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Find video protocols related to scientific articles indexed in Pubmed.
Preparation of nano/submicron Ganoderma tsugae and its mutagenic potencies and cytotoxicity.
J. Agric. Food Chem.
PUBLISHED: 11-20-2014
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This was to explore the feasibility of preparing nano/submicron particles from Ganoderma tsugae for enhancing the contents of bioactive compounds and to assess its mutagenic potencies and cytotoxicity. Hot-water extract, a common product, was employed as a reference. After 3-hr media milling, almost all the particles were smaller than 1 ?m with a number-mean diameter of 0.11 ?m. There were about 62 % particles smaller than 0.1 m in terms of number of particles. Scanning electron microscopy (SEM) confirmed the presence of particles size at nano/submicron scale. The content of 1?3-ß-D-glucan in nano/submicron G. tsugae was 3.5 times of that in hot-water extract. Both nano/submicron and hot-water extract G. tsugae exhibited no mutagenic potential to Salmonella typhimurium tester strains. Cell toxicity test also confirmed the safety of both nano/submicron and hot-water extract G. tsugae. The effect of media milling on the structural change of hyphae was also discussed.
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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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Effect of surface Si redistribution on the alignment of Ge dots grown on pit-patterned Si(001) substrates.
Nanotechnology
PUBLISHED: 11-05-2014
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Thermally activated redistribution of Si surface atoms is found to be a crucial factor for the growth of aligned Ge dots on pit-patterned Si(001) substrates. A phenomenon of Si accumulation around the edge of pits significantly alters the substrate surface morphology. As the pit spacing is reduced to below 100 nm, a convex morphology developed between adjacent pits causes a chemical potential distribution that drives the Ge dots into the pits. In addition, the pits of an etching depth greater than 60 nm will evolve into truncated inverted pyramids with sharp base corners that provide deep potential wells for the confinement of Ge dots. Perfectly aligned Ge dots are obtained on pit-patterned Si substrates with this range of pit spacing and etching depth. We also find that the initial geometric shape of the pits does not affect the spatial arrangement of Ge dots.
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Genomic and transcriptomic analyses of the medicinal fungus Antrodia cinnamomea for its metabolite biosynthesis and sexual development.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 10-21-2014
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Antrodia cinnamomea, a polyporus mushroom of Taiwan, has long been used as a remedy for cancer, hypertension, and hangover, with an annual market of over $100 million (US) in Taiwan. We obtained a 32.15-Mb genome draft containing 9,254 genes. Genome ontology enrichment and pathway analyses shed light on sexual development and the biosynthesis of sesquiterpenoids, triterpenoids, ergostanes, antroquinonol, and antrocamphin. We identified genes differentially expressed between mycelium and fruiting body and 242 proteins in the mevalonate pathway, terpenoid pathways, cytochrome P450s, and polyketide synthases, which may contribute to the production of medicinal secondary metabolites. Genes of secondary metabolite biosynthetic pathways showed expression enrichment for tissue-specific compounds, including 14-?-demethylase (CYP51F1) in fruiting body for converting lanostane to ergostane triterpenoids, coenzymes Q (COQ) for antroquinonol biosynthesis in mycelium, and polyketide synthase for antrocamphin biosynthesis in fruiting body. Our data will be useful for developing a strategy to increase the production of useful metabolites.
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OSU-T315: a novel targeted therapeutic that antagonizes AKT membrane localization and activation of chronic lymphocytic leukemia cells.
Blood
PUBLISHED: 10-09-2014
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Aberrant regulation of endogenous survival pathways plays a major role in progression of chronic lymphocytic leukemia (CLL). Signaling via conjugation of surface receptors within the tumor environmental niche activates survival and proliferation pathways in CLL. Of these, the PI3K/AKT pathway appears to be pivotal to support CLL pathogenesis, and pharmacologic inhibitors targeting this axis have shown clinical activity. Here we investigate OSU-T315, a compound that disrupts the Phosphoinositide 3-kinase (PI3K)/AKT pathway in a novel manner. Dose-dependent, selective cytotoxicity by OSU-T315 is noted in both CLL-derived cell lines and primary CLL cells relative to normal lymphocytes. In contrast to the highly successful BTK and PI3K inhibitors that inhibit BCR signaling pathway at proximal kinases, OSU-T315 directly abrogates AKT activation by preventing translocation of AKT into lipid rafts without altering the activation of receptor-associated kinases. Through this mechanism, the agent triggers caspase-dependent apoptosis in CLL by suppressing BCR, CD49d, CD40 and TLR9-mediated AKT activation in an ILK-independent manner. In vivo, OSU-T315 attains pharmacologically active drug levels and significantly prolongs survival in the TCL1 mouse model. Together, our findings indicate a novel mechanism of action of OSU-T315 with potential therapeutic application in CLL.
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Sensitization of Intracellular Salmonella enterica Serovar Typhimurium to Aminoglycosides In Vitro and In Vivo by a Host-Targeted Antimicrobial Agent.
Antimicrob. Agents Chemother.
PUBLISHED: 09-29-2014
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Aminoglycosides exhibit relatively poor activity against intracellular Salmonella enterica serovar Typhimurium due to their low permeativity across eukaryotic cell membranes. Previously, we identified the unique ability of AR-12, a celecoxib-derived small-molecule agent, to eradicate intracellular Salmonella Typhimurium in macrophages by facilitating autophagosome formation and suppressing Akt kinase signaling. In light of this unique mode of antibacterial action, we investigated the ability of AR-12 to sensitize intracellular Salmonella to aminoglycosides in macrophages and in an animal model. The antibacterial activities of AR-12 combined with various aminoglycosides, including streptomycin, kanamycin, gentamicin, and amikacin, against intracellular S. Typhimurium in murine RAW264.7 macrophages were assessed. Cells were infected with S. Typhimurium followed by treatment with AR-12 or individual aminoglycosides or with combinations for 24 h. The in vivo efficacies of AR-12, alone or in combination with gentamicin or amikacin, were also assessed by treating S. Typhimurium-infected BALB/c mice daily for 14 consecutive days. Exposure of S. Typhimurium-infected RAW264.7 cells to a combination of AR-12 with individual aminoglycosides led to a reduction in bacterial survival (P < 0.05), both intracellular and extracellular, that was greater than that seen with the aminoglycosides alone. This sensitizing effect, however, was not associated with increased aminoglycoside penetration into bacteria or macrophages. Moreover, daily intraperitoneal injection of AR-12 at 0.1 mg/kg of body weight significantly increased the in vivo efficacy of gentamicin and amikacin in prolonging the survival of S. Typhimurium-infected mice. These findings indicate that the unique ability of AR-12 to enhance the in vivo efficacy of aminoglycosides might have translational potential for efforts to develop novel strategies for the treatment of salmonellosis.
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Highly stretchable and conductive silver nanowire thin films formed by soldering nanomesh junctions.
Phys Chem Chem Phys
PUBLISHED: 08-21-2014
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Silver nanowires (AgNWs) have been widely used for stretchable and foldable conductors due to their percolating network nanostructure. To enhance the mechanical strength of AgNW thin films under extreme stretching conditions, in this study, we utilize a simple chemical reaction to join AgNW network connections. Upon applying a reactive ink over AgNW thin films, silver nanoparticles are preferentially generated over the nanowire junctions and solder the nanomesh structures. The soldered nanostructure reinforces the conducting network and exhibits no obvious change in electrical conductivity in the stretching or rolling process with elongation strains up to 120%. Several examples are also demonstrated to show potential applications of this material in stretchable electronic devices.
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Colchicine suppresses atrial fibrillation in failing heart.
Int. J. Cardiol.
PUBLISHED: 08-17-2014
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This study aimed to investigate the mechanism by which colchicine suppresses atrial fibrillation (AF) in a rabbit heart failure (HF) model.
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Sleep Apnea and the Risk of Chronic Kidney Disease: A Nationwide Population-Based Cohort Study.
Sleep
PUBLISHED: 08-06-2014
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Sleep apnea (SA) is characterized by apnea during sleep and is associated with cardiovascular diseases and an increase in all-cause mortality. Chronic kidney disease (CKD) is a global health problem that has placed a substantial burden on healthcare resources. However, the relationship between SA and the incidence of CKD is not clear. This study aimed to determine whether SA is an independent risk factor for the development of CKD.
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Troglitazone and ?2Troglitazone enhance adiponectin expression in monocytes/macrophages through the AMP-activated protein kinase pathway.
