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Find video protocols related to scientific articles indexed in Pubmed.
Synthesis of 2-Pyridyl-benzimidazole Iridium(III), Ruthenium(II), and Platinum(II) Complexes. Study of the Activity as Inhibitors of Amyloid-? Aggregation and Neurotoxicity Evaluation.
Inorg Chem
PUBLISHED: 11-20-2014
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The design of small molecules that can target the aggregation of A? as potential therapeutic agents for Alzheimer's disease is an area of study that has attracted a lot of attention recently. The novel ligand methyl 1-butyl-2-pyridyl-benzimidazole carboxylate was prepared for the synthesis of a series of new iridium(III), ruthenium(II), and platinum(II) 2-pyridyl-benzimidazole complexes. The crystal structure of the half-sandwich iridium(III) complex was established by X-ray diffraction. An arrangement of two cationic complexes in the unit cell is observed, and it seems to be organized by weak ?···? interactions that are taking place between two symmetry-related benzimidazole ring systems. All new compounds inhibited aggregation of A?1-42 in vitro as shown by both thioflavin T fluorescence assay and transmission electron microscopy. Among them the Ir compound rescued the toxicity of A?1-42 in primary cortical neurons effectively.
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Addressing the Knowledge Gap in Clinical Recommendations for Management and Complete Excision of Clinically Atypical Nevi/Dysplastic Nevi: Pigmented Lesion Subcommittee Consensus Statement.
JAMA Dermatol
PUBLISHED: 11-20-2014
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The management of clinically atypical nevi/dysplastic nevi (CAN/DN) is controversial, with few data to guide the process. Management recommendations for DN with positive histologic margins were developed by the Delphi method to achieve consensus among members of the Pigmented Lesion Subcommittee (PLS) of the Melanoma Prevention Working Group (MPWG) after reviewing the current evidence.
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Protective Effects of Kojic Acid on the Periphery Blood and Survival of Beagle Dogs after Exposure to a Lethal Dose of Gamma Radiation.
Radiat. Res.
PUBLISHED: 11-20-2014
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In previous studies, it has been shown that pretreatment with kojic acid (KA) not only increased the 30 day survival rate of mice after exposed to a lethal dose of gamma radiation but also had significant radioprotective effects on the hematopoietic system, the immune system and DNA of mice exposed to a 4 Gy sublethal dose of radiation. Furthermore, pretreatment with KA has also been shown to protect Chinese hamster ovary (CHO) cells against ionizing radiation-induced damage. In this investigation, beagle dogs were used to evaluate whether KA could also be radioprotective in a large animal model. Dogs in the group pretreated with kojic acid after whole-body exposure to a lethal dose of 3 Gy gamma radiation had a 51 day survival rate of 66.7% versus the dogs in the 3 Gy irradiation only group, which all died within 16 days of postirradiation. General vital signs (body weight or temperature) of animals in the kojic acid pretreated group reduced and increased maximally at day 14 postirradiation and then reverted to normal levels gradually. The hematopoiesis studies indicated that the white blood cells/red blood cells, hemoglobin content and hematocrit of dogs pretreated with kojic acid decreased sharply at day 23/day 21 postirradiation, and then gradually elevated. In addition, the DNA content of dogs pretreated with KA were significantly increased compared with that of dogs in the irradiation group at day 4 postirradiation and the number of micronuclei in the group pretreated with kojic acid declined sharply compared with that of the irradiation only group. KA appears to possess marked protective effects from radiation-induced damage and therefore, may be a promising novel radioprotective agent.
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Three-dimensionalization of ultrathin nanosheets in a two-dimensional nano-reactor: macroporous CuO microstructures with enhanced cycling performance.
Chem. Commun. (Camb.)
PUBLISHED: 11-20-2014
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Three-dimensional (3D) macroporous CuO structures composed of ultrathin nanosheets were successfully synthesized by employing a liquid-liquid interface as a two-dimensional (2D) nano-reactor. The macroporous structure helped CuO to retain the exposed surface during reactions, thus significantly enhancing the long term cycling performance both in photocatalysis and lithium ion batteries.
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HF-Free Synthesis of Anatase TiO2 Nanosheets with Largely Exposed and Clean {001} facets and Their Enhanced Rate Performance As Anodes of Lithium-Ion Battery.
ACS Appl Mater Interfaces
PUBLISHED: 10-17-2014
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An interface between toluene and water was utilized to synthesize ca. 10 nm thick of anatase TiO2 nanosheets (NSs) with 82% exposure of {001} facets. In this procedure, highly corrosive and toxic HF, which was generally used to prepare TiO2 NSs with largely exposed high energy facets, was avoided. Furthermore, the surfaces of the NSs were quite clean as suggested by XPS analysis. Serving as anode materials in lithium-ion batteries, these as-prepared anatase TiO2 NSs manifested a low initial irreversible capacity loss (12.5% at 1 C), an excellent capacity retention at 10 C charge-discharge rate (101.9 mA h g(-1) after 100 cycles), and enhanced rate performance at 0.5-10 C current rates in compared with Degussa P25 TiO2 nanoparticles (NPs). Their excellent electrochemical performances were mainly derived from the large proportion of {001} exposed facets and a very short diffusion pathway, which allowed fast and efficient Li(+) transportation in the electrodes.
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Monocrystalline mesoporous metal oxide with perovskite structure: a facile solid-state transformation of a coordination polymer.
Chem. Commun. (Camb.)
PUBLISHED: 09-27-2014
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Monocrystalline mesoporous BiFeO3 crystals were obtained via a multi-step single-crystal to single-crystal transformation of a coordination polymer, Bi[Fe(CN)6]·4H2O. This unique transformation process significantly decreased the crystallization temperature of perovskite oxide without losing high crystallinity.
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Rhodium(III)-Catalyzed [3+2] Annulation of 5-Aryl-2,3-dihydro-1H-pyrroles with Internal Alkynes through C(sp(2) )?H/Alkene Functionalization.
Angew. Chem. Int. Ed. Engl.
PUBLISHED: 07-14-2014
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This study describes a new rhodium(III)-catalyzed [3+2] annulation of 5-aryl-2,3-dihydro-1H-pyrroles with internal alkynes using a Cu(OAc)2 oxidant for building a spirocyclic ring system, which includes the functionalization of an aryl C(sp(2) )?H bond and addition/protonolysis of an alkene C?C bond. This method is applicable to a wide range of 5-aryl-2,3-dihydro-1H-pyrroles and internal alkynes, and results in the assembly of the spiro[indene-1,2'-pyrrolidine] architectures in good yields with excellent regioselectivities.
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Significantly Decreased and More Variable Expression of Major CYPs and UGTs in Liver Microsomes Prepared from HBV-Positive Human Hepatocellular Carcinoma and Matched Pericarcinomatous Tissues Determined Using an Isotope Label-free UPLC-MS/MS Method.
Pharm. Res.
PUBLISHED: 07-02-2014
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To determine the liver expression of cytochrome P450 (CYPs) and uridine 5'-diphosphate-glucuronosyltransferases (UGTs), the major phase I and II metabolism enzymes responsible for clearance and detoxification of drugs, xenobiotic and endogenous substances.
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Coordination polymers for catalysis: enhancement of catalytic activity through hierarchical structuring.
Chem. Commun. (Camb.)
PUBLISHED: 06-24-2014
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We utilized a novel strategy, hierarchical structuring, to enhance the catalytic activity of coordination polymers. Hierarchical Prussian white crystals with hollow structures and kinked surfaces were synthesized by using a self-aggregation and etching strategy. The hierarchical structure significantly enhanced the catalytic activity of Prussian white in the degradation of methylene blue in comparison to the non-hierarchical Prussian white crystals.
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Single-Crystal-like Nanoporous Spinel Oxides: A Strategy for Synthesis of Nanoporous Metal Oxides Utilizing Metal-Cyanide Hybrid Coordination Polymers.
Chemistry
PUBLISHED: 06-20-2014
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Development of a new method to synthesize nanoporous metal oxides with highly crystallized frameworks is of great interest because of their wide use in practical applications. Here we demonstrate a thermal decomposition of metal-cyanide hybrid coordination polymers (CPs) to prepare nanoporous metal oxides. During the thermal treatment, the organic units (carbon and nitrogen) are completely removed, and only metal contents are retained to prepare nanoporous metal oxides. The original nanocube shapes are well-retained even after the thermal treatment. When both Fe and Co atoms are contained in the precursors, nanoporous Fe?Co oxide with a highly oriented crystalline framework is obtained. On the other hand, when nanoporous Co oxide and Fe oxide are obtained from Co- and Fe-contacting precursors, their frameworks are amorphous and/or poorly crystallized. Single-crystal-like nanoporous Fe?Co oxide shows a stable magnetic property at room temperature compared to poly-crystalline metal oxides. We further extend this concept to prepare nanoporous metal oxides with hollow interiors. Core-shell heterostructures consisting of different metal-cyanide hybrid CPs are prepared first. Then the cores are dissolved by chemical etching using a hydrochloric acid solution (i.e., the cores are used as sacrificial templates), leading to the formation of hollow interiors in the nanocubes. These hollow nanocubes are also successfully converted to nanoporous metal oxides with hollow interiors by thermal treatment. The present approach is entirely different from the surfactant-templating approaches that traditionally have been utilized for the preparation of mesoporous metal oxides. We believe the present work proves a new way to synthesize nanoporous metal oxides with controlled crystalline frameworks and architectures.
