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Find video protocols related to scientific articles indexed in Pubmed.
Trisulfur Radical Anion as the Key Intermediate for the Synthesis of Thiophene via the Interaction between Elemental Sulfur and NaOtBu.
Org. Lett.
PUBLISHED: 11-20-2014
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A facile base-promoted sulfur-centered radical generation mode and a single-step protocol for the synthesis of thiophene derivatives using 1,3-diynes via the interaction between elemental sulfur and NaOtBu has been reported. EPR experiments revealed that the trisulfur radical anion acts as a key intermediate of this process. A plausible mechanism has been proposed.
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Revealing the halide effect on the kinetics of the aerobic oxidation of Cu(i) to Cu(ii).
Chem. Commun. (Camb.)
PUBLISHED: 11-20-2014
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In situ infrared (IR) and X-ray absorption near-edge structure (XANES) spectroscopic investigations reveal that different halide ligands have distinct effects on the aerobic oxidation of Cu(i) to Cu(ii) in the presence of TMEDA (tetramethylethylenediamine). The iodide ligand gives the lowest rate and thus leads to the lowest catalytic reaction rate of aerobic oxidation of hydroquinone to benzoquinone. Further DFT calculations suggest that oxidation of CuI-TMEDA involves a side-on transition state, while oxidation of CuCl-TMEDA involves an end-on transition state which has a lower activation energy.
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Phenylimidazoles as Potent and Selective Inhibitors of Coagulation Factor XIa with In Vivo Antithrombotic Activity.
J. Med. Chem.
PUBLISHED: 11-19-2014
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Novel inhibitors of FXIa containing an (S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine core have been optimized to provide compound 16b, a potent, reversible inhibitor of FXIa (Ki = 0.3 nM) having in vivo antithrombotic efficacy in the rabbit AV-shunt thrombosis model (ID50 = 0.6 mg/kg + 1 mg/kg/h). Initial analog selection was informed by molecular modeling using compounds 11a and 11h overlayed onto the X-ray crystal structure of tetrahydroquinoline 3 complexed to FXIa. Further optimization was achieved by specific modifications derived from careful analysis of the X-ray crystal structure of the FXIa/11h complex. Compound 16b was well tolerated and enabled extensive pharmacologic evaluation of the FXIa mechanism up to the ID90 for thrombus inhibition.
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Diamagnetic Levitation Promotes Osteoclast Differentiation from RAW264.7 Cells.
IEEE Trans Biomed Eng
PUBLISHED: 11-15-2014
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The superconducting magnet with a high magnetic force field can levitate diamagnetic materials. In this study, a specially designed superconducting magnet with large gradient high magnetic field (LGHMF), which provides three apparent gravity levels (? g, 1 g and 2 g), was used to study its influence on receptor activator of nuclear factor-?B ligand (RANKL)-induced osteoclast differentiation from pre-osteoclast cell line RAW264.7. The effects of LGHMF on the viability, nitric oxide (NO) production, morphology in RAW264.7 cells were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method, Griess method and immunofluorescence staining, respectively. The changes induced by LGHMF in osteoclast formation, mRNA expression and bone resorption were determined by tartrate-resistant acid phosphatase staining, semi-quantity PCR and bone resorption test, respectively. The results showed that: 1) LGHMF had no lethal effect on osteoclast precursors but attenuated NO release in RAW264.7 cells. 2) Diamagnetic levitation (? g) enhanced both the formation and bone resorption capacity of osteoclast. Moreover, diamagnetic levitation up-regulated mRNA expression of RANK, Cathepsin K, MMP-9 and NFATc1 while down-regulated RunX2 in comparison with controls. Furthermore, diamagnetic levitation induced obvious morphological alterations in osteoclast, including active cytoplasmic peripheral pseudopodial expansion, formation of pedosome belt and aggregation of actin ring. 3) Magnetic field produced by LGHMF attenuated osteoclast resorption activity. Collectively, LGHMF with combined effects has multiple effects on osteoclast, which attenuated osteoclast resorption with magnetic field whereas promoted osteoclast differentiation with diamagnetic levitation. Therefore, these findings indicate that diamagnetic levitation could be used as a novel ground-based microgravity simulator which facilitates bone cell research of weightlessness condition.
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Cu(II)/Cu(I)-Synergistic Cooperation to Lead the Alkyne C-H Activation.
J. Am. Chem. Soc.
PUBLISHED: 11-11-2014
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An efficient alkyne C-H activation procedure has been well studied which indicated that a Cu(II)/Cu(I) synergistic co-operation might be involved. In situ Raman spectroscopy was engaged to study kinetic behavior, drawing the conclusion that Cu(II) didn't participate in the rate determining step. IR and X-ray absorption spectroscopy evidence were provided for structural information, indicating that Cu(II) alone couldn't accelerate the reduction procedure by simply coordinating with C-C triple bond to activate the terminal alkynes; meanwhile, X-band EPR spectra and solubility showed that Cu(I) and Cu(II) could affect the complication environment of each other. A distinctive Cu(I)-Cu(II) synergistic cooperation intermediate was proposed for the putative mechanism.
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Biocompatible Flavone-Based Fluorogenic Probes for Quick Wash-Free Mitochondrial Imaging in Living Cells.
ACS Appl Mater Interfaces
PUBLISHED: 11-11-2014
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Mitochondria, vital organelles existing in almost all eukaryotic cells, play a crucial role in energy metabolism and apoptosis of aerobic organisms. In this work, we report two new flavone-based fluorescent probes, MC-Mito1 and MC-Mito2, for monitoring mitochondria in living cells. These two probes exhibit remarkably low toxicity, good cell permeability, and high specificity; these probes complement the existing library of mitochondrial imaging agents. The new dyes give nearly no background fluorescence, and their application does not require tedious postwashing after cell staining. The appreciable tolerance of MC-Mito2 encourages a broader range of biological applications for understanding the cell degeneration and apoptosis mechanism.
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[Expression of CD20 in B-cell precursor acute lymphoblastic leukemia and its correlation with clinical outcomes].
Sichuan Da Xue Xue Bao Yi Xue Ban
PUBLISHED: 10-08-2014
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To determine whether expression of CD20 is associated with clinical outcomes of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
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A single molecular probe for multi-analyte (Cr³?, Al³? and Fe³?) detection in aqueous medium and its biological application.
Chem. Commun. (Camb.)
PUBLISHED: 09-03-2014
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An ESIPT based fluorescent sensor 1 was developed, which could selectively detect and differentiate trivalent metal ions Cr(3+), Al(3+) and Fe(3+) in aqueous medium. The cell imaging experiments confirmed that 1 can be used for monitoring intracellular Cr(3+) and Al(3+) levels in living cells.
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Progress and perspectives of biomarker discovery in Chinese medicine research.
Chin J Integr Med
PUBLISHED: 09-02-2014
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Biomarker discovery in Chinese medicine (CM) has recently attracted a great deal of attention, owing to the promise of high-throughput technologies development and the potential of Chinese herbal medicine. Furthermore, it seems that pattern classification in CM might be serving as inspirational analogy and a practical guide, which might contribute to biomarkers discovery rather than just being used as diagnostic method. Although much work is still needed to identify markers, efforts are now being directed towards discovering biomarkers or biomarkers based network that could target herbal formulae. In this article, we review progress in biomarker discovery development, discuss current biomarker discovery in CM highlighting challenges and opportunities of pattern classification and presenting a perspective of the future integrative modeling approaches as an emerging trend in biomarker discovery.
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Assessing right ventricular function in patients with hypertrophic cardiomyopathy with cardiac MRI: correlation with the New York Heart Function Assessment (NYHA) classification.
PLoS ONE
PUBLISHED: 09-02-2014
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To determine whether 3.0-T magnetic resonance imaging (MRI) could assess right ventricular (RV) function in patients with hypertrophic cardiomyopathy (HCM), and if this assessment is correlated with the New York Heart Function Assessment (NYHA) classification.
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De Novo Design of Self-Assembled Hexapeptides as ?-Amyloid (A?) Peptide Inhibitors.