Mediators Inflamm.
PUBLISHED: 07-11-2014
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Accumulating evidence indicates that the regimen to increase adiponectin will provide a novel therapeutic strategy for inflammation and cardiovascular disorders. Here, we tested the effect of troglitazone (TG) and its newly synthesized derivative, 5-[4-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-yl-methoxy)-benzylidene]-2,4-thiazolidinedione (?2troglitazone, (?2TG)), on the adiponectin expression in monocytes/macrophages and the relative mechanisms. The expression of adiponectin was located in macrophages of atherosclerotic lesions from patients and cholesterol-fed rabbits. TG and ?2TG enhanced adiponectin mRNA and protein expression in THP-1 cells by quantitative real-time PCR, Western blot, and immunocytochemistry. TG induced adiponectin mRNA expression through a PPAR?-dependent pathway whereas ?2TG enhanced adiponectin mRNA expression through a PPAR?-independent pathway in THP-1 cells. Both TG and ?2TG enhanced adiponectin mRNA expression through AMP-activated protein kinase (AMPK) activation. TG and ?2TG decreased the adhesion of THP-1 cells to TNF-?-treated HUVECs and the inhibitory effect was abolished by specific antiadiponectin antibodies. TG- and ?2TG-induced suppression on monocyte adhesion were inhibited by a selective AMPK inhibitor compound C. Our data suggest that the inhibitory effect of TG and ?2TG on monocyte adhesion might be at least in part through de novo adiponectin expression and activation of an AMPK-dependent pathway, which might play an important role in anti-inflammation and antiatherosclerosis.
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PKC-? as a therapeutic target in CLL: PKC inhibitor AEB071 demonstrates preclinical activity in CLL.
Blood
PUBLISHED: 07-07-2014
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Targeting B-cell receptor (BCR) signaling in chronic lymphocytic leukemia (CLL) has been successful with durable remissions observed with several targeted therapeutics. Protein kinase C-? (PKC-?) is immediately downstream of BCR and has been shown to be essential to CLL cell survival and proliferation in vivo. We therefore evaluated sotrastaurin (AEB071), an orally administered potent PKC inhibitor, on CLL cell survival both in vitro and in vivo. AEB071 shows selective cytotoxicity against B-CLL cells in a dose-dependent manner. Additionally, AEB071 attenuates BCR-mediated survival pathways, inhibits CpG-induced survival and proliferation of CLL cells in vitro, and effectively blocks microenvironment-mediated survival signaling pathways in primary CLL cells. Furthermore, AEB071 alters ?-catenin expression, resulting in decreased downstream transcriptional genes as c-Myc, Cyclin D1, and CD44. Lastly, our preliminary in vivo studies indicate beneficial antitumor properties of AEB071 in CLL. Taken together, our results indicate that targeting PKC-? has the potential to disrupt signaling from the microenvironment contributing to CLL cell survival and potentially drug resistance. Future efforts targeting PKC with the PKC inhibitor AEB071 as monotherapy in clinical trials of relapsed and refractory CLL patients are warranted.
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AMPK reverses the mesenchymal phenotype of cancer cells by targeting the Akt-MDM2-Foxo3a signaling axis.
Cancer Res.
PUBLISHED: 07-03-2014
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In cancer cells, the epithelial-mesenchymal transition (EMT) confers the ability to invade basement membranes and metastasize to distant sites, establishing it as an appealing target for therapeutic intervention. Here, we report a novel function of the master metabolic kinase AMPK in suppressing EMT by modulating the Akt-MDM2-Foxo3 signaling axis. This mechanistic link was supported by the effects of siRNA-mediated knockdown and pharmacologic activation of AMPK on epithelial and mesenchymal markers in established breast and prostate cancer cells. Exposure of cells to OSU-53, a novel allosteric AMPK activator, as well as metformin and AICAR, was sufficient to reverse their mesenchymal phenotype. These effects were abrogated by AMPK silencing. Phenotypic changes were mediated by Foxo3a activation, insofar as silencing or overexpressing Foxo3a mimicked the effects of AMPK silencing or OSU-53 treatment on EMT, respectively. Mechanistically, Foxo3a activation led to the transactivation of the E-cadherin gene and repression of genes encoding EMT-inducing transcription factors. OSU-53 activated Foxo3a through two Akt-dependent pathways, one at the level of nuclear localization by blocking Akt- and IKK?-mediated phosphorylation, and a second at the level of protein stabilization via cytoplasmic sequestration of MDM2, an E3 ligase responsible for Foxo3a degradation. The suppressive effects of OSU-53 on EMT had therapeutic implications illustrated by its ability to block invasive phenotypes in vitro and metastatic properties in vivo. Overall, our work illuminates a mechanism of EMT regulation in cancer cells mediated by AMPK, along with preclinical evidence supporting a tractable therapeutic strategy to reverse mesenchymal phenotypes associated with invasion and metastasis.
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Targeting the Warburg effect with a novel glucose transporter inhibitor to overcome gemcitabine resistance in pancreatic cancer cells.
Carcinogenesis
PUBLISHED: 05-30-2014
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Gemcitabine resistance remains a significant clinical challenge. Here, we used a novel glucose transporter (Glut) inhibitor, CG-5, as a proof-of-concept compound to investigate the therapeutic utility of targeting the Warburg effect to overcome gemcitabine resistance in pancreatic cancer. The effects of gemcitabine and/or CG-5 on viability, survival, glucose uptake and DNA damage were evaluated in gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cell lines. Mechanistic studies were conducted to determine the molecular basis of gemcitabine resistance and the mechanism of CG-5-induced sensitization to gemcitabine. The effects of CG-5 on gemcitabine sensitivity were investigated in a xenograft tumor model of gemcitabine-resistant pancreatic cancer. In contrast to gemcitabine-sensitive pancreatic cancer cells, the resistant Panc-1 and Panc-1(GemR) cells responded to gemcitabine by increasing the expression of ribonucleotide reductase M2 catalytic subunit (RRM2) through E2F1-mediated transcriptional activation. Acting as a pan-Glut inhibitor, CG-5 abrogated this gemcitabine-induced upregulation of RRM2 through decreased E2F1 expression, thereby enhancing gemcitabine-induced DNA damage and inhibition of cell survival. This CG-5-induced inhibition of E2F1 expression was mediated by the induction of a previously unreported E2F1-targeted microRNA, miR-520f. The addition of oral CG-5 to gemcitabine therapy caused greater suppression of Panc-1(GemR) xenograft tumor growth in vivo than either drug alone. Glut inhibition may be an effective strategy to enhance gemcitabine activity for the treatment of pancreatic cancer.
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Complementary Usage of Rhodiola crenulata (L.) in Chronic Obstructive Pulmonary Disease Patients: The Effects on Cytokines and T Cells.
Phytother Res
PUBLISHED: 05-29-2014
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Although chronic obstructive pulmonary disease (COPD) is an inflammatory disease predominantly involving T cells, no study of Rhodiola as an immunomodulator in COPD patients has been reported. In this study, COPD patients took Rhodiola crenulata 500?mg (n?=?38) or placebo (starch/phosphate buffered saline) (n?=?19) daily for 12?weeks and were compared with untreated, age-matched, and sex-matched non-COPD control subjects. Our results showed that serum levels of IL-2, IL-10, and IFN-? in COPD patients before treatment are significantly higher than levels in non-COPD controls (p??0.05). The results suggested that Rhodiola treatment had beneficial antiinflammation effects, lower COPD assessment test score and decreased high-sensitivity C-reactive protein, on COPD patients (p?
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Postoperative wound infection after posterior spinal instrumentation: analysis of long-term treatment outcomes.
Eur Spine J
PUBLISHED: 05-22-2014
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Postoperative spinal implant infection (PSII) places patients at risk for pseudarthrosis, correction loss, spondylodiscitis, adverse neurological sequelae, and even death; however, prognostic factors that predict long-term treatment outcomes have not been clearly investigated. In addition, few studies concerning the feasibility of reconstructing the failed spinal events have been published.
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Synaptic, transcriptional and chromatin genes disrupted in autism.
