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Find video protocols related to scientific articles indexed in Pubmed.
YM500v2: a small RNA sequencing (smRNA-seq) database for human cancer miRNome research.
Nucleic Acids Res.
PUBLISHED: 11-16-2014
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We previously presented YM500, which is an integrated database for miRNA quantification, isomiR identification, arm switching discovery and novel miRNA prediction from 468 human smRNA-seq datasets. Here in this updated YM500v2 database (http://ngs.ym.edu.tw/ym500/), we focus on the cancer miRNome to make the database more disease-orientated. New miRNA-related algorithms developed after YM500 were included in YM500v2, and, more significantly, more than 8000 cancer-related smRNA-seq datasets (including those of primary tumors, paired normal tissues, PBMC, recurrent tumors, and metastatic tumors) were incorporated into YM500v2. Novel miRNAs (miRNAs not included in the miRBase R21) were not only predicted by three independent algorithms but also cleaned by a new in silico filtration strategy and validated by wetlab data such as Cross-Linked ImmunoPrecipitation sequencing (CLIP-seq) to reduce the false-positive rate. A new function 'Meta-analysis' is additionally provided for allowing users to identify real-time differentially expressed miRNAs and arm-switching events according to customer-defined sample groups and dozens of clinical criteria tidying up by proficient clinicians. Cancer miRNAs identified hold the potential for both basic research and biotech applications.
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Rhizobium alvei sp. nov., isolated from a freshwater river.
Int. J. Syst. Evol. Microbiol.
PUBLISHED: 11-12-2014
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A bacterial strain designated TNR-22T was isolated from freshwater river in Taiwan and characterized using the polyphasic taxonomy approach. Cells of strain TNR-22T were faculative anaerobic, Gram-stain-negative, rod-shaped, motile by a single polar flagellum and forming cream colored colonies. Growth occurred at 4-45 °C (optimum, 25-30 °C), with 0-1.0 % NaCl (optimum, 0.5 %) and at pH 7.0-8.0 (optimum, pH 7.0). Strain TNR-22T did not form nodules on a legume plant, Macroptilium atropurpureum. The nifH gene encoding denitrogenase reductase was not detected by PCR. The major fatty acids (?10 %) of strain TNR-22T were C18:1 ?7c and C16:0. The DNA G+C content was 60.3 mol%. The polar lipid profile consisted of a mixture of phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, diphosphatidylglycerol, an uncharacterized aminoglycolipid and an uncharacterized phospholipid. Comparative analysis of the 16S rRNA gene sequences showed that strain TNR-22T constituted a distinct branch within the genus Rhizobium, showing the highest level of sequence similarity with respect to Rhizobium rosettiformans W3T (96.3 %). Phenotypic characteristics of the novel strain also differed from those of the closest related species of the genus Rhizobium. On the basis of the genotypic, chemotaxonomic and phenotypic data, strain TNR-22T represents a novel species in the genus Rhizobium, for which the name Rhizobium alvei sp. nov. is proposed. The type strain is TNR-22T (=BCRC 80408T =LMG 26895T =KCTC 23919T).
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AMACR amplification in myxofibrosarcomas: a mechanism of overexpression that promotes cell proliferation with therapeutic relevance.
Clin. Cancer Res.
PUBLISHED: 11-12-2014
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Purpose: Myxofibrosarcomas frequently display arm-level gains on 5p. We characterized the pathogenetic and therapeutic relevance of the alpha-methylacyl coenzyme A racemase (AMACR) at 5p13.3. Experimental Design: AMACR mRNA expression in myxofibrosarcomas was analyzed using the public transcriptome and laser-microdissected sarcoma cells. We performed FISH and immunohistochemistry in independent samples for clinical correlates. In AMACR-overexpressing myxofibrosarcoma cells and xenografts, we elucidated the biological function of AMACR using RNA interference and explored the therapeutic effect and mechanism of an AMACR inhibitor, ebselen oxide (EO). Results: AMACR protein overexpression and gene amplification were significantly associated with each other (p<0.001), with higher tumor grades (both p?0.002), and univariately with worse metastasis-free survival (MFS, both p<0.0001) and disease-specific survival (DSS, p=0.0002 for overexpression; p=0.0062 for amplification). AMACR protein overexpression also independently portended adverse outcome (DSS, p=0.007; MFS, p=0.001). However, 39% of AMACR-overexpression cases did not show gene amplification, implying alternative regulatory mechanisms. In myxofibrosarcoma cell lines, stable AMACR knockdown suppressed cell proliferation, anchorage-independent growth, and expression of cyclin D1 and cyclin T2. These growth-promoting attributes of AMACR were corroborated in the AMACR-silenced xenograft model and AMACR-underexpressed myxofibrosarcomas, showing decreased labeling for cyclin D1, cyclin T2, and Ki-67. Compared to fibroblasts, AMACR-expressing myxofibrosarcoma cells were more susceptible to EO, which not only decreased viable cells, promoted proteasome-mediated degradation of AMACR protein, and induced cellular apoptosis in vitro but also dose-dependently suppressed xenografted tumor growth in vivo. Conclusions: Overexpressed AMACR in myxofibrosarcomas can be amplification-driven, associated with tumor aggressiveness, and may be relevant as a druggable target.
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Anthracene/Phenothiazine ?-Conjugated Sensitizers for Dye-Sensitized Solar Cells using Redox Mediator in Organic and Water-based Solvents.
ChemSusChem
PUBLISHED: 09-18-2014
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Metal-free dyes (MD1 to MD5) containing an anthracene/phenothiazine unit in the spacer have been synthesized. The conversion efficiency (7.13?%) of the dye-sensitized solar cell using MD3 as the sensitizer reached approximately 85?% of the N719-based standard cell (8.47?%). The cell efficiency (8.42?%) of MD3-based dye-sensitized solar cells (DSSCs) with addition of chenodeoxycholic acid is comparable with that of N719-based standard cell. The MD3 water-based DSSCs using a dual-TEMPO (2,2,6,6-tetramethylpiperidine-N-oxyl)/iodide electrolyte exhibited very promising cell performance of 4.96?% with an excellent Voc of 0.77?V.
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Dipyrone & 2,5-dimethylcelecoxib suppress Th2-related chemokine production in monocyte.
Indian J. Med. Res.
PUBLISHED: 09-16-2014
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Selective cyclooxygenase-2 (COX-2) inhibitor is a form of thnon steroidal anti-inflammatory drug (NSAID) and is commonly used in autoimmune and rheumatic diseases to control inflammation and alleviate pain. Tumour necrosis factor-alpha (TNF-?) production and an imbalance of T helper 1 (Th1)/Th2 contribute to the pathogenesis of autoimmune and also anti-tumour activity. Dipyrone is a NSAID used to treat pain worldwide. The celecoxib analogue, 2,5-dimethylcelecoxib (DMC), lacks COX-2 inhibitory activity but exhibits anti-tumour properties. However, the effects and the mechanisms of dipyrone and 2,5-dimethylcelecoxib on tumour necrosis factor (TNF)-? and Th1- and Th2-related chemokines in monocytes remain poorly defined. This study was carried out to investigate the effects of dipyrone and 2,5-dimethylcelecoxib on the expression of Th1 (IP-10) and Th2 (I-309 and MDC) and TNF-? in human monocytes and the associated intracellular mechanism.
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Effects of sumatriptan nasal spray (Imigran) on isolated rat's tracheal smooth muscle.
Eur Arch Otorhinolaryngol
PUBLISHED: 09-10-2014
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Sumatriptan (Imigran) is a potent and highly selective 5-HT1 receptor agonist often used in treating acute migraine. Intranasal sumatriptan is well absorbed and is generally effective in relieving headache. However, the effects of Imigran given intratracheally have rarely been well explored. We aimed to verify the effect of Imigran, which acts on the tracheal smooth muscle directly in vitro. We examined the effectiveness of Imigran on isolated rat tracheal smooth muscle by testing: (1) effect on tracheal smooth muscle resting tension; (2) effect on contraction caused by 10(-6) M methacholine as a parasympathetic mimetic; (3) effect of the drugs on electrically induced tracheal smooth muscle contractions. The results indicated that the addition of methacholine to the incubation medium caused the trachea to contract in a dose-dependent manner. The addition of Imigran at doses of 10(-5) M or above elicited a significant relaxation response to 10(-6) M methacholine-induced contraction. Imigran could inhibit electrical field stimulation-induced spike contraction. It also had a minimal effect on the basal tension of trachea as the concentration increased. The study indicated high concentrations of Imigran could cause bronchodilation to reduce asthma attacks not only by blocking parasympathetic tone, but also by directly antagonizing the effect of cholinergic receptors.
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Protective effects of Hericium erinaceus mycelium and its isolated erinacine A against ischemia-injury-induced neuronal cell death via the inhibition of iNOS/p38 MAPK and nitrotyrosine.
Int J Mol Sci
PUBLISHED: 08-27-2014
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Hericium erinaceus, an edible mushroom, has been demonstrated to potentiate the effects of numerous biological activities. The aim of this study was to investigate whether H. erinaceus mycelium could act as an anti-inflammatory agent to bring about neuroprotection using a model of global ischemic stroke and the mechanisms involved. Rats were treated with H. erinaceus mycelium and its isolated diterpenoid derivative, erinacine A, after ischemia reperfusion brain injuries caused by the occlusion of the two common carotid arteries. The production of inflammatory cytokines in serum and the infracted volume of the brain were measured. The proteins from the stroke animal model (SAM) were evaluated to determine the effect of H. erinaceus mycelium. H. erinaceus mycelium reduced the total infarcted volumes by 22% and 44% at a concentration of 50 and 300 mg/kg, respectively, compared to the SAM group. The levels of acute inflammatory cytokines, including interleukin-1?, interleukin-6 and tumor necrosis factor á, were all reduced by erinacine A. Levels of nitrotyrosine-containing proteins, phosphorylation of p38 MAPK and CCAAT enhancer-binding protein (C/EBP) and homologous protein (CHOP) expression were attenuated by erinacine A. Moreover, the modulation of ischemia injury factors present in the SAM model by erinacine A seemed to result in the suppression of reactive nitrogen species and the downregulation of inducible NO synthase (iNOS), p38 MAPK and CHOP. These findings confirm the nerve-growth properties of Hericium erinaceus mycelium, which include the prevention of ischemic injury to neurons; this protective effect seems to be involved in the in vivo activity of iNOS, p38 MAPK and CHOP.
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Effect of prostaglandin I2 analogs on monocyte chemoattractant protein-1 in human monocyte and macrophage.
Clin. Exp. Med.
PUBLISHED: 08-26-2014
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Chemokines play essential roles during inflammatory responses and in pathogenesis of inflammatory diseases. Monocyte chemotactic protein-1 (MCP-1) is a critical chemokine in the development of atherosclerosis and acute cardiovascular syndromes. MCP-1, by its chemotactic activity, causes diapedesis of monocytes from the lumen to the subendothelial space that leads to atherosclerotic plaque formation. Prostaglandin I2 (PGI2) analogs are used clinically for patients with pulmonary hypertension and have anti-inflammatory effects. However, little is known about the effect of PGI2 analogs on the MCP-1 production in human monocytes and macrophages. We investigated the effects of three conventional (iloprost, beraprost and treprostinil) and one new (ONO-1301) PGI2 analogs, on the expression of MCP-1 expression in human monocytes and macrophages. Human monocyte cell line, THP-1 cell, was treated with PGI2 analogs after LPS stimulation. Supernatants were harvested to measure MCP-1 levels and measured by ELISA. To explore which receptors involved the effects of PGI2 analogs on the expression of MCP-1 expression, IP and EP, PPAR-? and PPAR-? receptor antagonists were used. Forskolin, a cAMP activator, was used to further confirm the involvement of cAMP on MCP-1 production in human monocytes. Three PGI2 analogs suppressed LPS-induced MCP-1 production in THP-1 cells and THP-1-induced macrophages. Higher concentrations of ONO-1301 also had the suppressive effect. CAY 10449, an IP receptor antagonist, could reverse the effects on MCP-1 production of iloprost on THP-1 cells. Other reported PGI2 receptor antagonists including EP1, EP2, EP4, PPAR-? and PPAR-? antagonists could not reverse the effect. Forskolin, a cAMP activator, also suppressed MCP-1 production in THP-1 cells. PGI2 analogs suppressed LPS-induced MCP-1 production in human monocytes and macrophages via the IP receptor and cAMP pathway. The new PGI2 analog (ONO-1301) was not better than conventional PGI2 analog in the suppression of MCP-1 production in human monocytes.