ACS Chem Neurosci
PUBLISHED: 08-22-2014
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The ability of peptides to construct specific secondary structures provides a useful function for biomaterial design that cannot be achieved with traditional organic molecules and polymers. Inhibition of amyloid formation is a promising therapeutic approach for the treatment of neurodegenerative diseases. Existing peptide-based inhibitors are mainly derived from original amyloid sequences, which have very limited sequence diversity and activity. It is highly desirable to explore other peptide-based inhibitors that are not directly derived from amyloid sequences. Here, we develop a hybrid high-throughput computational method to efficiently screen and design hexapeptide inhibitors against amyloid-? (A?) aggregation and toxicity from the first principle. Computationally screened/designed inhibitors are then validated for their inhibition activity using biophysical experiments. We propose and demonstrate a proof-of-concept of the "like-interacts-like" design principle that the self-assembling peptides are able to interact strongly with conformationally similar motifs of A? peptides and to competitively reduce A?-A? interactions, thus preventing A? aggregation and A?-induced toxicity. Such a de novo design can also be generally applicable to design new peptide inhibitors against other amyloid diseases, beyond traditional peptide inhibitors with homologous sequences to parent amyloid peptides.
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Snail regulated by PKC/GSK-3? pathway is crucial for EGF-induced epithelial-mesenchymal transition (EMT) of cancer cells.
Cell Tissue Res.
PUBLISHED: 08-16-2014
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Cancer metastasis is considered a major challenge in cancer therapy. Recently, epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR) signaling has been shown to induce epithelial-mesenchymal transition (EMT) and thereby to promote cancer metastasis. However, the underlying mechanism has not been fully elucidated. We demonstrate that EGF can induce EMT in human prostate and lung cancer cells and thus promote invasion and migration. EGF-induced EMT has been characterized by the cells acquiring mesenchymal spindle-like morphology and increasing their expression of N-cadherin and fibronectin, with a concomitant decrease of E-cadherin. Both protein and mRNA expression of transcription factor Snail rapidly increases after EGF treatment. The knockdown of Snail significantly attenuates EGF-induced EMT, suggesting that Snail is crucial for this process. To determine the way that Snail is accumulated, we demonstrate (1) that EGF promotes the stability of Snail via inhibiting the activity of glycogen synthase kinase 3 beta (GSK-3?), (2) that protein kinase C (PKC) rather than the phosphatidylinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway is responsible for GSK-3? inhibition and (3) that GSK-3? inhibition promotes the transcription of Snail. Taken together, these results reveal that the PKC/GSK-3? signaling pathway controls both the stability and transcription of Snail, which is crucial for EMT induced by EGF in PC-3 and A549 cells. Our study suggests a novel signaling pathway for Snail regulation and provides a better understanding of growth-factor-induced tumor EMT and metastasis.
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Analysis of the transcriptome of Marsdenia tenacissima discovers putative polyoxypregnane glycoside biosynthetic genes and genetic markers.
Genomics
PUBLISHED: 08-13-2014
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Marsdenia tenacissima is a well-known anti-cancer medicinal plant used in traditional Chinese medicine due to bioactive constituents of polyoxypregnane glycosides, such as tenacissosides, marsdenosides and tenacigenosides. Genomic information regarding this plant is very limited, and rare information is available about the biosynthesis of polyoxypregnane glycosides. To facilitate the basic understanding about the polyoxypregnane glycoside biosynthetic pathways, de novo assembling was performed to generate a total of 73,336 contigs and 65,796 unigenes, which represent the first transcriptome of this species. These included 27 unigenes that were involved in steroid biosynthesis and could be related to pregnane backbone biosynthesis. The expression patterns of six unigenes involved in polyoxypregnane biosynthesis were analyzed in leaf and stem tissues by quantitative real time PCR (qRT-PCR) to explore their putative function. Furthermore, a total of 15,295 simple sequence repeats (SSRs) were identified from 11,911 unigenes, of which di-nucleotide motifs were the most abundant.
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Validation and clinicopathologic associations of a urine-based bladder cancer biomarker signature.
Diagn Pathol
PUBLISHED: 08-12-2014
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BackgroundTo validate the expression of a urine-based bladder cancer associated diagnostic signature comprised of 10 targets; ANG, CA9, MMP9, MMP10, SERPINA1, APOE, SDC1, VEGFA, SERPINE1 and IL8 in bladder tumor tissues.MethodsImmunohistochemical analyses were performed on tumor specimens from 213 bladder cancer patients (transitional cell carcinoma only) and 74 controls. Staining patterns were digitally captured and quantitated (Aperio, Vista, CA), and expression was correlated with tumor stage, tumor grade and outcome measures.ResultsWe revealed a positive association of 9 of the 10 proteins (excluding VEGF) in bladder cancer. Relative to control cases, a reduction in SDC1 and overexpression of MMP9, MMP10, SERPINE1, IL8, APOE, SERPINA1, ANG were associated with high stage bladder cancer. Reduced VEGF and increased SERPINA1 were associated with high-grade bladder cancer. Disease-specific survival was significantly reduced in tumors with high expression of SERPINE1 and/or IL8.ConclusionsThese findings confirm that the proteins in a urine-based diagnostic signature are aberrantly expressed in bladder tumor tissues, and support the potential additional utility of selected biomarkers for the clinicopathological evaluation of excised tissue or biopsy material.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_200.
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Regulatory effect of astragalus polysaccharides on intestinal intraepithelial ??T cells of tumor bearing mice.
Molecules
PUBLISHED: 08-11-2014
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Astragalus polysaccharides (APS) possess multiple immunomodulatory activities. Due to its high molecular weight, orally administration of APS is not easily absorbed into the blood stream, and how APS exerts its capacity in vivo is still not well elucidated. We assume that enteric mucosal immune response might trigger the immune regulation of APS, and our previous studies demonstrated that APS had regulatory activity on intraepithelial lymphocytes (IELs). Therefore, this study aimed to investigate the functions of APS on intestinal intraepithelial ??T cells, a major subset in IELs and an essential component of maintaining homeostasis and immune regulation in enteric mucosa. Results showed that APS could promote proliferation and function of intestinal intraepithelial ??T cells in vitro, the IFN-?, FasL and GrB mRNA levels in ??T cells were all significantly increased. Moreover, APS also improved the activity of intestinal intraepithelial ??T cells in vivo, as cytokines production and cytotoxicity of ??T cells were all remarkably improved in tumor-bearing mice treated with APS. In addition, the levels of TNF-? and IFN-? were significantly increased, whereas the levels of IL-10 and TGF-? were significantly decreased in tumor-bearing mice treated with APS. In conclusion, this study demonstrated that APS could improve proliferation and function of intestinal intraepithelial ??T cells, which might an important pathway for immunomodulation of APS in cancer therapy.
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Assignment of the oxidation states of Zr and Co in a highly reactive heterobimetallic Zr/Co complex using X-ray absorption spectroscopy (XANES).
Dalton Trans
PUBLISHED: 08-11-2014
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The reduced heterobimetallic complex (THF)Zr(MesNP(i)Pr2)3CoN2 (1) has been examined along with a series of structurally similar reference compounds using X-ray absorption near edge structure (XANES) spectroscopy. Complex 1 has been shown to be highly reactive, often via one-electron pathways that might be expected for a d(1) Zr(III) complex. However, the presence of two strongly interacting metals in complex 1 renders the assignment of oxidation states ambiguous. Both Zr and Co K-edge XANES spectra reveal that the most accurate description of complex 1 is that of a Zr(IV)/Co(-I) zwitterion. Electronic structure calculations support this assignment.
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Wnt5A promotes an adaptive, senescent-like stress response, while continuing to drive invasion in melanoma cells.
Pigment Cell Melanoma Res
PUBLISHED: 08-06-2014
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We have previously shown that Wnt5A drives invasion in melanoma. We have also shown that Wnt5A promotes resistance to therapy designed to target the BRAF(V600E) mutation in melanoma. Here, we show that melanomas characterized by high levels of Wnt5A respond to therapeutic stress by increasing p21 and expressing classical markers of senescence, including positivity for senescence-associated ?-galactosidase (SA-?-gal), senescence associated heterochromatic foci (SAHF), H3K9Me chromatin marks, and PML bodies. We find that despite this, these cells retain their ability to migrate and invade. Further, despite the expression of classic markers of senescence like SA-?-gal and SAHF, these Wnt5A-high cells are able to colonize the lungs in in vivo tail-vein colony forming assays. This clearly underscores the fact that these markers do not indicate true senescence in these cells, but instead an adaptive stress response that allows the cells to evade therapy and invade. Notably, silencing Wnt5A reduces expression of these markers and decreases invasiveness. The combined data point to Wnt5A as a master regulator of an adaptive stress response in melanoma, which may contribute to therapy resistance. This article is protected by copyright. All rights reserved.
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Copper-catalysed direct radical alkenylation of alkyl bromides.
Org. Biomol. Chem.