Silvia De Rubeis, Xin He, Arthur P Goldberg, Christopher S Poultney, Kaitlin Samocha, A Ercument Cicek, Yan Kou, Li Liu, Menachem Fromer, Susan Walker, Tarjinder Singh, Lambertus Klei, Jack Kosmicki, Shih-Chen Fu, Branko Aleksic, Monica Biscaldi, Patrick F Bolton, Jessica M Brownfeld, Jinlu Cai, Nicholas G Campbell, Angel Carracedo, Maria H Chahrour, Andreas G Chiocchetti, Hilary Coon, Emily L Crawford, Lucy Crooks, Sarah R Curran, Geraldine Dawson, Eftichia Duketis, Bridget A Fernandez, Louise Gallagher, Evan Geller, Stephen J Guter, R Sean Hill, Iuliana Ionita-Laza, Patricia Jimenez Gonzalez, Helena Kilpinen, Sabine M Klauck, Alexander Kolevzon, Irene Lee, Jing Lei, Terho Lehtimäki, Chiao-Feng Lin, Avi Ma'ayan, Christian R Marshall, Alison L McInnes, Benjamin Neale, Michael J Owen, Norio Ozaki, Mara Parellada, Jeremy R Parr, Shaun Purcell, Kaija Puura, Deepthi Rajagopalan, Karola Rehnström, Abraham Reichenberg, Aniko Sabo, Michael Sachse, Stephan J Sanders, Chad Schafer, Martin Schulte-Rüther, David Skuse, Christine Stevens, Peter Szatmari, Kristiina Tammimies, Otto Valladares, Annette Voran, Li-San Wang, Lauren A Weiss, A Jeremy Willsey, Timothy W Yu, Ryan K C Yuen, , Edwin H Cook, Christine M Freitag, Michael Gill, Christina M Hultman, Thomas Lehner, Aarno Palotie, Gerard D Schellenberg, Pamela Sklar, Matthew W State, James S Sutcliffe, Christopher A Walsh, Stephen W Scherer, Michael E Zwick, Jeffrey C Barrett, David J Cutler, Kathryn Roeder, Bernie Devlin, Mark J Daly, Joseph D Buxbaum.
Nature
PUBLISHED: 05-18-2014
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The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.
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Using the CHA2DS2-VASc Score for Refining Stroke Risk Stratification in 'Low-Risk' Asian Patients With Atrial Fibrillation.
J. Am. Coll. Cardiol.
PUBLISHED: 05-13-2014
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A new scoring system, the anticoagulation and risk factors in atrial fibrillation (ATRIA) score, was proposed for risk stratification in patients with atrial fibrillation (AF). Whether the ATRIA scheme can adequately identify patients who are at low risk of ischemic stroke remains unknown.
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The Uremic Toxin Indoxyl Sulfate Increases Pulmonary Vein and Atrial Arrhythmogenesis.
J. Cardiovasc. Electrophysiol.
PUBLISHED: 05-09-2014
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Chronic kidney disease (CKD) is associated with a higher incidence of atrial fibrillation (AF) with unclear mechanisms. Indoxyl sulfate (IS) accumulates in CKD patients. IS increases oxidative stress, which contributes to the genesis of AF. The arrhythmogenic effect of IS is unclear.
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Acute myocardial infarction in patients with atrial fibrillation with a CHA2DS2-VASc score of 0 or 1: A nationwide cohort study.
Heart Rhythm
PUBLISHED: 04-28-2014
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The risk of acute myocardial infarction (AMI) in patients with atrial fibrillation (AF) with a CHA2DS2-VASc score of 0 (for men) or 1 (for women) has not been previously investigated.
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Extra-prostatic Transgene-associated Neoplastic Lesions in Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) Mice.
Toxicol Pathol
PUBLISHED: 04-19-2014
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Male transgenic adenocarcinoma of the mouse prostate (TRAMP) mice are frequently used in prostate cancer research because their prostates consistently develop a series of preneoplastic and neoplastic lesions. Disease progression in TRAMP mouse prostates culminates in metastatic, poorly differentiated carcinomas with neuroendocrine features. The androgen dependence of the rat probasin promoter largely limits transgene expression to the prostatic epithelium. However, extra-prostatic transgene-positive lesions have been described in TRAMP mice, including renal tubuloacinar carcinomas, neuroendocrine carcinomas of the urethra, and phyllodes-like tumors of the seminal vesicle. Here, we describe the histologic and immunohistochemical features of 2 novel extra-prostatic lesions in TRAMP mice: primary anaplastic tumors of uncertain cell origin in the midbrain and poorly differentiated adenocarcinomas of the submandibular salivary gland. These newly characterized tumors apparently result from transgene expression in extra-prostatic locations rather than representing metastatic prostate neoplasms because lesions were identified in both male and female mice and in male TRAMP mice without histologically apparent prostate tumors. In this article, we also calculate the incidences of the urethral carcinomas and renal tubuloacinar carcinomas, further elucidate the biological behavior of the urethral carcinomas, and demonstrate the critical importance of complete necropsies even when evaluating presumably well characterized phenotypes in genetically engineered mice.
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Selective apoptotic cell death effects of oral cancer cells treated with destruxin B.
BMC Complement Altern Med
PUBLISHED: 03-31-2014
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Recent studies have revealed that destruxins (Dtx) have potent cytotoxic activities on individual cancer cells, however, data on oral cancer cells especial human are absent.
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Reversible cerebral vasoconstriction syndrome after blood transfusion.
Headache
PUBLISHED: 03-13-2014
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To report 2 cases of reversible cerebral vasoconstriction syndrome (RCVS) with posterior reversible encephalopathy syndrome (PRES) after blood transfusion for severe anemia.
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Long-term prognosis of patients older than ninety years after permanent pacemaker implantation: does the procedure save the patients?
Can J Cardiol
PUBLISHED: 02-13-2014
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The implantation of a permanent pacemaker (PPM) is life-saving for patients with life-threatening bradycardia. However, the effectiveness and prognosis of PPM implantations for extremely old patients (? 90 years old) have not been investigated.
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Synergistic interaction between the HDAC inhibitor, MPT0E028, and sorafenib in liver cancer cells in vitro and in vivo.
Clin. Cancer Res.
PUBLISHED: 02-11-2014
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To investigate the antitumor activities of a histone deacetylase (HDAC) inhibitor, MPT0E028, plus sorafenib in liver cancer cells in vitro and in vivo.
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Calanquinone A induces anti-glioblastoma activity through glutathione-involved DNA damage and AMPK activation.
Eur. J. Pharmacol.
PUBLISHED: 02-08-2014
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Glioblastoma, a highly malignant glioma, is resistant to both radiation and chemotherapy and is an intractable problem in clinical treatment. New therapeutic approaches are in urgent need. Calanquinone A, an herbal constituent, displayed anti-proliferative activity against glioblastoma cells, including A172, T98 and U87. Flow cytometric analysis showed an S phase arrest and a subsequent apoptosis to calanquinone A action. Further identification demonstrated a rapid increase of ?H2A.X formation at S phase. The data together with comet tail formation and Chk1 activation indicated DNA damage response. N-acetyl cysteine (an antioxidant and a glutathione precursor) and exogenously applied glutathione, but not trolox (an antioxidant), completely abolished calanquinone A-induced effects. Immunofluorescence assay revealed that calanquinone A decreased the intracellular glutathione levels in both A172 and T98 cells. However, calanquinone A, by itself, did not conjugate glutathione. The data suggested that the decrease of cellular glutathione predominantly contributed to the anticancer mechanism. Furthermore, calanquinone A induced the activation of AMP-activated protein kinase (AMPK) and the inhibition of p70S6K activity. Rhodamine efflux assay showed that calanquinone A did not block efflux activity, indicating that calanquinone A was not a P-glycoprotein substrate. In summary, the data suggest that calanquinone A displays anti-glioblastoma activity through a decrease of cellular glutathione levels that subsequently induces DNA damage stress and AMPK activation, leading to cell cycle arrest at S-phase and apoptotic cell death. Furthermore, calanquinone A does not serve as a P-glycoprotein substrate, suggesting a potential for further development in anti-glioblastoma therapy.
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Does digoxin increase the risk of ischemic stroke and mortality in atrial fibrillation? A nationwide population-based cohort study.
Can J Cardiol
PUBLISHED: 01-10-2014
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Digoxin and related cardiac glycosides have been used for almost 100 years in atrial fibrillation (AF). However, 2 recent analyses of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) trial showed inconsistent results regarding the risk of mortality associated with digoxin use. The goal of the present study was to investigate the relationship between digoxin and the risk of ischemic stroke and mortality in Asians.
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Preparation and physicochemical properties of whole-bean soymilk.