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Arginine starvation-associated atypical cellular death involves mitochondrial dysfunction, nuclear DNA leakage, and chromatin autophagy.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 08-13-2014
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Autophagy is the principal catabolic prosurvival pathway during nutritional starvation. However, excessive autophagy could be cytotoxic, contributing to cell death, but its mechanism remains elusive. Arginine starvation has emerged as a potential therapy for several types of cancers, owing to their tumor-selective deficiency of the arginine metabolism. We demonstrated here that arginine depletion by arginine deiminase induces a cytotoxic autophagy in argininosuccinate synthetase (ASS1)-deficient prostate cancer cells. Advanced microscopic analyses of arginine-deprived dying cells revealed a novel phenotype with giant autophagosome formation, nucleus membrane rupture, and histone-associated DNA leakage encaptured by autophagosomes, which we shall refer to as chromatin autophagy, or chromatophagy. In addition, nuclear inner membrane (lamin A/C) underwent localized rearrangement and outer membrane (NUP98) partially fused with autophagosome membrane. Further analysis showed that prolonged arginine depletion impaired mitochondrial oxidative phosphorylation function and depolarized mitochondrial membrane potential. Thus, reactive oxygen species (ROS) production significantly increased in both cytosolic and mitochondrial fractions, presumably leading to DNA damage accumulation. Addition of ROS scavenger N-acetyl cysteine or knockdown of ATG5 or BECLIN1 attenuated the chromatophagy phenotype. Our data uncover an atypical autophagy-related death pathway and suggest that mitochondrial damage is central to linking arginine starvation and chromatophagy in two distinct cellular compartments.
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Sesamin suppresses macrophage-derived chemokine expression in human monocytes via epigenetic regulation.
Food Funct
PUBLISHED: 08-13-2014
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Chemokines play important roles in the pathogenesis of asthmatic inflammation. Sesamin, a class of phytoestrogen isolated from sesame seed Sesamum indicum, is recently regarded as an anti-inflammatory agent. However, the effects of sesamin on asthma-related chemokines are unknown. To this end, we investigated the effects of sesamin on the expression interferon-?-inducible protein-10 (IP-10/CXCL10), macrophage-derived chemokine (MDC/CCL22), growth-related oncogene-? (GRO-?/CXCL1) and tumor necrosis factor (TNF)-? in human monocytes.
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Steroids and antihistamines synergize to inhibit rat's airway smooth muscle contractility.
Eur Arch Otorhinolaryngol
PUBLISHED: 08-13-2014
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Both glucocorticoids and H1-antihistamines were widely used on patients with allergic rhinitis (AR) and obstructive airway diseases. However, their direct effects on airway smooth muscle were not fully explored. In this study, we tested the effectiveness of prednisolone (Kidsolone) and levocetirizine (Xyzal) on isolated rat trachea submersed in Kreb's solution in a muscle bath. Changes in tracheal contractility in response to the application of parasympathetic mimetic agents were measured. The following assessments of the drug were performed: (1) effect on tracheal smooth muscle resting tension; (2) effect on contraction caused by 10(-6) M methacholine; (3) effect of the drug on electrical field stimulation (EFS) induced tracheal smooth muscle contractions. The result revealed sole use of Kidsolone or Xyzal elicited no significant effect or only a little relaxation response on tracheal tension after methacholine treatment. The tension was 90.5 ± 7.5 and 99.5 ± 0.8 % at 10(-4) M for Xyzal and 10(-5) M for Kidsolone, respectively. However, a dramatically spasmolytic effect was observed after co-administration of Kidsolone and Xyzal and the tension dropped to 67.5 ± 13.6 %, with statistical significance (p < 0.05). As for EFS-induced contractions, Kidsolone had no direct effect but Xyzal could inhibit it, with increasing basal tension. In conclusion, using glucocorticoids alone had no spasmolytic effect but they can be synergized with antihistamines to dramatically relax the trachea smooth muscle within minutes. Therefore, for AR patients with acute asthma attack, combined use of those two drugs is recommended.
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Long Non-Coding RNA and Epigenetic Gene Regulation of KSHV.
Viruses
PUBLISHED: 08-01-2014
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Kaposi's sarcoma-associated herpesvirus (KSHV/human herpesvirus 8) is a ?-herpesvirus linked to Kaposi's sarcoma (KS) and two lymphoproliferative disorders, primary effusion lymphoma (PEL or body-cavity B-lymphoma [BCBL]) and a subset of Multicentric Castleman's Disease. During lytic growth, pervasive viral transcription generating a variety of transcripts with uncertain protein-coding potential has been described on a genome-wide scale in ?- and ?-herpesviruses. One class of such RNAs is called long non-coding RNAs (lncRNAs). KSHV encodes a viral lncRNA known as polyadenylated nuclear RNA (PAN RNA), a copious early gene product. PAN RNA has been implicated in KSHV gene expression, replication, and immune modulation. PAN RNA expression is required for optimal expression of the entire KSHV lytic gene expression program. Latent KSHV episomes are coated with viral latency-associated nuclear antigen (LANA). LANA rapidly dissociates from episomes during reactivation. Here we review recent studies suggesting that PAN RNA may function as a viral lncRNA, including a role in the facilitation of LANA-episomal dissociation during lytic replication.
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KDM4B as a target for prostate cancer: structural analysis and selective inhibition by a novel inhibitor.
J. Med. Chem.
PUBLISHED: 07-09-2014
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The KDM4/JMJD2 Jumonji C-containing histone lysine demethylases (KDM4A-KDM4D), which selectively remove the methyl group(s) from tri/dimethylated lysine 9/36 of H3, modulate transcriptional activation and genome stability. The overexpression of KDM4A/KDM4B in prostate cancer and their association with androgen receptor suggest that KDM4A/KDM4B are potential progression factors for prostate cancer. Here, we report the crystal structure of the KDM4B·pyridine 2,4-dicarboxylic acid·H3K9me3 ternary complex, revealing the core active-site region and a selective K9/K36 site. A selective KDM4A/KDM4B inhibitor, 4, that occupies three subsites in the binding pocket is identified by virtual screening. Pharmacological and genetic inhibition of KDM4A/KDM4B significantly blocks the viability of cultured prostate cancer cells, which is accompanied by increased H3K9me3 staining and transcriptional silencing of growth-related genes. Significantly, a substantial portion of differentially expressed genes are AR-responsive, consistent with the roles of KDM4s as critical AR activators. Our results point to KDM4 as a useful therapeutic target and identify a new inhibitor scaffold.
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SUMO and KSHV Replication.
Cancers (Basel)
PUBLISHED: 06-11-2014
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Small Ubiquitin-related MOdifier (SUMO) modification was initially identified as a reversible post-translational modification that affects the regulation of diverse cellular processes, including signal transduction, protein trafficking, chromosome segregation, and DNA repair. Increasing evidence suggests that the SUMO system also plays an important role in regulating chromatin organization and transcription. It is thus not surprising that double-stranded DNA viruses, such as Kaposi's sarcoma-associated herpesvirus (KSHV), have exploited SUMO modification as a means of modulating viral chromatin remodeling during the latent-lytic switch. In addition, SUMO regulation allows the disassembly and assembly of promyelocytic leukemia protein-nuclear bodies (PML-NBs), an intrinsic antiviral host defense, during the viral replication cycle. Overcoming PML-NB-mediated cellular intrinsic immunity is essential to allow the initial transcription and replication of the herpesvirus genome after de novo infection. As a consequence, KSHV has evolved a way as to produce multiple SUMO regulatory viral proteins to modulate the cellular SUMO environment in a dynamic way during its life cycle. Remarkably, KSHV encodes one gene product (K-bZIP) with SUMO-ligase activities and one gene product (K-Rta) that exhibits SUMO-targeting ubiquitin ligase (STUbL) activity. In addition, at least two viral products are sumoylated that have functional importance. Furthermore, sumoylation can be modulated by other viral gene products, such as the viral protein kinase Orf36. Interference with the sumoylation of specific viral targets represents a potential therapeutic strategy when treating KSHV, as well as other oncogenic herpesviruses. Here, we summarize the different ways KSHV exploits and manipulates the cellular SUMO system and explore the multi-faceted functions of SUMO during KSHV's life cycle and pathogenesis.
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Leveraging population admixture to characterize the heritability of complex traits.
Nat. Genet.
PUBLISHED: 06-09-2014
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Despite recent progress on estimating the heritability explained by genotyped SNPs (h(2)g), a large gap between h(2)g and estimates of total narrow-sense heritability (h(2)) remains. Explanations for this gap include rare variants or upward bias in family-based estimates of h(2) due to shared environment or epistasis. We estimate h(2) from unrelated individuals in admixed populations by first estimating the heritability explained by local ancestry (h(2)?). We show that h(2)? = 2FSTC?(1 - ?)h(2), where FSTC measures frequency differences between populations at causal loci and ? is the genome-wide ancestry proportion. Our approach is not susceptible to biases caused by epistasis or shared environment. We applied this approach to the analysis of 13 phenotypes in 21,497 African-American individuals from 3 cohorts. For height and body mass index (BMI), we obtained h(2) estimates of 0.55 ± 0.09 and 0.23 ± 0.06, respectively, which are larger than estimates of h(2)g in these and other data but smaller than family-based estimates of h(2).
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Interleukin-17 induces CC chemokine receptor 6 expression and cell migration in colorectal cancer cells.
J. Cell. Physiol.
PUBLISHED: 05-21-2014
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The CC chemokine receptor 6 (CCR6) and its ligand CCL20 are involved in human colorectal cancer (CRC) carcinogenesis and can promote the progression of CRC. In addition, interleukin-17 (IL-17), produced by a T cell subset named "Th17," has been identified as an important player in inflammatory responses, and has emerged as a mediator in inflammation-associated cancer. However, the relevance of IL-17 in the development and progression of CRC still remains to be explored. This study aimed to investigate the effect of IL-17 on the cell migration of CRC cells. Human CRC HCT-116 cells were used to study the effect of IL-17 on CCR6 expression and cell migration in CRC cells. IL-17 treatment induced migration of HCT-116 cells across the Boyden chamber membrane and increased the expression level of the CCR6. Inhibition of CCR6 by small interfering RNA (siRNA) and neutralizing antibody inhibited IL-17-induced cell migration. By using specific inhibitors and short hairpin RNA (shRNA), we demonstrated that the activation of ERK and p38 pathways are critical for IL-17-induced CCR6 expression and cell migration. Promoter activity and transcription factor ELISA assays showed that IL-17 increased NF-?B-DNA binding activity in HCT-116 cells. Inhibition of NF-?B activation by specific inhibitors and siRNA blocked the IL-17-induced CCR6 expression. Our findings support the hypothesis that CCR6 up-regulation stimulated by IL-17 may play an active role in CRC cell migration. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
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Generalizability of established prostate cancer risk variants in men of African ancestry.