PUBLISHED: 07-29-2014
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A copper-catalysed direct radical alkenylation of various benzyl bromides and ?-carbonyl alkyl bromides has been developed. Compared with the recent radical alkenylations which mostly focused on secondary or tertiary alkyl halides, this transformation shows good reactivity to primary alkyl halides and tertiary, secondary alkyl halides were also tolerated. The key initiation step of this transformation is a copper-induced single-electron reduction of C-Br bonds to generate alkyl radical species.
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Bispecific anti?CD3 x anti?HER2 antibody mediates T cell cytolytic activity to HER2?positive colorectal cancer in vitro and in vivo.
Int. J. Oncol.
PUBLISHED: 07-01-2014
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Targeting HER2 overexpressed breast cancer cells with anti?HER2 monoclonal antibodies inhibits tumor growth. Here we investigated whether HER2 can serve as a target for T cell?mediated immunotherapy of human colorectal carcinoma. Specific cytolytic activity of activated T cells (ATCs) armed with anti?CD3 x anti?HER2 bispecific antibody (HER2Bi?Ab) against HER2+ tumor cells was evaluated by bioluminescent signal generated by luciferase reporter on tumor cells in vitro and in vivo. In contrast to unarmed ATCs, increased cytotoxic activity of HER2Bi?armed ATCs against HER2+ tumor cells was observed. Moreover, HER2Bi?armed ATCs expressed higher level of activation marker CD69 and secreted significantly higher levels of IFN?? than the unarmed ATC counterpart. In addition, compared with anti?HER2 mAb (Herceptin®) or unarmed ATC, HER2Bi?armed ATCs showed significant suppression against colorectal carcinoma cells. In colorectal tumor cell xenograft mice, infusion of HER2Bi?armed ATCs successfully inhibited the growth of Colo205?luc cells. The HER2Bi?armed ATCs with anti?tumor effects may provide a promising immunotherapy for colorectal carcinoma in the future.
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Smoking and risk of venous thromboembolism: a systematic review.
Southeast Asian J. Trop. Med. Public Health
PUBLISHED: 07-01-2014
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The relationship between smoking and venous thromboembolism (VTE) is unclear, as a result we conducted a meta-analysis to assess the association between smoking and VTE. A comprehensive search was conducted to identify studies evaluating the relationship between smoking and VTE. Two reviewers independently selected studies and extracted data. The data were analyzed using Comprehensive Meta-Analysis software, version 2. Twenty-one studies were included. Our findings show current smoking (RR 1.24; 95% CI: 1.14-1.35) and former smoking (RR 1.05; 95% CI: 1.01-1.10) were associated with increased VTE risk. There was a dose-response relationship between cigarettes smoked per day and VTE: 1-14 cigarettes/day: RR 1.20; 95% CI: 1.08-1.34, I2 = 0%; 15-24 cigarettes/day: RR 1.33; 95% CI: 1.15-1.54, I2 = 0%; > 25 cigarettes/day: RR 1.63; 95% CI: 1.37-1.95, I2 = 6%. Our findings show smoking is a risk factor for VTE with a dose-response relationship.
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Structure-kinetic relationship study of organozinc reagents.
Chem. Commun. (Camb.)
PUBLISHED: 06-25-2014
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Phenylzinc reagents prepared from various zinc halides show distinct kinetic features in the palladium-catalyzed Negishi-type oxidative coupling reaction, in which the phenylzinc reagent prepared from ZnI2 gives the highest rate. In situ infrared and X-ray absorption spectroscopy studies show that the higher reaction rate was observed for longer Zn-C bond distances.
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Serum metabolomics reveals betaine and phosphatidylcholine as potential biomarkers for the toxic responses of processed Aconitum carmichaelii Debx.
Mol Biosyst
PUBLISHED: 06-21-2014
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We recently reported that processed Aconitum carmichaelii Debx (Bai-Fu-Pian in Chinese, BFP) elicits differential toxic responses in rats under various health conditions. The present study aimed to determine the graded toxicity of BFP so as to derive a safe therapeutic rationale in clinical practice. Sensitive and reliable biomarkers of toxicity were also identified, with the corresponding metabolic pathways being unveiled. Thirty male Sprague-Dawley rats were divided into five groups (n = 6) and received oral administration of BFP extract (0.32, 0.64, 1.28 or 2.56 g kg(-1) per day) or an equal volume of drinking water (control) for 15 days. The metabolomic profiles of rat serum were analyzed by liquid chromatography quadruple time-of-flight mass spectrometry (LC-Q-TOF-MS). Linear regression analysis and Ingenuity Pathway Analysis (IPA) were used to elucidate the differentiated altered metabolites and associated network relationships. Results from biochemical and histopathological examinations revealed that BFP could induce prominent toxicity in the heart, liver and kidneys at a dose of 2.56 g kg(-1) per day. Betaine up-regulation and phosphatidylcholine down-regulation were detected in the serum samples of drug-treated groups in a dose-dependent manner. In summary, betaine and phosphatidylcholine could be regarded as sensitive biomarkers for the toxic responses of BFP. Perturbations of RhoA signaling, choline metabolism and free radical scavenging were found to be partly responsible for the toxic effects of the herbal drug. Based on the metabolomics findings, we could establish a safe therapeutic range in the clinical use of BFP, with promising predictions of possible drug toxicity.
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Role of microRNAs in osteoblasts differentiation and bone disorders.
Curr. Med. Chem.
PUBLISHED: 06-20-2014
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Advanced studies of single stranded endogenous ~22 nt microRNAs (miRNAs) have demonstrated their diverse biological functions including control of cell differentiation, cell cycle and pathological conditions. Recent studies suggest the potential application of miRNAs in stem cell engineering. miRNAs play a vital role as post-transcriptional regulators of gene expression which controls osteoblasts-mediated bone formation and osteoclasts related bone remodeling. Transcriptional and post-transcriptional mechanisms regulate the differentiation of osteoblasts and osteogenesis. The differentiation of osteoblasts is a key step in the development of skeletal muscles and it is involved in triggering the signaling pathways. Signaling pathways like TGF?, BMP and Wnt are regulated by miRNAs which in turn are shown to be associated with bone dynamics and bone disorders. This recap highlights the role of miRNAs in osteoblasts differentiation and emphasizes their potential therapeutic role in metabolic bone disorders.
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Comparison of nitrous oxide emissions in partial nitrifying and full nitrifying granular sludge reactors treating ammonium-rich wastewater.
Bioresour. Technol.
PUBLISHED: 06-19-2014
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The objective of this study was to evaluate the nitrous oxide (N2O) emissions in partial nitrifying and full nitrifying granular sludge reactors treating ammonium-rich wastewater. During stable operation, there was no significant difference of NH4(+)-N removal efficiencies between the two granular reactors. Nitrate and nitrite were the main effluent nitrogen species of the two reactors, and nitrite accumulation rate of partial nitrifying reactor was high of 87.79±2.03%. However, partial nitrifying granular-reactor had better total nitrogen removal efficiency (41.84±3.35%) than that of full nitrifying granular-reactor (19.91±2.12%). According to typical cycles, the N2O emission amount per cycle of partial nitrifying reactor account for 11.48% of the incoming nitrogen load, which was 1.5 times higher than that of full nitrifying reactor (7.47%). The obtained results could provide more information for understanding of N2O emission in granular sludge systems.
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Copper-catalysed oxidative Csp(3)-H methylenation to terminal olefins using DMF.
Chem. Commun. (Camb.)
PUBLISHED: 06-05-2014
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A copper-catalysed direct oxidative Csp(3)-H methylenation to terminal olefins using DMF as one carbon source was developed. In this reaction, various functional groups were well tolerated, thus providing a simple way to construct arylvinylketones and arylvinylpyridines. The preliminary mechanistic investigations revealed that CH2 was from DMF (N-CH3).
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Aerobic granules formation and simultaneous nitrogen and phosphorus removal treating high strength ammonia wastewater in sequencing batch reactor.
Bioresour. Technol.
PUBLISHED: 05-26-2014
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The objective of this study was to evaluate aerobic granules formation and simultaneous nitrogen and phosphorus removal treating high strength ammonia wastewater in sequencing batch reactor (SBR). After successful aerobic granulation, mixed liquor suspended solids (MLSS) concentrations of the SBR increased from 3.11 to 14.52 g/L, while sludge volume index (SVI) values decreased from 144.61 to 30.32 mL/g. Protein (PN) and polysaccharide (PS) concentrations increased from 60.2 and 12.5 mg/L to 101.1 and 15.8 mg/L, respectively. Simultaneous nitrogen and phosphorus removal was enhanced by altering the influent chemical oxygen demand/nitrogen (COD/N) ratio. At COD/N ratio of 9, total nitrogen (TN) and total phosphorus (TP) removal efficiencies were up to 89.8% and 77.5%, respectively. Three-dimensional excitation-emission matrix (3D-EEM) spectroscopy showed that the chemical compositions of sludge EPS were changed during granulation process. The results could provide useful information to promote nitrogen and phosphorus removal using aerobic granular sludge technology.
