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Find video protocols related to scientific articles indexed in Pubmed.
Small-Molecule Inhibitors of the MDM2-p53 Protein-Protein Interaction (MDM2 Inhibitors) in Clinical Trials for Cancer Treatment.
J. Med. Chem.
PUBLISHED: 11-15-2014
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Design of small-molecule inhibitors (MDM2 inhibitors) to block the MDM2-p53 protein-protein interaction has been pursued as a new cancer therapeutic strategy. In recent years, potent, selective, and efficacious MDM2 inhibitors have been successfully obtained and seven such compounds have been advanced into early phase clinical trials for the treatment of human cancers. Here, we review the design, synthesis, properties, preclinical, and clinical studies of these clinical-stage MDM2 inhibitors.
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miR-141-CXCL1-CXCR2 signaling-induced Treg cells recruitment regulates metastases and survival of non-small cell lung cancer.
Mol. Cancer Ther.
PUBLISHED: 10-27-2014
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Non-small-cell lung cancer (NSCLC) patients with malignant pleural effusion (MPE) have a short median survival time and the increased Treg cells. However, it is unclear whether some specific factors in MPE are involved in Treg cell recruitment in the progression of NSCLC. Here, we found that Treg cell population was increased in MPE and inversely correlated with patient survival (P<0.001). Increased level of CXCL1 in MPE was associated with recruitment of Treg cells (P<0.01). Moreover, miR-141 regulated expression of CXCL1 in lung cancer cells while the luciferase test confirmed that CXCL1 is a target of miR-141. Chemotaxis assay showed that the miR-141-CXCL1-CXCR2 pathway regulates migration of Treg cells into MPE. Furthermore, miR-141 significantly inhibited tumor growth and metastasis in immune-competent mice model. This suppressive function was mediated by CXCL1-CXCR2 pathway and recruitment of Treg cells. Our study uncovered a causative link between microRNA and development of MPE. Mechanistically, decreased expressions of miR-141, associated with the survival of NSCLC patients with MPE, resulted in the increased production of CXCL1 and recruitment of Treg cells to promote immune-escape of tumor.
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[Long term follow-up and prognostic analysis of 85 cases with primary gastrointestinal diffuse large B cell lymphoma].
Zhonghua Xue Ye Xue Za Zhi
PUBLISHED: 10-24-2014
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To analyze the clinical characteristics, prognostic factors in patients with primary gastrointestinal diffuse large B cell lymphoma (PGI-DLBCL).
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Application of nano-carbon in lymph node dissection for thyroid cancer and protection of parathyroid glands.
Med. Sci. Monit.
PUBLISHED: 10-15-2014
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The aim of this study was to explore a new method to identify and protect parathyroid glands in neck lymph node dissection for patients with thyroid cancer.
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The Experimental Therapy on Brain Ischemia by Improvement of Local Angiogenesis with Tissue Engineering in The Mouse.
Cell Transplant
PUBLISHED: 10-11-2014
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Neural restoration has proven to be difficult after brain stroke, especially in its chronic stage. This is mainly due to the generation of an unpropitious niche in the injured area, including loss of vascular support but production of numerous inhibitors against neuronal regeneration. Reconstruction of a proper niche for promoting local angiogenesis, therefore, should be a key approach for neural restoration after stroke. In the present study, a new biomaterial composite that could be implanted in injured area of the brain was created for experimental therapy of brain ischemia in the mouse. This composite was made using a hyaluronic acid (HA) based biodegradable hydrogel scaffold, mixed with poly(lactic-co-glycolic acid) (PLGA) microspheres containing vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang1), two factors that stimulate angiogenesis. In addition, the antibody of Nogo receptor (NgR-Ab), which can bind to multiple inhibitory myelin proteins and promote neural regeneration, was covalently attached to the hydrogel, making the hydrogel more bioactive and suitable for neural survival. This composite (HA-PLGA) was implanted into the mouse model with middle cerebral artery occlusion (MCAO), to explore a new approach for restoration of brain function after ischemia. A good survival and proliferation of human umbilical artery endothelial cells (HUAECs) and neural stem cells (NSCs) were seen on the HA hydrogel with PLGA microspheres in vitro. This new material was shown to have good compatibility with the brain tissue and inhibition to gliosis and inflammation after its implantation in the normal or ischemic brain of mice. Particularly, good angiogenesis was found around the implanted HA-PLGA hydrogel and the mouse models clearly showed a behavioral improvement. The results in this present study indicate, therefore, that the HA-PLGA hydrogel is a promising material which is able to induce angiogenesis in the ischemic region by releasing VEGF and Ang1, thus create a suitable niche for neural restoration in later stages of stroke. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.
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Experimental evaluation of myocardial fibrosis in a rapid atrial pacing model in New Zealand rabbits using quantitative analysis of ultrasonic backscatter.
Med. Sci. Monit.
PUBLISHED: 10-10-2014
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The aim of this study was the establishment of a rapid atrial pacing (RAP)-induced atrial fibrillation (AF) model with electrophotoluminescence and the application of ultrasonic backscatter quantitative analysis of the degree of myocardial fibrosis in New Zealand white rabbits.
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Porous Spherical CaO-based Sorbents via PSS-Assisted Fast Precipitation for CO2 Capture.
ACS Appl Mater Interfaces
PUBLISHED: 10-06-2014
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In this paper, we report the development of synthetic CaO-based sorbents via a fast precipitation method with the assistance of sodium poly(styrenesulfonate) (PSS). The effect of PSS on physical properties of the CaO sorbents and their CO2 capture performance were investigated. The presence of PSS dispersed the CaO particles effectively as well as increased their specific surface area and pore volume remarkably. The obtained porous spherical structure facilitated CO2 to diffuse and react with inner CaO effectively, resulting in a significant improvement in initial CO2 carbonation capacity. A proper amount of Mg(2+) precursor solution was doped during a fast precipitation process to gain CaO-based sorbents with a high anti-sintering property, which maintained the porous spherical structure with the high specific surface area. CaO-based sorbents derived from a MgxCa1-xCO3 precursor existed in the form of CaO and MgO. The homogeneous distribution of MgO in the CaO-based sorbents effectively prevented the CaO crystallite from growing and sintering, further resulting in the favorable long-term durability with carbonation capacity of about 52.0% after 30 carbonation/calcination cycles.
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High-efficiency inverted polymer solar cells controlled by the thickness of polyethylenimine ethoxylated (PEIE) interfacial layers.
Phys Chem Chem Phys
PUBLISHED: 10-02-2014
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In this work, we investigate the effect of the thickness of the polyethylenimine ethoxylated (PEIE) interface layer on the performance of two types of polymer solar cells based on inverted poly(3-hexylthiophene) (P3HT):phenyl C61-butryric acid methyl ester (PCBM) and thieno[3,4-b]thiophene/benzodithiophene (PTB7):[6,6]-phenyl C71-butyric acid methyl ester (PC71BM). Maximum power conversion efficiencies of 4.18% and 7.40% were achieved at a 5.02 nm thick PEIE interface layer, for the above-mentioned solar cell types, respectively. The optimized PEIE layer provides a strong enough dipole for the best charge collection while maintaining charge tunneling ability. Optical transmittance and atomic force microscopy measurements indicate that all PEIE films have the same high transmittance and smooth surface morphology, ruling out the influence of the PEIE layer on these two parameters. The measured external quantum efficiencies for the devices with thick PEIE layers are quite similar to those of the optimized devices, indicating the poor charge collection ability of thick PEIE layers. The relatively low performance of devices with a PEIE layer of thickness less than 5 nm is the result of a weak dipole and partial coverage of the PEIE layer on ITO.
