sh-RhoA) to efficiently silence target gene expression in RhoA-expressing Eca-109 ESCC cells at both protein and mRNA levels. Consequently, Ad-sh-RhoA reduced the proliferation and migration of Eca-109 cells assayed by MTT assay and cell wound healing, respectively. Moreover, Ad-sh-RhoA increased cell apoptosis and inhibited the cell cycle G1-S-phase progression of Eca-109 cells assessed by flow cytometry. Finally, in a nude mouse model, intratumoral injections of adenovirus-delivered RhoA shRNA every 3 days for 20 days significantly inhibited the growth and angiogenesis of xenografted Eca-109 tumors. In summary, these data indicate that RhoA may b...
Asian Pacific journal of cancer prevention : APJCP, 2010
Breast cancer is the most common malignancy in women in the world. High incidence and poor clinic... more Breast cancer is the most common malignancy in women in the world. High incidence and poor clinical outcomes underly the need for a better understanding of its tumor biology and how to effectively inhibit tumor progression. In the present study the question of whether NDRG2 might be a useful target for breast cancer therapy was addressed. With the increase or decrease of NDRG2 levels in MCF-7 and Bcap-37 cells by adenovirus-NDRG2 infection or NDRG2 siRNA transfection, CD24 expression was significantly decreased or increased, respectively. Furthermore, NDRG2 overexpression suppressed breast cancer cell adhesion and invasion, whereas knockdown of NDRG2 promoted these events. In conclusion, the data from the current study indicated that NDRG2, the product of a tumor suppressor gene, can regulate CD24 expression to decrease the metastatic potential of breast cancer cells.
2011 Third International Conference on Measuring Technology and Mechatronics Automation, 2011
ABSTRACT A innovative pretreatment technique and its kinetics for treating waste klebsiella pneum... more ABSTRACT A innovative pretreatment technique and its kinetics for treating waste klebsiella pneumoniae strains from 1, 3-propanediol (1,3-PD) fermented product by auto thermal thermophilic aerobic digestion (ATAD) process were investigated in laboratory scale to inactivate and reduce pathogens, which was a pretreatment process of the up-flow anaerobic sludge bed (UASB). The feed total suspended solids (TSS), pH value, Redox potential, temperature released by self-heating, and the numbers of pathogens were conducted. The results showed that TSS removal rate and the temperature reached 62.75% and 65¿ respectively, the pathogens' removal rate was 100%, the results from new kinetic model developed for the ATAD process had a good agreement with actual results.
We report the identification of a PDE10A clinical candidate by optimizing potency and in vivo eff... more We report the identification of a PDE10A clinical candidate by optimizing potency and in vivo efficacy of promising keto-benzimidazole leads 1 and 2. Significant increase in biochemical potency was observed when the saturated rings on morpholine 1 and N-acetyl piperazine 2 were changed by a single atom to tetrahydropyran 3 and N-acetyl piperidine 5. A second single atom modification from pyrazines 3 and 5 to pyridines 4 and 6 improved the inhibitory activity of 4 but not 6. In the in vivo LC-MS/MS target occupancy (TO) study at 10 mg/kg, 3, 5, and 6 achieved 86-91% occupancy of PDE10A in the brain. Furthermore, both CNS TO and efficacy in PCP-LMA behavioral model were observed in a dose dependent manner. With superior in vivo TO, in vivo efficacy and in vivo PK profiles in multiple preclinical species, compound 5 (AMG 579) was advanced as our PDE10A clinical candidate.