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Linking SOX10 to a slow-growth resistance phenotype.
Cell Res.
PUBLISHED: 05-23-2014
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Slow-cycling BRAF melanoma cells are notoriously resistant to standard chemotherapy or targeted therapy but the underlying mechanism remains elusive. Now a new study unlocks this mystery and offers novel insights into developing more effective therapeutic interventions.
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AKT/GSK-3? regulates stability and transcription of snail which is crucial for bFGF-induced epithelial-mesenchymal transition of prostate cancer cells.
Biochim. Biophys. Acta
PUBLISHED: 05-15-2014
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Epithelial-mesenchymal transition (EMT) plays a pivotal role in the development of metastatic cancers. Basic fibroblast growth factor (bFGF) is significantly elevated in metastatic prostate cancers, which has been mentioned mainly to induce EMT in normal cells. However, there is no description about bFGF induced EMT and its underlying mechanism in prostate cancer cells.
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Equilibrium and dynamic spectroscopic studies of the interaction of monomeric ?-lactoglobulin with lipid vesicles at low pH.
Biochemistry
PUBLISHED: 05-12-2014
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?-Lactoglobulin (?LG) is a member of the lipocalin protein family that changes structure upon interacting with anionic surfactants and lipid vesicles under higher-pH conditions at which ?LG is dimeric. In this study, a ?-sheet to ?-helix transformation was also observed for monomeric ?LG obtained at pH 2.6 when it was mixed with small unilamellar vesicles (SUVs) of zwitterionic lipids, but being mixed with anionic lipids produced little change. The dynamics and extent of this change were quite dependent on the lipid character, phase, and vesicle size. With 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), at ~50 °C and pH 2.6, the ?LG converted to a substantially helical form upon addition of ~10 mM lipid in a two-step kinetic process having time constants of ~1 and ~25 h, as monitored by circular dichroism (CD). Fluorescence changes were simpler but implied a rapid initial change in the Trp environments followed by a slower process paralleling the change in secondary structure. Polarization attenuated total reflectance Fourier transform infrared results indicate the formed helices are at least partially inserted into the lipid bilayer and the sheet segments are on the surface. Thermal behavior showed that the secondary structure of the lipid-bound ?LG had two phases, the first being characteristic of the protein-lipid vesicle interaction and the second following the DSPC phase change after which the protein apparently dissociated from the vesicle. Large unilamellar vesicles had a weaker interaction, as judged by CD, which may correlate to the partial exposure of the hydrophobic parts of the SUV bilayer. Other zwitterionic lipids bound ?LG with much slower kinetics and often required sonication to induce interaction, but these also showed dissociation upon lipid phase change. These thermal and kinetic behaviors suggest a mechanism for the interaction of monomeric ?LG with zwitterionic lipids different from that seen previously for the dimeric form.
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Discovery of highly selective alkyne semihydrogenation catalysts based on first-row transition-metallated porous organic polymers.
Angew. Chem. Int. Ed. Engl.
PUBLISHED: 05-07-2014
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Five different first-row transition metal precursors (V(III) , Cr(III) , Mn(II) , Co(II) , Ni(II) ) were successfully incorporated into a catechol porous organic polymer (POP) and characterized using ATR-IR and XAS analysis. The resulting metallated POPs were then evaluated for catalytic alkyne hydrogenation using high-throughput screening techniques. All POPs were unexpectedly found to be active and selective catalysts for alkyne semihydrogenation. Three of the metallated POPs (V, Cr, Mn) are the first of their kind to be active single-site hydrogenation catalysts. These results highlight the advantages of using a POP platform to develop new catalysts which are otherwise difficult to achieve through traditional heterogeneous and homogeneous routes.
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Aptamer-based exonuclease protection and enzymatic recycling cleavage amplification homogeneous assay for the highly sensitive detection of thrombin.
Analyst
PUBLISHED: 05-07-2014
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Critical challenges in homogeneous solution-based biomolecular detection are the separation and sensitivity compared to biomolecular detection in heterogeneous solutions. In this work, a novel, separation-free and sensitive homogeneous protein detection assay based on combining aptameric exonuclease protection with nicking enzyme assisted fluorescence signal amplification (NEFSA) is developed for highly sensitive protein detection. We applied a special oligonucleotide probe containing a protein aptamer sequence at the 3'-terminus, which has the capacity to recognize the protein target with high affinity and specificity. Specifically, the aptamer probe is protected from exonuclease-catalyzed digestion upon binding to the protein target. The protected aptamer probe hybridizes with the molecular beacon (MB) probe, a reporter signal oligo-DNA. Consequently, the NEFSA process is triggered in the presence of a nicking enzyme, resulting in the continuous enzyme cleavage of many MBs, providing a fluorescent cascadic amplification detection signal for the target. Thrombin was used as the model analyte in the current proof-of-concept experiments. This method permits the detection of human thrombin specifically with a detection limit as low as 1.0 pM without using washes or separations. Our method exhibits excellent sensitivity. In addition, this new method is simple and avoids the specific conformational design of an aptasensor probe for the elimination of washing and separation steps. The mechanism, moreover, may be generalized and used for other forms of protein analysis by changing the corresponding aptamer without changing the other conditions. So our new strategy may provide a homogeneous fluorescence detection platform for many proteins.
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Research on testing the nonlinear optical performance of nonlinear optical materials based on the effect of second-harmonic generation.
Guang Pu Xue Yu Guang Pu Fen Xi
PUBLISHED: 05-03-2014
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In the present paper the authors report a research on testing the nonlinear optical performance of optical materials in visible and infrared band. Based on the second order nonlinear optic principle and the photoelectric signal detection technology, the authors have proposed a new testing scheme in which a infrared OPO laser and a method for separating the beams arising from frequency matching and the light produced by other optical effects were used. The OPO laser is adopted as light source to avoid the error of measurement caused by absorption because the double frequency signal of the material is in the transmittance band Our research work includes testing system composition, operational principle and experimental method. The experimental results of KTP, KDP, AGS tested by this method were presented. In the experiment several new infrared non-linear materials were found. This method possesses the merits of good stability and reliability, high sensitivity, simple operation and good reproducibility, which can effectively make qualitative and semi-quantitative test for optical material's nonlinear optical properties from visible to infrared. This work provides an important test -method for the research on second order nonlinear optical materials in visible, infrared and ultraviolet bands.
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Cross-sequence interactions between human and rat islet amyloid polypeptides.
Langmuir
PUBLISHED: 05-01-2014
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Human islet amyloid polypeptide (hIAPP) can assemble into toxic oligomers and fibrils, which are associated with cell degeneration and the pathogenesis of type 2 diabetes. Cross-interaction of hIAPP with rat IAPP (rIAPP)--a non-amyloidogenic peptide with high sequence similarity to hIAPP--might influence the aggregation and toxicity of hIAPP. However, the exact role of rIAPP in hIAPP aggregation and toxicity still remains unclear. In this work, we investigated the effect of cross-sequence interactions between full-length hIAPP(1-37) and rIAPP(1-37) on hybrid amyloid structures, aggregation kinetics, and cell toxicity using combined computational and experimental approaches. Experimental results indicate a contrasting role of rIAPP in hIAPP aggregation, in which rIAPP initially inhibits the early aggregation and nuclei formation of hIAPP, but hIAPP seeds can also recruit both hIAPP and rIAPP to form more hybrid fibrils, thus promoting amyloid fibrillation ultimately. The coincubation of hIAPP and rIAPP also decreases cell viability, presumably due to the formation of more toxic hybrid oligomers at the prolonged lag phase. Comparative MD simulations confirm that the cross-sequence interactions between hIAPP and rIAPP stabilize ?-sheet structure and thus likely promote their fibrillization. This work provides valuable insights into a critical role of cross-amyloid interactions in protein aggregation.
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Fei-Liu-Ping ointment inhibits lung cancer growth and invasion by suppressing tumor inflammatory microenvironment.
BMC Complement Altern Med
PUBLISHED: 04-29-2014
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Lung cancer is one of the leading causes of cancer-related mortality worldwide. Conventional chemotherapy and radiotherapy are the primary therapeutic methods for lung cancer with the use of combination therapies gaining popularity. The frequency and duration of treatment, as well as, managing lung cancer by targeting multiple aspects of cancer biology is often limited by toxicity to the patient. There are many naturally occurring anticancer agents that have a high degree of efficacy and low toxicity, offering a viable and safe approach for the treatment of lung cancer. The herbs traditionally used in Chinese medicine for anticancer treatment offer great potential to enhance the efficacy of conventional therapy. In this study, we evaluated the synergistic effects of Fei-Liu-Ping (FLP) ointment in treating lung cancer; a known anticancer Chinese herbal based formula.