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Yersinia Protein Kinase A Phosphorylates Vasodilator-Stimulated Phosphoprotein to Modify the Host Cytoskeleton.
Cell. Microbiol.
PUBLISHED: 09-13-2014
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Pathogenic Yersinia species evolved a type III secretion system that injects a set of effectors into the host cell cytosol to promote infection. One of these effectors, Yersinia protein kinase A (YpkA), is a multidomain effector that harbors a Ser/Thr kinase domain and a guanine dissociation inhibitor (GDI) domain. The intercellular targets of the kinase and GDI domains of YpkA were identified to be G?q and the small GTPases RhoA and Rac1, respectively, which synergistically induce cytotoxic effects on infected cells. In this study, we demonstrate that vasodilator-stimulated phosphoprotein (VASP), which is critical for regulation of actin assembly, cell adhesion, and motility is a direct substrate of YpkA kinase activity. Ectopic coexpression of YpkA and VASP in HEK293T cells lead to the phosphorylation of VASP at S157, and YpkA kinase activity is essential for VASP phosphorylation at this site. Moreover, YpkA directly phosphorylates VASP in in vitro kinase assay. YpkA-mediated VASP phosphorylation significantly inhibits actin polymerization and promotes the disruption of actin cytoskeleton, which inhibits the phagocytosis. Taken together, our study found a novel molecular mechanism used by YpkA to disrupt cytoskeleton dynamics, thereby promoting the anti-phagocytosis ability of pathogenic Yersiniae.
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SAR405838: An Optimized Inhibitor of MDM2-p53 Interaction That Induces Complete and Durable Tumor Regression.
Cancer Res.
PUBLISHED: 08-21-2014
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Blocking the oncoprotein murine double minute 2 (MDM2)-p53 protein-protein interaction has long been considered to offer a broad cancer therapeutic strategy, despite the potential risks of selecting tumors harboring p53 mutations that escape MDM2 control. In this study, we report a novel small-molecule inhibitor of the MDM2-p53 interaction, SAR405838 (MI-77301), that has been advanced into phase I clinical trials. SAR405838 binds to MDM2 with Ki = 0.88 nmol/L and has high specificity over other proteins. A cocrystal structure of the SAR405838:MDM2 complex shows that, in addition to mimicking three key p53 amino acid residues, the inhibitor captures additional interactions not observed in the p53-MDM2 complex and induces refolding of the short, unstructured MDM2 N-terminal region to achieve its high affinity. SAR405838 effectively activates wild-type p53 in vitro and in xenograft tumor tissue of leukemia and solid tumors, leading to p53-dependent cell-cycle arrest and/or apoptosis. At well-tolerated dose schedules, SAR405838 achieves either durable tumor regression or complete tumor growth inhibition in mouse xenograft models of SJSA-1 osteosarcoma, RS4;11 acute leukemia, LNCaP prostate cancer, and HCT-116 colon cancer. Remarkably, a single oral dose of SAR405838 is sufficient to achieve complete tumor regression in the SJSA-1 model. Mechanistically, robust transcriptional upregulation of PUMA induced by SAR405838 results in strong apoptosis in tumor tissue, leading to complete tumor regression. Our findings provide a preclinical basis upon which to evaluate SAR405838 as a therapeutic agent in patients whose tumors retain wild-type p53. Cancer Res; 74(20); 5855-65. ©2014 AACR.
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MicroRNA networks in regulatory T cells.
J. Physiol. Biochem.
PUBLISHED: 08-10-2014
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MicroRNAs (miRNAs) are small regulatory RNAs that bind directly to complementary sequences on target messenger RNA (mRNA) transcripts, resulting in translational repression and/or target mRNA degradation. MiRNAs have been proven to play critical roles on the development, differentiation, and function of immune cells. Regulatory T cells (Tregs) are of importance in maintaining immune homeostasis and self-tolerance. Although many transcription factors and cytokines are known to regulate Tregs, scientists began to focus on the role of noncoding RNA on the regulation of Treg cells. This review provides an overview of the entire microRNA network and specific miRNAs in the development, differentiation, and function of Tregs.
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A novel PCR-based genotyping scheme for clinical Klebsiella pneumoniae.
Future Microbiol
PUBLISHED: 07-30-2014
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To establish a PCR-based genotyping method for clinical Klebsiella pneumoniae.
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[Clinical analysis of 29 cases of cervical necrotizing fasciitis].
Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi
PUBLISHED: 07-17-2014
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To study the experience of clinical features and treatment of deep cervical necrotizing fasciitis.
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Apoptotic events induced by high glucose in human hepatoma HepG2 cells involve endoplasmic reticulum stress and MAPK's activation.
Mol. Cell. Biochem.
PUBLISHED: 06-18-2014
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To investigate whether endoplasmic reticulum (ER) stress participates in the induction of apoptosis in HepG2 cells exposed to high glucose and explore its probable mechanism. A series of experiments were performed following HepG2 cells treated with different concentrations of glucose for 48 h. The apoptosis was detected by means of Hoechst staining and flow cytometry. Caspase-3 activity assay was performed by measuring the pNA (p-nitroaniline) to indirectly reveal the catalytic activity of caspase-3. The expression levels of apoptosis-, ER stress-associated proteins and MAPKs were analyzed by western blot. To further characterize the molecular mechanisms, the effects of antioxidant alpha-lipoic acid (ALA) and specific inhibitors for JNK and p38 (SP600125 and SB203580, respectively) were examined by Hoechst staining, immunofluorescence, and western blot. After HepG2 cells were incubated with high glucose for 48 h, both Hoechst staining and flow cytometry analyses unveiled the apoptosis of HepG2 cells. Caspase-3 activity assay revealed that the activity of caspase-3 was enhanced. Western blot showed an enhancement of pro-caspase-9 degradation, a reduction of Bcl-2/Bax ratio, a decrease in GRP78 expression, and increases in CHOP and p47/phox levels. In addition, western blot analysis presented that phosphorylation of p38 and JNK was triggered and that the expression of ASK1 was elevated. In the case of the contributions of oxidative stress and the MAPK signaling pathways, all ALA, SP600125 and SB203580 were able to largely rescue high glucose-induced apoptosis. High glucose induced the apoptosis in HepG2 cells through the activation of ASK1-p38/JNK pathway mediated by ER stress and oxidative stress.
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The effect of Lactobacillus rhamnosus hsryfm 1301 on the intestinal microbiota of a hyperlipidemic rat model.
BMC Complement Altern Med
PUBLISHED: 06-09-2014
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Growing evidence indicates that intestinal microbiota regulate our metabolism. Probiotics confer health benefits that may depend on their ability to affect the gut microbiota. The objective of this study was to examine the effect of supplementation with the probiotic strain, Lactobacillus rhamnosus hsryfm 1301, on the gut microbiota in a hyperlipidemic rat model, and to explore the associations between the gut microbiota and the serum lipids.
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Estrogen upregulates MICA/B expression in human non-small cell lung cancer through the regulation of ADAM17.
Cell. Mol. Immunol.
PUBLISHED: 06-05-2014
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Estrogen is involved in promoting lung cancer cell division and metastasis. MICA and MICB function as ligands for NKG2D, an important immunoreceptor expressed on natural killer (NK) cells. However, whether estrogen regulates MICA/B expression and affects tumor immune escape remains unknown. In this study, we measured the mRNA levels of MICA, MICB and ADAM17in non-small cell lung cancer (NSCLC) cell lines treated with estrogen. Surface expression of MICA/B on LTEP-a2 and A549 was detected using flow cytometry. We demonstrate that both mRNA and secretory protein levels of MICA/B in lung adenocarcinoma cell lines were upregulated by estradiol. Estradiol enhanced the expression of ADAM17, which was associated with the secretion of MICA/B. This secretion of MICA/B downregulated the NKG2D receptor on the surface of NK92 cells and impaired the cytotoxic activity of NK cells. Estradiol enhanced the expression of ADAM17, which was associated with the secretion of MICA/B. Furthermore, a significant correlation between the concentration of estradiol and the expression of MICA was found in tumor tissues of NSCLC patients. Therefore, we conclude that estrogen can regulate the expression and secretion of MICA/B through ADAM17, which helps lung cancer cells escape NKG2D-mediated immune surveillance.Cellular & Molecular Immunology advance online publication, 3 November 2014; doi:10.1038/cmi.2014.101.