J. Agric. Food Chem.
PUBLISHED: 01-10-2014
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Whole-bean soymilk has been prepared by using media-milling. Some characteristics of media-milled soymilk have been determined and compared with filtered soymilk (similar to commercial ones) and whole-bean soymilk prepared by blending. There existed particles in the nano/submicrometer scale in both media-milled and filtered soymilk. The particles in blended soymilk were greater than 1 ?m. Media-milled soymilk was the most stable among three samples, even after autoclaving. Solid recovery (98.44 ± 0.16%), viscosity (160.59 ± 4.26 cps), dietary fiber (22.68 ± 0.97% on dry basis), total polyphenol recovery (95.15 ± 7.09%), and isoflavone content (4.42 ± 0.03 mg/g dry solid) of media-milled samples were greater than those of filtered ones. Aglycones, the most bioactive form of isoflavone, in autoclaved media-milled soymilk were more than 2-fold those in autoclaved filtered soymilk. With almost no okara generated, the media-milled soymilk retained fiber in soybeans which would be beneficial to human health.
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Quantification of OSU-2S, a novel derivative of FTY720, in mouse plasma by liquid chromatography-tandem mass spectrometry.
J Pharm Biomed Anal
PUBLISHED: 01-06-2014
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OSU-2S is a novel anti-cancer and immune modulatory agent designed specifically to avert the immunosuppressive effects and related toxicities observed in clinical studies with its predecessor analog, FTY720. To characterize its preclinical pharmacokinetics, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of OSU-2S in mouse plasma. Ethyl acetate extraction of samples containing OSU-2S and the internal standard, Sph-17, was followed by separation with a 6min gradient (water/0.1% formic acid and methanol/0.1% formic acid) on a reverse-phase C18 column at room temperature. Selected reaction monitoring was used for detection on a triple quadrupole mass spectrometer with positive ionization. The assay was linear over the concentration range 3-3000ng/mL with accuracy ranging from 103 to 111%, and both within- and between-run precision (CV%) ?11%. All stability samples were within ±15% of nominal values, and replicates were within 15% CV. The assay was successfully applied to a mouse pharmacokinetic study of OSU-2S with intravenous and intraperitoneal administration. OSU-2S non-compartmental pharmacokinetic parameters, area under the concentration-time curve, clearance, and elimination half-life were estimated at 1522h?g/L, 3.06L/h/kg and 15.6h, respectively, for intravenous injection. Systemic availability after intraperitoneal injection was approximately 46%. These data demonstrate the OSU-2S compound displays acceptable pharmacokinetic properties for further in vivo pharmacologic evaluation, which can be facilitated by the validated LC-MS/MS assay.
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Color-tunable mixed photoluminescence emission from Alq3 organic layer in metal-Alq3-metal surface plasmon structure.
Nanoscale Res Lett
PUBLISHED: 01-01-2014
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This work reports the color-tunable mixed photoluminescence (PL) emission from an Alq3 organic layer in an Au-Alq3-Au plasmonic structure through the combination of organic fluorescence emission and another form of emission that is enabled by the surface plasmons in the plasmonic structure. The emission wavelength of the latter depends on the Alq3 thickness and can be tuned within the Alq3 fluorescent spectra. Therefore, a two-color broadband, color-tunable mixed PL structure was obtained. Obvious changes in the Commission Internationale d'Eclairage (CIE) coordinates and the corresponding emission colors of Au-Alq3-Au samples clearly varied with the Alq3 thickness (90, 130, and 156 nm).
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Novel pharmacologic targeting of tight junctions and focal adhesions in prostate cancer cells.
PLoS ONE
PUBLISHED: 01-01-2014
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Cancer cell resistance to anoikis driven by aberrant signaling sustained by the tumor microenvironment confers high invasive potential and therapeutic resistance. We recently generated a novel lead quinazoline-based Doxazosin® derivative, DZ-50, which impairs tumor growth and metastasis via anoikis. Genome-wide analysis in the human prostate cancer cell line DU-145 identified primary downregulated targets of DZ-50, including genes involved in focal adhesion integrity (fibronectin, integrin-?6 and talin), tight junction formation (claudin-11) as well as insulin growth factor binding protein 3 (IGFBP-3) and the angiogenesis modulator thrombospondin 1 (TSP-1). Confocal microscopy demonstrated structural disruption of both focal adhesions and tight junctions by the downregulation of these gene targets, resulting in decreased cell survival, migration and adhesion to extracellular matrix (ECM) components in two androgen-independent human prostate cancer cell lines, PC-3 and DU-145. Stabilization of cell-ECM interactions by overexpression of talin-1 and/or exposing cells to a fibronectin-rich environment mitigated the effect of DZ-50. Loss of expression of the intracellular focal adhesion signaling effectors talin-1 and integrin linked kinase (ILK) sensitized human prostate cancer to anoikis. Our findings suggest that DZ-50 exerts its antitumor effect by targeting the key functional intercellular interactions, focal adhesions and tight junctions, supporting the therapeutic significance of this agent for the treatment of advanced prostate cancer.
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13% Efficiency Hybrid Organic/Silicon-Nanowire Heterojunction Solar Cell via Interface Engineering.
ACS Nano
PUBLISHED: 11-19-2013
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Interface carrier recombination currently hinders the performance of hybrid organic-silicon heterojunction solar cells for high-efficiency low-cost photovoltaics. Here, we introduce an intermediate 1,1-bis[(di-4-tolylamino)phenyl]cyclohexane (TAPC) layer into hybrid heterojunction solar cells based on silicon nanowires (SiNWs) and conjugate polymer poly(3,4-ethylenedioxy-thiophene):poly(styrenesulfonate) (PEDOT:PSS). The highest power conversion efficiency reaches a record 13.01%, which is largely ascribed to the modified organic surface morphology and suppressed saturation current that boost the open-circuit voltage and fill factor. We show that the insertion of TAPC increases the minority carrier lifetime because of an energy offset at the heterojunction interface. Furthermore, X-ray photoemission spectroscopy reveals that TAPC can effectively block the strong oxidation reaction occurring between PEDOT:PSS and silicon, which improves the device characteristics and assurances for reliability. These learnings point toward future directions for versatile interface engineering techniques for the attainment of highly efficient hybrid photovoltaics.
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Autonomic dysfunction in reversible cerebral vasoconstriction syndromes.
J Headache Pain
PUBLISHED: 11-07-2013
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Autonomic imbalance may play an important role in the pathogenesis of reversible cerebral vasoconstriction syndromes (RCVS). This study aimed to assess the autonomic function by analyzing heart rate variability (HRV) in patients with RCVS.
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Psychiatric comorbidities in allodynic migraineurs.
Cephalalgia
PUBLISHED: 09-18-2013
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To evaluate the prevalence and the association of psychological disturbance in migraine patients with allodynia.
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Angiomatoid fibrous histiocytoma: clinicopathological and molecular characterisation with emphasis on variant histomorphology.
J. Clin. Pathol.
PUBLISHED: 09-16-2013
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Angiomatoid fibrous histiocytoma (AFH) is histologically typified by nodules of histiocytoid spindle cells with pseudoangiomatoid spaces, fibrous pseudocapsules and lymphocytic cuffs. The principal goal was to expand the spectrum of AFHs through clinicopathological and molecular characterisation.
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Leptin modulates electrophysiological characteristics and isoproterenol-induced arrhythmogenesis in atrial myocytes.
J. Biomed. Sci.
PUBLISHED: 09-13-2013
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Obesity is an important risk factor for atrial fibrillation (AF). Leptin is an important adipokine. However, it is not clear whether leptin directly modulates the electrophysiological characteristics of atrial myocytes.
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Comparison among load-, ROM-, and displacement-controlled methods used in the lumbosacral nonlinear finite-element analysis.
Spine
PUBLISHED: 08-22-2013
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For lumbosacral nonlinear analysis, the characteristics and differences between the load- and range-of-motion (ROM)-controlled methods (LCM and RCM) were compared using the numerical approach.
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Kinetics of Changes in Oxyhemoglobin Saturation during Walking and Cycling Tests in Chronic Obstructive Pulmonary Disease.
Respir Care
PUBLISHED: 08-13-2013
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The patterns and kinetics of changes in oxyhemoglobin saturation measured with pulse oximetry (?SpO2) in six-minute walking test (6MWT) and cycling test has not been addressed in patients with chronic obstructive pulmonary disease (COPD).