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Human cytomegalovirus inhibits apoptosis by regulating the activating transcription factor 5 signaling pathway in human malignant glioma cells.
Oncol Lett
PUBLISHED: 06-18-2014
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The activating transcription factor 5 (ATF5), also termed ATFx, is a member of the ATF/cAMP response element-binding protein (CREB) family of basic zipper proteins. ATF5 is an anti-apoptotic protein that is highly expressed in malignant glioma and is essential for glioma cell survival. Accumulating evidence indicates that human malignant gliomas are universally infected with human cytomegalovirus (HCMV). Recent studies have shown that HCMV may be resistant to the induction of apoptosis by disrupting cellular pathways in glioblastoma. To investigate the potential anti-apoptotic function of HCMV in glioma, malignant U87 glioma cells were infected with HCMV. The present study showed that HCMV infection suppressed apoptosis in glioblastoma U87 cells by regulating the expression of ATF5. Furthermore, in glioblastoma U87 cells, HCMV infection induced cellular proliferation in parallel with an increase in the expression level of ATF5 and B-cell lymphoma/leukemia-2 to Bcl-2-associated X protein ratio. Loss of ATF5 function was achieved using a dominant-negative form of ATF5 in U87 cells, whereby cells appeared to grow marginally following HCMV infection when compared with the control. However, the anti-apoptotic ability was appeared to decline in the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. These results indicate that ATF5 signaling pathways may be important in the anti-apoptotic activity of HCMV-infected glioblastoma cells; therefore, the anti-apoptotic molecular mechanisms of HCMV in human glioblastoma cells were investigated in the current study. Prevention of HCMV infection may present a potential and promising approach for the treatment of malignant gliomas.
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[The interventional effect of Xuebijing injection on expression of mitochondrial fusion protein 2 and the ultrastructure changes in lung tissues in rats with paraquat poisoning].
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue
PUBLISHED: 06-11-2014
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To investigate the mechanism of pulmonary fibrosis induced by paraquat (PQ), and the effect of Xuebijing injection in treatment of PQ poisoning.
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Thermal transport and thermoelectric properties of beta-graphyne nanostructures.
Nanotechnology
PUBLISHED: 05-23-2014
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Graphyne, an allotrope of graphene, is currently a hot topic in the carbon-based nanomaterials research community. Taking beta-graphyne as an example, we performed a comprehensive study of thermal transport and related thermoelectric properties by means of nonequilibrium Green's function (NEGF). Our simulation demonstrated that thermal conductance of beta-graphyne is only approximately 26% of that of the graphene counterpart and also shows evident anisotropy. Meanwhile, thermal conductance of armchair beta-graphyne nanoribbons (A-BGYNRs) presents abnormal stepwise width dependence. As for the thermoelectric property, we found that zigzag beta-graphyne nanoribbons (Z-BGYNRs) possess superior thermoelectric performance with figure of merit value achieving 0.5 at room temperature, as compared with graphene nanoribbons (~0.05). Aiming at obtaining a better thermoelectric coefficient, we also investigated Z-BGYNRs with geometric modulations. The results show that the thermoelectric performance can be enhanced dramatically (figure of merit exceeding 1.5 at room temperature), and such enhancement strongly depends on the width of the nanoribbons and location and quantity of geometric modulation. Our findings shed light on transport properties of beta-graphyne as high efficiency thermoelectrics. We anticipate that our simulation results could offer useful guidance for the design and fabrication of future thermoelectric devices.
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Uptake of polymyxin B into renal cells.
Antimicrob. Agents Chemother.
PUBLISHED: 04-14-2014
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Polymyxin B is increasingly used as a treatment of last resort against multidrug-resistant Gram-negative infections. Using a mammalian kidney cell line, we demonstrated that polymyxin B uptake into proximal tubular epithelial cells was saturable and occurred primarily through the apical membrane, suggesting the involvement of transporters in the renal uptake of polymyxin B. Megalin might play a role in the uptake and accumulation of polymyxin B into renal cells.
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HCMV Induces Dysregulation of Glutamate Uptake and Transporter Expression in Human Fetal Astrocytes.
Neurochem. Res.
PUBLISHED: 04-11-2014
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Human cytomegalovirus (HCMV) infections are the leading cause of viral induced birth defects, affecting the central nervous system (CNS) primarily. Fetal CNS is especially vulnerable to CMV induced injury. As HCMV permissive cells, astrocytes are responsible for major glutamate transport and regulate extracellular levels of glutamate avoiding its accumulation which is implicated in neurodegenerative disorders. In this study, highly purified astrocytes isolated from human first trimester aborted fetal brain were infected with HCMV AD169, glutamate uptake function was detected by (3)H labeling technic, and the expression level alterations of glutamate transporters (GLAST, GLT-1), glutamine synthetase (GS) and its activity were also investigated. Protein kinases C (PKC) inhibitor treatment was to identify whether PKC signalling involved in regulating glutamate uptake, protein expression of GLAST, GLT-1, GS and GS activity. Results indicated HCMV AD169 infection could modulate glutamate uptake, expression levels of GLAST, GLT-1, GS and it activity through PKC signalling, suggesting a great susceptibility of human fetal astrocytes to HCMV infection, which significantly alters the uptake and metabolism of an important excitatory amino acid, glutamate, may be a potential mechanism for HCMV associated neurological disease, and an effective therapeutic target in neural diseases.
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Amino acid facilitates absorption of copper in the Caco-2 cell culture model.
Life Sci.
PUBLISHED: 03-27-2014
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Copper deficiency could cause fatal hematological and neurological disorders or other diseases. Amino acids are involved in the absorption of copper ions. The purpose of this study is to evaluate the absorption of copper in amino acid complex forms and determine its mechanism in the Caco-2 cell culture model.
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A turn-on fluorescent Fe(3+) sensor derived from an anthracene-bearing bisdiene macrocycle and its intracellular imaging application.
Chem. Commun. (Camb.)
PUBLISHED: 03-27-2014
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Integrating N(2)-hydroxyethyldiethylenetriamine with anthracene gives a [2+2] macrocycle fluorescent sensor. This sensor displays an instant/reversible turn-on response specific to Fe(3+), which allows facile visualization of the Fe(3+)/Fe(2+) transition and intracellular Fe(3+) imaging.
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Transformation of ginsenosides from notoginseng by artificial gastric juice can increase cytotoxicity toward cancer cells.
J. Agric. Food Chem.
PUBLISHED: 03-11-2014
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Multicomponent metabolic profile of notoginseng saponins in artificial gastric juice was qualitatively and quantitatively investigated, showing that ginsenosides were transformed via multiple pathways including deglycosylation, dehydration, hydration, and oxygenation. A total of 83 metabolites was identified by using UPLC-Q-TOF-MS, among which 16 new dammarane glycosides were further characterized by comparing with synthesized authentic compounds. Transformation time-course of notoginseng saponins in artificial gastric juice was quantitatively measured for the first time, showing rapid degradation of primary ginsenosides and concomitant formation of deglycosylation, hydration, and dehydration products. It was further demonstrated that the resultant metabolites exhibited enhanced cytotoxicity toward cancer cells. The extensive metabolism of ginsenosides within a transit time span in stomach, together with the formation of metabolites with diversified chemical structures possessing enhanced biological activities, indicated an important role of transformation in gastric juice in the systematic effects of ginsenosides.
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Direct synthesis of MOF-derived nanoporous carbon with magnetic Co nanoparticles toward efficient water treatment.
Small
PUBLISHED: 03-07-2014
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Nanoporous carbon particles with magnetic Co nanoparticles (Co/NPC particles) are synthesized by one-step carbonization of zeolitic imidazolate framework-67 (ZIF-67) crystals. After the carbonization, the original ZIF-67 shapes are preserved well. Fine magnetic Co nanoparticles are well dispersed in the nanoporous carbon matrix, with the result that the Co/NPC particles show a strong magnetic response. The obtained nanoporous carbons show a high surface area and well-developed graphitized wall, thereby realizing fast molecular diffusion of methylene blue (MB) molecules with excellent adsorption performance. The Co/NPC possesses an impressive saturation capacity for MB dye compared with the commercial activated carbon. Also, the dispersed magnetic Co nanoparticles facilitate easy magnetic separation.
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Ratio of ?-H2AX level in lymphocytes to that in granulocytes detected using flow cytometry as a potential biodosimeter for radiation exposure.
Radiat Environ Biophys
PUBLISHED: 02-24-2014
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This study aims to assess utilisation of the ratio of ?-H2AX in lymphocytes to that in granulocytes (RL/G of ?-H2AX) in blood as a rapid method for population triage and dose estimation during large-scale radiation emergencies. Blood samples from healthy volunteers exposed to 0-10 Gy of (60)Co irradiation were collected. The samples were cultured for 0-24 h and then analysed using flow cytometry to measure the levels of ?-H2AX in lymphocytes and granulocytes. The basal RL/G levels of ?-H2AX in healthy human blood, the response of RL/G of ?-H2AX to ionising radiation and its relationship with doses, time intervals after exposure and individual differences were also analysed. The level of ?-H2AX in lymphocytes increased in a dose-dependent manner after irradiation, whereas the level in granulocytes was not affected. A linear dose-effect relationship with low inter-experimental and inter-individual variations was observed. The RL/G of ?-H2AX may be used as a biomarker for population triage and dose estimation during large-scale radiation emergencies if blood samples can be collected within 24 h.