Int. J. Cancer
PUBLISHED: 05-16-2014
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Genome-wide association studies have identified more than eighty risk variants for prostate cancer, mainly in European or Asian populations. The generalizability of these variants in other racial/ethnic populations needs to be understood before the loci can be utilized widely in risk modeling. In this study, we examined 82 previously reported risk variants in 4,853 prostate cancer cases and 4,678 controls of African ancestry. We performed association testing for each variant using logistic regression adjusted for age, study, and global ancestry. Of the 82 known risk variants, 68 (83%) had effects that were directionally consistent in their association with prostate cancer risk and 30 (37%) were significantly associated with risk at p<0.05, with the most statistically significant variants being rs116041037 (p=3.7×10(-26) ) and rs6983561 (p=1.1×10(-16) ) at 8q24, as well as rs7210100 (p=5.4×10(-8) ) at 17q21. By exploring each locus in search of better markers, the number of variants that captured risk in men of African ancestry (p<0.05) increased from 30 (37%) to 44 (54%). An aggregate score comprised of these 44 markers was strongly associated with prostate cancer risk (per-allele odds ratio (OR)=1.12, p=7.3×10(-98) ). In summary, the consistent directions of effects for the vast majority of variants in men of African ancestry indicate common functional alleles that are shared across populations. Further exploration of these susceptibility loci is needed to identify the underlying biologically relevant variants to improve prostate cancer risk modeling in populations of African ancestry. © 2014 Wiley Periodicals, Inc.
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Effects of the mTOR inhibitor Rapamycin on Monocyte-Secreted Chemokines.
BMC Immunol.
PUBLISHED: 04-18-2014
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BackgroundMammalian target of rapamycin (mTOR) inhibitors, such as sirolimus and its derivative, everolimus, are potent immunosuppressive and antiproliferative drugs. Inflammatory diseases are characterized by immunological dysfunction, and monocyte recruitment underlies the mechanism of cell damage. Chemokines attract inflammatory cells to sites of inflammation. Interleukin-8 (IL-8/CXCL8); the monocyte chemoattractant protein-1 (MCP-1/CCL2); the regulated on activation, normal T cell expressed, presumably secreted protein (RANTES/CCL5); the macrophage inflammatory protein (MIP)-1¿ (CCL3); and MIP-1ß (CCL4) are involved in the pathogenesis of inflammation. However, whether mTOR inhibitors moderate the production of chemokines in monocytes remains unclear.MethodsA human monocyte cell line, THP-1, and primary monocytes obtained from human volunteers, were stimulated using lipopolysaccharide (LPS), and then treated with sirolimus. The expression of the MCP-1, RANTES, IL-8, MIP-1¿, MIP-1ß, and TNF-¿ proteins was measured using enzyme-linked immunosorbent assays, and intracellular signalling was examined using western blotting.ResultsSirolimus significantly suppressed the LPS-induced expression of MCP-1, IL-8, RANTES, MIP-1¿, and MIP-1ß in the THP-1 cells and human primary monocytes. The mitogen-activated protein kinase (MAPK) inhibitors that were examined suppressed the LPS-induced expression of MCP-1, IL-8, RANTES, MIP-1¿, and MIP-1ß. In addition, sirolimus suppressed the LPS-induced phosphorylation of p38 and p65 in the THP-1 and human primary monocytes.ConclusionSirolimus downregulates the expression of chemokines in monocytes, including MCP-1, RANTES, IL-8, MIP-1¿, and MIP-1ß, by inhibiting the NF-¿B-p65 and MAPK-p38 signalling pathways.
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Arginine starvation impairs mitochondrial respiratory function in ASS1-deficient breast cancer cells.
Sci Signal
PUBLISHED: 04-03-2014
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Autophagy is the principal catabolic response to nutrient starvation and is necessary to clear dysfunctional or damaged organelles, but excessive autophagy can be cytotoxic or cytostatic and contributes to cell death. Depending on the abundance of enzymes involved in molecule biosynthesis, cells can be dependent on uptake of exogenous nutrients to provide these molecules. Argininosuccinate synthetase 1 (ASS1) is a key enzyme in arginine biosynthesis, and its abundance is reduced in many solid tumors, making them sensitive to external arginine depletion. We demonstrated that prolonged arginine starvation by exposure to ADI-PEG20 (pegylated arginine deiminase) induced autophagy-dependent death of ASS1-deficient breast cancer cells, because these cells are arginine auxotrophs (dependent on uptake of extracellular arginine). Indeed, these breast cancer cells died in culture when exposed to ADI-PEG20 or cultured in the absence of arginine. Arginine starvation induced mitochondrial oxidative stress, which impaired mitochondrial bioenergetics and integrity. Furthermore, arginine starvation killed breast cancer cells in vivo and in vitro only if they were autophagy-competent. Thus, a key mechanism underlying the lethality induced by prolonged arginine starvation was the cytotoxic autophagy that occurred in response to mitochondrial damage. Last, ASS1 was either low in abundance or absent in more than 60% of 149 random breast cancer biosamples, suggesting that patients with such tumors could be candidates for arginine starvation therapy.
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Effects of antidepressants on IP-10 production in LPS-activated THP-1 human monocytes.
Int J Mol Sci
PUBLISHED: 04-01-2014
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Major depressive disorder and cardiovascular disease are common serious illnesses worldwide. Selective serotonin reuptake inhibitors and norepinephrine-dopamine reuptake inhibitors may reduce the mortality of cardiovascular disease patients with comorbid depression. Interferon-?-inducible protein 10 (IP-10), a type 1 T helper cell (Th1)-related chemokine, contributes to manifestations of atherosclerosis during cardiovascular inflammations; however, the pathophysiological mechanisms linking cardiovascular disease and effective antidepressants have remained elusive. We investigated the in vitro effects of six different classes of antidepressants on the IP-10 chemokine expression in lipopolysaccharide (LPS)-stimulated monocytes, and their detailed intracellular mechanisms. The human monocytes were pretreated with antidepressants (10??-10?? M) before LPS-stimulation. IP-10 was measured by enzyme-linked immunosorbent assay (ELISA) and then intracellular signaling was investigated using Western blotting and chromatin immunoprecipitation. Fluoxetine and bupropion suppressed LPS-induced IP-10 expression in monocytes, and they had no cytotoxic effects. Furthermore, fluoxetine inhibited LPS-induced IP-10 expression via the mitogen-activated protein kinase (MAPK)-p38 pathway. Fluoxetine and bupropion could not only treat depression but also reduce Th1-related chemokine IP-10 production in human monocytes. Our results may indicate a possible mechanism related to how particular antidepressants reduce the risk of cardiovascular disease.
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The effects of environmental toxins on allergic inflammation.
Allergy Asthma Immunol Res
PUBLISHED: 03-27-2014
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The prevalence of asthma and allergic disease has increased worldwide over the last few decades. Many common environmental factors are associated with this increase. Several theories have been proposed to account for this trend, especially those concerning the impact of environmental toxicants. The development of the immune system, particularly in the prenatal period, has far-reaching consequences for health during early childhood, and throughout adult life. One underlying mechanism for the increased levels of allergic responses, secondary to exposure, appears to be an imbalance in the T-helper function caused by exposure to the toxicants. Exposure to environmental endocrine-disrupting chemicals can result in dramatic changes in cytokine production, the activity of the immune system, the overall Th1 and Th2 balance, and in mediators of type 1 hypersensitivity mediators, such as IgE. Passive exposure to tobacco smoke is a common risk factor for wheezing and asthma in children. People living in urban areas and close to roads with a high volume of traffic, and high levels of diesel exhaust fumes, have the highest exposure to environmental compounds, and these people are strongly linked with type 1 hypersensitivity disorders and enhanced Th2 responses. These data are consistent with epidemiological research that has consistently detected increased incidences of allergies and asthma in people living in these locations. During recent decades more than 100,000 new chemicals have been used in common consumer products and are released into the everyday environment. Therefore, in this review, we discuss the environmental effects on allergies of indoor and outside exposure.
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Activation of neutral-sphingomyelinase, MAPKs, and p75 NTR-mediating caffeic acid phenethyl ester-induced apoptosis in C6 glioma cells.
J. Biomed. Sci.
PUBLISHED: 03-25-2014
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Caffeic acid phenethyl ester (CAPE), a component of propolis, is reported to possess anti-inflammatory, anti-bacterial, anti-viral, and anti-tumor activities. Previously, our laboratory demonstrated the in vitro and in vivo bioactivity of CAPE and addressed the role of p53 and the p38 mitogen-activated protein kinase (MAPK) pathway in regulating CAPE-induced apoptosis in C6 glioma cells.
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Magnolol protects neurons against ischemia injury via the downregulation of p38/MAPK, CHOP and nitrotyrosine.
Toxicol. Appl. Pharmacol.
PUBLISHED: 03-20-2014
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Magnolol is isolated from the herb Magnolia officinalis, which has been demonstrated to exert pharmacological effects. Our aim was to investigate whether magnolol is able to act as an anti-inflammatory agent that brings about neuroprotection using a global ischemic stroke model and to determine the mechanisms involved. Rats were treated with and without magnolol after ischemia reperfusion brain injury by occlusion of the two common carotid arteries. The inflammatory cytokine production in serum and the volume of infarction in the brain were measured. The proteins present in the brains obtained from the stroke animal model (SAM) and control animal groups with and without magnolol treatment were compared. Magnolol reduces the total infarcted volume by 15% and 30% at dosages of 10 and 30mg/kg, respectively, compared to the untreated SAM group. The levels of acute inflammatory cytokines, including interleukin-1 beta, tumor necrosis factor alpha, and interleukin-6 were attenuated by magnolol. Magnolol was also able to suppress the production of nitrotyrosine, 4-hydroxy-2-nonenal (4-HNE), inducible NO synthase (iNOS), various phosphorylated p38 mitogen-activated protein kinases and various C/EBP homologues. Furthermore, this modulation of ischemia injury factors in the SAM model group treated with magnolol seems to result from a suppression of reactive oxygen species production and the upregulation of p-Akt and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B). These findings confirm the anti-oxidative properties of magnolol, including the inhibition of ischemic injury to neurons; this protective effect seems to involve changes in the in vivo activity of Akt, GSK3? and NF-?B.
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Skin rash related to once-daily boosted darunavir-containing antiretroviral therapy in HIV-infected Taiwanese: incidence and associated factor.
J. Infect. Chemother.
PUBLISHED: 03-10-2014
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The study aimed to investigate the incidence of and associated factors with skin rashes among HIV-infected Taiwanese patients who received once-daily darunavir (DRV) boosted by ritonavir (RTV) (800/100 mg) plus 2 nucleoside reverse-transcriptase inhibitors (NRTIs).
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The effect of temperature on basal tension and thyroarytenoid muscle contraction in an isolated rat glottis model.
Eur Arch Otorhinolaryngol
PUBLISHED: 03-05-2014
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The pitch of voice is closely related to the vocal fold tension, which is the end result of coordinated movement of the intralaryngeal muscles, and especially the thyroarytenoid muscle. It is known that vocal quality may be affected by surrounding temperature; however, the effect of temperature on vocal fold tension is mostly unknown. Thus, the aim of this study was to evaluate the effect of temperature on isolated rat glottis and thyroarytenoid muscle contraction induced by electrical field stimulation. In vitro isometric tension of the glottis ring from 30 Sprague-Dawley rats was continuously recorded by the tissue bath method. Electrical field stimulation was applied to the glottis ring with two wire electrodes placed parallel to the glottis and connected to a direct-current stimulator. The tension changes of the rat glottis rings that were either untreated or treated with electrical field stimulation were recorded continuously at temperatures from 37 to 7 °C or from 7 to 37 °C. Warming from 7 to 37 °C increased the basal tension of the glottis rings and decreased the electrical field stimulation-induced glottis ring contraction, which was chiefly due to thyroarytenoid muscle contraction. In comparison, cooling from 37 to 7 °C decreased the basal tension and enhanced glottis ring contraction by electrical field stimulation. We concluded that warming increased the basal tension of the glottis in vitro and decreased the amplitude of electrical field stimulation-induced thyroarytenoid muscle contraction. Thus, vocal pitch and the fine tuning of vocal fold tension might be affected by temperature in vivo.