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Clinical approach of using Onyx via transarterial access in treating tentorial dural arteriovenous fistula.
Neurol. Res.
PUBLISHED: 05-12-2014
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In this study, based on clinical presentation and angiographic findings, we try to investigate the possibility to do transarterial embolization using Onyx to treat tentorial dural arteriovenous fistula (TDAVF). Particular attention will be given to the relationship between vascular anatomic characteristics and clinical management.
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Automatic identification and removal of ocular artifacts in EEG--improved adaptive predictor filtering for portable applications.
IEEE Trans Nanobioscience
PUBLISHED: 04-29-2014
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Electroencephalogram (EEG) signals have a long history of use as a noninvasive approach to measure brain function. An essential component in EEG-based applications is the removal of Ocular Artifacts (OA) from the EEG signals. In this paper we propose a hybrid de-noising method combining Discrete Wavelet Transformation (DWT) and an Adaptive Predictor Filter (APF). A particularly novel feature of the proposed method is the use of the APF based on an adaptive autoregressive model for prediction of the waveform of signals in the ocular artifact zones. In our test, based on simulated data, the accuracy of noise removal in the proposed model was significantly increased when compared to existing methods including: Wavelet Packet Transform (WPT) and Independent Component Analysis (ICA), Discrete Wavelet Transform (DWT) and Adaptive Noise Cancellation (ANC). The results demonstrate that the proposed method achieved a lower mean square error and higher correlation between the original and corrected EEG. The proposed method has also been evaluated using data from calibration trials for the Online Predictive Tools for Intervention in Mental Illness (OPTIMI) project. The results of this evaluation indicate an improvement in performance in terms of the recovery of true EEG signals with EEG tracking and computational speed in the analysis. The proposed method is well suited to applications in portable environments where the constraints with respect to acceptable wearable sensor attachments usually dictate single channel devices.
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Medical applications of microwave imaging.
ScientificWorldJournal
PUBLISHED: 04-25-2014
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Ultrawide band (UWB) microwave imaging is a promising method for the detection of early stage breast cancer, based on the large contrast in electrical parameters between malignant tumour tissue and the surrounding normal breast-tissue. In this paper, the detection and imaging of a malignant tumour are performed through a tomographic based microwave system and signal processing. Simulations of the proposed system are performed and postimage processing is presented. Signal processing involves the extraction of tumour information from background information and then image reconstruction through the confocal method delay-and-sum algorithms. Ultimately, the revision of time-delay and the superposition of more tumour signals are applied to improve accuracy.
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Transcriptomic response to Yersinia pestis: RIG-I like receptor signaling response is detrimental to the host against plague.
J Genet Genomics
PUBLISHED: 04-24-2014
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Bacterial pathogens have evolved various mechanisms to modulate host immune responses for successful infection. In this study, RNA-sequencing technology was used to analyze the responses of human monocytes THP1 to Yersinia pestis infection. Over 6000 genes were differentially expressed over the 12 h infection. Kinetic responses of pathogen recognition receptor signaling pathways, apoptosis, antigen processing, and presentation pathway and coagulation system were analyzed in detail. Among them, RIG-I-like receptor (RLR) signaling pathway, which was established for antiviral defense, was significantly affected. Mice lacking MAVS, the adaptor of the RLR signaling pathway, were less sensitive to infection and exhibited lower IFN-? production, higher Th1-type cytokines IFN-? and IL-12 production, and lower Th2-type cytokines IL-4 and IL-13 production in the serum compared with wild-type mice. Moreover, infection of pathogenic bacteria other than Y. pestis also altered the expression of the RLR pathway, suggesting that the response of RLR pathway to bacterial infection is a universal mechanism.
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Method for perfusion decellularization of porcine whole liver and kidney for use as a scaffold for clinical-scale bioengineering engrafts.
Xenotransplantation
PUBLISHED: 04-23-2014
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Whole-organ engineering provides a new alternative source of donor organs for xenotransplantation. Utilization of decellularized whole-organ scaffolds, which can be created by detergent perfusion, is a strategy for tissue engineering. In this article, our aim is to scale up the decellularization process to human-sized liver and kidney to generate a decellularized matrix with optimal and stable characteristics on a clinically relevant scale.
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Protective effects of Lactobacillus plantarum NDC 75017 against lipopolysaccharide-induced liver injury in mice.
Inflammation
PUBLISHED: 04-17-2014
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This study investigated the protective effect of Lactobacillus plantarum NDC 75017 (L. plantarum NDC 75017) against acute liver injury induced by lipopolysaccharide (LPS). Thirty male mice were randomly divided into the control, LPS, and LPS + L. plantarum NDC 75017 groups. In the LPS + L. plantarum group, the mice were orally pretreated with L. plantarum NDC 75017 for 15 days. At 16 days, the mice in the LPS and LPS + L. plantarum NDC 75017 groups were intraperitoneally injected with LPS at 4 mg/kg body weight, whereas the control mice were treated with an equal amount of saline. After 8 h, the serum alanine transaminase (ALT), aspartate aminotransferase (AST), and histology changes were examined. The oxidative stress markers and pro-inflammatory cytokines in the liver were also examined. Meanwhile, the expression of nuclear factor ?B (NF-?B) mRNA and toll-like receptor 4 (TLR4) in the liver was determined by qRT-PCR. The LPS group showed an increase in ALT and AST, whereas the LPS + L. plantarum NDC 75017 group showed a significant decrease. In addition, pretreatment with L. plantarum NDC 75017 can attenuate LPS-induced oxidative stress and inflammatory response. Furthermore, the increase of hepatic NF-?B and TLR4 mRNA induced by LPS was significantly downregulated by the pretreatment with L. plantarum NDC 75017. These data show that pretreatment with L. plantarum NDC 75017 protects against LPS-induced oxidative stress and inflammatory injury in the liver of mice, which may be attributed to the inhibition of the TLR4-NF-?B pathway.
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Integration of platinum nanoparticles with a volumetric bar-chart chip for biomarker assays.
Angew. Chem. Int. Ed. Engl.
PUBLISHED: 04-15-2014
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Platinum nanoparticles (PtNPs) efficiently catalyze the transformation of H2 O2 into oxygen gas. However, owing to the lack of an efficient approach or device that can measure the produced oxygen gas, the catalytic reaction has never been used for diagnostic applications. Microfluidics technology provides a platform that meets these requirements. The volumetric bar-chart chip (V-Chip) volumetrically measures the production of oxygen gas by PtNPs and can be integrated with ELISA technology to provide visible and quantitative readouts without expensive instrumentation or complicated data processing. Herein we show that PtNPs outperform catalase with respect to stability at high H2 O2 concentrations or temperatures or in long-term reactions, and are resistant to most catalase inhibitors. We also show that the catalase-like activity of PtNPs can be used in combination with the V-Chip to sensitively and specifically detect cancer biomarkers both in serum and on the cell surface.
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Cyclodextrin-functionalized silica nanoparticles with dendrimer-like spacers for enantioselective capillary electrochromatography.