Acute myeloid leukemia (AML) remains a serious unmet medical need. Despite high remission rates w... more Acute myeloid leukemia (AML) remains a serious unmet medical need. Despite high remission rates with chemotherapy standard-of-care treatment, the disease eventually relapses in a major proportion of patients. Activating Fms-like tyrosine kinase 3 (FLT3) mutations are found in approximately 30% of patients with AML. Targeting FLT3 receptor tyrosine kinase has shown encouraging results in treating FLT3-mutated AML. Responses, however, are not sustained and acquired resistance has been a clinical challenge. Treatment options to overcome resistance are currently the focus of research. We report here the preclinical evaluation of AMG 925, a potent, selective, and bioavailable FLT3/cyclin-dependent kinase 4 (CDK4) dual kinase inhibitor. AMG 925 inhibited AML xenograft tumor growth by 96% to 99% without significant body weight loss. The antitumor activity of AMG 925 correlated with the inhibition of STAT5 and RB phosphorylation, the pharmacodynamic markers for inhibition of FLT3 and CDK4, respectively. In addition, AMG 925 was also found to inhibit FLT3 mutants (e.g., D835Y) that are resistant to the current FLT3 inhibitors (e.g., AC220 and sorafenib). CDK4 is a cyclin D-dependent kinase that plays an essential central role in regulating cell proliferation in response to external growth signals. A critical role of the CDK4-RB pathway in cancer development has been well established. CDK4-specific inhibitors are being developed for treating RB-positive cancer. AMG 925, which combines inhibition of two kinases essential for proliferation and survival of FLT3-mutated AML cells, may improve and prolong clinical responses.
The two‐dimensional (2D) electrically tuneable grating exhibits a bright future in the fields of ... more The two‐dimensional (2D) electrically tuneable grating exhibits a bright future in the fields of optics and communication. A 2D grating based on a polymer‐dispersed liquid crystal (PDLC) with good electro‐optical (E‐O) properties was fabricated through a single‐step ...
Http Dx Doi Org 10 1080 02678290802245468, Jul 1, 2008
To improve the morphological and electro‐optical properties of a polymer‐dispersed liquid crystal... more To improve the morphological and electro‐optical properties of a polymer‐dispersed liquid crystal (PDLC) grating, a type of highly fluorine‐substituted acrylate monomer was added to the prepolymer mixture. The morphologies of the PDLC gratings were investigated using ...
An integral part of drug discovery and development is the identification of drug metabolites that... more An integral part of drug discovery and development is the identification of drug metabolites that indicate intrinsic pharmacokinetic mechanism, pharmacological activity or specific toxicity. We describe the use of MSM, which utilizes multiple collision cells, dissociation methods, scan modes, mass analyzers and detectors to perform intelligent metabolite identification experiments. A modified LTQ Orbitrap XL with an HCD (Higher-energy Collisional Dissociation) collision cell was used. An isolation mass window up to 600 amu for HCD scans was enabled. In this experiment, a high resolution full scan was acquired followed by a high resolution HCD MS/MS of all incoming ions within that 600amu window. In parallel, the linear ion trap (LIT) acquired data dependent MSn spectra. Accela UPLC and Hypersil Gold C18 column(1x100mm, 1.9m) with a 20-minute gradient was used. 10M and 1M of rat and human hepatocytes incubation samples from verapamil and haloperidol were analyzed. The performance of ...
Abstract: Cell migration plays the essential role in embryogenesis, wound healing, immunization, ... more Abstract: Cell migration plays the essential role in embryogenesis, wound healing, immunization, infection, and cancer metastasis. To study actions of cell migration-associated genes in liver regeneration, these genes were obtained by seaching for the related ...
Transforming growth factor (TGF)beta is implicated in the pathogenesis of cyclosporine A (CsA) ne... more Transforming growth factor (TGF)beta is implicated in the pathogenesis of cyclosporine A (CsA) nephrotoxicity. We examined the efficacy of TGF beta receptor (R)II/immunoglobulin (Ig)G Fc, a soluble chimeric protein consisting of the extracellular domain of human TGF beta RII and IgG1 Fc, on CsA nephrotoxicity in mice. Subcutaneous injection of CsA (25 mg/kg/d) was given daily to mice maintained on a low-sodium diet. On days 1 and 7, an expression vector carrying cDNA for either TGF beta RII/IgG Fc or beta-galactosidase was transfected into the skeletal muscles by electroporation. At 2 or 3 weeks of CsA administration, plasma and renal TGF beta 1 levels, and tubulointerstitial injury and fibrosis were evaluated. After 2 weeks of CsA administration, plasma and renal TGF beta 1 levels increased to the maximum and then declined toward the baseline levels. Renal TGF beta 1 mRNA remained elevated until 3 weeks. Tubulointerstitial alterations became appreciable in 2 weeks and intensified b...