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Reevesioside F induces potent and efficient anti-proliferative and apoptotic activities through Na?/K?-ATPase ?3 subunit-involved mitochondrial stress and amplification of caspase cascades.
Biochem. Pharmacol.
PUBLISHED: 08-05-2013
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Reevesioside F, isolated from Reevesia formosana, induced anti-proliferative activity that was highly correlated with the expression of Na?/K?-ATPase ?? subunit in several cell lines, including human leukemia HL-60 and Jurkat cells, and some other cell lines. Knockdown of ?? subunit significantly inhibited cell apoptosis suggesting a crucial role of the ?? subunit. Reevesioside F induced a rapid down-regulation of survivin protein, followed by release of cytochrome c from mitochondria and loss of mitochondrial membrane potential (??m). Further examination demonstrated the mitochondrial damage in leukemic cells through Mcl-1 down-regulation, Noxa up-regulation and an increase of the formation of truncated Bid, tBim and a 23-kDa cleaved Bcl-2 fragment. Furthermore, reevesioside F induced an increase of mitochondria-associated acetyl ?-tubulin that may also contribute to apoptosis. The caspase cascade was profoundly activated by reevesioside F. Notably, the specific caspase-3 inhibitor z-DEVD-fmk significantly blunted reevesioside F-induced loss of ??m and apoptosis, suggesting that caspase-3 activation may further amplify mitochondrial damage and apoptotic signaling cascade. In spite of being a cardiac glycoside, reevesioside F did not increase the intracellular Ca²? levels. Moreover, CGP-37157 which blocked Na?/Ca²? exchanger on plasma membrane and mitochondria did not modify reevesioside F-mediated effect. In summary, the data suggest that reevesioside F induces apoptosis through the down-regulation of survivin and Mcl-1, and the formation of pro-apoptotic fragments from Bcl-2 family members. The loss of ??m and mitochondrial damage are responsible for the activation of caspases. Moreover, the amplification of caspase-3-mediated signaling pathway contributes largely to the execution of apoptosis in leukemic cells.
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Insulin-like growth factor-I receptor is suppressed through transcriptional repression and mRNA destabilization by a novel energy restriction-mimetic agent.
Carcinogenesis
PUBLISHED: 07-16-2013
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Insulin-like growth factor-I receptor (IGF-IR) represents one of the major targets by which dietary or chemically induced energy restriction mediates chemopreventive effects in animal tumor models. However, the mechanism underlying this cellular response remains unclear. In the course of investigating the suppressive effect of the energy restriction-mimetic agent CG-5 on IGF-IR expression in prostate cancer cells, we identified a novel posttranscriptional mechanism by which the RNA-binding protein human antigen R (HuR) regulates IGF-IR expression through messenger RNA (mRNA) stabilization. Previously, we demonstrated that Sp1 and HuR proteins were concomitantly targeted for ubiquitin-dependent degradation by ?-transducin repeat-containing protein in response to CG-5. Although this loss of Sp1 expression contributed to CG-5-mediated IGF-IR downregulation, enforced specific protein 1 (Sp1) expression could only partially protect cells from the drug effect. The small interfering RNA-mediated silencing of HuR suppressed IGF-IR expression by reducing mRNA stability, whereas ectopic HuR expression increased IGF-IR mRNA stability and protein expression and, when coexpressed with Sp1, blocked CG-5-mediated IGF-IR ablation. RNA pull-down and immunoprecipitation analyses indicated that HuR selectively bound to the distal region of the IGF-IR 3 untranslated region (UTR), whereas no interaction with the 5UTR was noted. Evaluation of a series of truncated HuR mutants revealed that the RNA recognition motifs (RRM2 and RRM3) were involved in IGF-IR 3UTR binding and the consequent increase in IGF-IR mRNA stability. Although these data contrast with a previous report that HuR acted as a translation repressor of IGF-IR mRNA through 5UTR binding, our finding is consistent with the reported oncogenic role of HuR in conferring stability to target mRNAs encoding tumor-promoting proteins.
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A novel liposomal formulation of FTY720 (Fingolimod) for promising enhanced targeted delivery.
Nanomedicine
PUBLISHED: 07-15-2013
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We describe here the development and characterization of the physicochemical and pharmacokinetic properties of a novel liposomal formulation for FTY720 delivery, LP-FTY720. The mean diameter of LP-FTY720 was ~157nm, and the FTY720 entrapment efficiency was ~85%. The liposomal formulation protected FTY720 from degradation in aqueous buffer and showed toxicity in CLL patient B cells comparable to that of free FTY720. Following intravenous injection in ICR mice, LP-FTY720 had an increased elimination phase half-life (~28 vs. ~19hr) and decreased clearance (235 vs. 778mL/h/kg) compared to the free drug. Antibodies against CD19, CD20 and CD37 were incorporated into LP-FTY720, which provided targeted delivery to CLL patient B cells and thus achieved higher killing efficacy. The novel liposomal carrier of FTY720 demonstrated improved pharmacokinetic properties, comparable activity, and a potential platform for targeted delivery to CLL by overcoming the limited application of free FTY720 to B malignancy treatment.
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Incidence and risk factors of chronic daily headache in young adolescents: a school cohort study.
Pediatrics
PUBLISHED: 06-17-2013
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This study investigated the incidence and risk factors of chronic daily headache (CDH) and its major subtypes in young adolescents.
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Sensitive liquid chromatography/mass spectrometry methods for quantification of pomalidomide in mouse plasma and brain tissue.
J Pharm Biomed Anal
PUBLISHED: 05-27-2013
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Pomalidomide was recently approved by the United States Food and Drug Administration for the treatment of patients with relapsed or refractory multiple myeloma who have received at least two prior therapies. As pomalidomide is increasingly evaluated in other diseases and animal disease models, this paper presents development and validation of a sensitive liquid chromatography tandem mass spectrometry assay for quantification of pomalidomide in mouse plasma and brain tissue to fill a gap in published preclinical pharmacokinetic and analytical data with this agent. After acetonitrile protein precipitation, pomalidomide and internal standard, hesperitin, were separated with reverse phase chromatography on a C-18 column with a gradient mobile phase of water and acetonitrile with 0.1% fomic acid. Positive atmospheric pressure chemical ionization mass spectrometry with selected reaction monitoring mode was applied to achieve 0.3-3000nM (0.082-819.73ng/mL) linear range in mouse plasma and 0.6-6000pmol/g in brain tissue. The within- and between-batch accuracy and precision were less than 15% for both plasma and brain tissue. The method was applied to measure pomalidomide concentrations in plasma and brain tissue in a pilot mouse pharmacokinetic study with an intravenous dose of 0.5mg/kg. This assay can be applied for thorough characterization of pomalidomide pharmacokinetics and tissue distribution in mice.
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Development of p21 activated kinase-targeted multikinase inhibitors that inhibit thyroid cancer cell migration.
J. Clin. Endocrinol. Metab.
PUBLISHED: 05-24-2013
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The p21 activated kinases (PAKs) are a family of serine/threonine kinases that are downstream effectors of small GTPase Cdc42 and Rac. PAKs regulate cell motility, proliferation, and cytoskeletal rearrangement. PAK isoform expression and activity have been shown to be enhanced in cancer and to function as an oncogene in vivo. PAKs also have been implicated in cancer progression.
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Influence of atrial fibrillation on survival in patients with hepatocellular carcinoma: Experience from a single center in Taiwan.
J Chin Med Assoc
PUBLISHED: 05-09-2013
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It is unclear whether atrial fibrillation (AF) adversely influences the clinical course of patients with hepatocellular carcinoma (HCC).
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A free vascularized tibia-fibular composite graft for the traumatic femoral bony defect of a 6-year-old boy with 10-year follow up: a case report.
J Med Case Rep
PUBLISHED: 04-03-2013
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Free vascularized fibular grafts have been widely used for the reconstruction of long bone defects. However, the use of a vascularized tibial graft is precluded by its weight-bearing function and unacceptable donor site morbidity.
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Association of p53 codon 72 genotypes and clinical outcome in human papillomavirus-infected lung cancer patients.
Ann. Thorac. Surg.
PUBLISHED: 03-26-2013
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We recently reported that high-risk human papillomavirus (HPV) 16/18 E6 protein was associated with p53 protein degradation in lung cancer. The present study addressed the relationship between the different p53 genotypes and HPV oncoprotein expression with respect to p53 protein degradation and clinical outcome in primary lung cancer patients.