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In vitro assessment and multicenter cohort study of comparative nephrotoxicity rates associated with colistimethate versus polymyxin B therapy.
Antimicrob. Agents Chemother.
PUBLISHED: 02-24-2014
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Despite concerns of nephrotoxicity, polymyxin antibiotics often remain the only susceptible agents for multidrug-resistant (MDR) Gram-negative bacteria. Colistin has been more commonly used clinically due to a perceived safety benefit. We compared the nephrotoxicity of colistin to polymyxin B. The in vitro cytotoxicity of colistin was compared to polymyxin B in two mammalian renal cell lines. To validate the clinical relevance of the findings, we evaluated adult patients with normal renal function who received a minimum of 72 h of polymyxin therapy in a multicenter study. The primary outcome was the prevalence of nephrotoxicity, as defined by the RIFLE (risk, injury, failure, loss, end-stage kidney disease) criteria. Colistin exhibited an in vitro cytotoxicity profile similar to polymyxin B. A total of 225 patients (121 receiving colistimethate, 104 receiving polymyxin B) were evaluated. Independent risk factors for colistimethate-associated nephrotoxicity included age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.00 to 1.07; P = 0.03), duration of therapy (OR 1.08; 95% CI, 1.02 to 1.15; P = 0.02), and daily dose by ideal body weight (OR 1.40; 95% CI, 1.05 to 1.88; P = 0.02). In contrast, cystic fibrosis was found to be a protective factor in patients who received colistimethate (OR, 0.03; 95% CI, 0.001 to 0.79; P = 0.04). In a matched analysis based on the risk factors identified (n = 76), the prevalence of nephrotoxicity was higher with colistimethate than with polymyxin B (55.3% versus 21.1%; P = 0.004). Polymyxin B was not found to be more nephrotoxic than colistin and may be the preferred polymyxin for MDR infections. A prospective study comparing the two polymyxins directly is warranted.
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Development and current status of clinical pharmacy education in china.
Am J Pharm Educ
PUBLISHED: 02-19-2014
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Objective. To describe the current status and developing trend of clinical pharmacy education in China. Methods. Descriptive analysis of data and information about the clinical pharmacy specialty, pharmacy colleges, and curriculum from literature, college websites, and statistics from the Ministry of Health (MOH) and Ministry of Education (MOE) websites was conducted. Results. Clinical pharmacy programs were established in China in 1989 but developed more fully after 2006. In 2012, there were 30 pharmacy colleges with clinical pharmacy undergraduate programs, which included a bachelor's degree in clinical pharmacy and a clinical pharmacy concentration within the BS programs of pharmacy or medicine. More than 40 colleges within the university system offer 4 types of master's degree programs in clinical pharmacy. Five universities offer a PhD program in clinical pharmacy. Three postgraduate programs exist, which train hospital pharmacists and clinical pharmacists: the 3+2 year Hospital Pharmacist Standardized Training Program at Peking hospitals; the 1-year Clinical Pharmacist Training Program sponsored by the MOH; and the 2-year Clinical Pharmacist Residency Program provided by West China Hospital at Sichuan University. Conclusion. A growing clinical pharmacy education system has been established and has become an important subfield in Chinese pharmacy education. Measures should be taken to further promote the development of clinical pharmacy education in China.
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The distribution of genomic variations in human iPSCs is related to replication-timing reorganization during reprogramming.
Cell Rep
PUBLISHED: 02-18-2014
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Cell-fate change involves significant genome reorganization, including changes in replication timing, but how these changes are related to genetic variation has not been examined. To study how a change in replication timing that occurs during reprogramming impacts the copy-number variation (CNV) landscape, we generated genome-wide replication-timing profiles of induced pluripotent stem cells (iPSCs) and their parental fibroblasts. A significant portion of the genome changes replication timing as a result of reprogramming, indicative of overall genome reorganization. We found that early- and late-replicating domains in iPSCs are differentially affected by copy-number gains and losses and that in particular, CNV gains accumulate in regions of the genome that change to earlier replication during the reprogramming process. This differential relationship was present irrespective of reprogramming method. Overall, our findings reveal a functional association between reorganization of replication timing and the CNV landscape that emerges during reprogramming.
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The identification, typing, and antimicrobial susceptibility of Pseudomonas aeruginosa isolated from mink with hemorrhagic pneumonia.
Vet. Microbiol.
PUBLISHED: 02-10-2014
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The biological characteristics and molecular epidemiology of Pseudomonas aeruginosa associated with mink hemorrhagic pneumonia from Shandong province of eastern China were determined in this study. From 2010 to 2011, 30 mink P. aeruginosa isolates were identified from lung, fecal and feed samples of clinical cases and subjected to serotyping, antimicrobial susceptibility testing and pulsed-field gel electrophoresis (PFGE) using SpeI. The P. aeruginosa isolates belonged to four serotypes-21 of type G, four of type I, three of type M, one of type B, and one non-typable strain. The strains were divided into four large groups as determined by PFGE. Isolates from the group 2 were highly homologous and were obtained from the same region as an epidemic. All of the isolates were sensitive to piperacillin, piperacillin/tazobactam, ceftazidime, cefepime, imipenem, amikacin, gentamicin and tobramycin and resistant to ampicillin, cefuroxime and cefuroxime axetil. A high frequency of resistance was found to ampicillin/sulbactam, cefazolin, cefotetan, ceftriaxone, nitrofurantoin, and trimethoprim/sulfamethoxazole (96.7%). Resistance to ticarcillin/clavulanic acid, ciprofloxacin and levofloxacin was less common (13.3%). There was no relationship between antibiotic resistance and serotype distribution of the isolates. The epidemic serotype of P. aeruginosa from the mink hemorrhagic pneumonia in Shandong province was type G, which was a clone of commonly found in this province. These findings reveal the genetic similarities and antimicrobial susceptibility profiles of P. aeruginosa from clinical cases of mink hemorrhagic pneumonia and will facilitate the prevention and control of the disease in Shandong province of China.
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Controlled crystallization of cyano-bridged Cu-Pt coordination polymers with two-dimensional morphology.
Chem Asian J
PUBLISHED: 01-20-2014
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Two-dimensional (2D) coordination polymers (CPs) have a highly accessible surface area that permits guest molecules to effectively access the micropores in the CPs. Here we report a bottom-up synthesis of 2D cyano-bridged Cu-Pt CP nanoflakes using trisodium citrate as a chelating agent, which controls the nucleation rate and the crystal growth. The lateral sizes of the CP nanoflakes are controlled by changing the amount of trisodium citrate used. We strongly believe that our method will be useful for the preparation of other types of 2D CP nanoflakes. The 2D CPs have many active sites for catalytic and electrochemical reactions, and furthermore the assembled CPs can be used as membrane filters.
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Reduced expression of Phospholipase C beta in hippocampal interneuron during pilocarpine induced status epilepticus in mice.
Neurochem. Int.
PUBLISHED: 01-02-2014
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We investigated localization of Phospholipase C beta (PLC?1 and PLC?4) in laminaes of dorsal hippocampus and different subtypes of hippocampal interneurons in normal Kunming mouse, and their progressive changes during pilocarpine induced status epilepticus (SE) by quantitative immunohistochemistry and real time PCR. PLC?1 was observed in the pyramidal layer of CA1-3 area, hilus of the dentate gyrus, whereas PLC?4 was mainly expressed in calcium binding protein positive interneurons, i.e. calbindin, calretinin, parvalbumin positive interneurons in the strata oriens, radiatum of the CA area and hilus of the dentate gyrus. During pilocarpine induced SE, a temporary down-regulation of PLC?4 in the interneurons of CA area at SE 30min, and a progressive reduction of PLC?1/PLC?4 in dentate hilar cells were demonstrated. These findings confirm and extend the regional specific distribution of PLC?1 and PLC?4 immunoreactivity in mouse hippocampus, and suggest that PLC?1 and PLC?4 may play an important role in maintenance of the status epilepticus.
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A heuristic placement selection of live virtual machine migration for energy-saving in cloud computing environment.
PLoS ONE
PUBLISHED: 01-01-2014
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The field of live VM (virtual machine) migration has been a hotspot problem in green cloud computing. Live VM migration problem is divided into two research aspects: live VM migration mechanism and live VM migration policy. In the meanwhile, with the development of energy-aware computing, we have focused on the VM placement selection of live migration, namely live VM migration policy for energy saving. In this paper, a novel heuristic approach PS-ES is presented. Its main idea includes two parts. One is that it combines the PSO (particle swarm optimization) idea with the SA (simulated annealing) idea to achieve an improved PSO-based approach with the better global search's ability. The other one is that it uses the Probability Theory and Mathematical Statistics and once again utilizes the SA idea to deal with the data obtained from the improved PSO-based process to get the final solution. And thus the whole approach achieves a long-term optimization for energy saving as it has considered not only the optimization of the current problem scenario but also that of the future problem. The experimental results demonstrate that PS-ES evidently reduces the total incremental energy consumption and better protects the performance of VM running and migrating compared with randomly migrating and optimally migrating. As a result, the proposed PS-ES approach has capabilities to make the result of live VM migration events more high-effective and valuable.