Electrophoresis
PUBLISHED: 04-11-2014
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In this report, ?-cyclodextrin (?-CD)-functionalized silica nanoparticles (SNPs) with dendrimer-like spacers were synthesized by first grafting the SNPs with different generations of polyamidoamines (PAMAMs), followed by modifying the grafted SNPs with mono-6-deoxy-(p-tolylsulfonyl)-?-CD. The ?-cyclodextrin-modified silica nanoparticle-cored PAMAMs (SNP-PAMAM-?-CDs) were studied as chiral pseudostationary phases for separating three racemic drugs, namely, chlorpheniramine, nefopam, and verapamil. The ?-CD-functionalized SNPs with dendrimer-like spacers were more enantioselective than native ?-CD, and the structures of the dendritic spacers were highly influential on the separation. In 20 mM NaH2 PO4 , addition of 4.00 mg/mL SNP-G1.0-?-CD (corresponding to 1.12 mM ?-CD) could baseline separate the enantiomers of chlorpheniramine and nefopam, and introduction of 7.00 mg/mL SNP-G0-?-CD (corresponding to 1.68 mM ?-CD) resulted in enantioseparation of the verapamil racemates. On the contrary, the enantiomers of nefopam and verapamil could not be resolved in the presence of 15 mM native ?-CD. Our results suggest that SNP-PAMAM-?-CDs hold great promise for enantioselective separations.
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Primary malignant melanoma of the breast: A case report and review of the literature.
Oncol Lett
PUBLISHED: 04-10-2014
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Malignant melanoma predominantly occurs in the skin and mucous membranes, thus, malignant melanoma of the breast is particularly rare. In the current study, a case of a 26-year-old female with a malignant melanoma of the breast is presented. On diagnosis of the patient, extensive metastasis had occurred. The patient refused any treatment and succumbed two months after the initial diagnosis. The prognosis for patients with this rare tumour of the breast is somewhat poor. Early diagnosis, correct surgical resection and comprehensive adjuvant therapy are the key procedures that may improve the patient survival rate. The current case report aims to increase the awareness of uncommon tumours of the breast.
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White matter pathway supporting phonological encoding in speech production: a multi-modal imaging study of brain damage patients.
Brain Struct Funct
PUBLISHED: 03-30-2014
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In speech production, an important step before motor programming is the retrieval and encoding of the phonological elements of target words. It has been proposed that phonological encoding is supported by multiple regions in the left frontal, temporal and parietal regions and their underlying white matter, especially the left arcuate fasciculus (AF) or superior longitudinal fasciculus (SLF). It is unclear, however, whether the effects of AF/SLF are indeed related to phonological encoding for output and whether there are other white matter tracts that also contribute to this process. We comprehensively investigated the anatomical connectivity supporting phonological encoding in production by studying the relationship between the integrity of all major white matter tracts across the entire brain and phonological encoding deficits in a group of 69 patients with brain damage. The integrity of each white matter tract was measured both by the percentage of damaged voxels (structural imaging) and the mean fractional anisotropy value (diffusion tensor imaging). The phonological encoding deficits were assessed by various measures in two oral production tasks that involve phonological encoding: the percentage of nonword (phonological) errors in oral picture naming and the accuracy of word reading aloud with word comprehension ability regressed out. We found that the integrity of the left SLF in both the structural and diffusion tensor imaging measures consistently predicted the severity of phonological encoding impairment in the two phonological production tasks. Such effects of the left SLF on phonological production remained significant when a range of potential confounding factors were considered through partial correlation, including total lesion volume, demographic factors, lesions on phonological-relevant grey matter regions, or effects originating from the phonological perception or semantic processes. Our results therefore conclusively demonstrate the central role of the left SLF in phonological encoding in speech production.
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Unraveling the complex chemistry using dimethylsilane as a precursor gas in hot wire chemical vapor deposition.
Phys Chem Chem Phys
PUBLISHED: 03-21-2014
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The gas-phase reaction chemistry when using dimethylsilane (DMS) as a source gas in a hot-wire chemical vapor deposition (CVD) process has been studied in this work. The complex chemistry is unraveled by using a soft 10.5 eV single photon ionization technique coupled with time-of-flight mass spectrometry in combination with the isotope labelling and chemical trapping methods. It has been demonstrated that both free-radical reactions and those involving silylene/silene intermediates are important. The reaction chemistry is characterized by the formation of 1,1,2,2-tetramethyldisilane (TMDS) from dimethylsilylene insertion into the Si-H bond of DMS, trimethylsilane (TriMS) from free-radical recombination, and 1,3-dimethyl-1,3-disilacyclobutane (DMDSCB) from the self dimerization of either dimethylsilylene or 1-methylsilene. At low filament temperatures and short reaction time, silylene chemistry dominates. The free-radical reactions become more important with increasing temperature and time. The same three products have been detected when using tantalum and tungsten filaments, indicating that changing the filament material from Ta to W does not affect much the gas-phase reaction chemistry when using DMS as a source gas in a hot-wire CVD reactor.
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Co-expression of CD133, CD44v6 and human tissue factor is associated with metastasis and poor prognosis in pancreatic carcinoma.
Oncol. Rep.
PUBLISHED: 03-14-2014
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The metastasis-related molecules CD133, CD44v6 and human tissue factor (TF) have been shown to be associated with tumor invasion and metastasis. This study aimed to determine whether co-expression of these three molecules was associated with metastasis and overall prognosis in pancreatic carcinoma. We analyzed the expression profiles of these three molecules by immunohistochemistry and evaluated the relationship of their expression profiles with metastasis and prognosis in 109 pancreatic carcinomas. The results showed that the expression levels of CD133, CD44v6 and TF were increased in pancreatic carcinoma. Co-expression of CD133, CD44v6 and TF (tri-expression) was also detected in pancreatic carcinoma. Clinical analysis showed that individual expression of CD133, CD44v6 or TF was associated with vessel invasion, lymph node metastasis and liver metastasis, while tri-expression was associated with lymph node metastasis. Survival analysis showed that patients with co-expression of CD133 and TF or tri-expression had lower and the lowest overall survival rates, respectively. Univariate analysis showed that T-factor, lymph node metastasis, TNM stage, and individual levels or tri-expression of CD133, CD44v6 and TF were survival risk factors. Multivariate analysis showed that tri-expression of CD133, CD44v6 and TF was an independent predictor of survival. These results suggest that overexpression of CD133, CD44v6 and TF is associated with pancreatic carcinoma metastasis. Tri-expression of these three molecules may be a useful predictor for pancreatic carcinoma prognosis.
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The glucosyltransferase Xiantuan of the endoplasmic reticulum specifically affects E-Cadherin expression and is required for gastrulation movements in Drosophila.
Dev. Biol.
PUBLISHED: 03-13-2014
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The majority of membrane and secreted proteins, including many developmentally important signalling proteins, receptors and adhesion molecules, are cotranslationally N-glycosylated in the endoplasmic reticulum. The structure of the N-glycan is invariant for all substrates and conserved in eukaryotes. Correspondingly, the enzymes are conserved, which successively assemble the glycan precursor from activated monosaccharides prior to transfer to nascent proteins. Despite the well-defined biochemistry, the physiological and developmental role of N-glycosylation and of the responsible enzymes has not been much investigated in metazoa. We identified a mutation in the Drosophila gene, xiantuan (xit, CG4542), which encodes one of the conserved enzymes involved in addition of the terminal glucose residues to the glycan precursor. xit is required for timely apical constriction of mesoderm precursor cells and ventral furrow formation in early embryogenesis. Furthermore, cell intercalation in the lateral epidermis during germband extension is impaired in xit mutants. xit affects glycosylation and intracellular distribution of E-Cadherin, albeit not the total amount of E-Cadherin protein. As depletion of E-Cadherin by RNAi induces a similar cell intercalation defect, E-Cadherin may be the major xit target that is functionally relevant for germband extension.