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Resistin-induced stromal cell-derived factor-1 expression through Toll-like receptor 4 and activation of p38 MAPK/ NF?B signaling pathway in gastric cancer cells.
J. Biomed. Sci.
PUBLISHED: 03-04-2014
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Stromal cell-derived factor-1 (SDF-1) (CXC chemokine ligand-12)/CXC chemokine receptor 4 (CXCR4) is involved in the carcinogenesis of human gastric cancer, where it stimulates angiogenesis and favors metastasis of tumor cells to distant organs. In addition, resistin is suggested to be an important link between obesity and the development of gastric cancer. Resistin has identified as an important player in inflammatory responses, and emerged as a mediator in inflammation-associated cancer. A limited number of studies have investigated the association of resistin and SDF-1 with gastric cancer. Herein, we investigated the molecular mechanisms by which resistin influences the expression of SDF-1 in gastric carcinoma cells.
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Effects of low-level laser therapy on M1-related cytokine expression in monocytes via histone modification.
Mediators Inflamm.
PUBLISHED: 02-19-2014
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Low-level laser therapy (LLLT) has been used in the treatment of radiotherapy-induced oral mucositis and allergic rhinitis. However, the effects of LLLT on human monocyte polarization into M1 macrophages are unknown. To evaluate the effects of LLLT on M1-related cytokine and chemokine production and elucidate the mechanism, the human monocyte cell line THP-1 was treated with different doses of LLLT. The expression of M1-related cytokines and chemokines (CCL2, CXCL10, and TNF-?) was determined by ELISA and real-time PCR. LLLT-associated histone modifications were examined by chromatin immunoprecipitation (ChIP) assays. Mitochondrial involvement in the LLLT-induced M1-related cytokine expression was evaluated by quantitative real-time PCR. Flow cytometry was used to detect the cell surface markers for monocyte polarization. The results showed that LLLT (660?nm) significantly enhanced M1-related cytokine and chemokine expression in mRNA and protein levels. Mitochondrial copy number and mRNA levels of complex I-V protein were increased by LLLT (1?J/cm(2)). Activation of M1 polarization was concomitant with histone modification at TNF-? gene locus and IP-10 gene promoter area. This study indicates that LLLT (660?nm) enhanced M1-related cytokine and chemokine expression via mitochondrial biogenesis and histone modification, which may be a potent immune-enhancing agent for the treatment of allergic diseases.
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The impact of HAART initiation timing on HIV-TB co-infected patients, a retrospective cohort study.
BMC Infect. Dis.
PUBLISHED: 02-18-2014
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Optimal timing for initiating highly active antiretroviral therapy (HAART) in HIV-TB coinfected patients is challenging for clinicians. We aim to evaluate the impact of different timing of HAART initiation on TB outcome of HIV-infected adults in Taiwan.
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An improved ChIP-seq peak detection system for simultaneously identifying post-translational modified transcription factors by combinatorial fusion, using SUMOylation as an example.
BMC Genomics
PUBLISHED: 01-24-2014
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Post-translational modification (PTM) of transcriptional factors and chromatin remodelling proteins is recognized as a major mechanism by which transcriptional regulation occurs. Chromatin immunoprecipitation (ChIP) in combination with high-throughput sequencing (ChIP-seq) is being applied as a gold standard when studying the genome-wide binding sites of transcription factor (TFs). This has greatly improved our understanding of protein-DNA interactions on a genomic-wide scale. However, current ChIP-seq peak calling tools are not sufficiently sensitive and are unable to simultaneously identify post-translational modified TFs based on ChIP-seq analysis; this is largely due to the wide-spread presence of multiple modified TFs. Using SUMO-1 modification as an example; we describe here an improved approach that allows the simultaneous identification of the particular genomic binding regions of all TFs with SUMO-1 modification.
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Tacrolimus suppresses atopic dermatitis-associated cytokines and chemokines in monocytes.
J Microbiol Immunol Infect
PUBLISHED: 01-15-2014
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Calcineurin inhibitors (CNIs) exhibit remarkable efficacy in atopic dermatitis (AD). Tacrolimus, one type of CNI, is prevalently used to treat AD. AD is a chronic inflammatory disease that exhibits predominant infiltration of T-helper type 2 (Th2) cell in the acute phase and a mixed Th1 and Th0 cell pattern in chronic lesions. Cytokines such as tumor necrosis factor-? (TNF-?), Th2-related chemokines [e.g., macrophage-derived chemokine (MDC)/CCL22 and I-309/CCL1], Th1-related chemokines [e.g., interferon ?-induced protein 10 (IP-10)/CXCL10], and neutrophil chemoattractant growth-related oncogene-? (GRO-?)/CXCL1 are involved in the pathogenesis of AD. However, whether tacrolimus modulates the expression of AD-associated cytokines and chemokines remains unknown. The intracellular mechanisms of tacrolimus are also unclear.
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Effect of prostaglandin I2 analogs on macrophage inflammatory protein 1? in human monocytes via I prostanoid receptor and cyclic adenosine monophosphate.
J. Investig. Med.
PUBLISHED: 01-10-2014
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Inflammation plays critical roles in atherosclerosis. Chemokines are responsible for leukocyte trafficking and involve in inflammatory diseases. Macrophage inflammatory protein 1? (MIP-1?) has been implicated in atherosclerotic lesion formation. Prostaglandin I2 (PGI2) analog, used in pulmonary hypertension, has been reported to have anti-inflammatory functions. However, little is known about its role in the MIP-1? production in human monocytes.
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Epigenetic regulation in allergic diseases and related studies.
Asia Pac Allergy
PUBLISHED: 01-08-2014
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Asthma, a chronic inflammatory disorder of the airway, has features of both heritability as well as environmental influences which can be introduced in utero exposures and modified through aging, and the features may attribute to epigenetic regulation. Epigenetic regulation explains the association between early prenatal maternal smoking and later asthma-related outcomes. Epigenetic marks (DNA methylation, modifications of histone tails or noncoding RNAs) work with other components of the cellular regulatory machinery to control the levels of expressed genes, and several allergy- and asthma-related genes have been found to be susceptible to epigenetic regulation, including genes important to T-effector pathways (IFN-?, interleukin [IL] 4, IL-13, IL-17) and T-regulatory pathways (FoxP3). Therefore, the mechanism by which epigenetic regulation contributes to allergic diseases is a critical issue. In the past most published experimental work, with few exceptions, has only comprised small observational studies and models in cell systems and animals. However, very recently exciting and elegant experimental studies and novel translational research works were published with new and advanced technologies investigating epigenetic mark on a genomic scale and comprehensive approaches to data analysis. Interestingly, a potential link between exposure to environmental pollutants and the occurrence of allergic diseases is revealed recently, particular in developed and industrialized countries, and endocrine disrupting chemicals (EDCs) as environmental hormone may play a key role. This review addresses the important question of how EDCs (nonylphenol, 4 octylphenol, and phthalates) influences on asthma-related gene expression via epigenetic regulation in immune cells, and how anti-asthmatic agents prohibit expression of inflammatory genes via epigenetic modification. The discovery and validation of epigenetic biomarkers linking exposure to allergic diseases might lead to better epigenotyping of risk, prognosis, treatment prediction, and development of novel therapies.
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Aryl hydrocarbon receptor (AhR) agonists increase airway epithelial matrix metalloproteinase activity.
J. Mol. Med.
PUBLISHED: 01-08-2014
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The aryl hydrocarbon receptor (AhR) agonists may upregulate matrix metalloproteinases (MMPs) and contribute to many airway diseases, such as asthma and chronic obstructive pulmonary disease. Elucidation of the detailed molecular mechanisms regulating MMPs may provide the scientific basis for diagnostic and therapeutic opportunities to improve the care of various pulmonary diseases, especially those related to xenobiotic agents. In this study, we investigated the detailed mechanisms of how AhR agonists modulated the expressions and activities of MMPs in bronchial epithelial cells. Treating the cells (Beas-2B or HBE135-E6E7) with 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester or 2,3,7,8-tetrachlorodibenzo-p-dioxin, we found these AhR agonists increased the expression and activity of MMP-1 via a noncanonical AhR pathway and increased the activity of MMP-2 and MMP-9 in an MMP-1-dependent manner. AhR agonists increased the expression of MMP-1 via the activation of mitogen-activated protein kinase (MAPK) pathways by increased cytosolic calcium level and activated calcium/calmodulin-dependent protein kinase II (CaMKII). The activated MAPK pathways phosphorylated c-Jun, c-Fos, and ATF-2, resulting in their nuclear translocation and binding to the activator protein-1 (AP-1) elements of the MMP-1 promoter region. These findings correlated clinically to the significantly higher plasma/serum MMP-1 level in asthmatic patients. In conclusion, the present study demonstrated a novel signaling pathway by which AhR agonists elevated intracellular calcium levels, which activated CaMKII, leading to increased MMP-1 expression through MAPK pathways in bronchial epithelial cell lines. This novel regulatory pathway may serve as a potential target for the treatment of airway remodeling of many pulmonary diseases, such as asthma.
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Exploring the effects of tert-butylhydroperoxide induced liver injury using proteomic approach.
Toxicology
PUBLISHED: 01-03-2014
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Tert-butyl hydroperoxide (t-BHP), an organic lipid hydroperoxide analog, has been demonstrated to exert pro-oxidant effects to evaluate mechanisms involving oxidative stress in hepatocyte cells and rat liver. Herein, we present an investigation of the event of molecular mechanism of t-BHP related acute liver injury. A proteomic approach was used to identify proteins which are differentially expressed in liver cells following t-BHP treatment and the mechanism of its action in apoptotic and endoplasmic reticulum stress pathways. Our results demonstrate that the t-BHP treatment of liver cells increased cell cytoxicity and apoptosis. t-BHP dose-dependent induction of cell apoptosis and stained liver sections relieved the acute rat liver injury were accompanied by sustained phosphorylation of JNK1/2 and p65. In addition, there were 13 differentially displayed proteins between the t-BHP-induced and untreated were assayed and validated in vivo. Furthermore, we demonstrated that t-BHP induced human Chang liver cell viability and apoptosis properties by up-regulating the levels of ETFA (electron transfer flavoprotein subunit alpha). This study demonstrated that there was an increase in the cellular levels of ETFA in the t-BHP induction in viability and apoptosis via the activation of JNK1/2 and NF?B signaling modules. NAC administration and shRNA ETFA conferred resistance to t-BHP-increased ETFA and CHOP expression via IRE1-alpha/TRAF2 complex formation, activation of JNK1/2 and p50. We concluded that the mechanism of t-BHP-induced an apoptosis cascade and endoplasmic reticulum stress in hepatocyte cells by up-regulation of ETFA, providing a new mechanism for liver injury.
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Differential Regulation of Human Aortic Smooth Muscle Cell Proliferation by Monocyte-Derived Macrophages from Diabetic Patients.
PLoS ONE
PUBLISHED: 01-01-2014
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Macrophage accumulation in the arterial wall and smooth muscle cell (SMC) proliferation are features of type 2 diabetes mellitus (DM) and its vascular complications. However, the effects of diabetic monocyte-derived macrophages on vascular SMC proliferation are not clearly understood. In the present study, we investigated the pro-proliferative effect of macrophages isolated from DM patients on vascular SMCs. Macrophage-conditioned media (MCM) were prepared from macrophages isolated from DM patients. DM-MCM treatment induced HASMC proliferation, decreased p21Cip1 and p27Kip1 expressions, and increased microRNA (miR)-17-5p and miR-221 expressions. Inhibition of either miR-17-5p or miR-221 inhibited DM-MCM-induced cell proliferation. Inhibition of miR-17-5p abolished DM-MCM-induced p21Cip1 down-regulation; and inhibition of miR-221 attenuated the DM-MCM-induced p27Kip1 down-regulation. Furthermore, blocking assays demonstrated that PDGF-CC in DM-MCM is the major mediators of cell proliferation in SMCs. In conclusion, our present data support the hypothesis that SMC proliferation stimulated by macrophages may play critical roles in vascular complications in DM patients and suggest a new mechanism by which arterial disease is accelerated in diabetes.