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Stacked stem cell sheets enhance cell-matrix interactions.
Organogenesis
PUBLISHED: 04-25-2014
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Cell sheet engineering has enabled the production of confluent cell sheets stacked together for use as a cardiac patch to increase cell survival rate and engraftment after transplantation, thereby providing a promising strategy for high density stem cell delivery for cardiac repair. One key challenge in using cell sheet technology is the difficulty of cell sheet handling due to its weak mechanical properties. A single-layer cell sheet is generally very fragile and tends to break or clump during harvest. Effective transfer and stacking methods are needed to move cell sheet technology into widespread clinical applications. In this study, we developed a simple and effective micropipette based method to aid cell sheet transfer and stacking. The cell viability after transfer was tested and multi-layer stem cell sheets were fabricated using the developed method. Furthermore, we examined the interactions between stacked stem cell sheets and fibrin matrix. Our results have shown that the preserved ECM associated with the detached cell sheet greatly facilitates its adherence to fibrin matrix and enhances the cell sheet-matrix interactions. Accelerated fibrin degradation caused by attached cell sheets was also observed.
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Leukemias involving abdominal and pelvic lymph nodes: evaluation with contrast-enhanced MDCT.
Abdom Imaging
PUBLISHED: 04-25-2014
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To clarify features of lymph nodes associated with leukemia purposing to offer help for imaging diagnosis and differential diagnosis of leukemia.
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Synthesis of poly(N-isopropylacrylamide)-co-poly(phenylboronate ester) acrylate and study on their glucose-responsive behavior.
J Colloid Interface Sci
PUBLISHED: 04-23-2014
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We introduced thermo-sensitive poly(N-isopropylacrylamide) (PNIPAM) into the polymer structure of poly(ethylene glycol)-block-poly(phenylboronate ester) acrylate (MPEG-block-PPBDEMA) by block and random polymerization pathways in order to investigate the effect of polymer architecture on the glucose-responsiveness and enhance their insulin release controllability. By following the structure, the continuous PNIPAM shell of the triblock polymer MPEG-block-PNIPAM-block-PPBDEMA collapsing on the glucose-responsive PPBDEMA core formed the polymeric micelles with a core-shell-corona structure, and MPEG-block-(PNIPAM-rand-PPBDEMA) exhibited core-corona micelles in which the hydrophobic core consisted of PNIPAM and PPBDEMA segments when the environmental temperature was increased above low critical solution temperature (LCST) of PNIPAM. The micellar morphologies can be precisely controlled by temperature change between 15 and 37°C. As a result, the introduction of PNIPAM greatly enhanced the overall stability of insulin encapsulated in the polymeric micelles in the absence of glucose over incubation 80 h at 37°C. Comparing to MPEG-block-PNIPAM-block-PPBDEMA, the nanocarriers from MPEG-block-(PNIPAM-rand-PPBDEMA) showed great insulin release behavior which is zero insulin release without glucose, low release at normal blood glucose concentration (1.0 mg/mL). Therefore, these nanocarriers may be served as promising self-regulated insulin delivery system for diabetes treatment.
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A clinical study of patients with coronary heart disease complicated with hypertriglyceridemic waist phenotype.
Cell Biochem. Biophys.
PUBLISHED: 04-18-2014
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The objective of this study was to investigate the characteristics of coronary lesions in patients with coronary heart disease complicated with hypertriglyceridemic waist phenotype and determine the relation to risk factors. For this purpose, 105 patients with ? 50 % stenosis in one branch of coronary arteries as confirmed by coronary angiography were enrolled. Further, in this regard, 41 cases (i.e., case group) were complicated with hypertriglyceridemic waist phenotype, while 64 patients (i.e., control group) were not complicated with this phenotype. The data show that, as compared with control group, the patients in case group had higher coronary artery scores. The coronary lesions in case group were associated with waist triglycerides index and tumor necrosis factor (TNF)-?; partial regression coefficients were 0.774 (P < 0.001) and 0.250 (P = 0.001), respectively. Therefore, it was concluded that the patients with hypertriglyceridemic waist phenotype had a worse coronary heart disease condition, whereas waist triglycerides index and TNF-? related closely to the severity of coronary lesions.
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Strategies for combination of aptamer and targeted drug delivery.
J Nanosci Nanotechnol
PUBLISHED: 04-16-2014
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Cell-specific delivery of active agents for treatment of human disease is a long cherished object for scientific researchers. Nanoscience generated nanosized carriers, such as liposome, micelle and nanoparticle, provides potential to realize such purpose based on the nanometer size effect (< 1000 nm), however, the sole nanocarrier with no specific ligands are not sufficient to deliver drugs to target sites. Aptamers are single-stranded oligonucleotides which can specifically recognize and bind to target cells by distinct secondary and tertiary structures even without knowledge of characteristic protein profiles on cell surface. Thus, aptamer, as a target moiety, provides a potential approach to realize pathological site-specific delivery of active agents. This review highlighted the strategies for combination of aptamer and targeted drug delivery, further summarized their preparation methods, strengths and weaknesses to facilitate the development of targeted drug delivery system.
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Salvianolic acid A, a matrix metalloproteinase-9 inhibitor of Salvia miltiorrhiza, attenuates aortic aneurysm formation in apolipoprotein E-deficient mice.
Phytomedicine
PUBLISHED: 04-10-2014
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Aortic aneurysm (AA) is a life-threatening vascular disease in defect of effective pharmaceutical therapy. Matrix metalloproteinase-9 (MMP-9) is implicated in the development of chronic vascular diseases including aneurysm, but the effective MMP-9 inhibitors are far from development. To develop new candidate for AA therapy, we evaluated the efficiency of salvianolic acid A (SalA), a novel MMP-9 inhibitor, on AA progression in a mouse model and characterized the mechanism of action. SalA is a water soluble compound of the herbal drug Rhizoma Salviae miltiorrhizae (Danshen) which in China is widely used for the treatment of hypertension, coronary artery diseases and myocardial infarction. MMPs activity was evaluated by enzyme kinetic analysis in vitro and in-gel gelatin zymography in vivo. SalA showed selectivity on gelatinase (MMP-2 and MMP-9) than on collagenase (MMP-8 and MMP-13) in vitro, and specificity on MMP-9 than MMP-2 in vivo. Aortic aneurysm was induced by angiotension II (AngII) in apolipoprotein E-deficient (ApoE(-/-)) mice. Aortic structure was evaluated by hematoxylin and eosin, picrosirius red, orein stain. Macrophage infiltration was detected by immunohistochemistry in vivo and transwell in vitro. Comparing with doxycycline (Dox), a well-known MMPs inhibitor, SalA showed similar efficiency against AA progression. SalA significantly decreased aortic diameter and aneurysm severity, ameliorated integrity of vascular structure, inhibited elastin fragmentation and macrophage infiltration. Furthermore, SalA showed greater safety than Dox based on hepatotoxicity evaluation. Our results demonstrated that SalA held great potential for AA therapy.
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Efficient RTP-based OPO intracavity pumped by an acousto-optic Q-switched Nd:YVO? laser.
Opt Lett
PUBLISHED: 04-03-2014
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This Letter describes an intracavity pumped optical parametric oscillator (OPO) based on noncritical phase matching RbTiOPO4 (RTP) crystal driven by a laser diode end-pumping acousto-optic Q-switched Nd:YVO4 laser. Simultaneous efficient signal light at 1.6 ?m and idler light at 3.1 ?m outputs were obtained. At an incident pump power of 10.5 W and a Q-switching pulse repetition frequency of 60 kHz, 1.42 W at center wavelength of about 1619 nm and 0.38 W at 3108 nm were achieved, with the diode to OPO total output conversion efficiency up to 17.1%. The pulse width is about 6.5 ns for the signal light corresponding to the fundamental light at 1064 nm of about 10 ns. The spectral widths of the signal and idler light are narrower than 0.5 and 1.0 nm. The result shows that the RTP crystal is an efficient crystal to generate eye-safe and mid-infrared lights by making full use of noncritical phase matching.
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Epstein-Barr virus infection induces indoleamine 2,3-dioxygenase expression in human monocyte-derived macrophages through p38/mitogen-activated protein kinase and NF-?B pathways: impairment in T cell functions.