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Lactobacillus plantarum NDC 75017 alleviates the learning and memory ability in aging rats by reducing mitochondrial dysfunction.
Exp Ther Med
PUBLISHED: 03-11-2014
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The aim of the present study was to investigate the protective effect of Lactobacillus plantarum NDC 75017 on D-galactose (D-gal)-induced mitochondrial dysfunction in the rat cerebral cortex. Fifty rats were randomly divided into five groups (n=10 in each group). The rats in the aging model group were subcutaneously injected with 100 mg/kg D-gal and those in the protective groups were additionally orally administered L. plantarum NDC 75017 at doses of 1×10(8), 1×10(9) or 1×10(10) CFU/100 mg body weight/day, respectively. The control rats were administrated an equal volume of the vehicle. Following continuous treatment for seven weeks, the learning and memory abilities and mitochondrial ultrastructure, function and adenosine triphosphate (ATP) levels were examined. The results showed that the learning and memory abilities and mitochondrial levels of ATP were significantly decreased in the D-gal-induced aging model group compared with those in the control group (P<0.01). In addition, marked changes in the mitochondrial functions and ultrastructure were observed between the groups. Seven weeks of L. plantarum NDC 75017 and D-gal coadministration significantly improved the learning and memory abilities of the rats compared with the D-gal-induced aging model group. Furthermore, the combination regime significantly improved the mitochondrial ultrastructure and functions, including the mitochondrial respiratory chain, mitochondrial membrane potential and mitochondrial permeability transition. The results revealed that the L. plantarum NDC 75017 was able to alleviate learning and memory injuries in aging rats by reducing the mitochondrial dysfunction induced by D-gal.
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Polyamidoamine dendrimers as sweeping agent and stationary phase for rapid and sensitive open-tubular capillary electrophoretic determination of heavy metal ions.
Talanta
PUBLISHED: 03-11-2014
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Polyamidoamine (PAMAM) dendrimer generation 2.5 was synthesized and evaluated as sweeping agent for in-column enrichment and as stationary phase for capillary electrochromatographic separation of heavy metal ions, viz., Pb(II), Cu(II), Hg(II), Zn(II) and Co(II), in a running buffer containing 4-(2-pyridylazo)resorcinol (PAR) as a chromogenic reagent. During experiment, a plug of aqueous PAMAM generation 2.5 solution was first introduced to the capillary, followed by electrokinetic injection of the heavy metal ions under a positive voltage. In this step, PAMAM acted as a sweeping agent, stacking the metal ions on the analyte/PAMAM boundary by forming metal ion-PAMAM complexes. The second preconcentration process occurred when PAR, a stronger ligand, moving toward the injection end under the electric field, reached and re-swept the metal ion-PAMAM zone, forming metal ion-PAR complexes. During separation, the neutral PAMAM moved toward the detector with the electroosmotic flow, dynamically coating the capillary wall, forming stationary phases that affected the separation of the metal ions. Due to the function of PAMAM, the detection sensitivity and resolution of the heavy metal ions improved significantly. Under the optimum conditions, the detection limits were 0.299, 0.184, 0.774, 0.182 and 0.047 ?g/L for Pb(II), Cu(II), Hg(II), Zn(II) and Co(II), respectively. The method was successfully applied to the determination of heavy metals in snow, tap and rain water samples.
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Insulin-like growth factor-1 regulates the SIRT1-p53 pathway in cellular senescence.
Aging Cell
PUBLISHED: 02-23-2014
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Cellular senescence, which is known to halt proliferation of aged and stressed cells, plays a key role against cancer development and is also closely associated with organismal aging. While increased insulin-like growth factor (IGF) signaling induces cell proliferation, survival and cancer progression, disrupted IGF signaling is known to enhance longevity concomitantly with delay in aging processes. The molecular mechanisms involved in the regulation of aging by IGF signaling and whether IGF regulates cellular senescence are still poorly understood. In this study, we demonstrate that IGF-1 exerts a dual function in promoting cell proliferation as well as cellular senescence. While acute IGF-1 exposure promotes cell proliferation and is opposed by p53, prolonged IGF-1 treatment induces premature cellular senescence in a p53-dependent manner. We show that prolonged IGF-1 treatment inhibits SIRT1 deacetylase activity, resulting in increased p53 acetylation as well as p53 stabilization and activation, thus leading to premature cellular senescence. In addition, either expression of SIRT1 or inhibition of p53 prevented IGF-1-induced premature cellular senescence. Together, these findings suggest that p53 acts as a molecular switch in monitoring IGF-1-induced proliferation and premature senescence, and suggest a possible molecular connection involving IGF-1-SIRT1-p53 signaling in cellular senescence and aging.
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Hemodynamic Study with Duplex Ultrasonography on Combined (Direct/Indirect) Revascularization in Adult Moyamoya Disease.
J Stroke Cerebrovasc Dis
PUBLISHED: 02-21-2014
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To evaluate the hemodynamic changes by duplex ultrasonography in adult moyamoya disease (MMD) patients who underwent combined direct and indirect revascularization surgery.
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Glycation of human serum albumin in diabetes: impacts on the structure and function.
Curr. Med. Chem.
PUBLISHED: 02-10-2014
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Diabetes mellitus is one of the most serious diseases in the world. The levels of glycated proteins in the blood of diabetics are higher than that of non-diabetic subjects. The glycation of proteins is believed to link to the occurrence of diabetic complications and related diseases. This review focuses on the influence of glycation of human serum albumin (HSA) on its structure and function. The glycation leads to change the HSA conformation, which will further influence its ligand binding properties. The levels of glycated HSA in hyperglycemic conditions showed a significant relationship to the germination of serious complications for diabetics, especially by affecting various cells functions. The conclusion from individual report is contradictory to each other; therefore, it is very difficult to give an univocal comment on the impact of glycation on the binding behaviors of HSA for small molecules. The influence of glycation of HSA on the binding affinities for small molecules is decided by the assay, the structures of small molecules, as well as the degree of glycation. However, the glycation of HSA is believed to reduce the binding affinities for acidic drugs such as polyphenols and phenolic acids.
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Genetic variations of live attenuated plague vaccine strains (Yersinia pestis EV76 lineage) during laboratory passages in different countries.
Infect. Genet. Evol.
PUBLISHED: 02-08-2014
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Plague, one of the most devastating infectious diseases in human history, is caused by the bacterial species Yersinia pestis. A live attenuated Y. pestis strain (EV76) has been widely used as a plague vaccine in various countries around the world. Here we compared the whole genome sequence of an EV76 strain used in China (EV76-CN) with the genomes of Y. pestis wild isolates to identify genetic variations specific to the EV76 lineage. We identified 6 SNPs and 6 Indels (insertions and deletions) differentiating EV76-CN from its counterparts. Then, we screened these polymorphic sites in 28 other strains of EV76 lineage that were stored in different countries. Based on the profiles of SNPs and Indels, we reconstructed the parsimonious dissemination history of EV76 lineage. This analysis revealed that there have been at least three independent imports of EV76 strains into China. Additionally, we observed that the pyrE gene is a mutation hotspot in EV76 lineages. The fine comparison results based on whole genome sequence in this study provide better understanding of the effects of laboratory passages on the accumulation of genetic polymorphisms in plague vaccine strains. These variations identified here will also be helpful in discriminating different EV76 derivatives.
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Discrimination of three dimensional fluorescence spectra based on wavelet analysis and independent component analysis.