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Antiretroviral therapy (ART) management of Low-Level Viremia in Taiwan (ALLEVIATE).
J Int AIDS Soc
PUBLISHED: 01-01-2014
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This retrospective study aimed to investigate that if switch of combination antiretroviral therapy (cART) would result in viral suppression (<40 copies/mL) at 48 weeks for patients with persistent low-level viremia after having received cART for six months or more at two hospitals designated for HIV care in Taiwan.
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Safety, tolerability and effectiveness of HIV non-occupational prophylaxis in Taiwan.
J Int AIDS Soc
PUBLISHED: 01-01-2014
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Increasing numbers of new HIV infection is an important issue of public health in Taiwan. We aim to evaluate the safety, tolerability and effectiveness of HIV non-occupational prophylaxis (nPEP) in Taiwan.
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Safety of rilpivirine plus nucleoside reverse-transcriptase inhibitors in HIV-infected Taiwanese with a higher prevalence of hepatitis virus infection.
J Int AIDS Soc
PUBLISHED: 01-01-2014
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Combination antiretroviral therapy (cART) containing rilpivirine plus 2 NRTIs are effective antiretroviral (ARV) regimens for ARV-naive HIV-infected patients who had baseline plasma HIV RNA load (PVL) <5 log10 copies/mL and as switch therapy for those with viral suppression. In this study, we aimed to assess the short-term safety of rilpivirine-containing regimens among HIV-infected patients who initiated or switched to rilpivirine plus two NRTIs in Taiwan.
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Lipid-lowering agents for dyslipidemia in patients who were infected with HIV in Taoyuan, Taiwan.
J Int AIDS Soc
PUBLISHED: 01-01-2014
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There is no doubt that highly active antiretroviral therapy (ART) has decreased the total mortality of HIV-infected populations drastically, and HIV has become a chronic and manageable condition. However, complications after long-term treatment of ART tarnished the great efforts. We aimed to study the effects of add-on lipid-lowering agents on ART for patients who developed hyperlipidemia after HIV treatment. The risk factors for failure to normalize lipid profile were analyzed.
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Diabetes mellitus and risk of thyroid cancer: a meta-analysis.
PLoS ONE
PUBLISHED: 01-01-2014
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Diabetes mellitus (DM) is an important risk factor for endocrine cancers; however, the association with thyroid cancer is not clear. We performed a systematic review and meta-analysis to clarify the association between thyroid cancer and DM.
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Autophagy pathway is required for IL-6 induced neuroendocrine differentiation and chemoresistance of prostate cancer LNCaP cells.
PLoS ONE
PUBLISHED: 01-01-2014
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Prostate cancer (PCa) cells undergoing neuroendocrine differentiation (NED) are clinically relevant to the development of relapsed castration-resistant PCa. Increasing evidences show that autophagy involves in the development of neuroendocrine (NE) tumors, including PCa. To clarify the effect of autophagy on NED, androgen-sensitive PCa LNCaP cells were examined. Treatment of LNCaP cells with IL-6 resulted in an induction of autophagy. In the absence of androgen, IL-6 caused an even stronger activation of autophagy. Similar result was identified in NED induction. Inhibition of autophagy with chloroquine (CQ) markedly decreased NED. This observation was confirmed by beclin1 and Atg5 silencing experiments. Further supporting the role of autophagy in NED, we found that LC3 was up-regulated in PCa tissue that had relapsed after androgen-deprivation therapy when compared with their primary tumor counterpart. LC3 staining in relapsed PCa tissue showed punctate pattern similar to the staining of chromogranin A (CgA), a marker for NED cells. Moreover, autophagy inhibition induced the apoptosis of IL-6 induced NE differentiated PCa cells. Consistently, inhibition of autophagy by knockdown of beclin1 or Atg5 sensitized NE differentiated LNCaP cells to etoposide, a chemotherapy drug. To identify the mechanisms, phosphorylation of IL-6 downstream targets was analyzed. An increase in phospho-AMPK and a decrease in phospho-mTOR were found, which implies that IL-6 regulates autophagy through the AMPK/mTOR pathway. Most important to this study is the discovery of REST, a neuronal gene-specific transcriptional repressor that is involved in autophagy activation. REST was down-regulated in IL-6 treatment. Knockdown experiments suggest that REST is critical to NED and autophagy activation by IL-6. Together, our studies imply that autophagy is involved in PCa progression and plays a cytoprotective role when NED is induced in PCa cells by IL-6 treatment. These results reveal the potential of targeting autophagy as part of a combined therapeutic regime for NE tumors.
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JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1?-mediated glucose metabolism.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 12-16-2013
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JMJD5, a Jumonji C domain-containing dioxygenase, is important for embryonic development and cancer growth. Here, we show that JMJD5 is up-regulated by hypoxia and is crucial for hypoxia-induced cell proliferation. JMJD5 interacts directly with pyruvate kinase muscle isozyme (PKM)2 to modulate metabolic flux in cancer cells. The JMJD5-PKM2 interaction resides at the intersubunit interface region of PKM2, which hinders PKM2 tetramerization and blocks pyruvate kinase activity. This interaction also influences translocation of PKM2 into the nucleus and promotes hypoxia-inducible factor (HIF)-1?-mediated transactivation. JMJD5 knockdown inhibits the transcription of the PKM2-HIF-1? target genes involved in glucose metabolism, resulting in a reduction of glucose uptake and lactate secretion in cancer cells. JMJD5, along with PKM2 and HIF-1?, is recruited to the hypoxia response element site in the lactate dehydrogenase A and PKM2 loci and mediates the recruitment of the latter two proteins. Our data uncover a mechanism whereby PKM2 can be regulated by factor-binding-induced homo/heterooligomeric restructuring, paving the way to cell metabolic reprogram.
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Biphasic Euchromatin-to-Heterochromatin Transition on the KSHV Genome Following De Novo Infection.
PLoS Pathog.
PUBLISHED: 12-01-2013
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The establishment of latency is an essential step for the life-long persistent infection and pathogenesis of Kaposis sarcoma-associated herpesvirus (KSHV). While the KSHV genome is chromatin-free in the virions, the viral DNA in latently infected cells has a chromatin structure with activating and repressive histone modifications that promote latent gene expression but suppress lytic gene expression. Here, we report a comprehensive epigenetic study of the recruitment of chromatin regulatory factors onto the KSHV genome during the pre-latency phase of KSHV infection. This demonstrates that the KSHV genome undergoes a biphasic chromatinization following de novo infection. Initially, a transcriptionally active chromatin (euchromatin), characterized by high levels of the H3K4me3 and acetylated H3K27 (H3K27ac) activating histone marks, was deposited on the viral episome and accompanied by the transient induction of a limited number of lytic genes. Interestingly, temporary expression of the RTA protein facilitated the increase of H3K4me3 and H3K27ac occupancy on the KSHV episome during de novo infection. Between 24-72 hours post-infection, as the levels of these activating histone marks declined on the KSHV genome, the levels of the repressive H3K27me3 and H2AK119ub histone marks increased concomitantly with the decline of lytic gene expression. Importantly, this transition to heterochromatin was dependent on both Polycomb Repressive Complex 1 and 2. In contrast, upon infection of human gingiva-derived epithelial cells, the KSHV genome underwent a transcription-active euchromatinization, resulting in efficient lytic gene expression. Our data demonstrate that the KSHV genome undergoes a temporally-ordered biphasic euchromatin-to-heterochromatin transition in endothelial cells, leading to latent infection, whereas KSHV preferentially adopts a transcriptionally active euchromatin in oral epithelial cells, resulting in lytic gene expression. Our results suggest that the differential epigenetic modification of the KSHV genome in distinct cell types is a potential determining factor for latent infection versus lytic replication of KSHV.
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A Lytic Viral Long Non-coding RNA Modulates the Function of a Latent Protein.
J. Virol.
PUBLISHED: 11-20-2013
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Latent Kaposis sarcoma-associated herpesvirus (KSHV) episomes are coated with viral latency-associated nuclear antigen (LANA). In contrast, LANA rapidly disassociates from episomes during reactivation. Lytic KSHV expresses polyadenylated nuclear RNA (PAN RNA), a long non-coding RNA (lncRNA). We report that PAN RNA promotes LANA-episomal disassociation through an interaction with LANA which facilitates LANA sequestration away from KSHV episomes during reactivation. These findings suggest that KSHV may have evolved an "RNA aptamer" to regulate latent protein function.
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DriverDB: an exome sequencing database for cancer driver gene identification.
Nucleic Acids Res.
PUBLISHED: 11-07-2013
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Exome sequencing (exome-seq) has aided in the discovery of a huge amount of mutations in cancers, yet challenges remain in converting oncogenomics data into information that is interpretable and accessible for clinical care. We constructed DriverDB (http://ngs.ym.edu.tw/driverdb/), a database which incorporates 6079 cases of exome-seq data, annotation databases (such as dbSNP, 1000 Genome and Cosmic) and published bioinformatics algorithms dedicated to driver gene/mutation identification. We provide two points of view, Cancer and Gene, to help researchers to visualize the relationships between cancers and driver genes/mutations. The Cancer section summarizes the calculated results of driver genes by eight computational methods for a specific cancer type/dataset and provides three levels of biological interpretation for realization of the relationships between driver genes. The Gene section is designed to visualize the mutation information of a driver gene in five different aspects. Moreover, a Meta-Analysis function is provided so researchers may identify driver genes in customer-defined samples. The novel driver genes/mutations identified hold potential for both basic research and biotech applications.
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Screening and risk factors for anal cancer precursors in men infected with HIV in Taiwan.
J. Med. Virol.
PUBLISHED: 09-24-2013
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Homosexual men infected with human immunodeficiency virus (HIV) are at a greater risk of developing anal cancer. Men who are infected with HIV and visited the outpatient clinics in Taoyuan General Hospital were enrolled to this study. During March to December 2011, thin preparation anal Pap smear and human papillomavirus (HPV) genotyping were performed in 230 subjects, of which 69 subjects underwent anoscopic biopsy. Their mean age was 32.9?±?8.1 years, and 181 (78.6%) men were homosexual. The proportion and 95% confidence interval (CI) of subjects with anal dysplasia in cytology was 23.0% (17.56-28.44), including 13.4% (9.26-18.14) with atypical squamous cells of undetermined significance, 7.0% (3.70-10.30) with low-grade squamous intraepithelial lesions, and 2.6% (0.54-4.66) with high-grade squamous intraepithelial lesions. For participants having atypical squamous cells of undetermined significance or higher grades, multivariate logistic regression models yielded adjusted odds ratios (95% CI) of 12.61 (1.63-97.56) for homosexuality, 1.62 (1.31-2.00) for number of oncogenic HPV types, and 1.01 (1.00-1.02) for number of lifetime sexual partners. For detection of histological grade II or III anal intraepithelial neoplasm in anoscopic biopsies, the sensitivity of sequential tests for oncogenic HPV and cytology with atypical squamous cells of undetermined significance or higher grades was 100%. The positive likelihood ratio was 3.09 (P?=?0.05). It is important to consider anal cancer precursors among homosexual men who are infected with HIV. Anal cytology and oncogenic HPV genotyping testing are effective screening methods. J. Med. Virol. 86:193-201, 2014. © 2013 Wiley Periodicals, Inc.
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Using image processing technology and mathematical algorithm in the automatic selection of vocal cord opening and closing images from the larynx endoscopy video.