J. Virol.
PUBLISHED: 04-02-2014
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Epstein-Barr virus (EBV) infection has been observed in tumor-infiltrated macrophages, but its infection effects on macrophage immune functions are poorly understood. Here, we showed that some macrophages in the tumor stroma of nasopharyngeal carcinoma (NPC) tissue expressed the immunosuppressive protein indoleamine 2,3-dioxygenase (IDO) more strongly than did tumor cells. EBV infection induced mRNA, protein, and enzymatic activity of IDO in human monocyte-derived macrophages (MDMs). Infection increased the production of tumor necrosis factor alpha (TNF-?) and interleukin-6 (IL-6), whereas the neutralizing antibodies against TNF-? and IL-6 inhibited IDO induction. EBV infection also activated the mitogen-activated protein kinase (MAPK) p38 and NF-?B, and the inhibition of these two pathways with SB202190 and SN50 almost abrogated TNF-? and IL-6 production and inhibited IDO production. Moreover, the activation of IDO in response to EBV infection of MDMs suppressed the proliferation of T cells and impaired the cytotoxic activity of CD8(+) T cells, whereas the inhibition of IDO activity with 1-methyl-l-tryptophan (1-MT) did not affect T cell proliferation and function. These findings indicate that EBV-induced IDO expression in MDMs is substantially mediated by IL-6- and TNF-?-dependent mechanisms via the p38/MAPK and NF-?B pathways, suggesting that a possible role of EBV-mediated IDO expression in tumor stroma of NPC may be to create a microenvironment of suppressed T cell immune responses.
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Manipulation of linearly polarized states in a diode-pumped YAG/Tm:YAG/YAG bulk laser.
Opt Lett
PUBLISHED: 04-02-2014
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We experimentally demonstrated the manipulation of 2 ?m linearly polarized states in a diode-pumped YAG/Tm:YAG/YAG laser with high polarization extinction ratio of 28 dB for the very first time to the best of our knowledge. A stable linearly polarized state of 2 ?m was achieved without using any specific intracavity optical polarization-selected elements. The unexpected phenomenon of tunable linear polarization directions was observed. Multidistinct linear polarization directions were experimentally obtained, including the peculiar case of switchable orthogonally linear polarization directions.
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Simultaneous multi-analyte urinary protein assay for bladder cancer detection.
BMC Biotechnol.
PUBLISHED: 03-28-2014
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The ability to accurately measure multiple proteins simultaneously in a single assay has the potential to markedly improve the efficiency of a myriad of clinical assays. Here, we tested the performance of a new, multiplex protein array platform to quantitate three bladder cancer-associated proteins in urine samples. The following analytes, interleukin 8 (IL8), matrix metallopeptidase 9 (MMP9), and vascular endothelial growth factor A (VEGFA) were monitored using Q-plex, a customized multiplex ELISA system from Quansys Biosciences, and individual target commercial ELISA kits. The performance of the two approaches was compared by evaluating the diagnostic accuracy of the biomarker assays in samples from a cohort of 73 subjects of known bladder cancer status.
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Identification of potential pathways involved in the induction of cell cycle arrest and apoptosis by a new 4-arylidene curcumin analogue T63 in lung cancer cells: a comparative proteomic analysis.
Mol Biosyst
PUBLISHED: 03-20-2014
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Curcumin (diferuloylmethane) is a polyphenol natural product of the plant Curcuma longa, and has a diversity of antitumor activities. However, the clinical application of curcumin remains limited due to its poor pharmacokinetic characteristics. It is therefore critical to develop structural analogues of curcumin with increasing anticancer activity. T63, a new 4-arylidene curcumin analogue, was synthesized in our previous studies and exhibited higher in vitro and in vivo anti-tumor activities compared to curcumin. However, the precise molecular mechanism of its anti-tumor effects has not been well elucidated. Using a two-dimensional gel electrophoresis (2-DE)-based proteomic approach, we identified 66 differentially expressed proteins. Similarly to curcumin, T63 showed a diverse range of molecular targets. We proposed that induction of ROS generation and mitochondrial dysfunction, inhibition of proteasome, HSP90, and 14-3-3 proteins play important roles in T63-induced cell cycle arrest and apoptosis. These data indicate that the novel curcumin analogue T63 is a potent anti-tumor agent, which can induce cell cycle arrest and apoptosis, and also provided valuable resources for further study of the anti-tumor effects and molecular mechanisms of T63.
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Physiological effects of microgravity on bone cells.
Calcif. Tissue Int.
PUBLISHED: 03-12-2014
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Life on Earth developed under the influence of normal gravity (1g). With evidence from previous studies, scientists have suggested that normal physiological processes, such as the functional integrity of muscles and bone mass, can be affected by microgravity during spaceflight. During the life span, bone not only develops as a structure designed specifically for mechanical tasks but also adapts for efficiency. The lack of weight-bearing forces makes microgravity an ideal physical stimulus to evaluate bone cell responses. One of the most serious problems induced by long-term weightlessness is bone mineral loss. Results from in vitro studies that entailed the use of bone cells in spaceflights showed modification in cell attachment structures and cytoskeletal reorganization, which may be involved in bone loss. Humans exposed to microgravity conditions experience various physiological changes, including loss of bone mass, muscle deterioration, and immunodeficiency. In vitro models can be used to extract valuable information about changes in mechanical stress to ultimately identify the different pathways of mechanotransduction in bone cells. Despite many in vivo and in vitro studies under both real microgravity and simulated conditions, the mechanism of bone loss is still not well defined. The objective of this review is to summarize the recent research on bone cells under microgravity conditions based on advances in the field.
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Effect of spinal cord extracts after spinal cord injury on proliferation of rat embryonic neural stem cells and Notch signal pathway in vitro.
Asian Pac J Trop Med
PUBLISHED: 03-10-2014
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To investigate the effect of the spinal cord extracts (SCE) after spinal cord injuries (SCIs) on the proliferation of rat embryonic neural stem cells (NSCs) and the expressions of mRNA of Notch1 as well as of Hes1 in this process in vitro.
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Flavone-based ESIPT ratiometric chemodosimeter for detection of cysteine in living cells.
ACS Appl Mater Interfaces
PUBLISHED: 03-06-2014
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We have designed and synthesized a novel ratiometric fluorescent chemodosimeter MHF-based ESIPT process for specific detection of cysteine among the biological thiols. The probe MHF shows very weak blue fluorescence under UV excitation. Upon addition of cysteine (Cys), the reaction of Cys with MHF induces acrylate hydrolysis, thereby enabling the ESIPT process to shift the weak blue emission to a strong green emission with about 20-fold enhancement. We utilized (1)H NMR spectra to elucidate the fluorescence sensing mechanism. Moreover, the cellular imaging experiment indicated the MHF possessed excellent selectivity, low cytotoxicity, and desirable cell permeability for biological applications.
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Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma.
J. Clin. Invest.
PUBLISHED: 02-24-2014
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Melanomas that result from mutations in the gene encoding BRAF often become resistant to BRAF inhibition (BRAFi), with multiple mechanisms contributing to resistance. While therapy-induced autophagy promotes resistance to a number of therapies, especially those that target PI3K/mTOR signaling, its role as an adaptive resistance mechanism to BRAFi is not well characterized. Using tumor biopsies from BRAF(V600E) melanoma patients treated either with BRAFi or with combined BRAF and MEK inhibition, we found that BRAFi-resistant tumors had increased levels of autophagy compared with baseline. Patients with higher levels of therapy-induced autophagy had drastically lower response rates to BRAFi and a shorter duration of progression-free survival. In BRAF(V600E) melanoma cell lines, BRAFi or BRAF/MEK inhibition induced cytoprotective autophagy, and autophagy inhibition enhanced BRAFi-induced cell death. Shortly after BRAF inhibitor treatment in melanoma cell lines, mutant BRAF bound the ER stress gatekeeper GRP78, which rapidly expanded the ER. Disassociation of GRP78 from the PKR-like ER-kinase (PERK) promoted a PERK-dependent ER stress response that subsequently activated cytoprotective autophagy. Combined BRAF and autophagy inhibition promoted tumor regression in BRAFi-resistant xenografts. These data identify a molecular pathway for drug resistance connecting BRAFi, the ER stress response, and autophagy and provide a rationale for combination approaches targeting this resistance pathway.
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The role of indoleamine 2,3-dioxygenase (IDO) in immune tolerance: focus on macrophage polarization of THP-1 cells.
Cell. Immunol.