Spectrochim Acta A Mol Biomol Spectrosc
PUBLISHED: 01-28-2014
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Fluorescence spectroscopy is a rapid and non-destructive method for monitoring water quality. In this work, wavelet analysis, together with independent component analysis (ICA), was applied for component recognition of seriously overlapped, multi-component, three dimensional fluorescence spectra. Wavelet analysis extracts the features of the spectra and amplifies differences among phenolic homologs. ICA analysis in blind signal separation was used to separate single component before multiple linear regression (MLR). The proposed method increases the correct classification rate and enriches the spectra library. As such, it is a useful alternative to traditional techniques in component recognition.
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Shortening of the 3' untranslated region: an important mechanism leading to overexpression of HMGA2 in serous ovarian cancer.
Chin. Med. J.
PUBLISHED: 01-24-2014
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Oncofetal protein high-mobility-group AT-hook protein 2 (HMGA2) is reactivated in serous ovarian cancer (SOC) and its overexpression correlates with poor prognosis. To explore the mechanism, we investigated whether HMGA2 could avoid microRNA regulation due to gene truncation or 3' UTR shortening by alternative polyadenylation.
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Primordial dwarfism gene maintains Lin28 expression to safeguard embryonic stem cells from premature differentiation.
Cell Rep
PUBLISHED: 01-15-2014
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Primordial dwarfism (PD) is characterized by global growth failure, both during embryogenesis and postnatally. Loss-of-function germline mutations in La ribonucleoprotein domain family, member 7 (LAPR7) have recently been linked to PD. Paradoxically, LARP7 deficiency was previously assumed to be associated with increased cell growth and proliferation via activation of positive transcription elongation factor b (P-TEFb). Here, we show that Larp7 deficiency likely does not significantly increase P-TEFb activity. We further discover that Larp7 knockdown does not affect pluripotency but instead primes embryonic stem cells (ESCs) for differentiation via downregulation of Lin28, a positive regulator of organismal growth. Mechanistically, we show that Larp7 interacts with a poly(A) polymerase Star-PAP to maintain Lin28 mRNA stability. We propose that proper regulation of Lin28 and PTEFb is essential for embryonic cells to achieve a sufficient number of cell divisions prior to differentiation and ultimately to maintain proper organismal size.
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Influenza H7N9 and H9N2 viruses: coexistence in poultry linked to human H7N9 infection and genome characteristics.
J. Virol.
PUBLISHED: 01-08-2014
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Avian influenza virus A of the novel H7N9 reassortant subtype was recently found to cause severe human respiratory infections in China. Live poultry markets were suspected locations of the human H7N9 infection sources, based on the cases' exposure histories and sequence similarities between viral isolates. To explore the role of live poultry markets in the origin of the novel H7N9 virus, we systematically examined poultry and environmental specimens from local markets and farms in Hangzhou, using real-time reverse transcription-PCR (RT-PCR) as well as high-throughput next-generation sequencing (NGS). RT-PCR identified specimens positive for the H7 and N9 genomic segments in all of the 12 poultry markets epidemiologically linked to 10 human H7N9 cases. Chickens, ducks, and environmental specimens from the markets contained heavily mixed subtypes, including H7, N9, H9, and N2 and sometimes H5 and N1. The idea of the coexistence of H7N9 and H9N2 subtypes in chickens was further supported by metagenomic sequencing. In contrast, human H7N9 infection cases (n = 31) were all negative for H9N2 virus according to real-time RT-PCR. The six internal segments were indistinguishable for the H7N9 and H9N2 viruses. The H9, N2, and internal-segment sequences were very close to the sequence of the H9N2 virus circulating in chickens in China recently. Our results provide direct evidence that H9N2 strains coexisted with the novel human-pathogenic H7N9 influenza virus in epidemiologically linked live poultry markets. Avian influenza A virus of the H9N2 subtype likely made a recent contribution to the evolution of the H7N9 virus and continues to do so.
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Point-of-care technologies for molecular diagnostics using a drop of blood.
Trends Biotechnol.
PUBLISHED: 01-07-2014
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Molecular diagnostics is crucial for prevention, identification, and treatment of disease. Traditional technologies for molecular diagnostics using blood are limited to laboratory use because they rely on sample purification and sophisticated instruments, are labor and time intensive, expensive, and require highly trained operators. This review discusses the frontiers of point-of-care (POC) diagnostic technologies using a drop of blood obtained from a finger prick. These technologies, including emerging biotechnologies, nanotechnologies, and microfluidics, hold the potential for rapid, accurate, and inexpensive disease diagnostics.
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Smart soup, a traditional chinese medicine formula, ameliorates amyloid pathology and related cognitive deficits.
PLoS ONE
PUBLISHED: 01-01-2014
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Alzheimer's disease (AD) is a progressive neurodegenerative disease that causes substantial public health care burdens. Intensive efforts have been made to find effective and safe disease-modifying treatment and symptomatic intervention alternatives against AD. Smart Soup (SS), a Chinese medicine formula composed of Rhizoma Acori Tatarinowii (AT), Poria cum Radix Pini (PRP) and Radix Polygalae (RP), is a typical prescription against memory deficits. Here, we assessed the efficacy of SS against AD. Oral administration of SS ameliorated the cognitive impairment of AD transgenic mice, with reduced A? levels, retarded A? amyloidosis and reduced A?-induced gliosis and neuronal loss in the brains of AD mice. Consistently, SS treatment reduced amyloid-related locomotor dysfunctions and premature death of AD transgenic Drosophila. Mechanistic studies showed that RP reduced A? generation, whereas AT and PRP exerted neuroprotective effects against A?. Taken together, our study indicates that SS could be effective against AD, providing a practical therapeutic strategy against the disease.
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Effects of vagus nerve stimulation via cholinergic anti-inflammatory pathway activation on myocardial ischemia/reperfusion injury in canine.
Int J Clin Exp Med
PUBLISHED: 01-01-2014
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Acute myocardial infarction (AMI) was a type of disease with high mortality rate and high disability rate. And about 50% of the final area of myocardial infarction after AMI was led by ischemia/reperfusion (I/R) injury. The I/R injury was a kind of systemic inflammatory response, in which the main performance laid in the release of the large quantity of inflammatory cytokines. The basic experiments, clinical studies and the large scaled epidemiology investigations found that the low functions of vagus nerves had close relevance with the occurrence, development and prognosis of the cardiovascular diseases. This study investigate the effects of cholinergic anti-inflammatory pathway with with vagus never stimulation I/R injury in canine.
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Functional analysis LRP6 novel mutations in patients with coronary artery disease.
PLoS ONE
PUBLISHED: 01-01-2014
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Genetic architecture of coronary artery disease (CAD) is still to be defined. Since low density lipoprotein receptor-related protein 6 (LRP6) gene play critical roles in Wnt signal transduction which are important for vascular development and endodermis specification, we therefore resequenced it to search for mutations in CAD patients.
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Two-step source tracing strategy of Yersinia pestis and its historical epidemiology in a specific region.
PLoS ONE
PUBLISHED: 01-01-2014
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Source tracing of pathogens is critical for the control and prevention of infectious diseases. Genome sequencing by high throughput technologies is currently feasible and popular, leading to the burst of deciphered bacterial genome sequences. Utilizing the flooding genomic data for source tracing of pathogens in outbreaks is promising, and challenging as well. Here, we employed Yersinia pestis genomes from a plague outbreak at Xinghai county of China in 2009 as an example, to develop a simple two-step strategy for rapid source tracing of the outbreak. The first step was to define the phylogenetic position of the outbreak strains in a whole species tree, and the next step was to provide a detailed relationship across the outbreak strains and their suspected relatives. Through this strategy, we observed that the Xinghai plague outbreak was caused by Y. pestis that circulated in the local plague focus, where the majority of historical plague epidemics in the Qinghai-Tibet Plateau may originate from. The analytical strategy developed here will be of great help in fighting against the outbreaks of emerging infectious diseases, by pinpointing the source of pathogens rapidly with genomic epidemiological data and microbial forensics information.