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HuR cytoplasmic expression is associated with increased cyclin A expression and inferior disease-free survival in patients with gastrointestinal stromal tumours (GISTs).
Histopathology
PUBLISHED: 03-21-2013
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HuR is an RNA-binding protein that post-transcriptionally modulates the expression of various target genes involved in carcinogenesis, such as CCNA2, which encodes cyclin A. The aim of this study was to evaluate the significance of HuR expression and subcellular localization in a large cohort of gastrointestinal stromal tumours (GISTs).
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Vitamin E facilitates the inactivation of the kinase Akt by the phosphatase PHLPP1.
Sci Signal
PUBLISHED: 03-21-2013
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Vitamin E is a fat-soluble vitamin with antioxidant properties. Tocopherols are the predominant form of vitamin E found in the diet and in supplements and have garnered interest for their potential cancer therapeutic and preventive effects, such as the dephosphorylation of Akt, a serine/threonine kinase with a pivotal role in cell growth, survival, and metabolism. Dephosphorylation of Akt at Ser473 substantially reduces its catalytic activity and inhibits downstream signaling. We found that the mechanism by which ?-tocopherol and ?-tocopherol facilitate this site-specific dephosphorylation of Akt was mediated through the pleckstrin homology (PH) domain-dependent recruitment of Akt and PHLPP1 (PH domain leucine-rich repeat protein phosphatase, isoform 1) to the plasma membrane. We structurally optimized these tocopherols to obtain derivatives with greater in vitro potency and in vivo tumor-suppressive activity in two prostate xenograft tumor models. Binding affinities for the PH domains of Akt and PHLPP1 were greater than for other PH domain-containing proteins, which may underlie the preferential recruitment of these proteins to membranes containing tocopherols. Molecular modeling revealed the structural determinants of the interaction with the PH domain of Akt that may inform strategies for continued structural optimization. By describing a mechanism by which tocopherols facilitate the dephosphorylation of Akt at Ser473, we provide insights into the mode of antitumor action of tocopherols and a rationale for the translational development of tocopherols into novel PH domain-targeted Akt inhibitors.
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Effectiveness of botulinum toxin A in treatment of refractory erythromelalgia.
J Chin Med Assoc
PUBLISHED: 03-17-2013
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Erythromelalgia is characterized by intense burning pain, erythema, and heat in affected areas after precipitating factors such as warm temperature or stress. It is refractory to treatment in some situations. We describe a woman with adenosquamous cell carcinoma of the lung and medically refractory erythromelalgia. The symptoms of erythromelalgia presented as refractory to any medical treatment. Due to the unresponsive nature of her condition, botulinum toxin type A (onabotulinumtoxin A) was injected over both of her cheeks, periodically for six cycles. Her symptoms responded dramatically to subcutaneous and intradermal injection of botulinum toxin type A. Repetitive injection demonstrated consistent and reproducible responses, and the efficacy was maintained for approximately 1 month. No adverse effects or complications were noted. Botulinum toxin type A might be safe and effective as an alternative treatment for refractory erythromelalgia, but further large-scale studies are required.
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Relationship between idiopathic sudden sensorineural hearing loss and subsequent stroke.
Laryngoscope
PUBLISHED: 03-15-2013
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The correlation between idiopathic sudden sensorineural hearing loss and subsequent stroke is unclear. This study aimed to review stroke incidence after idiopathic sudden sensorineural hearing loss among patients admitted to a tertiary referral center and aimed to compare the characteristics of patients with and without stroke.
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Histone deacetylase inhibitor AR42 regulates telomerase activity in human glioma cells via an Akt-dependent mechanism.
Biochem. Biophys. Res. Commun.
PUBLISHED: 03-08-2013
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Epigenetic regulation via abnormal activation of histone deacetylases (HDACs) is a mechanism that leads to cancer initiation and promotion. Activation of HDACs results in transcriptional upregulation of human telomerase reverse transcriptase (hTERT) and increases telomerase activity during cellular immortalization and tumorigenesis. However, the effects of HDAC inhibitors on the transcription of hTERT vary in different cancer cells. Here, we studied the effects of a novel HDAC inhibitor, AR42, on telomerase activity in a PTEN-null U87MG glioma cell line. AR42 increased hTERT mRNA in U87MG glioma cells, but suppressed total telomerase activity in a dose-dependent manner. Further analyses suggested that AR42 decreases the phosphorylation of hTERT via an Akt-dependent mechanism. Suppression of Akt phosphorylation and telomerase activity was also observed with PI3K inhibitor LY294002 further supporting the hypothesis that Akt signaling is involved in suppression of AR42-induced inhibition of telomerase activity. Finally, ectopic expression of a constitutive active form of Akt restored telomerase activity in AR42-treated cells. Taken together, our results demonstrate that the novel HDAC inhibitor AR42 can suppress telomerase activity by inhibiting Akt-mediated hTERT phosphorylation, indicating that the PI3K/Akt pathway plays an important role in the regulation of telomerase activity in response to this HDAC inhibitor.
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Biomechanical comparison of three stand-alone lumbar cages--a three-dimensional finite element analysis.
BMC Musculoskelet Disord
PUBLISHED: 03-06-2013
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For anterior lumbar interbody fusion (ALIF), stand-alone cages can be supplemented with vertebral plate, locking screws, or threaded cylinder to avoid the use of posterior fixation. Intuitively, the plate, screw, and cylinder aim to be embedded into the vertebral bodies to effectively immobilize the cage itself. The kinematic and mechanical effects of these integrated components on the lumbar construct have not been extensively studied. A nonlinearly lumbar finite-element model was developed and validated to investigate the biomechanical differences between three stand-alone (Latero, SynFix, and Stabilis) and SynCage-Open plus transpedicular fixation. All four cages were instrumented at the L3-4 level.
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Finite element comparison of retrograde intramedullary nailing and locking plate fixation with/without an intramedullary allograft for distal femur fracture following total knee arthroplasty.
Knee
PUBLISHED: 03-03-2013
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PURPOSE: Periprosthetic distal femur fracture after total knee arthroplasty due to the stress-shielding phenomenon is a challenging problem. Retrograde intramedullary nail (RIMN) or locking plate (LP) fixation with/without a strut allograft has been clinically used via less invasive stabilization surgery (LISS) for the treatment of these periprosthetic fractures. However, their biomechanical differences in construct stability and implant stress have not been extensively studied, especially for the osteoporotic femur. METHODS: This study used a finite-element method to evaluate the differences between RIMN, LP, and LP/allograft fixation in treating periprosthetic distal femur fractures. There were sixteen variations of two fracture angles (transverse and oblique), two loading conditions (compression and rotation), and four bony conditions (one normal and three osteoporotic). Construct stiffness, fracture micromotion, and implant stress were chosen as the comparison indices. RESULTS: The LP/allograft construct provides both lateral and middle supports to the displaced femur. Comparatively, the LP and RIMN constructs, respectively, transmit the loads through the lateral and middle paths, thus providing more unstable support to the construct and high stressing on the implants. The fracture pattern plays a minor role in the construct stabilization of the three implants. In general, the biomechanical performances of the RIMN and LP constructs were comparable and significantly inferior to those of the LP/allograft construct. The bone quality should be evaluated prior to the selection of internal fixators. CONCLUSIONS: The LP/allograft construct significantly stabilizes the fracture gap, reduces the implant stress, and serves as the recommended fixation for periprosthetic distal femur fracture.
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Reducing anterior tibial translation by applying functional electrical stimulation in dynamic knee extension exercises: quantitative results acquired via marker tracking.
Clin Biomech (Bristol, Avon)
PUBLISHED: 02-27-2013
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Pain that accompanies anterior cruciate ligament deficiency during dynamic knee extension exercises is usually caused by excessive anterior tibial translation, which can be restricted if the anterior cruciate ligament was intact.
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The force synergy of human digits in static and dynamic cylindrical grasps.