PUBLISHED: 02-23-2014
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Macrophages can be divided into two groups as M1 and M2 phenotype. Our results and other groups revealed that IFN-? can up-regulate the IDO expression and differentiate THP-1 cells to M1 phenotype. Therefore we hypothesized that IDO may play potential roles in macrophage differentiation. Interesting, our results indicated that the ectopic IDO increases the expression of M2 markers such as IL-10 and CXCR4 while decreases the M1 markers such as CCR7 and IL-12p35. In contrast, the knockdown of IDO expression in THP-1 cells resulted in increased M1 markers and lower M2 markers. Our results suggested that the expression intensity of IDO modulates macrophages differentiation. These finding support the counter-regulatory role for IDO with regarding to the polarization of macrophages to restrain excessive or inappropriate immune activation in inflammatory or tumor microenvironment. It throws new light on the mechanisms about the immunosuppressive effect of IDO in tumor or inflammatory diseases.
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Identification of ?2-macroglobulin as a master inhibitor of cartilage-degrading factors that attenuates the progression of posttraumatic osteoarthritis.
PUBLISHED: 02-20-2014
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To determine if supplemental intraarticular ?2-macroglobulin (?2 M) has a chondroprotective effect in a rat model of osteoarthritis (OA).
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The ErbB2-targeting antibody trastuzumab and the small-molecule SRC inhibitor saracatinib synergistically inhibit ErbB2-overexpressing gastric cancer.
MAbs
PUBLISHED: 02-05-2014
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The anti-ErbB2 antibody trastuzumab has shown significant clinical benefits in ErbB2-overexpressing breast and gastric cancer, but resistance to the drug is common. Here, we investigated the antitumor activity of the combination of trastuzumab and the SRC inhibitor saracatinib in ErbB2-overexpressing trastuzumab-resistant gastric cancer. The ErbB2-overexpressing human gastric cancer cell line NCI-N87 was treated with trastuzumab to obtain the trastuzumab-resistant cell line NCI-N87R. The NCI-N87R cell line showed a marked increase in SRC activity and ErbB signaling compared with the NCI-N87 cell line. Our data demonstrated that trastuzumab plus saracatinib was much more potent than either agent alone in reducing the phosphorylation of ErbB3 and AKT in both NCI-N87 and NCI-N87R gastric cancer cell lines. Trastuzumab and saracatinib synergistically inhibited the in vitro growth of NCI-N87 and NCI-N87R cell lines. Further data showed that combination therapy of trastuzumab with saracatinib resulted in a significant benefit over either agent alone in both NCI-N87 and NCI-N87R xenograft models, suggesting its potential use for treating ErbB2-overexpressing gastric cancer.
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Protein Kinase C Inhibitor, GF109203X Attenuates Osteoclastogenesis, Bone Resorption and RANKL-induced NF-?B and NFAT activity.
J. Cell. Physiol.
PUBLISHED: 01-29-2014
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Osteolytic bone diseases are characterized by excessive osteoclast formation and activation. Protein kinase C (PKC)-dependent pathways regulate cell growth, differentiation and apoptosis in many cellular systems, and have been implicated in cancer development and osteoclast formation. A number of PKC inhibitors with anti-cancer properties have been developed, but whether they might also influence osteolysis (a common complication of bone invading cancers) is unclear. We studied the effects of the PKC inhibitor compound, GF109203X on osteoclast formation and activity, processes driven by receptor activator of NF?B ligand (RANKL). We found that GF109203X strongly and dose dependently suppresses osteoclastogenesis and osteoclast activity in RANKL-treated primary mouse bone marrow cells. Consistent with this GF109203X reduced expression of key osteoclastic genes, including cathepsin K, calcitonin receptor, tartrate resistant acid phosphatase (TRAP) and the proton pump subunit V-ATPase-d2 in RANKL-treated primary mouse bone marrow cells. Expression of these proteins is dependent upon RANKL-induced NF-?B and NFAT transcription factor actions; both were reduced in osteoclast progenitor populations by GF109203X treatment, notably NFATc1 levels. Furthermore, we showed that GF109203X inhibits RANKL-induced calcium oscillation. Together, this study shows GF109203X may block osteoclast functions, suggesting that pharmacological blockade of PKC-dependent pathways has therapeutic potential in osteolytic diseases. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
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Palladium-catalyzed oxidative carbonylation of N-allylamines for the synthesis of ?-lactams.
Angew. Chem. Int. Ed. Engl.
PUBLISHED: 01-28-2014
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?-Lactam scaffolds are considered to be ideal building blocks for the synthesis of nitrogen-containing compounds. A new palladium-catalyzed oxidative carbonylation of N-allylamines for the synthesis of ?-methylene-?-lactams is reported. DFT calculations suggest that the formation of ?-lactams via a four-membered-ring transition state is favorable.
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Maximizing integrated optical and electrical properties of a single ZnO nanowire through native interfacial doping.
Adv. Mater. Weinheim
PUBLISHED: 01-22-2014
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A native interfacial doping layer introduced in core-shell type ZnO nano-wires by a simple vapor phase re-growth procedure endows the produced nano-wires with both excellent electrical and optical performances compared to conventional homogeneous ZnO nanowires. The unique Zn-rich interfacial structure in the core-shell nanowires plays a crucial role in the outstanding performances.
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Design, synthesis, and SAR of embelin analogues as the inhibitors of PAI-1 (plasminogen activator inhibitor-1).
Bioorg. Med. Chem. Lett.
PUBLISHED: 01-20-2014
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The natural product embelin was found to have PAI-1 inhibitory activity with the IC50 value of 4.94?M. Based on the structure of embelin, a series of analogues were designed, synthesized, and evaluated for their ability to inhibit PAI-1. The SAR study on these compounds disclosed that the inhibitory potency largely depended on the hydroxyl groups at C2 and C5, and the length of the alkyl chains at C3 and C6. Compound 11 displayed the best PAI-1 inhibitory potency with the IC50 value of 0.18?M.
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Involvement of activating ERK1/2 through G protein coupled receptor 30 and estrogen receptor ?/? in low doses of bisphenol A promoting growth of Sertoli TM4 cells.
Toxicol. Lett.
PUBLISHED: 01-14-2014
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Sertoli cells play a pivotal role in supporting proliferation of germ cells and differentiation during spermatogenesis in mammals. Nanomolar concentrations of Bisphenol A (BPA) can significantly stimulate the proliferation of mouse immature Sertoli (TM4) cells. However, mechanisms by which BPA caused these effects were still unclear. In the present study, an inverse U-shaped curve was observed when treating TM4 cells with increasing doses of BPA: 1 to 10nM BPA significantly stimulated the proliferation of TM4 cells and increased the proportion of cells in S phase; >1 ?M BPA caused lesser proliferation of cells. Exposure of TM4 cells to G15 or ICI 182,780, which are specific antagonists of GPR30 and estrogen receptor ?/? (ER?/?), respectively, abolished BPA-induced proliferation of cells, which suggests that both GPR30 and ER?/? were involved in the observed effects of BPA. Furthermore, exposure to BPA caused rapid (5 min) activation of ERK1/2 via both GPR30 and ER?/?. Blocking the GPR30/EGFR signal transduction pathway by antagonists suppressed both phosphorylation of ERK and BPA-induced cell proliferation. BPA up-regulated mRNA and protein expression of GPR30 in a concentration-dependent manner. In summary, the results reported here indicated that activating ERK1/2 through GPR30 and ER?/? is involved in low doses of BPA that promoted growth of Sertoli TM4 cells. The GPR30/EGFR/ERK signal is the downstream transduction pathway in BPA-induced proliferation of TM4 Sertoli cells.
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Synthesis of 6-acyl phenanthridines by oxidative radical decarboxylation-cyclization of ?-oxocarboxylates and isocyanides.
Chem. Commun. (Camb.)
PUBLISHED: 01-14-2014
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A silver catalysed synthesis of 6-acyl phenanthridines by oxidative radical decarboxylation-cyclization of ?-oxocarboxylates and isocyanides was developed. This reaction provided a novel method to realize C1 insertion via a radical process and various functional groups were well-tolerated.
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Matrix metalloproteinase-10 promotes tumor progression through regulation of angiogenic and apoptotic pathways in cervical tumors.
BMC Cancer
PUBLISHED: 01-13-2014
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Cancer invasion and metastasis develops through a series of steps that involve the loss of cell to cell and cell to matrix adhesion, degradation of extracellular matrix and induction of angiogenesis. Different protease systems (e.g., matrix metalloproteinases, MMPs) are involved in these steps. MMP-10, one of the lesser studied MMPs, is limited to epithelial cells and can facilitate tumor cell invasion by targeting collagen, elastin and laminin. Enhanced MMP-10 expression has been linked to poor clinical prognosis in some cancers, however, mechanisms underlying a role for MMP-10 in tumorigenesis and progression remain largely unknown. Here, we report that MMP-10 expression is positively correlated with the invasiveness of human cervical and bladder cancers.