Comput Methods Programs Biomed
PUBLISHED: 08-06-2013
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The human larynx is an important organ for voice production and respiratory mechanisms. The vocal cord is approximated for voice production and open for breathing. The videolaryngoscope is widely used for vocal cord examination. At present, physicians usually diagnose vocal cord diseases by manually selecting the image of the vocal cord opening to the largest extent (abduction), thus maximally exposing the vocal cord lesion. On the other hand, the severity of diseases such as vocal palsy, atrophic vocal cord is largely dependent on the vocal cord closing to the smallest extent (adduction). Therefore, diseases can be assessed by the image of the vocal cord opening to the largest extent, and the seriousness of breathy voice is closely correlated to the gap between vocal cords when closing to the smallest extent. The aim of the study was to design an automatic vocal cord image selection system to improve the conventional selection process by physicians and enhance diagnosis efficiency. Also, due to the unwanted fuzzy images resulting from examination process caused by human factors as well as the non-vocal cord images, texture analysis is added in this study to measure image entropy to establish a screening and elimination system to effectively enhance the accuracy of selecting the image of the vocal cord closing to the smallest extent.
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Kaposis sarcoma-associated herpesvirus K-Rta exhibits SUMO-targeting ubiquitin ligase (STUbL) like activity and is essential for viral reactivation.
PLoS Pathog.
PUBLISHED: 08-01-2013
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The small ubiquitin-like modifier (SUMO) is a protein that regulates a wide variety of cellular processes by covalent attachment of SUMO moieties to a diverse array of target proteins. Sumoylation also plays an important role in the replication of many viruses. Previously, we showed that Kaposis sarcoma-associated herpesvirus (KSHV) encodes a SUMO-ligase, K-bZIP, which catalyzes sumoylation of host and viral proteins. We report here that this virus also encodes a gene that functions as a SUMO-targeting ubiquitin-ligase (STUbL) which preferentially targets sumoylated proteins for degradation. K-Rta, the major transcriptional factor which turns on the entire lytic cycle, was recently found to have ubiquitin ligase activity toward a selected set of substrates. We show in this study that K-Rta contains multiple SIMs (SUMO interacting motif) and binds SUMOs with higher affinity toward SUMO-multimers. Like RNF4, the prototypic cellular STUbL, K-Rta degrades SUMO-2/3 and SUMO-2/3 modified proteins, including promyelocytic leukemia (PML) and K-bZIP. PML-NBs (nuclear bodies) or ND-10 are storage warehouses for sumoylated proteins, which negatively regulate herpesvirus infection, as part of the intrinsic immune response. Herpesviruses have evolved different ways to degrade or disperse PML bodies, and KSHV utilizes K-Rta to inhibit PML-NBs formation. This process depends on K-Rtas ability to bind SUMO, as a K-Rta SIM mutant does not effectively degrade PML. Mutations in the K-Rta Ring finger-like domain or SIM significantly inhibited K-Rta transactivation activity in reporter assays and in the course of viral reactivation. Finally, KSHV with a mutation in the Ring finger-like domain or SIM of K-Rta replicates poorly in culture, indicating that reducing SUMO-conjugates in host cells is important for viral replication. To our knowledge, this is the first virus which encodes both a SUMO ligase and a SUMO-targeting ubiquitin ligase that together may generate unique gene regulatory programs.
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The chromatin modification by SUMO-2/3 but not SUMO-1 prevents the epigenetic activation of key immune-related genes during Kaposis sarcoma associated herpesvirus reactivation.
BMC Genomics
PUBLISHED: 07-15-2013
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SUMOylation, as part of the epigenetic regulation of transcription, has been intensively studied in lower eukaryotes that contain only a single SUMO protein; however, the functions of SUMOylation during mammalian epigenetic transcriptional regulation are largely uncharacterized. Mammals express three major SUMO paralogues: SUMO-1, SUMO-2, and SUMO-3 (normally referred to as SUMO-1 and SUMO-2/3). Herpesviruses, including Kaposis sarcoma associated herpesvirus (KSHV), seem to have evolved mechanisms that directly or indirectly modulate the SUMO machinery in order to evade host immune surveillance, thus advancing their survival. Interestingly, KSHV encodes a SUMO E3 ligase, K-bZIP, with specificity toward SUMO-2/3 and is an excellent model for investigating the global functional differences between SUMO paralogues.
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Integrated analyses of genome-wide DNA occupancy and expression profiling identify key genes and pathways involved in cellular transformation by a Mareks disease virus oncoprotein, Meq.
J. Virol.
PUBLISHED: 06-05-2013
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Mareks disease (MD) is an economically significant disease in chickens that is caused by the highly oncogenic Mareks disease virus (MDV). A major unanswered question is the mechanism of MDV-induced tumor formation. Meq, a bZIP transcription factor discovered in the 1990s, is critically involved in viral oncogenicity, but only a few of its host target genes have been described, impeding our understanding of MDV-induced tumorigenesis. Using chromatin immunoprecipitation-sequencing (ChIP-seq) and microarray analysis, a high-confidence list of Meq binding sites in the chicken genome and a global transcriptome of Meq-responsive genes were generated. Meq binding sites were found to be enriched in the promoter regions of upregulated genes but not in those of downregulated genes. ChIP-seq was also performed for c-Jun, a known heterodimeric partner of Meq. The close location of binding sites of Meq and c-Jun was noted, suggesting cooperativity between these two factors in modulating transcription. Pathway analysis indicated that Meq transcriptionally regulates many genes that are part of several signaling pathways including the extracellular signal-regulated kinase /mitogen-activated protein kinase (ERK/MAPK), Jak-STAT, and ErbB pathways, which are critical for oncogenesis and/or include signaling mediators involved in apoptosis. Meq activates oncogenic signaling cascades by transcriptionally activating major kinases in the ERK/MAPK pathway and simultaneously repressing phosphatases, as verified using inhibitors of MEK and ERK1/2 in a cell proliferation assay. This study provides significant insights into the mechanistic basis of Meq-dependent cell transformation.
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Development of laryngeal video stroboscope with laser marking module for dynamic glottis measurement.
Comput Med Imaging Graph
PUBLISHED: 05-31-2013
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Physicians clinically use laryngeal video stroboscope as an auxiliary instrument to test glottal diseases, and read vocal fold images and voice quality for diagnosis. As the position of vocal fold varies in each person, the proportion of the vocal fold size as presented in the vocal fold image is different, making it impossible to directly estimate relevant glottis physiological parameters, such as the length, area, perimeter, and opening angle of the glottis. Hence, this study designs an innovative laser projection marking module for the laryngeal video stroboscope to provide reference parameters for image scaling conversion. This innovative laser projection marking module to be installed on the laryngeal video stroboscope using laser beams to project onto the glottis plane, in order to provide reference parameters for scaling conversion of images of laryngeal video stroboscope.
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Using image processing technology combined with decision tree algorithm in laryngeal video stroboscope automatic identification of common vocal fold diseases.
Comput Methods Programs Biomed
PUBLISHED: 05-20-2013
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This study used the actual laryngeal video stroboscope videos taken by physicians in clinical practice as the samples for experimental analysis. The samples were dynamic vocal fold videos. Image processing technology was used to automatically capture the image of the largest glottal area from the video to obtain the physiological data of the vocal folds. In this study, an automatic vocal fold disease identification system was designed, which can obtain the physiological parameters for normal vocal folds, vocal paralysis and vocal nodules from image processing according to the pathological features. The decision tree algorithm was used as the classifier of the vocal fold diseases. The identification rate was 92.6%, and the identification rate with an image recognition improvement processing procedure after classification can be improved to 98.7%. Hence, the proposed system has value in clinical practices.
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Quantitative analysis of autophagy using advanced 3D fluorescence microscopy.
J Vis Exp
PUBLISHED: 05-14-2013
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Prostate cancer is the leading form of malignancies among men in the U.S. While surgery carries a significant risk of impotence and incontinence, traditional chemotherapeutic approaches have been largely unsuccessful. Hormone therapy is effective at early stage, but often fails with the eventual development of hormone-refractory tumors. We have been interested in developing therapeutics targeting specific metabolic deficiency of tumor cells. We recently showed that prostate tumor cells specifically lack an enzyme (argininosuccinate synthase, or ASS) involved in the synthesis of the amino acid arginine(1). This condition causes the tumor cells to become dependent on exogenous arginine, and they undergo metabolic stress when free arginine is depleted by arginine deiminase (ADI)(1,10). Indeed, we have shown that human prostate cancer cells CWR22Rv1 are effectively killed by ADI with caspase-independent apoptosis and aggressive autophagy (or macroautophagy)(1,2,3). Autophagy is an evolutionarily-conserved process that allows cells to metabolize unwanted proteins by lysosomal breakdown during nutritional starvation(4,5). Although the essential components of this pathway are well-characterized(6,7,8,9), many aspects of the molecular mechanism are still unclear - in particular, what is the role of autophagy in the death-response of prostate cancer cells after ADI treatment? In order to address this question, we required an experimental method to measure the level and extent of autophagic response in cells - and since there are no known molecular markers that can accurately track this process, we chose to develop an imaging-based approach, using quantitative 3D fluorescence microscopy(11,12). Using CWR22Rv1 cells specifically-labeled with fluorescent probes for autophagosomes and lysosomes, we show that 3D image stacks acquired with either widefield deconvolution microscopy (and later, with super-resolution, structured-illumination microscopy) can clearly capture the early stages of autophagy induction. With commercially available digital image analysis applications, we can readily obtain statistical information about autophagosome and lysosome number, size, distribution, and degree of colocalization from any imaged cell. This information allows us to precisely track the progress of autophagy in living cells and enables our continued investigation into the role of autophagy in cancer chemotherapy.
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Glycyrrhizin represses total parenteral nutrition-associated acute liver injury in rats by suppressing endoplasmic reticulum stress.
Int J Mol Sci
PUBLISHED: 04-22-2013
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Total parenteral nutrition (TPN) is an artificial way to support daily nutritional requirements by bypassing the digestive system, but long-term TPN administration may cause severe liver dysfunction. Glycyrrhizin is an active component of licorice root that has been widely used to treat chronic hepatitis. The aim of this study is to investigate the hepatoprotective effect of glycyrrhizin on TPN-associated acute liver injury in vivo. Liver dysfunction was induced by intravenous infusion of TPN at a flow rate of 20 mL/kg/h for three h in Sprague Dawley rats. The rats were pretreated with Glycyrrhizin (1, 3 and 10 mg/kg intravenously). After receiving TPN or saline (control group) for three h, the rats were sacrificed, blood samples were collected for biochemical analyses and liver tissue was removed for histopathological and immunohistochemical examination. We found that aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TB) and triglyceride (TG) levels were significantly increased in the TPN group without glycyrrhizin pretreatment and decreased in the glycyrrhizin-pretreated TPN group in a dose-dependent manner. The stained liver sections showed that glycyrrhizin relieved acute liver injury. The upregulation of serum protein biomarkers of reactive nitrogen species, including nitrotyrosine and inducible NO synthase (iNOS), were attenuated by glycyrrhizin pretreatment. Levels of endoplasmic reticulum (ER) stress factors, such as phosphorylation of JNK1/2, p38 MAPK and CHOP, were decreased by glycyrrhizin pretreatment. In summary, our results suggest that glycyrrhizin decreases TPN-associated acute liver injury factors by suppressing endoplasmic reticulum stress and reactive nitrogen stress.
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Shear stress modulates macrophage-induced urokinase plasminogen activator expression in human chondrocytes.
Arthritis Res. Ther.