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IL-17A Produced by Neutrophils Protects against Pneumonic Plague through Orchestrating IFN-?-Activated Macrophage Programming.
J. Immunol.
PUBLISHED: 12-13-2013
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Innate immune cells, including neutrophils and macrophages, are critically involved in host antimicrobial defense responses. Intrinsic regulatory mechanisms controlling neutrophil and macrophage activities are poorly defined. In this study, we found that IL-17A, a natural signal factor, could provide protection against early pneumonic plague inflammation by coordinating the functions of neutrophils and programming of macrophages. The IL-17A level is promptly increased during the initial infection. Importantly, abrogation of IL-17A or IL-17AR significantly aggravated the infection, but mIL-17A treatment could significantly alleviate inflammatory injury, revealing that IL-17A is a critical requirement for early protection of infection. We also demonstrated that IL-17A was predominantly produced by CD11b(+)Ly6G(+) neutrophils. Although IL-17A could not significantly affect the antimicrobial responses of neutrophils, it could target the proinflammatory macrophage (M1) programming and potentiate the M1s defense against pneumonic plague. Mechanistically, IFN-? treatment or IFN-?-activated M1 macrophage transfer could significantly mitigate the aggravated infection of IL-17A(-/-) mice. Finally, we showed that IL-17A and IFN-? could synergistically promote macrophage anti-infection immunity. Thus, our findings identify a previously unrecognized function of IL-17A as an intrinsic regulator in coordinating neutrophil and macrophage antimicrobial activity to provide protection against acute pneumonic plague.
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Effect of the stellate ganglion on atrial fibrillation and atrial electrophysiological properties and its left-right asymmetry in a canine model.
Exp Clin Cardiol
PUBLISHED: 12-03-2013
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To investigate the effect of the stellate ganglion (SG) and its left-right asymmetry on atrial fibrillation (AF) inducibility, AF duration and atrial electrophysiological properties.
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A multistage volumetric bar chart chip for visualized quantification of DNA.
J. Am. Chem. Soc.
PUBLISHED: 10-29-2013
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Nucleic acid detection is critical in disease diagnosis as well as in the environmental assays of harmful bacteria or viruses and forensic applications. Current methods for visualized quantification of DNA require costly and sophisticated instruments. Here, we report a multistage propelled volumetric bar chart chip (MV-Chip) for multiplexing and quantitative detection of DNA. Because of its "rocket-like" propelling reaction, the predeposited platinum films could perform cascade amplification and detect as low as 20 pM DNA targets after three stages of platinum-catalyzed propulsion. The resulting ink bar charts can be directly read out by the naked eye, and the signal shows little interference from serum. Single-nucleotide polymorphism and multiplex DNA detection were carried out to demonstrate this powerful application.
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Evaluating bandgap distributions of carbon nanotubes via scanning electron microscopy imaging of the Schottky barriers.
Nano Lett.
PUBLISHED: 10-22-2013
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We show that the Schottky barrier at the metal-single walled carbon nanotube (SWCNT) contact can be clearly observed in scanning electron microscopy (SEM) images as a bright contrast segment with length up to micrometers due to the space charge distribution in the depletion region. The lengths of the charge depletion increase with the diameters of semiconducting SWCNTs (s-SWCNTs) when connected to one metal electrode, which enables direct and efficient evaluation of the bandgap distributions of s-SWCNTs. Moreover, this approach can also be applied for a wide variety of semiconducting nanomaterials, adding a new function to conventional SEM.
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The making of I-BET762, a BET bromodomain inhibitor now in clinical development.
J. Med. Chem.
PUBLISHED: 09-25-2013
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Bromodomain and extra-terminal (BET) proteins belong to a class of proteins collectively called epigenetic "readers". BET bromodomains have emerged as promising drug targets for treatment of cancers, inflammatory diseases, and other medical conditions. GlaxoSmithKline scientists have successfully optimized a class of benzodiazepines as inhibitors of BET bromodomains, without any prior knowledge of identified molecular targets. It thus is possible to hit a target without aiming at it. The optimized lead compound I-BET762 is currently being evaluated in a phase I clinical trial for treatment of human cancer.
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Outer membrane proteins ail and OmpF of Yersinia pestis are involved in the adsorption of T7-related bacteriophage Yep-phi.
J. Virol.
PUBLISHED: 09-04-2013
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Yep-phi is a T7-related bacteriophage specific to Yersinia pestis, and it is routinely used in the identification of Y. pestis in China. Yep-phi infects Y. pestis grown at both 20°C and 37°C. It is inactive in other Yersinia species irrespective of the growth temperature. Based on phage adsorption, phage plaque formation, affinity chromatography, and Western blot assays, the outer membrane proteins of Y. pestis Ail and OmpF were identified to be involved, in addition to the rough lipopolysaccharide, in the adsorption of Yep-phi. The phage tail fiber protein specifically interacts with Ail and OmpF proteins, and residues 518N, 519N, and 523S of the phage tail fiber protein are essential for the interaction with OmpF, whereas residues 518N, 519N, 522C, and 523S are essential for the interaction with Ail. This is the first report to demonstrate that membrane-bound proteins are involved in the adsorption of a T7-related bacteriophage. The observations highlight the importance of the tail fiber protein in the evolution and function of various complex phage systems and provide insights into phage-bacterium interactions.
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Bioluminescent tracking of colonization and clearance dynamics of plasmid-deficient Yersinia pestis strains in a mouse model of septicemic plague.
Microbes Infect.
PUBLISHED: 08-30-2013
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Yersinia pestis 201 contains 4 plasmids pPCP1, pMT1, pCD1 and pCRY, but little is known about the effects of these plasmids on the dissemination of Y. pestis. We developed a plasmid-based luxCDABE bioreporter in Y. pestis 201, Y. pestis 201-pCD1(+), Y. pestis 201-pMT1(+), Y. pestis 201-pPCP1(+), Y. pestis 201-pCRY(+), Y. pestis 201-p(-) and Yersinia pseudotuberculosis Pa36060 strains, and investigated their dissemination by bioluminescence imaging during primary septicemic plague in a mouse model. These strains mainly colonized the livers and spleens shortly after intravenous inoculation. Y. pestis 201-pMT1(+) appeared to have a stronger ability to survive in the livers, spleens and blood, and to be more virulent than other plasmid-deficient strains. Y. pestis 201-pPCP1(+) appeared to have a stronger ability to colonize lungs than other plasmid-deficient strains. Pa36060 has the strongest ability to colonize intestines and lungs. Y. pestis 201 has the strongest ability to survive in blood, and the strongest virulence. These results indicated that the plasmid pMT1 was an important determinent in the colonization of livers, spleens and blood, whereas the plasmid pPCP1 appeared to correlate with the colonization in lungs. The resistance to killing in mouse blood seemed to be the critical factor causing animal death.
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White matter structural connectivity underlying semantic processing: evidence from brain damaged patients.