Chemical communications (Cambridge, England), Jan 21, 2004
Bioassay-guided fractionation of an extract prepared from Alangium javanicum using an assay to mo... more Bioassay-guided fractionation of an extract prepared from Alangium javanicum using an assay to monitor Cu(2+)-dependent DNA strand scission led to the isolation of javaniside, a new type of oxindole glycoside.
Bioassay-guided fractionation of an active organic extract of Piper caninum, using a sensitive ye... more Bioassay-guided fractionation of an active organic extract of Piper caninum, using a sensitive yeast assay to monitor putative double-strand DNA-damaging activity, resulted in the isolation of the 4,5-dioxoaporphine alkaloid cepharadione A (1). Compound 1 exhibited potent inhibitory activity in a yeast cytotoxicity assay with IC(50) values of 50.2 nM toward RS321NpRAD52 grown on glucose versus 293 nM toward the same yeast strain grown on galactose.
A crude extract prepared from roots of Mallotus resinosus exhibited significant Cu(2+)-dependent ... more A crude extract prepared from roots of Mallotus resinosus exhibited significant Cu(2+)-dependent DNA strand scission activity and was thus selected for bioassay-guided fractionation. Scopoletin (1), a simple coumarin, was identified as the active principle responsible for DNA cleavage activity of the crude extract. The DNA strand scission activity of 1, as well as that of three structural analogues, is reported.
Medical oncology (Northwood, London, England), 2012
Over-expression of RhoA in esophageal squamous cell carcinoma (ESCC) indicates a poor prognosis a... more Over-expression of RhoA in esophageal squamous cell carcinoma (ESCC) indicates a poor prognosis and is correlated with the tumor-node-metastasis (TNM) clinical classification. However, until now RhoA function in the ESCC progression remains to be established. We employed adenovirus-mediated small hairpin RNA (shRNA) against human RhoA (Ad-sh-RhoA) to efficiently silence target gene expression in RhoA-expressing Eca-109 ESCC cells at both protein and mRNA levels. Consequently, Ad-sh-RhoA reduced the proliferation and migration of Eca-109 cells assayed by MTT assay and cell wound healing, respectively. Moreover, Ad-sh-RhoA increased cell apoptosis and inhibited the cell cycle G1-S-phase progression of Eca-109 cells assessed by flow cytometry. Finally, in a nude mouse model, intratumoral injections of adenovirus-delivered RhoA shRNA every 3 days for 20 days significantly inhibited the growth and angiogenesis of xenografted Eca-109 tumors. In summary, these data indicate that RhoA may b...
Asian Pacific journal of cancer prevention : APJCP, 2010
Breast cancer is the most common malignancy in women in the world. High incidence and poor clinic... more Breast cancer is the most common malignancy in women in the world. High incidence and poor clinical outcomes underly the need for a better understanding of its tumor biology and how to effectively inhibit tumor progression. In the present study the question of whether NDRG2 might be a useful target for breast cancer therapy was addressed. With the increase or decrease of NDRG2 levels in MCF-7 and Bcap-37 cells by adenovirus-NDRG2 infection or NDRG2 siRNA transfection, CD24 expression was significantly decreased or increased, respectively. Furthermore, NDRG2 overexpression suppressed breast cancer cell adhesion and invasion, whereas knockdown of NDRG2 promoted these events. In conclusion, the data from the current study indicated that NDRG2, the product of a tumor suppressor gene, can regulate CD24 expression to decrease the metastatic potential of breast cancer cells.