PUBLISHED: 04-16-2013
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INTRODUCTION: Synovial macrophages, which can release proinflammatory factors, are responsible for the upregulation of cartilage-breakdown proteases and play critical roles in cartilage degradation during the progression of osteoarthritis (OA). In addition, shear stress exerts multifunctional effects on chondrocytes by inducing the synthesis of catabolic or anabolic genes. However, the interplay of macrophages, chondrocytes, and shear stress during the regulation of cartilage function remains poorly understood. We investigated the mechanisms underlying the modulation of human chondrocyte urokinase plasminogen activator (uPA) expression by macrophages and shear stress. METHODS: Human chondrocytes were stimulated by peripheral blood-macrophage- conditioned medium (PB-MCM), or exposure of chondrocytes cultured in PB-MCM to different levels of shear stress (2 to 20 dyn/cm2). Real-time polymerase chain reaction was used to analyze uPA gene expression. Inhibitors and small interfering RNA were used to investigate the mechanism for the effects of PB-MCM and shear stress in chondrocytes. RESULTS: Stimulation of human chondrocytes with PB-MCM was found to induce uPA expression. We demonstrated that activation of the JNK and Akt pathways and NF-?B are critical for PB-MCM-induced uPA expression. Blocking assays by using IL-1ra further demonstrated that IL-1? in PB-MCM is the major mediator of uPA expression in chondrocytes. PB-MCM-treated chondrocytes subjected to a lower level of shear stress showed inhibition of MCM-induced JNK and Akt phosphorylation, NF-?B activation, and uPA expression. The PB-MCM-induced uPA expression was suppressed by AMP-activated protein kinase (AMPK) agonist. The inhibitor or siRNA for AMPK abolished the shear-mediated inhibition of uPA expression. CONCLUSIONS: These data support the hypothesis that uPA upregulation stimulated by macrophages may play an active role in the onset of OA and in the shear-stress protection against this induction.
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Kaposis sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen regulates the KSHV epigenome by association with the histone demethylase KDM3A.
J. Virol.
PUBLISHED: 04-10-2013
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Kaposis sarcoma-associated herpesvirus (KSHV) latent genomes are tethered to host histones to form a minichromosome also known as an "episome." Histones, which are core components of chromatin, are heavily modified by various histone-targeting enzymes. Posttranslational modifications of histones significantly influence accessibility of transcriptional factors and thus have profound effects on gene expression. Recent studies showed that epigenetic marks on the KSHV episome are well organized, exemplified by the absence of histone H3 lysine 9 (H3K9) methylation, a heterochromatic histone mark, from immediate early and latent gene promoters in naturally infected cells. The present study revealed a mechanistic insight into KSHV epigenome regulation via a complex consisting of LANA and the H3K9me1/2 histone demethylase JMJD1A/KDM3A. This complex was isolated from HeLa cell nuclear extracts stably expressing LANA and was verified by coimmunoprecipitation analyses and with purified proteins. LANA recruitment sites on the KSHV genome inversely correlated with H3K9me2 histone marks in naturally infected cells, and methylation of H3K9 significantly inhibited LANA binding to the histone H3 tail. Chromatin immunoprecipitation coupled with KSHV tiling arrays identified the recruitment sites of the complex, while depletion of LANA expression or overexpression of a KDM3A binding-deficient mutant decreased KDM3A recruitment to the KSHV genome. Finally, ablation of KDM3A expression from latently KSHV-infected cells significantly inhibited KSHV gene expression, leading to decreased KSHV replication during reactivation. Taken together, our results suggest that LANA may play a role in regulation of epigenetic marks on the KSHV genome, which is in part through association with the histone demethylase KDM3A.
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Inhibitory effect of liposome-encapsulated anthocyanin on melanogenesis in human melanocytes.
Pharm Biol
PUBLISHED: 04-09-2013
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Melanin plays an important role in preventing ultraviolet (UV) light-induced skin damage. Overexposure to UV radiation can lead to the formation of free radicals and trigger inflammation and hyperpigmentation of the skin. Anthocyanin can combat excessive free radicals in the body and can reduce the occurrence of inflammation. However, anthocyanin molecules are unstable and highly susceptible to degradation.
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Quantitative proteomic analysis of the inhibitory effects of CIL-102 on viability and invasiveness in human glioma cells.
Toxicol. Appl. Pharmacol.
PUBLISHED: 04-02-2013
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CIL-102 (1-[4-(furo[2,3-b]quinolin-4-ylamino)phenyl]ethanone), the major active agent of the alkaloid derivative, has been demonstrated to exert anticancer effects. Herein, we present an investigation focused on the identification of the target(s) of CIL-102s action and the mechanism of its action in apoptotic and anti-invasive pathways. Proteomic approaches were used to purify and identify the protein substrates using 2D difference gel electrophoresis (2D SDS-PAGE) to assess changes in the expression of relevant protein treatment with CIL-102 that resulted in the inhibition of viability and invasion. Our results demonstrate that CIL-102 treatment of U87 cells decreased cell proliferation and invasiveness. CIL-102 dose-dependent induction of apoptosis and inhibitory invasiveness were accompanied by sustained phosphorylation of JNK1/2 and p70S6K as well as generation of the reactive oxygen species. In addition, differential proteins displayed between CIL-102-treated and untreated U87 were determined and validated. There were 11 differentially expressed proteins between the CIL-102-treated and untreated groups. Furthermore, we demonstrated that CIL-102 inhibited cancer cell proliferation and reduced anti-invasion properties by up-regulating the levels of FUMH (Fumarate hydratase). The investigation demonstrated that there was an increase in the cellular levels of FUMH in the CIL-102 reduction in viability and invasion via the activation of JNK1/2 and mTOR signaling modules. NAC administration and shRNA FUMH conferred resistance to CIL-102-inhibited HIF1? and MMP-2 levels via inhibition of JNK1/2 and mTOR activation. We concluded that CIL-102-induced an apoptosis cascade and decreased aggressiveness in astrocytoma cells by modulation of mitochondria function, providing a new mechanism for CIL-102 treatment.
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Regulation of ICAM-1 expression in gingival fibroblasts infected with high-glucose-treated P.?gingivalis.
Cell. Microbiol.
PUBLISHED: 03-21-2013
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Porphyromonas gingivalis is a major pathogen in the initiation and progression of periodontal disease, which is recognized as a common complication of diabetes. ICAM-1 expression by human gingival fibroblasts (HGFs) is crucial for regulating local inflammatory responses in inflamed periodontal tissues. However, the effect of P.?gingivalis in a high-glucose situation in regulating HGF function is not understood. The P.?gingivalis strain CCUG25226 was used to study the mechanisms underlying the modulation of HGF ICAM-1 expression by invasion of high-glucose-treated P.?gingivalis (HGPg). A high-glucose condition upregulated fimA?mRNA expression in P.?gingivalis and increased its invasion ability in HGFs. HGF invasion with HGPg induced increases in the expression of ICAM-1. By using specific inhibitors and short hairpin RNA (shRNA), we have demonstrated that the activation of p38 MAPK and Akt pathways is critical for HGPg-induced ICAM-1 expression. Luciferase reporters and chromatin immunoprecipitation assays suggest that HGPg invasion increases NF-?B- and Sp1-DNA-binding activities in HGFs. Inhibition of NF-?B and Sp1 activations blocked the HGPg-induced ICAM-1 promoter activity and expression. The effect of HGPg on HGF signalling and ICAM-1 expression is mediated by CXC chemokine receptor 4 (CXCR4). Our findings identify the molecular pathways underlying HGPg-dependent ICAM-1 expression in HGFs, providing insight into the effect of P.?gingivalis invasion in HGFs.
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A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry.
Keri L Monda, Gary K Chen, Kira C Taylor, Cameron Palmer, Todd L Edwards, Leslie A Lange, Maggie C Y Ng, Adebowale A Adeyemo, Matthew A Allison, Lawrence F Bielak, Guanjie Chen, Mariaelisa Graff, Marguerite R Irvin, Suhn K Rhie, Guo Li, Yongmei Liu, Youfang Liu, Yingchang Lu, Michael A Nalls, Yan V Sun, Mary K Wojczynski, Lisa R Yanek, Melinda C Aldrich, Adeyinka Ademola, Christopher I Amos, Elisa V Bandera, Cathryn H Bock, Angela Britton, Ulrich Broeckel, Quiyin Cai, Neil E Caporaso, Chris S Carlson, John Carpten, Graham Casey, Wei-Min Chen, Fang Chen, Yii-Der I Chen, Charleston W K Chiang, Gerhard A Coetzee, Ellen Demerath, Sandra L Deming-Halverson, Ryan W Driver, Patricia Dubbert, Mary F Feitosa, Ye Feng, Barry I Freedman, Elizabeth M Gillanders, Omri Gottesman, Xiuqing Guo, Talin Haritunians, Tamara Harris, Curtis C Harris, Anselm J M Hennis, Dena G Hernandez, Lorna H McNeill, Timothy D Howard, Barbara V Howard, Virginia J Howard, Karen C Johnson, Sun J Kang, Brendan J Keating, Suzanne Kolb, Lewis H Kuller, Abdullah Kutlar, Carl D Langefeld, Guillaume Lettre, Kurt Lohman, Vaneet Lotay, Helen Lyon, JoAnn E Manson, William Maixner, Yan A Meng, Kristine R Monroe, Imran Morhason-Bello, Adam B Murphy, Josyf C Mychaleckyj, Rajiv Nadukuru, Katherine L Nathanson, Uma Nayak, Amidou N'Diaye, Barbara Nemesure, Suh-Yuh Wu, M Cristina Leske, Christine Neslund-Dudas, Marian Neuhouser, Sarah Nyante, Heather Ochs-Balcom, Adesola Ogunniyi, Temidayo O Ogundiran, Oladosu Ojengbede, Olufunmilayo I Olopade, Julie R Palmer, Edward A Ruiz-Narváez, Nicholette D Palmer, Michael F Press, Evandine Rampersaud, Laura J Rasmussen-Torvik, Jorge L Rodriguez-Gil, Babatunde Salako, Eric E Schadt, Ann G Schwartz, Daniel A Shriner, David Siscovick, Shad B Smith, Sylvia Wassertheil-Smoller, Elizabeth K Speliotes, Margaret R Spitz, Lara Sucheston, Herman Taylor, Bamidele O Tayo, Margaret A Tucker, David J Van Den Berg, Digna R Velez Edwards, Zhaoming Wang, John K Wiencke, Thomas W Winkler, John S Witte, Margaret Wrensch, Xifeng Wu, James J Yang, Albert M Levin, Taylor R Young, Neil A Zakai, Mary Cushman, Krista A Zanetti, Jing Hua Zhao, Wei Zhao, Yonglan Zheng, Jie Zhou, Regina G Ziegler, Joseph M Zmuda, Jyotika K Fernandes, Gary S Gilkeson, Diane L Kamen, Kelly J Hunt, Ida J Spruill, Christine B Ambrosone, Stefan Ambs, Donna K Arnett, Larry Atwood, Diane M Becker, Sonja I Berndt, Leslie Bernstein, William J Blot, Ingrid B Borecki, Erwin P Bottinger, Donald W Bowden, Gregory Burke, Stephen J Chanock, Richard S Cooper, Jingzhong Ding, David Duggan, Michele K Evans, Caroline Fox, W Timothy Garvey, Jonathan P Bradfield, Hakon Hakonarson, Struan F A Grant, Ann Hsing, Lisa Chu, Jennifer J Hu, Dezheng Huo, Sue A Ingles, Esther M John, Joanne M Jordan, Edmond K Kabagambe, Sharon L R Kardia, Rick A Kittles, Phyllis J Goodman, Eric A Klein, Laurence N Kolonel, Loic Le Marchand, Simin Liu, Barbara McKnight, Robert C Millikan, Thomas H Mosley, Badri Padhukasahasram, L Keoki Williams, Sanjay R Patel, Ulrike Peters, Curtis A Pettaway, Patricia A Peyser, Bruce M Psaty, Susan Redline, Charles N Rotimi, Benjamin A Rybicki, Michèle M Sale, Pamela J Schreiner, Lisa B Signorello, Andrew B Singleton, Janet L Stanford, Sara S Strom, Michael J Thun, Mara Vitolins, Wei Zheng, Jason H Moore, Scott M Williams, Shamika Ketkar, Xiaofeng Zhu, Alan B Zonderman, , Charles Kooperberg, George J Papanicolaou, Brian E Henderson, Alex P Reiner, Joel N Hirschhorn, Ruth J F Loos, Kari E North, Christopher A Haiman.
Nat. Genet.
PUBLISHED: 03-18-2013
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Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.