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Experimental study on the inhibitory effect of sodium cantharidinate on human hepatoma HepG2 cells.
Afr J Tradit Complement Altern Med
PUBLISHED: 01-01-2014
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Cantharidin, and its derivatives can not only inhibit the proliferation of tumor cells, but can also induce tumor cell apoptosis. It shows cantharidin exhibits a wide range of reactivity in anticancer. The objective of this paper was to study the inhibitory effect of sodium cantharidinate on human hepatoma HepG2 cells.
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The role of contrast adaptation in saccadic suppression in humans.
PLoS ONE
PUBLISHED: 01-01-2014
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The idea of retinal and ex-retinal sources of saccadic suppression has long been established in previous studies. However, how they are implemented in local circuit remains unknown. Researchers have suggested that saccadic suppression was probably achieved by contrast gain control, but this possibility has never been directly tested. In this study, we manipulated contrast gain control by contrast-adapting observers with sinusoidal gratings of different contrasts. Presaccadic and fixational contrast thresholds were measured and compared to give estimates of saccadic suppression at different adaptation states. Our results reconfirmed the selective saccadic suppression in achromatic condition, and further showed that, achromatic saccadic suppression diminished as contrast adaptation was accentuated, whereas no significant chromatic saccadic suppression was induced by greater contrast adaptation. Our data provided evidence for the involvement of contrast gain control in saccadic suppression in achromatic channel. We also discussed how the negative correlation between contrast adaptation and saccadic suppression could be interpreted with contrast gain control.
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Validation of IMP dehydrogenase inhibitors in a mouse model of cryptosporidiosis.
Antimicrob. Agents Chemother.
PUBLISHED: 12-23-2013
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Cryptosporidium parasites are a major cause of diarrhea and malnutrition in the developing world, a frequent cause of waterborne disease in the developed world and a potential bioterrorism agent. Currently available treatment is limited and Cryptosporidium drug discovery remains largely unsuccessful. As a result, the pharmacokinetic properties required for in vivo efficacy have not been established. We have been engaged in a Cryptosporidium drug discovery program targeting inosine 5 -monophosphate dehydrogenase (CpIMPDH). Here we report the activity of eight potent and selective inhibitors of CpIMPDH in the IL-12 knockout mouse model, which mimics acute human cryptosporidiosis. Two compounds displayed significant antiparasitic activity, validating CpIMPDH as a drug target. The best compound, P131 (250 mg/kg-day), performed equivalently to paromomycin (2000 mg/kg-day) when administered in a single dose, and better than paromomycin when administered in three daily doses. One compound, A110, appeared to promote Cryptosporidium infection. The pharmacokinetic, uptake and permeability properties of the eight compounds were measured. P131 had the lowest systemic distribution, but accumulated to high concentrations within intestinal cells. A110 had the highest systemic distribution. These observations suggest that systemic distribution is not required, and may be a liability, for in vivo antiparasitic activity. Intriguingly, A110 caused specific alterations in fecal microbiota that were not observed with P131 or vehicle alone. Such changes may explain how A110 promotes parasitemia. Collectively, these observations suggest a blueprint for the development of anticryptosporidial therapy.
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Prognostic and predictive value of a microRNA signature in stage II colon cancer: a microRNA expression analysis.
Lancet Oncol.
PUBLISHED: 11-13-2013
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Current staging methods do not accurately predict the risk of disease recurrence and benefit of adjuvant chemotherapy for patients who have had surgery for stage II colon cancer. We postulated that expression patterns of multiple microRNAs (miRNAs) could, if combined into a single model, improve postoperative risk stratification and prediction of chemotherapy benefit for these patients.
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Deletion of SIRT1 from Hepatocytes in Mice Disrupts Lipin-1 Signaling and Aggravates Alcoholic Fatty liver.
Gastroenterology
PUBLISHED: 11-08-2013
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Sirtuin (SIRT1) is a NAD+-dependent protein deacetylase that regulates hepatic lipid metabolism by modifying histones and transcription factors. Ethanol exposure disrupts SIRT1 activity and contributes to alcoholic liver disease (ALD) in rodents, but the exact pathogenic mechanism is not clear. We compared mice with liver-specific deletion of Sirt1 (Sirt1LKO) mice with their LOX littermates (controls).
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[Etiologic characteristics of adult patients with community-acquired pneumonia in Beijing].
Zhonghua Yi Xue Za Zhi
PUBLISHED: 10-31-2013
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To explore the etiologic characteristics of adult patients with community-acquired pneumonia (CAP) in Beijing.
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Gender-dependent differences in uridine 5-diphospho-glucuronosyltransferase have implications in metabolism and clearance of xenobiotics.
Expert Opin Drug Metab Toxicol
PUBLISHED: 09-06-2013
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Gender differences have a significant impact on absorption, disposition and overall systemic bioavailability of various xenobiotics in rodents as well as humans. Over the past few years, significant research has explored and investigated the effects of gender differences on the expression profiles of uridine 5-diphospho-glucuronosyltransferases (or UGTs) in rodents but no data is available that could effectively help predict the metabolic clearance or systemic bioavailability of xenobiotics predominantly metabolized by UGT enzymes in vivo.
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Mutual regioselective inhibition of human UGT1A1-mediated glucuronidation of four flavonoids.
Mol. Pharm.
PUBLISHED: 07-17-2013
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UDP-glucuronosyltransferase (UGT) 1A1-catalyzed glucuronidation is an important elimination pathway of flavonoids, and mutually inhibitory interactions may occur when two or more flavonoids are coadministered. Our recent research suggested that glucuronidation of flavonoids displayed distinct positional preferences, but whether this will lead to the mutually regioselective inhibition of UGT1A1-mediated glucuronidation of flavonoids is unknown. Therefore, we chose three monohydroxyflavone isomers, 3-hydroxyflavone (3HF), 7-hydroxyflavone (7HF), and 4-hydroxyflavone (4HF), and one trihydroxyflavone, 3,7,4-trihydroxyflavone (3,7,4THF), as the model compounds to characterize the possible mutually regioselective inhibition of glucuronidation using expressed human UGT1A1. Apparent kinetic parameters [e.g., reaction velocity (V), Michaelis-Menten constant (Km), maximum rate of metabolism (Vmax), concentration at which inhibitor achieves 50% inhibition (IC50), and the Lineweaver-Burk plots were used to evaluate the apparent kinetic mechanisms of inhibition of glucuronidation. The results showed that UGT1A1-mediated glucuronidation of three monohydroxyflavones (i.e., 3HF, 7HF, and 4HF) and 3,7,4THF was mutually inhibitory, and the mechanisms of inhibition appeared to be the mixed-typed inhibition. Specifically, the inhibitory effects displayed certain positional preference. Glucuronidation of 3HF was more easily inhibited by 3,7,4THF than that of 7HF or 4HF. Compared to 7-O-glucuronidation of 3,7,4THF, 3-O-glucuronidation of 3,7,4THF was more inhibited by 3HF and 4HF, whereas glucuronidation at both 3-OH and 7-OH positions of 3,7,4THF was more easily inhibited by 7HF than by 3HF and 4HF. In conclusion, 3HF, 7HF, 4HF, and 3,7,4THF were both substrates and inhibitors of UGT1A1, and they exhibited mutually regioselective inhibition of UGT1A1-mediated glucuronidation via a mixed-type inhibitory mechanism.
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Absolute quantification of UGT1A1 in various tissues and cell lines using isotope label-free UPLC-MS/MS method determines its turnover number and correlates with its glucuronidation activities.
J Pharm Biomed Anal
PUBLISHED: 06-10-2013
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Uridine 5-diphosphate-glucuronosyltransferase (UGT)1A1 is a major phase II metabolism enzyme responsible for glucuronidation of drugs and endogenous compounds. The purpose of this study was to determine the expression level of UGT1A1 in human liver microsomes and human cell lines by using an isotope label-free LC-MS/MS method. A Waters Ultra performance liquid chromatography (UPLC) system coupled with an API 5500Qtrap mass spectrometer was used for the analysis. Two signature peptides (Pep-1, and Pep-2) were employed to quantify UGT1A1 by multiple reaction monitoring (MRM) approach. Standard addition method was used to validate the assay to account for the matrix effect. 17?-Estradiol was used as the marker substrate to determine UGT1A1 activities. The validated method has a linear range of 200-0.0195nM for both signature peptides. The precision, accuracy, and matrix effect were in acceptable ranges. UGT1A1 expression levels were then determined using 8 individual human liver microsomes, a pooled human liver microsomes, three UGT1A1 genotyped human liver microsomes, and four cell lines (Caco-2, MCF-7, Hela, and HepG2). The correlations study showed that the UGT1A1 protein levels were strongly correlated with its glucuronidation activities in human liver microsomes (R(2)=0.85) and in microsomes prepared from cell lines (R(2)=0.95). Isotope-labeled peptides were not necessary for LC-MS/MS quantitation of proteins. The isotope label-free absolute quantification method used here had good accuracy, sensitivity, linear range, and reproducibility, and were used successfully for the accurate determination of UGT1A1 from tissues and cell lines.