2011 Third International Conference on Measuring Technology and Mechatronics Automation, 2011
ABSTRACT A innovative pretreatment technique and its kinetics for treating waste klebsiella pneum... more ABSTRACT A innovative pretreatment technique and its kinetics for treating waste klebsiella pneumoniae strains from 1, 3-propanediol (1,3-PD) fermented product by auto thermal thermophilic aerobic digestion (ATAD) process were investigated in laboratory scale to inactivate and reduce pathogens, which was a pretreatment process of the up-flow anaerobic sludge bed (UASB). The feed total suspended solids (TSS), pH value, Redox potential, temperature released by self-heating, and the numbers of pathogens were conducted. The results showed that TSS removal rate and the temperature reached 62.75% and 65¿ respectively, the pathogens' removal rate was 100%, the results from new kinetic model developed for the ATAD process had a good agreement with actual results.
We report the identification of a PDE10A clinical candidate by optimizing potency and in vivo eff... more We report the identification of a PDE10A clinical candidate by optimizing potency and in vivo efficacy of promising keto-benzimidazole leads 1 and 2. Significant increase in biochemical potency was observed when the saturated rings on morpholine 1 and N-acetyl piperazine 2 were changed by a single atom to tetrahydropyran 3 and N-acetyl piperidine 5. A second single atom modification from pyrazines 3 and 5 to pyridines 4 and 6 improved the inhibitory activity of 4 but not 6. In the in vivo LC-MS/MS target occupancy (TO) study at 10 mg/kg, 3, 5, and 6 achieved 86-91% occupancy of PDE10A in the brain. Furthermore, both CNS TO and efficacy in PCP-LMA behavioral model were observed in a dose dependent manner. With superior in vivo TO, in vivo efficacy and in vivo PK profiles in multiple preclinical species, compound 5 (AMG 579) was advanced as our PDE10A clinical candidate.
Acute myeloid leukemia (AML) remains a serious unmet medical need. Despite high remission rates w... more Acute myeloid leukemia (AML) remains a serious unmet medical need. Despite high remission rates with chemotherapy standard-of-care treatment, the disease eventually relapses in a major proportion of patients. Activating Fms-like tyrosine kinase 3 (FLT3) mutations are found in approximately 30% of patients with AML. Targeting FLT3 receptor tyrosine kinase has shown encouraging results in treating FLT3-mutated AML. Responses, however, are not sustained and acquired resistance has been a clinical challenge. Treatment options to overcome resistance are currently the focus of research. We report here the preclinical evaluation of AMG 925, a potent, selective, and bioavailable FLT3/cyclin-dependent kinase 4 (CDK4) dual kinase inhibitor. AMG 925 inhibited AML xenograft tumor growth by 96% to 99% without significant body weight loss. The antitumor activity of AMG 925 correlated with the inhibition of STAT5 and RB phosphorylation, the pharmacodynamic markers for inhibition of FLT3 and CDK4, respectively. In addition, AMG 925 was also found to inhibit FLT3 mutants (e.g., D835Y) that are resistant to the current FLT3 inhibitors (e.g., AC220 and sorafenib). CDK4 is a cyclin D-dependent kinase that plays an essential central role in regulating cell proliferation in response to external growth signals. A critical role of the CDK4-RB pathway in cancer development has been well established. CDK4-specific inhibitors are being developed for treating RB-positive cancer. AMG 925, which combines inhibition of two kinases essential for proliferation and survival of FLT3-mutated AML cells, may improve and prolong clinical responses.
The two‐dimensional (2D) electrically tuneable grating exhibits a bright future in the fields of ... more The two‐dimensional (2D) electrically tuneable grating exhibits a bright future in the fields of optics and communication. A 2D grating based on a polymer‐dispersed liquid crystal (PDLC) with good electro‐optical (E‐O) properties was fabricated through a single‐step ...
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