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Early life exposure to antibiotics and the risk of childhood allergic diseases: an update from the perspective of the hygiene hypothesis.
J Microbiol Immunol Infect
PUBLISHED: 03-08-2013
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The prevalence of allergic diseases has been growing rapidly in industrial countries during recent decades. It is postulated that growing up with less microbial exposure may render the immune system susceptible to a T helper type 2 (Th2)-predominant allergic response-also known as the hygiene hypothesis. This review delineates recent epidemiological and experimental evidence for the hygiene hypothesis, and integrates this hypothesis into the association between early life exposure to antibiotics and the development of allergic diseases and asthma. Several retrospective or prospective epidemiological studies reveal that early exposure to antibiotics may be positively associated with the development of allergic diseases and asthma. However, the conclusion is inconsistent. Experimental studies show that antibiotics may induce the Th2-skewed response by suppressing the T helper type 1 (Th1) response through inhibition of Th1 cytokines and disruption of the natural course of infection, or by disturbing the microflora of the gastrointestinal (GI) tract and therefore jeopardizing the establishment of oral tolerance and regulatory T cell immune responses. The hygiene hypothesis may not be the only explanation for the rapid increase in the prevalence of allergic diseases and asthma. Further epidemiological and experimental studies addressing the issue of the impact of environmental factors on the development of allergic diseases and the underlying mechanisms may unveil novel strategies for the prevention and treatment of allergic diseases in the future.
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Evaluation of Thioperamide Effects Using Rats Trachea Model.
Clin Exp Otorhinolaryngol
PUBLISHED: 03-08-2013
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Thioperamide is used as an antagonist to the histamine H3 receptor. During administration of the drug, the trachea may be affected via nasal or oral inhalation. This study was to determine the effects of thioperamide on the trachea of rats in vitro.
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Structures, molecular orbitals and UV-vis spectra investigations on Br2C6H4: a computational study.
Spectrochim Acta A Mol Biomol Spectrosc
PUBLISHED: 03-05-2013
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The dibromobenzenes (1,2-, 1,3- and 1,4-Br2C6H4) have been studied by theoretical methods. The structures of these species are optimized and the structural characteristics are determined by density functional theory (DFT) and the second order Møller-Plesset perturbation theory (MP2) levels. The geometrical structures of Br2C6H4 show a little distortion of benzene ring due to the substitution of highly electronegativity of bromine atoms. The electronegativity of bromine atoms in 1,4-Br2C6H4 is predicted to be more negative than 1,2- and 1,3-Br2C6H4. In addition, dipole moment and frontier molecular orbitals (FMOs) of these Br2C6H4 are performed as well. The 1,4-Br2C6H4 is slightly more reactive than 1,2- and 1,3-Br2C6H4 because of its small HOMO-LUMO energy gap. The simulated UV-vis spectra are investigated by time-dependent density functional theory (TD-DFT) approach, which are in excellent agreement with the available experimental value. Our calculations show that a few of absorption features are between 140nm and 250nm, which is in ultraviolet C range, and the red shift of 1,3- and 1,4-Br2C6H4 are predicted. Moreover, the UV absorption features of these Br2C6H4 in water or methanol are predicted to be more intense than in gas phase due to solvent effect.
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Aryl hydrocarbon receptor controls murine mast cell homeostasis.
Blood
PUBLISHED: 03-05-2013
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We propose that the aryl hydrocarbon receptor (AhR), a unique chemical sensor, is critical in controlling mast cell differentiation, growth, and function in vitro and in vivo. In antigen-stimulated mast cells, exposure to AhR ligands resulted in a calcium- and reactive oxygen species (ROS)-dependent increase of reversible oxidation in and reduced activity of SHP-2 phosphatase, leading to enhanced mast cell signaling, degranulation, and mediator and cytokine release, as well as the in vivo anaphylactic response. Surprisingly, significant mast cell deficiency was noted in AhR-null mice due to defective calcium signaling and mitochondrial function, concomitant with reduced expression of c-kit and cytosolic STAT proteins, as well as enhanced intracellular ROS and apoptosis. Consequently, AhR-null mast cells responded poorly to stimulation, demonstrating a critical role of AhR signaling in maintaining mast cell homeostasis.
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Highly active antiretroviral therapy is associated with decreased incidence of sexually transmitted diseases in a Taiwanese HIV-positive population.
AIDS Patient Care STDS
PUBLISHED: 02-26-2013
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There are reports of increased sexual risk behaviors in the HIV-positive population since the introduction of highly active antiretroviral therapy (HAART). Little is known about the effects of the case management (CM) program and HAART on sexually transmitted diseases (STDs) in Taiwan. HIV-positive subjects, who visited the outpatient clinics of Taoyuan General Hospital between 2007 and 2010, were enrolled. A total of 574 subjects and 14,462 person-months were reviewed. Incident STDs occurred in 104 (18.1%) subjects, and the incidence rate was 8.6 (95% confidence interval [CI], 7.1-10.5) per 100 person-years (PY). For men who have sex with men (MSM), heterosexual men and women, and injection drug users (IDU), 19.4 per 100 PY(95% CI, 15.7-24.0), 3.5 per 100 PY (95% CI, 1.4-7.3), and 1.1 per 100 PY (95% CI, 0.4-2.4) of STDs were noted, respectively; (MSM versus IDU and MSM versus heterosexual subjects, p<0.000001; heterosexual subjects versus IDU, p=0.061). Syphilis (59.6%) was the most common STD. Regular CM and no HAART (hazard ratio, 2.58; 95% CI, 1.14-5.84; p=0.02) was significantly associated with STDs in MSM. Though this retrospective study might underestimate the incidence of STDs and not draw the conclusion of causality, we concluded that the CM program and HAART are associated with lower acquisition of STDs in the Taiwanese HIV-positive population.
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Genotyping and genomic profiling of non-small-cell lung cancer: implications for current and future therapies.
J. Clin. Oncol.
PUBLISHED: 02-11-2013
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Substantial advances have been made in understanding critical molecular and cellular mechanisms driving tumor initiation, maintenance, and progression in non-small-cell lung cancer (NSCLC). Over the last decade, these findings have led to the discovery of a variety of novel drug targets and the development of new treatment strategies. Already, the standard of care for patients with advanced-stage NSCLC is shifting from selecting therapy empirically based on a patients clinicopathologic features to using biomarker-driven treatment algorithms based on the molecular profile of a patients tumor. This approach is currently best exemplified by treating patients with NSCLC with first-line tyrosine kinase inhibitors when their cancers harbor gain-of-function hotspot mutations in the epidermal growth factor receptor (EGFR) gene or anaplastic lymphoma kinase (ALK) gene rearrangements. These genotype-based targeted therapies represent the first step toward personalizing NSCLC therapy. Recent technology advances in multiplex genotyping and high-throughput genomic profiling by next-generation sequencing technologies now offer the possibility of rapidly and comprehensively interrogating the cancer genome of individual patients from small tumor biopsies. This advance provides the basis for categorizing molecular-defined subsets of patients with NSCLC in whom a growing list of novel molecularly targeted therapeutics are clinically evaluable and additional novel drug targets can be discovered. Increasingly, practicing oncologists are facing the challenge of determining how to select, interpret, and apply these new genetic and genomic assays. This review summarizes the evolution, early success, current status, challenges, and opportunities for clinical application of genotyping and genomic tests in therapeutic decision making for NSCLC.
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Joint effects between five identified risk variants, allergy, and autoimmune conditions on glioma risk.
Cancer Causes Control
PUBLISHED: 01-29-2013
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Common variants in two of the five genetic regions recently identified from genome-wide association studies (GWAS) of risk of glioma were reported to interact with a history of allergic symptoms. In a pooled analysis of five epidemiologic studies, we evaluated the association between the five GWAS implicated gene variants and allergies and autoimmune conditions (AIC) on glioma risk (851 adult glioma cases and 3,977 controls). We further evaluated the joint effects between allergies and AIC and these gene variants on glioma risk. Risk estimates were calculated as odds ratios (OR) and 95 % confidence intervals (95 % CI), adjusted for age, gender, and study. Joint effects were evaluated by conducting stratified analyses whereby the risk associations (OR and 95 % CI) with the allergy or autoimmune conditions for glioma were evaluated by the presence or absence of the at-risk variant, and estimated p interaction by fitting models with the main effects of allergy or autoimmune conditions and genotype and an interaction (product) term between them. Four of the five SNPs previously reported by others were statistically significantly associated with increased risk of glioma in our study (rs2736100, rs4295627, rs4977756, and rs6010620); rs498872 was not associated with glioma in our study. Reporting any allergies or AIC was associated with reduced risks of glioma (allergy: adjusted OR = 0.71, 95 % CI 0.55-0.91; AIC: adjusted OR = 0.65, 95 % CI 0.47-0.90). We did not observe differential association between allergic or autoimmune conditions and glioma by genotype, and there were no statistically significant p interactions. Stratified analysis by glioma grade (low and high grade) did not suggest risk differences by disease grade. Our results do not provide evidence that allergies or AIC modulate the association between the four GWAS-identified SNPs examined and risk of glioma.
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Difference in Protein Expression Profile and Chemotherapy Drugs Response of Different Progression Stages of LNCaP Sublines and Other Human Prostate Cancer Cells.
PLoS ONE
PUBLISHED: 01-01-2013
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Androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, 80-90% of the patients who receive androgen ablation therapy ultimately develop recurrent tumors in 12-33 months after treatment with a median overall survival time of 1-2 years after relapse. LNCaP is a commonly used cell line established from a human lymph node metastatic lesion of prostatic adenocarcinoma. We previously established two relapsed androgen receptor (AR)-rich androgen-independent LNCaP sublines 104-R1 (androgen depleted for 12 months) and 104-R2 cells (androgen depleted for 24 months) from AR-positive androgen-dependent LNCaP 104-S cells. LNCaP 104-R1 and 104-R2 mimics the AR-positive hormone-refractory relapsed tumors in patients receiving androgen ablation therapy. Androgen treatment stimulates proliferation of 104-S cells, but causes growth inhibition and G1 cell cycle arrest in 104-R1 and 104-R2 cells. We investigated the protein expression profile difference between LNCaP 104-S vs. LNCaP 104-R1, 104-R2, PC-3, and DU-145 cells as well as examined the sensitivity of these prostate cancer cells to different chemotherapy drugs and small molecule inhibitors. Compared to 104-S cells, 104-R1 and 104-R2 cells express higher protein levels of AR, PSA, c-Myc, Skp2, BCL-2, P53, p-MDM2 S166, Rb, and p-Rb S807/811. The 104-R1 and 104-R2 cells express higher ratio of p-Akt S473/Akt, p-EGFR/EGFR, and p-Src/Src, but lower ratio of p-ERK/ERK than 104-S cells. PC-3 and DU-145 cells express higher c-Myc, Skp2, Akt, Akt1, and phospho-EGFR but less phospho-Akt and phospho-ERK. Overexpression of Skp2 increased resistance of LNCaP cells to chemotherapy drugs. Paclitaxel, androgen, and inhibitors for PI3K/Akt, EGFR, Src, or Bcl-2 seem to be potential choices for treatment of advanced prostate cancers. Our study provides rationale for targeting Akt, EGFR, Src, Bcl-2, and AR signaling as a treatment for AR-positive relapsed prostate tumors after hormone therapy.
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Environmental alkylphenols modulate cytokine expression in plasmacytoid dendritic cells.
PLoS ONE
PUBLISHED: 01-01-2013
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Alkylphenols, such as nonylphenol (NP) and 4-octylphenol (4-OP), have the potential to disturb immune system due to their weak estrogen-like activity, an effect with potential serious public health impact due to the worldwide distribution of these substances. Plasmacytoid dendritic cells (PDCs) can secrete large amounts of type I IFNs and are critical in immune regulation. However, there has been limited study about the influence of alkylphenols on the function of pDCs.
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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.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.