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Validated LC-MS/MS method for the determination of 3-hydroxflavone and its glucuronide in blood and bioequivalent buffers: application to pharmacokinetic, absorption, and metabolism studies.
J Pharm Biomed Anal
PUBLISHED: 05-15-2013
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The purpose of this study is to develop an UPLC-MS/MS method to quantify 3-hydroxyflavone (3-HF) and its metabolite, 3-hydroxyflavone-glucuronide (3-HFG) from biological samples. A Waters BEH C8 column was used with acetonitrile/0.1% formic acid in water as mobile phases. The mass analysis was performed in an API 5500 Qtrap mass spectrometer via multiple reaction monitoring (MRM) with positive scan mood. The one-step protein precipitation by acetonitrile was used to extract the analytes from blood. The results showed that the linear response range was 0.61-2500.00 nM for 3-HF and 0.31-2500.00 nM for 3-HFG. The intra-day variance is less than 16.5% and accuracy is in 77.7-90.6% for 3-HF and variance less than 15.9%, accuracy in 85.1-114.7% for 3-HFG. The inter-day variance is less than 20.2%, accuracy is in 110.6-114.2% for 3-HF and variance less than 15.6%, accuracy in 83.0-89.4% for 3-HFG. The analysis was done within 4.0 min. Only 10 ?l of blood is needed due to the high sensitivity of this method. The validated method was successfully used to pharmacokinetic study in A/J mouse, transport study in the Caco-2 cell culture model, and glucuronidation study using mice liver and intestine microsomes. The applications revealed that this method can be used for 3-HF and 3-HFG analysis in blood as well as in bioequivalent buffers such HBSS and KPI.
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Human cytomegalovirus infection modulates thrombospondins 1 and 2 in primary fetal astrocytes.
Neuroreport
PUBLISHED: 05-11-2013
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Transmission of human cytomegalovirus (HCMV) to the fetus is the most common type of intrauterine infection; the mechanism of HCMV pathogenesis in the developing central nervous system remains unclear. Thrombospondins 1 and 2 (TSP1, TSP2) produced by immature astrocytes are critical for fetal synaptogenesis. To examine the effect of HCMV on fetal astrocytes, human fetal astrocytes were isolated and cultured with HCMV AD169. Cells were harvested at different time points. Protein and mRNA expressions of TSP1 and TSP2 were determined using RT-qPCR, western blotting analysis, and enzyme-linked immunosorbent assay. The results showed that HCMV infection induced time-dependent decreases in mRNA and protein expressions of both TSP1 and TSP2 in astrocytes. Flow cytometry was used to detect apoptosis of HCMV-infected astrocytes, and the result indicated that there was no linkage between cell apoptosis and the decrease in TSP1 and TSP2 expressions induced by HCMV infection. When ganciclovir treatment was performed on HCMV-infected astrocytes, results showed that ganciclovir treatment inhibited the reduction of TSP1 and TSP2 expression in astrocytes. In the further study, pEGFP-N3-IE1 was transfected into astrocytes to identify that it was not IE1 but active viral replication that was essential in the continuous decrease of TSP1 and TSP2 expressions in HCMV-infected astrocytes.
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Modified chemical vapor deposition synthesis of ultralong V2O5 nanobelt and its electronic properties.
J Nanosci Nanotechnol
PUBLISHED: 05-08-2013
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The fascinating properties and wide applications of the V2O5 nanostructures have attracted significant attention over the past decades. In this paper, ultralong (centimeter-scale) single-crystal V2O5 nanobelts are successfully fabricated by modified chemical vapor deposition. The wide of the V2O5 nanobelts are 20-500 nm. The aspect ratio exceeds 10(5). The structure and crystal orientation of the nanobelts are investigated. X-ray diffractometer (XRD) patterns and Raman spectrum show the substrate temperature affecting the size and morphology of the V2O5 nanobelts. And the growth mechanism and electronic properties of the ultralong V2O5 nanobelt are studied in detail. The activation energy 0.12 eV is calculated. The fastest growth orientation along the [010] direction has been observed. Our work demonstrates that the single-crystal V2O5 nanobelt has potential applications in field-emitters, lithium-ion batteries, photodetectors, interconnect, and optoelectronic devices, etc.
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Quantitative prediction of glucuronidation in humans using the in vitro- in vivo extrapolation approach.
Curr Top Med Chem
PUBLISHED: 04-22-2013
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Glucuronidation has been recognized as an important clearance mechanism in humans. Therefore, knowledge about the contribution of glucuronidation to clearance of drug candidates is of great value in early drug development. In this article, we discuss the recent progress made to predict in vivo glucuronidation parameters (e.g., hepatic clearance, and intestinal availability) using in vitro data, which are readily obtained using microsomes and hepatocytes, so called "in vitro- in vivo extrapolation" (IVIVE). Of note the intrinsic clearances obtained from microsomal incubations in the presence of bovine serum albumin (BSA) provide accurate predictions of the in vivo clearances in addition to those from hepatocytes. Further, we describe the lack of correlation between cellular and microsomal production of glucuronide and provide possible reasons. Due to the high prediction accuracy, those who study in vitro glucuronidation are encouraged to map their data to in vivo using IVIVE strategy for more informative data interpretation.
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[An investigation into perception of preventability of injuries and knowledge needs on injury prevention among 684 among undergraduates of a university].
Wei Sheng Yan Jiu
PUBLISHED: 04-20-2013
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To examine the perception of the preventability of injury and needs on injury prevention knowledge among undergraduates.
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Accuracy of IgM antibody testing, FQ-PCR and culture in laboratory diagnosis of acute infection by Mycoplasma pneumoniae in adults and adolescents with community-acquired pneumonia.
BMC Infect. Dis.
PUBLISHED: 04-08-2013
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BACKGROUND: Diagnosis of community-acquired pneumonia (CAP) caused by Mycoplasma pneumoniae in adults and adolescents is hampered by a lack of rapid and standardized tests for detection. METHODS: CAP patients from 12 teaching hospitals were prospectively and consecutively recruited. Basic and clinical information, throat swabs and paired sera were collected. Mycoplasma pneumoniae was detected by IgG and IgM antibody tests, fluorescence quantitative polymerase chain reaction (FQ-PCR) and culture. A comparative study of the diagnostic values of three methods, including sensitivity, specificity, positive and negative predictive values and positive likelihood ratio (PLR) was conducted. A fourfold or greater increase of IgG antibody titers of paired sera was set as the diagnostic "gold standard". RESULTS: One hundred and twenty-five CAP patients (52.8% males, median age 47 years, range 14--85) were enrolled. Twenty-seven (21.6%) patients were diagnosed with acute Mycoplasma pneumoniae infections by the "gold standard". Specificity values of all three methods were around 90%. An increasing trend of sensitivity, positive predictive value and PLR was found, with the lowest in IgM testing (7.4%, 28.6% and 1.45), intermediate in FQ-PCR (40.7%, 50% and 3.63), and highest in culture (55.6%, 75% and 10.9). CONCLUSIONS: In the defined group of patients, there was a good agreement between positive rate of MP cultivation of throat swabs and acute M. pneumoniae infection (PLR of 10.9). Since the sensitivity is low in all of the evaluated methods, the logical approach would be to incorporate PCR, culture and serological tests for optimum diagnosis of acute Mycoplasma pneumoniae infections in adults and adolescents.
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Hepatic-specific lipin-1 deficiency exacerbates experimental alcohol-induced steatohepatitis in mice.
Hepatology
PUBLISHED: 04-05-2013
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Lipin-1 regulates lipid metabolism by way of its function as an enzyme in the triglyceride synthesis pathway and as a transcriptional coregulatory protein and is highly up-regulated in alcoholic fatty liver disease. In the present study, using a liver-specific lipin-1-deficient (lipin-1LKO) mouse model, we aimed to investigate the functional role of lipin-1 in the development of alcoholic steatohepatitis and explore the underlying mechanisms. Alcoholic liver injury was achieved by pair feeding wild-type and lipin-1LKO mice with modified Lieber-DeCarli ethanol-containing low-fat diets for 4 weeks. Surprisingly, chronically ethanol-fed lipin-1LKO mice showed markedly greater hepatic triglyceride and cholesterol accumulation, and augmented elevation of serum liver enzymes accompanied by increased hepatic proinflammatory cytokine expression. Our studies further revealed that hepatic removal of lipin-1 in mice augmented ethanol-induced impairment of hepatic fatty acid oxidation and lipoprotein production, likely by way of deactivation of peroxisome proliferator-activated receptor ? coactivator-1alpha, a prominent transcriptional regulator of lipid metabolism. Conclusions: Liver-specific lipin-1 deficiency in mice exacerbates the development and progression of experimental alcohol-induced steatohepatitis. Pharmacological or nutritional modulation of hepatic lipin-1 may be beneficial for the prevention or treatment of human alcoholic fatty liver disease. (Hepatology 2013; 58:1953-1963).