PLoS ONE
PUBLISHED: 02-27-2013
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This study explores the force synergy of human digits in both static and dynamic cylindrical grasping conditions. The patterns of digit force distribution, error compensation, and the relationships among digit forces are examined to quantify the synergetic patterns and coordination of multi-finger movements. This study recruited 24 healthy participants to perform cylindrical grasps using a glass simulator under normal grasping and one-finger restricted conditions. Parameters such as the grasping force, patterns of digit force distribution, and the force coefficient of variation are determined. Correlation coefficients and principal component analysis (PCA) are used to estimate the synergy strength under the dynamic grasping condition. Specific distribution patterns of digit forces are identified for various conditions. The compensation of adjacent fingers for the force in the normal direction of an absent finger agrees with the principle of error compensation. For digit forces in anti-gravity directions, the distribution patterns vary significantly by participant. The forces exerted by the thumb are closely related to those exerted by other fingers under all conditions. The index-middle and middle-ring finger pairs demonstrate a significant relationship. The PCA results show that the normal forces of digits are highly coordinated. This study reveals that normal force synergy exists under both static and dynamic cylindrical grasping conditions.
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PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells.
J. Clin. Invest.
PUBLISHED: 01-23-2013
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The success of tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML) depends on the requirement for BCR-ABL1 kinase activity in CML progenitors. However, CML quiescent HSCs are TKI resistant and represent a BCR-ABL1 kinase-independent disease reservoir. Here we have shown that persistence of leukemic HSCs in BM requires inhibition of the tumor suppressor protein phosphatase 2A (PP2A) and expression--but not activity--of the BCR-ABL1 oncogene. Examination of HSCs from CML patients and healthy individuals revealed that PP2A activity was suppressed in CML compared with normal HSCs. TKI-resistant CML quiescent HSCs showed increased levels of BCR-ABL1, but very low kinase activity. BCR-ABL1 expression, but not kinase function, was required for recruitment of JAK2, activation of a JAK2/?-catenin survival/self-renewal pathway, and inhibition of PP2A. PP2A-activating drugs (PADs) markedly reduced survival and self-renewal of CML quiescent HSCs, but not normal quiescent HSCs, through BCR-ABL1 kinase-independent and PP2A-mediated inhibition of JAK2 and ?-catenin. This led to suppression of human leukemic, but not normal, HSC/progenitor survival in BM xenografts and interference with long-term maintenance of BCR-ABL1-positive HSCs in serial transplantation assays. Targeting the JAK2/PP2A/?-catenin network in quiescent HSCs with PADs (e.g., FTY720) has the potential to treat TKI-refractory CML and relieve lifelong patient dependence on TKIs.
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Histone deacetylase inhibitor AR-42 enhances E7-specific CD8? T cell-mediated antitumor immunity induced by therapeutic HPV DNA vaccination.
J. Mol. Med.
PUBLISHED: 01-17-2013
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We have previously created a potent DNA vaccine encoding calreticulin linked to the human papillomavirus (HPV) oncogenic protein E7 (CRT/E7). While treatment with the CRT/E7 DNA vaccine generates significant tumor-specific immune responses in vaccinated mice, the potency with the DNA vaccine could potentially be improved by co-administration of a histone deacetylase inhibitor (HDACi) as HDACi has been shown to increase the expression of MHC class I and II molecules. Thus, we aimed to determine whether co-administration of a novel HDACi, AR-42, with therapeutic HPV DNA vaccines could improve the activation of HPV antigen-specific CD8(+) T cells, resulting in potent therapeutic antitumor effects. To do so, HPV-16 E7-expressing murine TC-1 tumor-bearing mice were treated orally with AR-42 and/or CRT/E7 DNA vaccine via gene gun. Mice were monitored for E7-specific CD8(+) T cell immune responses and antitumor effects. TC-1 tumor-bearing mice treated with AR-42 and CRT/E7 DNA vaccine experienced longer survival, decreased tumor growth, and enhanced E7-specific immune response compared to mice treated with AR-42 or CRT/E7 DNA vaccine alone. Additionally, treatment of TC-1 cells with AR-42 increased the surface expression of MHC class I molecules and increased the susceptibility of tumor cells to the cytotoxicity of E7-specific T cells. This study indicates the ability of AR-42 to significantly enhance the potency of the CRT/E7 DNA vaccine by improving tumor-specific immune responses and antitumor effects. Both AR-42 and CRT/E7 DNA vaccines have been used in independent clinical trials; the current study serves as foundation for future clinical trials combining both treatments in cervical cancer therapy.
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Long-term retrospective analysis of surgical treatment for irretrievable tuberculosis of the ankle.
Foot Ankle Int
PUBLISHED: 01-14-2013
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Although antituberculosis medication is the first step in the management of skeletal tuberculosis (TB), surgical debridement, biopsy, synovectomy, or arthrodesis may be needed for the definitive diagnosis and treatment of the symptomatic ankle.
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Detection of suppressed maturation of the human COQ5 protein in the mitochondria following mitochondrial uncoupling by an antibody recognizing both precursor and mature forms of COQ5.
Mitochondrion
PUBLISHED: 01-14-2013
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Yeast Coq5p is required for the biosynthesis of coenzyme Q6 (CoQ6), but its human homolog has not been studied. We purified soluble recombinant human COQ5 protein under native conditions and generated an antibody recognizing both precursor and mature forms of COQ5. Mitochondrial localization of the mature form in 143B cells was demonstrated with this antibody. Moreover, a chemical uncoupler in a dose that suppressed CoQ10 levels downregulated the mature form but augmented the precursor form of COQ5. The results that knockdown of the COQ5 gene reduced CoQ10 levels further indicated the critical role of COQ5 in the biosynthesis of CoQ10.
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Oxidative stress and increased formation of vasoconstricting F2-isoprostanes in patients with reversible cerebral vasoconstriction syndrome.
Free Radic. Biol. Med.
PUBLISHED: 01-13-2013
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The pathophysiology of reversible cerebral vasoconstriction syndrome (RCVS) is unknown. Oxidative stress is detrimental to endothelial function and vascular reactivity. We hypothesized that the oxidative stress marker 8-iso-prostaglandin F2?, which is also a potent vasoconstrictor, might contribute to the pathogenesis of RCVS. Recruited participants included 103RCVS patients, 53 patients with primary headache with acute severe attacks, and 54 healthy controls. Subjects recruited prior to 2009 were discovery cohort, whereas those after 2009, replication cohort. Urine samples were obtained from all patients at registration and from 79 patients with RCVS again at remission stage. Urine 8-iso-prostaglandin F2? was analyzed by liquid chromatography-tandem mass spectrometry. Patients with RCVS received magnetic resonance angiography and transcranial color-coded sonography. In RCVS patients, the urine 8-iso-prostaglandin F2? level was higher than that in the other groups in discovery, replication, and combined cohorts (RCVS, 0.29±0.18; primary headache with acute severe attacks, 0.21±0.19; control, 0.18±0.09ng/mg creatinine; P<0.001), and it was positively correlated with the flow velocities of major intracranial arteries, especially within the first week of disease onset (middle cerebral artery, Spearmans correlation coefficient [rs]=0.580, P=0.002; anterior cerebral artery, rs=0.472, P=0.042; posterior cerebral artery, rs=0.457, P=0.022; basilar artery, rs= 0.530, P=0.002). The 8-iso-prostaglandin F2? level decreased from the ictalto remission stage in RCVS patients (0.31±0.21 vs 0.16±0.10ng/mg creatinine, P<0.001). 8-Iso-prostaglandin F2? was higher in patients with RCVS and correlated with the severity of vasoconstrictions. Further studies are required to explore its potential pathogenic role.
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Efficacy, safety, and predictors of response to botulinum toxin type A in refractory chronic migraine: A retrospective study.
J Chin Med Assoc
PUBLISHED: 01-10-2013
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Due to its persistent and debilitating nature, refractory chronic migraine (RCM) can cause significant socioeconomic burden. This study retrospectively reviewed the efficacy and safety of botulinum toxin type A (BoNT-A) in the treatment of RCM. Predictors of treatment response were also investigated.
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Detection of Synchronous Cancers by Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography during Primary Staging Workup for Esophageal Squamous Cell Carcinoma in Taiwan.
PLoS ONE
PUBLISHED: 01-01-2013
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The aim of this retrospective study was to investigate the ability of fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in the detection of synchronous cancers during staging workup for esophageal squamous cell carcinoma.
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Functional Role of mTORC2 versus Integrin-Linked Kinase in Mediating Ser473-Akt Phosphorylation in PTEN-Negative Prostate and Breast Cancer Cell Lines.