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Direct observation of reduction of Cu(II) to Cu(I) by terminal alkynes.
J. Am. Chem. Soc.
PUBLISHED: 01-10-2014
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X-ray absorption spectroscopy and in situ electron paramagnetic resonance evidence were provided for the reduction of Cu(II) to Cu(I) species by alkynes in the presence of tetramethylethylenediamine (TMEDA), in which TMEDA plays dual roles as both ligand and base. The structures of the starting Cu(II) species and the obtained Cu(I) species were determined as (TMEDA)CuCl2 and [(TMEDA)CuCl]2 dimer, respectively.
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The regional myocardial microvascular dysfunction differences in hypertrophic cardiomyopathy patients with or without left ventricular outflow tract obstruction: assessment with first-pass perfusion imaging using 3.0-T cardiac magnetic resonance.
Eur J Radiol
PUBLISHED: 01-05-2014
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To assess regional myocardial microvascular dysfunction differences in hypertrophic cardiomyopathy (HCM) patients with or without left ventricular outflow tract obstruction using 3.0-T cardiac magnetic resonance (CMR) first-pass perfusion imaging.
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Sedum sarmentosum Bunge extract exerts renal anti-fibrotic effects in vivo and in vitro.
Life Sci.
PUBLISHED: 01-03-2014
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Sedum sarmentosum Bunge, a traditional Chinese herbal medicine, has a wide range of clinical effects, including anti-oxidation, anti-inflammation, and anti-cancer properties. In this study, we determined whether S. sarmentosum Bunge Extract (SSBE) has anti-fibrotic effects on renal tissues.
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Impaired Autophagy Contributes to Adverse Cardiac Remodeling in Acute Myocardial Infarction.
PLoS ONE
PUBLISHED: 01-01-2014
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Autophagy is activated in ischemic heart diseases, but its dynamics and functional roles remain unclear and controversial. In this study, we investigated the dynamics and role of autophagy and the mechanism(s), if any, during postinfarction cardiac remodeling.
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Intravesical ALT-803 and BCG treatment reduces tumor burden in a carcinogen induced bladder cancer rat model; a role for cytokine production and NK cell expansion.
PLoS ONE
PUBLISHED: 01-01-2014
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Intravesical Bacillus Calmette-Guérin (BCG) has been shown to induce a specific immunologic response (i.e., activation of IL-2 and effector T-cells), while preclinical studies using ALT-803 (mutated IL-15 analogue combined with IL-15R?-Fc fusion) have shown promising results by prolonging the agent's half-life and stimulating CD8+ T-cells. Based on these results, we hypothesized that the intravesical administration of ALT-803 along with BCG will generate an immunologic response leading to significant bladder tumor burden reduction. Using a well-established carcinogen induced rat non-muscle invasive bladder cancer (NMIBC) model, we studied the effects of intravesical ALT-803 with and without BCG. Rat tissues were evaluated to document treatment response. Intravesical ALT-803 was safe and well tolerated alone and in combination with BCG. As a single treatment agent, ALT-803 reduced tumor burden by 35% compared to control whereas BCG alone only reduced tumor burden by 15%. However, the combination of ALT-803 plus BCG reduced tumor burden by 46% compared to control. Immune monitoring suggested that the antitumor response was linked to the production and secretion of IL-1?, IL-1? and RANTES, which in turn, induced the proliferation and activation of NK cells. Lastly, tumoral responses of the combinational treatment were associated with 76% reduction in angiogenesis, which is significantly higher than when assessed with either agent alone. The enhanced therapeutic index seen with this duplet provides justification for the development of this regimen for future clinical trials.
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Cardiac differentiation of cardiosphere-derived cells in scaffolds mimicking morphology of the cardiac extracellular matrix.
Acta Biomater
PUBLISHED: 01-01-2014
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Stem cell therapy has the potential to regenerate heart tissue after myocardial infarction (MI). The regeneration is dependent upon cardiac differentiation of the delivered stem cells. We hypothesized that timing of the stem cell delivery determines the extent of cardiac differentiation as cell differentiation is dependent on matrix properties such as biomechanics, structure and morphology, and these properties in cardiac extracellular matrix (ECM) continuously vary with time after MI. In order to elucidate the relationship between ECM properties and cardiac differentiation, we created an in vitro model based on ECM-mimicking fibers and a type of cardiac progenitor cell, cardiosphere-derived cells (CDCs). A simultaneous fiber electrospinning and cell electrospraying technique was utilized to fabricate constructs. By blending a highly soft hydrogel with a relatively stiff polyurethane and modulating fabrication parameters, tissue constructs with similar cell adhesion property but different global modulus, single fiber modulus, fiber density and fiber alignment were achieved. The CDCs remained alive within the constructs during a 1week culture period. CDC cardiac differentiation was dependent on the scaffold modulus, fiber volume fraction and fiber alignment. Two constructs with relatively low scaffold modulus, ?50-60kPa, most significantly directed the CDC differentiation into mature cardiomyocytes as evidenced by gene expressions of cardiac troponin T (cTnT), calcium channel (CACNA1c) and cardiac myosin heavy chain (MYH6), and protein expressions of cardiac troponin I (cTnI) and connexin 43 (CX43). Of these two low-modulus constructs, the extent of differentiation was greater for lower fiber alignment and higher fiber volume fraction. These results suggest that cardiac ECM properties may have an effect on cardiac differentiation of delivered stem cells.
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Japanese medaka: a non-mammalian vertebrate model for studying sex and age-related bone metabolism in vivo.
PLoS ONE
PUBLISHED: 01-01-2014
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In human, a reduction in estrogen has been proposed as one of the key contributing factors for postmenopausal osteoporosis. Rodents are conventional models for studying postmenopausal osteoporosis, but the major limitation is that ovariectomy is needed to mimic the estrogen decline after menopause. Interestingly, in medaka fish (Oryzias latipes), we observed a natural drop in plasma estrogen profile in females during aging and abnormal spinal curvature was apparent in old fish, which are similar to postmenopausal women. It is hypothesized that estrogen associated disorders in bone metabolism might be predicted and prevented by estrogen supplement in aging O. latipes, which could be corresponding to postmenopausal osteoporosis in women.
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Facile Fabrication of PEDOT:PSS/Polythiophenes Bilayered Nanofilms on Pure Organic Electrodes and Their Thermoelectric Performance.
ACS Appl Mater Interfaces
PUBLISHED: 12-12-2013
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A pure organic PEDOT:PSS nanofilm was used as a working electrode for the first time to electrodeposit polymer films of polythiophene (PTh) and its derivatives in a boron trifluoride diethyl ether (BFEE) solution, fabricating a novel generation of bilayered nanofilms. Cyclic voltammetry (CV) demonstrated good electrochemical stability of the as-formed films. Structures and surface morphologies were systematically investigated by the characterizations of cross-section SEM, FT-IR, UV-vis, SEM, and AFM. The resulting films revealed stable and enhanced thermoelectric (TE) performances. The electrical conductivity values of PEDOT:PSS/PTh, PEDOT:PSS/P3MeT, and PEDOT:PSS/P3HT nanofilms were determined to be 123.9, 136.5, and 200.5 S cm(-1), respectively. The power factor reached up to be a maximum value of 5.79 ?W m(-1) k(-2). Thus, this technique offers a facile approach to a class of bilayered nanofilms, and it may provide a general strategy for fabricating a new generation of conducting polymers for more practical applications.
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Diagnosis and treatment of traumatic internal carotid artery pseudoaneurysm primarily manifested by repeated epistaxis.
Turk Neurosurg
PUBLISHED: 12-07-2013
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The current study aims to explore the diagnosis and treatment of traumatic internal carotid artery pseudoaneurysm (TICAP) primarily manifested by repeated epistaxis. MATERIAL and
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Spontaneous picosecond pulse generation in a diode-pumped Nd:YAP laser.
Opt Express
PUBLISHED: 10-24-2013
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We present the first observation, to the best of our knowledge, the spontaneous generation of picoseconds pulse trains in a diode-pumped Nd:YAP laser with gigahertz repetition rate. Spatially dependent temporal dynamics were experimentally observed. After theoretically reconstruct the experimental temporal-resolved patterns, we verify that the complicated spatially-dependent temporal dynamics were originated from simultaneous coherent locking combination of fundamental and several additional higher-order transverse modes.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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