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Facile synthesis of nanoporous carbons with controlled particle sizes by direct carbonization of monodispersed ZIF-8 crystals.
Chem. Commun. (Camb.)
PUBLISHED: 02-21-2013
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Nanoporous carbon particles with different particle sizes are synthesized by simple carbonization of monodispersed zeolitic imidazolate framework-8 (ZIF-8) crystals. Quartz crystal microbalance (QCM) study proves that the use of small-sized nanoporous carbon can lead to both a large adsorption uptake and a faster sensor response for toxic toluene molecules.
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Exon array analysis of alternative splicing of genes in SOD1G93A transgenic mice.
Appl. Biochem. Biotechnol.
PUBLISHED: 02-18-2013
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Alternative splicing is a common strategy for creating functional diversities of proteins. While conventional identification of splice variants generally targets individual genes in amyotrophic lateral sclerosis, we present a novel exon-centric array that allows genome-wide identification of splice variants and concurrently provides analysis of gene expression. Compare 1 was asymptomatic SOD1G93A transgenic mice with nontransgenic littermates; compare 2 was symptomatic with asymptomatic transgenic mice. RT-PCR was performed to validate. Pathway and GO analysis were performed on abnormal genes. These findings could guide us to demonstrated the potential influence of mutant human CuZn-SOD1 and of splicing regulation in pathological processes.
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Melanoma genetic testing, counseling, and adherence to skin cancer prevention and detection behaviors.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 02-07-2013
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Little is known about the impact of knowledge of CDKN2A and MC1R genotype on melanoma prevention behaviors like sun avoidance and skin examination in the context of familial melanoma.
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Effect of irradiation time on riboflavin-ultraviolet-A collagen crosslinking in rabbit sclera.
J Cataract Refract Surg
PUBLISHED: 02-06-2013
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To determine the effect of the duration of irradiation on the biomechanical parameters of combined riboflavin-ultraviolet-A (UVA) collagen crosslinking (CXL) in rabbit sclera.
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Breast Cancer Resistance Protein-Mediated Efflux of Luteolin Glucuronides in HeLa Cells Overexpressing UDP-Glucuronosyltransferase 1A9.
Pharm. Res.
PUBLISHED: 02-04-2013
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UDP-glucuronosyltransferases (UGTs) are responsible for the formation of glucuronides of polyphenolic flavonoids. This study investigated the UGT1A9-mediated glucuronidation of luteolin and the kinetics of luteolin glucuronide efflux.
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The effect of hydroxycamptothecin and pingyangmycin on human squamous cell carcinoma of the tongue.
Oncol Lett
PUBLISHED: 01-07-2013
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The purpose of this study was to test hydroxycamptothecin (HCPT) and pingyangmycin (PYM) for their ability to inhibit the squamous cells of tongue carcinoma (Tca8113 cells). The effect of these compounds was tested using the MTT assay in vitro, clonogenic assays, flow cytometry, morphological observation, telomeric repeat amplification protocol (TRAP), transplantation of tumors into athymic mice and TUNEL staining. Treatment with HCPT and PYM, alone or in combination, inhibited the tumor cells and showed a greater inhibition when the drugs were combined. The cloning efficiency of Tca8113 cells was decreased. The microstructure and cell cycle of the cells changed significantly as a result of treatment. Telomerase activity was significantly inhibited in a time-dependent manner. By appearing to promote apoptosis, the drugs demonstrated a significant level of inhibition of the tumor cells in an athymic mouse model, promoting prolonged survival. HCPT and PYM have a marked cytotoxic effect on Tca8113 cells which is improved when used in combination.
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Comparative study of visual acuity and aberrations after intralase femtosecond LASIK: small corneal flap versus big corneal flap.
Int J Ophthalmol
PUBLISHED: 01-01-2013
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To study the effect of different flap sizes on visual acuity, refractive outcomes, and aberrations after femtosecond laser for laser in situ keratomileusis (LASIK).
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Synthesis and NO2-sensing properties of one-dimensional tungsten oxide nanowire bundles.
J Nanosci Nanotechnol
PUBLISHED: 12-26-2011
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Tungsten oxide nanowires were synthesized by solvothermal method with tungsten hexachloride (WCl6) as precursor. X-ray diffraction, field emission scanning electron microscope and transmission electron microscope characterizations indicated that the as-synthesized nanowires are single phase monoclinic W18O49. With WCl6 concentration increasing, the bundled nanowire became shorter and thicker. The gas-sensing properties of W18O49 nanowire towards NO2 gas were evaluated and the results showed that the optimal gas sensitivity is achieved at 150 degrees C and the thinner nanowire exhibits the higher sensitivity. The results indicate that tungsten oxide nanowire is a promising gas-sensing material for high performance and low power cost NO2 gas sensor.
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Development and validation of a highly sensitive UPLC-MS/MS method for simultaneous determination of aconitine, mesaconitine, hypaconitine, and five of their metabolites in rat blood and its application to a pharmacokinetics study of aconitine, mesaconiti
Xenobiotica
PUBLISHED: 12-22-2011
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A rapid, specific and sensitive method was developed for the simultaneous determination of eight Aconitum alkaloids: aconitine (AC), mesaconitine (MA), hypaconitine (HA), benzoylaconine (BAC), benzoylmesaconine (BMA), benzoylhypaconine (BHA), aconine and mesaconine in rat blood by ultra-performance liquid chromatography coupled tandem mass spectrometry (UPLC-MS/MS). The UPLC-MS/MS system coupled with an electrospray ionization (ESI) source was operated in a positive mode via multiple-reaction monitoring (MRM). Samples were treated with methanol to remove protein prior to analysis by UPLC-MS/MS. The analytes were separated with a Waters C18 column (1.7 µm, 50?×?2.1?mm) and a gradient elution using acetonitrile and 0.1% formic acid-water as the mobile phases. The linear response range was from 0.125 to 1000 nmol/L for these eight alkaloids and the correlation coefficients (r(2) values) were all higher than 0.997. The method was validated with respect to precision, accuracy, recovery, matrix effect, carryover effect and sample stability, and found to be within the acceptable limits. The developed and validated method was successfully applied to simultaneously determine the eight Aconitum alkaloids in rats blood after intravenous administration of a mixture of AC, MA and HA.
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Cooperation between Polycomb and androgen receptor during oncogenic transformation.
Genome Res.
PUBLISHED: 12-16-2011
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Androgen receptor (AR) is a hormone-activated transcription factor that plays important roles in prostate development and function, as well as malignant transformation. The downstream pathways of AR, however, are incompletely understood. AR has been primarily known as a transcriptional activator inducing prostate-specific gene expression. Through integrative analysis of genome-wide AR occupancy and androgen-regulated gene expression, here we report AR as a globally acting transcriptional repressor. This repression is mediated by androgen-responsive elements (ARE) and dictated by Polycomb group protein EZH2 and repressive chromatin remodeling. In embryonic stem cells, AR-repressed genes are occupied by EZH2 and harbor bivalent H3K4me3 and H3K27me3 modifications that are characteristic of differentiation regulators, the silencing of which maintains the undifferentiated state. Concordantly, these genes are silenced in castration-resistant prostate cancer rendering a stem cell-like lack of differentiation and tumor progression. Collectively, our data reveal an unexpected role of AR as a transcriptional repressor inhibiting non-prostatic differentiation and, upon excessive signaling, resulting in cancerous dedifferentiation.
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Lymphatic invasion is independently prognostic of metastasis in primary cutaneous melanoma.
Clin. Cancer Res.
PUBLISHED: 11-17-2011
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Lymphatic invasion (LI) in primary cutaneous melanomas was recently found to be common. In this study, we evaluated LI as an independent prognostic factor.
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UDP-glucuronosyltransferase (UGT) 1A9-overexpressing HeLa cells is an appropriate tool to delineate the kinetic interplay between breast cancer resistance protein (BRCP) and UGT and to rapidly identify the glucuronide substrates of BCRP.
Drug Metab. Dispos.
PUBLISHED: 11-09-2011
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The interplay between phase II enzymes and efflux transporters leads to extensive metabolism and low bioavailability for flavonoids. To investigate the simplest interplay between one UDP-glucuronosyltransferase isoform and one efflux transporter in flavonoid disposition, engineered HeLa cells stably overexpressing UGT1A9 were developed, characterized, and further applied to investigate the metabolism of two model flavonoids (genistein and apigenin) and excretion of their glucuronides. The results indicated that the engineered HeLa cells overexpressing UGT1A9 rapidly excreted the glucuronides of genistein and apigenin. The kinetic characteristics of genistein or apigenin glucuronidation were similar with the use of UGT1A9 overexpressed in HeLa cells or the commercially available UGT1A9. Small interfering (siRNA)-mediated UGT1A9 silencing resulted in a substantial decrease in glucuronide excretion (>75%, p < 0.01). Furthermore, a potent inhibitor of breast cancer resistance protein (BCRP), 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino[1,2:1,6]pyrido[3,4-b]indol-3-yl)-propionic acid tert-butyl ester (Ko143), caused, in a dose-dependent manner, a substantial and marked reduction of the clearance (74-94%, p < 0.01), and a substantial increase in the intracellular glucuronide levels (4-8-fold, p < 0.01), resulting in a moderate decrease in glucuronide excretion (19-59%, p < 0.01). In addition, a significant, albeit moderate, reduction in the fraction of genistein metabolized (f(met)) in the presence of Ko143 was observed. In contrast, leukotriene C? and siRNA against multidrug resistance protein (MRP) 2 and MRP3 did not affect excretion of flavonoid glucuronides. In conclusion, the engineered HeLa cells overexpressing UGT1A9 is an appropriate model to study the kinetic interplay between UGT1A9 and BCRP in the phase II disposition of flavonoids. This simple cell model should also be very useful to rapidly identify whether a phase II metabolite is the substrate of BCRP.