PLoS ONE
PUBLISHED: 01-01-2013
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Although the rictor-mTOR complex (mTORC2) has been shown to act as phosphoinositide-dependent kinase (PDK)2 in many cell types, other kinases have also been implicated in mediating Ser473-Akt phosphorylation. Here, we demonstrated the cell line specificity of integrin-linked kinase (ILK) versus mTORC2 as PDK2 in LNCaP and PC-3 prostate and MDA-MB-468 breast cancer cells, of which the PTEN-negative status allowed the study of Ser473-Akt phosphorylation independent of external stimulation. PC-3 and MDA-MB-468 cells showed upregulated ILK expression relative to LNCaP cells, which expressed a high abundance of mTOR. Exposure to Ku-0063794, a second-generation mTOR inhibitor, decreased Ser473-Akt phosphorylation in LNCaP cells, but not in PC-3 or MDA-MB-468 cells. In contrast, treatment with T315, a novel ILK inhibitor, reduced the phosphorylation of Ser473-Akt in PC-3 and MDA-MB-468 cells without affecting that in LNCaP cells. This cell line specificity was verified by comparing Ser473-Akt phosphorylation status after genetic knockdown of rictor, ILK, and other putative Ser-473-Akt kinases. Genetic knockdown of rictor, but not ILK or the other kinases examined, inhibited Ser473-Akt phosphorylation in LNCaP cells. Conversely, PC-3 and MDA-MB-468 cells were susceptible to the effect of ILK silencing on Ser473-Akt phosphorylation, while knockdown of rictor or any of the other target kinases had no appreciable effect. Co-immunoprecipitation analysis demonstrated the physical interaction between ILK and Akt in PC-3 cells, and T315 blocked ILK-mediated Ser473 phosphorylation of bacterially expressed Akt. ILK also formed complexes with rictor in PC-3 and MDA-MB-468 cells that were disrupted by T315, but such complexes were not observed in LNCaP cells. In the PTEN-functional MDA-MB-231 cell line, both T315 and Ku-0063794 suppressed EGF-induced Ser473-Akt phosphorylation. Inhibition of ILK by T315 or siRNA-mediated knockdown suppressed epithelial-mesenchymal transition in MDA-MB-468 and PC-3 cells. Thus, we hypothesize that ILK might bestow growth advantage and metastatic potential in the course of tumor progression.
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Thermally induced morphology evolution of pit-patterned Si substrate and its effect on nucleation properties of Ge dots.
Nanotechnology
PUBLISHED: 12-08-2011
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We demonstrate the effect of the pre-growth heat treatment process on the nucleation properties of Ge dots grown on pit-patterned Si(001) substrates. The prefabricated 200 nm diameter pits inherently evolve into truncated inverted pyramids (TIPs) with (110) base edges and a 7°-9° sidewall slope during heat treatment; this morphology transformation is robust against variations in shape and orientation of the pit patterns. Uniform Ge dots with an areal density of 4 × 10(9) cm(-2) were obtained on the Si substrates having TIPs. Each TIP contains four aligned Ge dots locating symmetrically with respect to (110). These dots exhibit an elliptical dome shape with major axis oriented along (100). The nucleation position, shape and spatial orientation of these Ge dots coincide with the calculated surface chemical potential distribution of the TIP.
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High-sensitivity in vivo THz transmission imaging of early human breast cancer in a subcutaneous xenograft mouse model.
Opt Express
PUBLISHED: 11-24-2011
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We performed in vivo THz transmission imaging study on a subcutaneous xenograft mouse model for early human breast cancer detection. With a THz-fiber-scanning transmission imaging system, we continuously monitored the growth of human breast cancer in mice. Our in vivo study not only indicates that THz transmission imaging can distinguish cancer from the surrounding fatty tissue, but also with a high sensitivity. Our in vivo study on the subcutaneous xenograft mouse model will encourage broad and further investigations for future early cancer screening by using THz imaging system.
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FTY720 increases CD74 expression and sensitizes mantle cell lymphoma cells to milatuzumab-mediated cell death.
Blood
PUBLISHED: 10-31-2011
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Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with a short median survival despite multimodal therapy. FTY720, an immunosuppressive drug approved for the treatment of multiple sclerosis, promotes MCL cell death concurrent with down-modulation of phospho-Akt and cyclin D1 and subsequent cell-cycle arrest. However, the mechanism of FTY720-mediated MCL cell death remains to be fully clarified. In the present study, we show features of autophagy blockage by FTY720 treatment, including accumulation of autolysosomes and increased LC3-II and p62 levels. We also show that FTY720-induced cell death is mediated by lysosomal membrane permeabilization with subsequent translocation of lysosomal hydrolases to the cytosol. FTY720-mediated disruption of the autophagic-lysosomal pathway led to increased levels of CD74, a potential therapeutic target in MCL that is degraded in the lysosomal compartment. This finding provided rationale for examining combination therapy with FTY720 and milatuzumab, an anti-CD74 mAb. Treatment of MCL cell lines and primary tumor cells with FTY720 and milatuzumab resulted in statistically significant enhanced cell death, which was synergistic in blastic variant MCL cell lines. Significant in vivo therapeutic activity of combination treatment was also demonstrated in a preclinical, in vivo model of MCL. These findings support clinical evaluation of this combination in patients with MCL.
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A review of the existing grading schemes and a proposal for a modified grading scheme for prostatic lesions in TRAMP mice.
Toxicol Pathol
PUBLISHED: 10-21-2011
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The transgenic adenocarcinoma of the mouse prostate (TRAMP) model is well established and offers several advantages for the study of chemopreventive agents, including its well-defined course of disease progression and high incidence of poorly differentiated carcinomas within a relatively short length of time. However, there is no consensus on the grading of prostatic lesions in these mice. In particular, agreement is lacking on the criteria for differentiating prostatic intraepithelial neoplasia (PIN) from well-differentiated adenocarcinoma, specifically as it relates to evidence of invasion. This differentiation is critical for evaluating the effects of putative chemopreventive agents on progression to neoplasia. Moreover, only one of the published grading schemes assigns numerical grades to prostatic lesions, which facilitate statistical analysis. Here, we review five currently available grading schemes and propose a refined scheme that provides a useful definition of invasion for the differentiation of PIN from well-differentiated adenocarcinoma and includes a numerical scoring system that accounts for both the most severe and most common histopathological lesions in each of the lobes of the prostate and their distributions. We expect that researchers will find this refined grading scheme to be useful for chemoprevention studies in TRAMP mice.
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Targeting energy metabolic and oncogenic signaling pathways in triple-negative breast cancer by a novel adenosine monophosphate-activated protein kinase (AMPK) activator.
J. Biol. Chem.
PUBLISHED: 09-14-2011
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The antitumor activities of the novel adenosine monophosphate-activated protein kinase (AMPK) activator, OSU-53, were assessed in in vitro and in vivo models of triple-negative breast cancer. OSU-53 directly stimulated recombinant AMPK kinase activity (EC(50), 0.3 ?M) and inhibited the viability and clonogenic growth of MDA-MB-231 and MDA-MB-468 cells with equal potency (IC(50), 5 and 2 ?M, respectively) despite lack of LKB1 expression in MDA-MB-231 cells. Nonmalignant MCF-10A cells, however, were unaffected. Beyond AMPK-mediated effects on mammalian target of rapamycin signaling and lipogenesis, OSU-53 also targeted multiple AMPK downstream pathways. Among these, the protein phosphatase 2A-dependent dephosphorylation of Akt is noteworthy because it circumvents the feedback activation of Akt that results from mammalian target of rapamycin inhibition. OSU-53 also modulated energy homeostasis by suppressing fatty acid biosynthesis and shifting the metabolism to oxidation by up-regulating the expression of key regulators of mitochondrial biogenesis, such as a peroxisome proliferator-activated receptor ? coactivator 1? and the transcription factor nuclear respiratory factor 1. Moreover, OSU-53 suppressed LPS-induced IL-6 production, thereby blocking subsequent Stat3 activation, and inhibited hypoxia-induced epithelial-mesenchymal transition in association with the silencing of hypoxia-inducible factor 1a and the E-cadherin repressor Snail. In MDA-MB-231 tumor-bearing mice, daily oral administration of OSU-53 (50 and 100 mg/kg) suppressed tumor growth by 47-49% and modulated relevant intratumoral biomarkers of drug activity. However, OSU-53 also induced protective autophagy that attenuated its antiproliferative potency. Accordingly, cotreatment with the autophagy inhibitor chloroquine increased the in vivo tumor-suppressive activity of OSU-53. OSU-53 is a potent, orally bioavailable AMPK activator that acts through a broad spectrum of antitumor activities.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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

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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.