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Using Poisson mixed-effects model to quantify transcript-level gene expression in RNA-Seq.
Bioinformatics
PUBLISHED: 11-08-2011
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RNA sequencing (RNA-Seq) is a powerful new technology for mapping and quantifying transcriptomes using ultra high-throughput next-generation sequencing technologies. Using deep sequencing, gene expression levels of all transcripts including novel ones can be quantified digitally. Although extremely promising, the massive amounts of data generated by RNA-Seq, substantial biases and uncertainty in short read alignment pose challenges for data analysis. In particular, large base-specific variation and between-base dependence make simple approaches, such as those that use averaging to normalize RNA-Seq data and quantify gene expressions, ineffective.
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Evaluation of 3,3,4-trihydroxyflavone and 3,6,4-trihydroxyflavone (4-O-glucuronidation) as the in vitro functional markers for hepatic UGT1A1.
Mol. Pharm.
PUBLISHED: 10-21-2011
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Identifying uridine 5-diphospho-(UDP)-glucuronosyltransferase (UGT)-selective probes (substrates that are primarily glucuronidated by a single isoform) is complicated by the enzymes large overlapping substrate specificity. Here, regioselective glucuronidation of two flavonoids, 3,3,4-trihydroxyflavone (3,3,4-THF) and 3,6,4-trihydroxyflavone (3,6,4-THF), is used to probe the activity of hepatic UGT1A1. The glucuronidation kinetics of 3,3,4-THF and 3,6,4-THF was determined using 12 recombinant human UGT isoforms and pooled human liver microsomes (pHLM). The individual contribution of main UGT isoforms to the metabolism of the two flavonoids in pHLM was estimated using the relative activity factor approach. UGT1A1 activity correlation analyses using flavonoids-4-O-glucuronidation vs ?-estradiol-3-glucuronidation (a well-recognized marker for UGT1A1) or vs SN-38 glucuronidation were performed using a bank of HLMs (n = 12) including three UGT1A1-genotyped HLMs (i.e., UGT1A1*1*1, UGT1A1*1*28, and UGT1A1*28*28). The results showed that UGT1A1 and 1A9, followed by 1A7, were the main isoforms for glucuronidating the two flavonoids, where UGT1A1 accounted for 92 ± 7% and 91 ± 10% of 4-O-glucuronidation of 3,3,4-THF and 3,6,4-THF, respectively, and UGT1A9 accounted for most of the 3-O-glucuronidation. Highly significant correlations (R(2) > 0.944, p < 0.0001) between the rates of flavonoids 4-O-glucuronidation and that of estradiol-3-glucuronidation or SN-38 glucuronidation were observed across 12 HLMs. In conclusion, UGT1A1-mediated 4-O-glucuronidation of 3,3,4-THF and 3,6,4-THF was highly correlated with the glucuronidation of estradiol (3-OH) and SN-38. This study demonstrated for the first time that regioselective glucuronidation of flavonoids can be applied to probe hepatic UGT1A1 activity in vitro.
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Modulation of IFN-? receptor 1 expression by AP-2? influences IFN-? sensitivity of cancer cells.
Am. J. Pathol.
PUBLISHED: 08-12-2011
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Interferon (IFN)-? plays crucial roles in regulating both innate and adaptive immunity. The existence of IFN-? receptor 1 (IFNGR1) molecules on the cell surface is a prerequisite to the initiation of IFN-? signaling; low expression of IFNGR1 leads to a functional blockade of IFN-? signaling. However, the molecular mechanisms by which IFNGR1 expression is controlled are unclear. In the present study, we demonstrated that IFNGR1 expression was reduced or lost in breast cancer. Heterogeneous IFNGR1 immunoreactivity appeared to be associated with the morphological heterogeneity of breast cancer, and loss of IFNGR1 expression was predominantly observed in poorly differentiated areas. We identified the functional activating protein (AP)-2 and specificity protein (SP)-1 sites within the IFNGR1 promoter. Ectopic expression of AP-2? drastically repressed the expression of IFNGR1 and hindered IFN-? signaling, whereas AP-2? gene silencing elevated IFNGR1 levels. Overexpression of SP-1 effectively antagonized the repressive effects of AP-2?. Simultaneous recruitment of both transcription factors to the AP-2 and SP-1 motifs, respectively, in the IFNGR1 promoter was demonstrated, implying that AP-2? and SP-1 may synergistically modulate IFNGR1 transcription. Moreover, AP-2? overexpression in AP-2-deficient SW480 cells remarkably inhibited Stat1 phosphorylation and the anti-proliferative effects of IFN-?, whereas knockdown of the AP-2? expression dramatically enhanced the sensitivities of HeLa cells highly expressing AP-2 to IFN-?, indicating that dysregulation of AP-2? expression is associated with impaired IFN-? actions in cancer cells.
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Accurate assessment of antibiotic susceptibility and screening resistant strains of a bacterial population by linear gradient plate.
Sci China Life Sci
PUBLISHED: 08-08-2011
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The dynamics of a bacterial population exposed to the minimum inhibitory concentration (MIC) of an antibiotic is an important issue in pharmacological research. Therefore, a novel antibiotic susceptibility test is urgently needed that can both precisely determine the MIC and accurately select antibiotic-resistant strains from clinical bacterial populations. For this purpose, we developed a method based on Ficks laws of diffusion using agar plates containing a linear gradient of antibiotic. The gradient plate contained two layers. The bottom layer consisted of 15 mL agar containing the appropriate concentration of enrofloxacin and allowed to harden in the form of a wedge with the plate slanted such that the entire bottom was just covered. The upper layer consisted of 15 mL plain nutrient agar added with the plate held in the horizontal position. After allowing vertical diffusion of the drug from the bottom agar layer for 12 h, the enrofloxacin concentration was diluted in proportion to the ratio of the agar layer thicknesses. The uniform linear concentration gradient was verified by measuring the enrofloxacin concentration on the agar surface. When heavy bacterial suspensions were spread on the agar surface and incubated for more than 12 h, only resistant cells were able to form colonies beyond the boundary of confluent growth of susceptible cells. In this way, the true MIC of enrofloxacin was determined. The MICs obtained using this linear gradient plate were consistent with those obtained using conventional antibiotic susceptibility tests. Discrete colonies were then spread onto a gradient plate with higher antibiotic concentrations; the boundary line increased significantly, and gene mutations conferring resistance were identified. This new method enables the rapid identification of resistant strains in the bacterial population. Use of the linear gradient plate can easily identify the precise MIC and reveal the dynamic differentiation of bacteria near the MIC. This method allows the study of genetic and physiological characteristics of individual strains, and may be useful for early warning of antibiotic resistance that may occur after use of certain antimicrobial agents, and guide clinical treatment.
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Enhancement of oral bioavailability of 20(S)-ginsenoside Rh2 through improved understanding of its absorption and efflux mechanisms.
Drug Metab. Dispos.
PUBLISHED: 07-14-2011
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The development of 20(S)-ginsenoside Rh2 (Rh2s) as a chemoprevention agent is limited by its low oral bioavailability. The goals of this study were to determine the mechanisms responsible for its poor oral absorption and to improve its bioavailability by overcoming the barrier to its absorption. Comprehensive studies were conducted using the following models: 1) monolayers of Caco-2, parental, and multidrug resistance gene (MDR1)-overexpressing Madin-Darby canine kidney II (MDCKII) cells; 2) pharmacokinetics in wild-type (WT) FVB, MDR1a/b knockout [MDR1a/b?/?] FVB, and A/J mice; and 3) intestinal perfusion in WT, MDR1a/b?/? FVB, and A/J mice. Two P-glycoprotein (P-gp) inhibitors, verapamil and cyclosporine A, substantially decreased the efflux ratio of Rh2s from 28.5 to 1.0 and 1.2, respectively, in Caco-2 cells. The intracellular concentrations of Rh2s were also significantly increased (2.3- and 3.9-fold) in the presence of inhibitors. Similar results were obtained when transcellular transport of Rh2s were determined using MDR1-overexpressing MDCKII cells in the absence or presence of cyclosporine A. Compared with WT mice, the plasma C(max) and AUC?-? of Rh2s were substantially increased by 17- and 23-fold in MDR1a/b?/? FVB mice, respectively. In the A/J mice, the oral bioavailability of Rh2s (0.94% at 5 mg/kg and 0.52% at 20 mg/kg) was substantially increased by P-gp inhibitor to 33.18 and 27.14%, respectively. As expected, deletion or inhibition of P-gp significantly increased absorption and steady-state plasma concentration of Rh2s in a mouse intestinal perfusion model. In conclusion, Rh2s is a good substrate of P-gp, and inhibition of P-gp can significantly enhance its oral bioavailability.
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Deep sequencing reveals distinct patterns of DNA methylation in prostate cancer.
Genome Res.
PUBLISHED: 07-05-2011
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Beginning with precursor lesions, aberrant DNA methylation marks the entire spectrum of prostate cancer progression. We mapped the global DNA methylation patterns in select prostate tissues and cell lines using MethylPlex-next-generation sequencing (M-NGS). Hidden Markov model-based next-generation sequence analysis identified ?68,000 methylated regions per sample. While global CpG island (CGI) methylation was not differential between benign adjacent and cancer samples, overall promoter CGI methylation significantly increased from ~12.6% in benign samples to 19.3% and 21.8% in localized and metastatic cancer tissues, respectively (P-value < 2 × 10(-16)). We found distinct patterns of promoter methylation around transcription start sites, where methylation occurred not only on the CGIs, but also on flanking regions and CGI sparse promoters. Among the 6691 methylated promoters in prostate tissues, 2481 differentially methylated regions (DMRs) are cancer-specific, including numerous novel DMRs. A novel cancer-specific DMR in the WFDC2 promoter showed frequent methylation in cancer (17/22 tissues, 6/6 cell lines), but not in the benign tissues (0/10) and normal PrEC cells. Integration of LNCaP DNA methylation and H3K4me3 data suggested an epigenetic mechanism for alternate transcription start site utilization, and these modifications segregated into distinct regions when present on the same promoter. Finally, we observed differences in repeat element methylation, particularly LINE-1, between ERG gene fusion-positive and -negative cancers, and we confirmed this observation using pyrosequencing on a tissue panel. This comprehensive methylome map will further our understanding of epigenetic regulation in prostate cancer progression.
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Chemopreventive effect of a mixture of Chinese Herbs (antitumor B) on chemically induced oral carcinogenesis.
Mol. Carcinog.
PUBLISHED: 07-03-2011
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In this study, we evaluated chemopreventive efficacy of Antitumor B, a Chinese herbal mixture of six plants (Sophora tonkinensis, Polygonum bistorta, Prunella vulgaris, Sonchus arvensis L., Dictamnus dasycarpus, and Dioscorea bulbifera) on the development of 4-nitroquinoline-1-oxide (4NQO) induced oral squamous cell carcinomas in A/J mice. Antitumor B, delivered through diet, inhibited 4NQO-induced oral cancer development by 59.19%. The reduction of cell proliferation appears to be associated with efficacy of Antitumor B against 4NQO-induced oral cancer in A/J mice. The expression of epidermal growth factor receptor (EGFR) and phosphorylated EGFR (Tyr1173) were down-regulated by Antitumor B. Tissue distribution of Antitumor B was determined using obacunone, matrine, and maackiain as marker chemicals. We found significant amounts of obacunone, matrine, and maackiain in the blood after 1-wk treatment. The concentrations of these three compounds did not increase further at 18? wk, suggesting that plasma concentrations had reached a steady-state level at 1? wk. There was no significant body weight loss and there was no other obvious sign of toxicity in Antitumor B-treated mice. These results suggest that Antitumor B is a promising agent for human oral cancer chemoprevention.
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Regulation of hepatic lipin-1 by ethanol: role of AMP-activated protein kinase/sterol regulatory element-binding protein 1 signaling in mice.
Hepatology
PUBLISHED: 06-24-2011
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Lipin-1 is a protein that exhibits dual functions as a phosphatidic acid phosphohydrolase enzyme in the triglyceride synthesis pathways and a transcriptional coregulator. Our previous studies have shown that ethanol causes fatty liver by activation of sterol regulatory element-binding protein 1 (SREBP-1) and inhibition of hepatic AMP-activated protein kinase (AMPK) in mice. Here, we tested the hypothesis that AMPK-SREBP-1 signaling may be involved in ethanol-mediated up-regulation of lipin-1 gene expression. The effects of ethanol on lipin-1 were investigated in cultured hepatic cells and in the livers of chronic ethanol-fed mice. Ethanol exposure robustly induced activity of a mouse lipin-1 promoter, promoted cytoplasmic localization of lipin-1, and caused excess lipid accumulation, both in cultured hepatic cells and in mouse livers. Mechanistic studies showed that ethanol-mediated induction of lipin-1 gene expression was inhibited by a known activator of AMPK or overexpression of a constitutively active form of AMPK. Importantly, overexpression of the processed nuclear form of SREBP-1c abolished the ability of 5-aminoimidazole-4-carboxamide ribonucleoside to suppress ethanol-mediated induction of lipin-1 gene-expression level. Chromatin immunoprecipitation assays further revealed that ethanol exposure significantly increased the association of acetylated histone H3 at lysine 9 with the SRE-containing region in the promoter of the lipin-1 gene.
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Direct synthesis of nanoporous carbon nitride fibers using Al-based porous coordination polymers (Al-PCPs).
Chem. Commun. (Camb.)
PUBLISHED: 06-20-2011
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We report a new synthetic route for preparation of nanoporous carbon nitride fibers with graphitic carbon nitride polymers, by calcination of Al-based porous coordination polymers (Al-PCPs) with dicyandiamide (DCDA) under a nitrogen atmosphere.
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The search for a chemoprevention agent effective against melanoma: considerations and challenges.
J. Invest. Dermatol.
PUBLISHED: 06-16-2011
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Studies examining the potential chemopreventive properties of nonsteroidal anti-inflammatory drugs (NSAIDs) against melanoma report widely varying results. The construction and interpretation of these studies are hampered by many factors, including limited knowledge of the pathogenesis of melanoma, leading to difficulties in determining the relevant factors in the administration of chemopreventive agents and difficulties in assessing long-term use of nonprescription medications. The study by Curiel-Lewandrowski et al. reported in this issue is an important contribution to the literature, but the final verdict regarding the chemopreventive properties of NSAIDs against melanoma is yet to come.
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Uridine diphosphate glucuronosyltransferase isoform-dependent regiospecificity of glucuronidation of flavonoids.
J. Agric. Food Chem.
PUBLISHED: 06-06-2011
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The objective of this study was to determine the regiospecificity of the important uridine diphosphate glucuronosyltransferase (UGT) isoforms responsible for the glucuronidation of flavones and flavonols. We systematically studied the glucuronidation of 13 flavonoids (7 flavones and 6 flavonols, with hydroxyl groups at C-3, C-4, C-5, and/or C-7 positions in flavonoid structure) at a substrate concentration of 10 ?M by 8 recombinant human UGT isoforms mainly responsible for the metabolism of flavonoids, UGTs 1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10, and 2B7. At 10 ?M substrate concentration, different UGT isoforms gave different regiospecific glucuronidation patterns. UGT 1A1 equally glucuronidated 3-O (glucuronic acid substituted at C-3 hydroxyl group), 7-O, and 4-O, whereas UGTs 1A8 and 1A9 preferably glucuronidated only 3-O and 7-O positions. UGT 1A1 usually showed no regiospecificity for glucuronidating any position, whereas UGT 1A8 and UGT 1A9 showed dominant, moderate, or weak regiospecificity for 3-O or 7-O position, depending on the structure of the compound. UGT 1A3 showed dominant regiospecificity for the 7-O position, whereas UGT 1A7 showed dominant regiospecificity for the 3-O position. We also showed that the glucuronidation rates of 3-O and 7-O positions in flavones and flavonols were affected by the addition of multiple hydroxyl groups at different positions as well as by the substrate concentrations (2.5, 10, and 35 ?M). In conclusion, regiospecific glucuronidation of flavonols was isoform- and concentration-dependent, whereas flavones were dominantly glucuronidated at the 7-O position by most UGT isoforms. We also concluded that UGTs 1A3 and 1A7 showed dominant regiospecificity for only the 7-O and 3-O positions, respectively. UGTs 1A8 and 1A9 showed moderate or weak preference on glucuronidating position 3-O over the 7-O position, whereas other UGT isoforms did not prefer glucuronidating any particular positions.
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Sulfation of selected mono-hydroxyflavones by sulfotransferases in vitro: a species and gender comparison.
J. Pharm. Pharmacol.
PUBLISHED: 06-04-2011
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Sulfation via sulfotransferases is an important metabolic pathway contributing to the low bioavailability of flavonoids. This study aims to characterize the sulfation of mono-hydroxyflavones (MHFs) to obtain useful information on structure-metabolizing relationships in animal species and gender differences.
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[Surgical treatment for the thoracolumbar spinal tuberculosis with paraplegia].
Zhongguo Gu Shang
PUBLISHED: 05-25-2011
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To explore the long-term effects,operating opportunity,indication of anterior debridement and decompression and bone graft in treating thoracolumbar tuberculosis with paraplegia.
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[Application of Bioflex dynamic stabilization system in treating multi-segment lumbar degenerative disease].
Zhongguo Gu Shang
PUBLISHED: 05-25-2011
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To explore the value of application of Bioflex dynamic stabilization system in treating multi-segment lumbar degenerative disease.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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