Brain
PUBLISHED: 08-23-2013
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Widely distributed brain regions in temporal, parietal and frontal cortex have been found to be involved in semantic processing, but the anatomical connections supporting the semantic system are not well understood. In a group of 76 right-handed brain-damaged patients, we tested the relationship between the integrity of major white matter tracts and the presence of semantic deficits. The integrity of white matter tracts was measured by percentage of lesion voxels obtained in structural imaging and mean fractional anisotropy values obtained in diffusion tensor imaging. Semantic deficits were assessed by jointly considering the performance on three semantic tasks that vary in the modalities of input (visual and auditory stimuli) and output (oral naming and associative judgement). We found that the lesion volume and fractional anisotropy value of the left inferior fronto-occipital fasciculus, left anterior thalamic radiation, and left uncinate fasciculus significantly correlated with severity of impairment in all three semantic tasks. These associations remained significant even when we controlled for a wide range of potential confounding variables, including overall cognitive state, whole lesion volume, or type of brain damage. The effects of these three white matter tracts could not be explained by potential involvement of relevant grey matter, and were (relatively) specific to object semantic processing, as no correlation with performance on non-object semantic control tasks (oral repetition and number processing tasks) was observed. These results underscore the causal role of left inferior fronto-occipital fasciculus, left anterior thalamic radiation, and left uncinate fasciculus in semantic processing, providing direct evidence for (part of) the anatomical skeleton of the semantic network.
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Par-4 downregulation confers cisplatin resistance in pancreatic cancer cells via PI3K/Akt pathway-dependent EMT.
Toxicol. Lett.
PUBLISHED: 07-30-2013
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Cisplatin (CDDP) efficiency in pancreatic cancer therapy is limited due to development of drug resistance. However, the comprehensive mechanisms remain largely unclear. In this study, we first established a CDDP-resistant pancreatic cancer cell line-BXPC-3/CDDP from its parental cell line-BXPC-3. The results showed that CDDP resistance in BXPC-3/CDDP cells correlates with changes in cellular EMT phenotypes. Prostate apoptosis response-4 (Par-4) expression at both mRNA and protein levels were reduced in CDDP-resistant BXPC-3/CDDP cells compared with that in BXPC-3 cells. Ectopic expression of Par-4 reversed EMT and CDDP resistance in BXPC-3/CDDP cells. In BXPC-3 cells, knockdown of Par-4 expression induces EMT and CDDP insensitivity, however, these effects were blocked by inhibition of PI3K/Akt pathway using LY294002. Furthermore, Par-4 knockdown could significantly stimulate PI3K/Akt signaling in BXPC-3 cells. In vivo studies, xenograft BXPC-3 tumors were sensitive to CDDP treatment. Treatment with CDDP alone had little effect on the growth of Par-4 siRNA-transfected BXPC-3 tumors in nude mice and the survival rate compared with control. Inhibition of PI3K/Akt pathway using LY294002 reversed CDDP resistance in Par-4 siRNA-transfected BXPC-3 tumors. In conclusion, these results indicate that Par-4 downregulation confers CDDP resistance via PI3K/Akt pathway-dependent EMT in BXPC-3 cells. Therefore, Par-4 may be a potential target for overcoming CDDP resistance in pancreatic cancer.
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Efficacy and safety of standard-dose versus half-dose tirofiban in patients with non-ST elevation acute coronary syndromes undergoing early percutaneous coronary intervention.
Cardiovasc Ther
PUBLISHED: 07-03-2013
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To explore the optimal dosage of tirofiban associated with double benefits of efficacy and safety in patients with non-ST elevation acute coronary syndromes (NSTE-ACS) undergoing early percutaneous coronary intervention (PCI).
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Analysis of a silkworm F1 hybrid with yellow cocoon generated by crossing two white-cocoon strains: Further evidences for the roles of Cameo2 and CBP in formation of yellow cocoon.
Gene
PUBLISHED: 06-26-2013
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In this report, we examined the gene expression related to carotenoid transport for a silkworm F1 hybrid with yellow cocoon generated by crossing two white-cocoon strains, Qiubai and 12-260. Our results showed that, in Qiubai, Cameo2, a transmembrane protein gene belonging to the CD36 family genes, was expressed normally in the silk gland, but no intact carotenoid-binding protein (CBP) mRNA (only the truncated CBP mRNA) was detected in the midgut. In 12-260, we detected the intact CBP mRNA expression in the midgut, but no Cameo2 expression in the silk gland. Regarding the F1 hybrid from crossing Qiubai and 12-260, both Cameo2 and intact CBP mRNA expressed normally in the silk gland and midgut. HPLC detection confirmed that in the F1 hybrid the carotenoids could be absorbed from dietary mulberry leaves through the midgut and transferred to silk gland via the hemolymph, which eventually colored cocoons into yellow. We also identified four CBP mRNA isoforms expressed in the midgut of the F1 hybrid, subsequently named as variants 5-8. Our results provide further evidences for the roles of Cameo2 and CBP in the formation of yellow cocoon of silkworm.
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Interface interaction induced ultra-dense nanoparticles assemblies.
Nanoscale
PUBLISHED: 06-25-2013
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We demonstrate a simple and clean physical methodology for fabricating such nanoparticle assemblies (dense arrays and/or dendrites) related to the interfacial interaction between the constructed materials and the anodized aluminum oxide (AAO) porous templates. The interfacial interaction can be regulated by the surface tension of the constructed materials and the AAO membrane, and the AAO-template structure, such as pore size, membrane thickness and surface morphologies. Depending on the interfacial interaction between the constructed materials and the AAO templates, NP arrays with mean particle diameters from 3.8 ± 1.0 nm to 12.5 ± 2.9 nm, mean inter-edge spacings from 3.5 ± 1.4 nm to 7.9 ± 3.4 nm and areal densities from 5.6 × 10(11) NPs per cm(2) to 1.5 × 10(12) NPs per cm(2) are fabricated over large areas (currently ~2 cm × 3 cm). The fabrication process includes firstly thermal evaporation of metal layers no more than 10 nm thick on the pre-coated Si wafer by AAO templates with a thickness of less than 150 nm and mean pore sizes no more than 12 nm, and then removal of the AAO templates. The NP arrays can be stable for hours at a temperature slightly below the melting point of the constructed materials (e.g., ~800 °C for Au NPs for 4 hours) with little change in size and inter-particle separation. Using one of them (e.g., 11.8 nm Au NPs) as growth-oriented catalysts, ultra-thin (12.1 ± 2.3 nm) dense nanowires can be conveniently obtained. Furthermore, dendrite superstructures can be generated easily from eutectic alloy NPs with diameters of ~10 nm pre-formed by thermal evaporation of metal layers more than 20 nm thick on surface-patterned thick AAO templates (e.g., 500 nm). The resulting dendrites, dense arrays and other superstructures (i.e., nanorods and nanowires) formed using NP arrays as catalysts, should have broad applications in catalysis, information technology, photovoltaics and biomedical engineering.
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A Potent Small-Molecule Inhibitor of the MDM2-p53 Interaction (MI-888) Achieved Complete and Durable Tumor Regression in Mice.
J. Med. Chem.
PUBLISHED: 06-20-2013
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We previously reported the discovery of a class of spirooxindoles as potent and selective small-molecule inhibitors of the MDM2-p53 interaction (MDM2 inhibitors). We report herein our efforts to improve their pharmacokinetic properties and in vivo antitumor activity. Our efforts led to the identification of 9 (MI-888) as a potent MDM2 inhibitor (Ki = 0.44 nM) with a superior pharmacokinetic profile and enhanced in vivo efficacy. Compound 9 is capable of achieving rapid, complete, and durable tumor regression in two types of xenograft models of human cancer with oral administration and represents the most potent and efficacious MDM2 inhibitor reported to date.
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Morphology control of ceria nanocrystals for catalytic conversion of CO2 with methanol.
Nanoscale
PUBLISHED: 05-18-2013
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This paper describes the synthesis of ceria catalysts with octahedron, nanorod, nanocube and spindle-like morphologies via a template-free hydrothermal method. The surface morphologies, crystal plane and physical-chemical structures were investigated via field-emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HRTEM), X-ray diffraction (XRD) and temperature-programmed desorption of ammonia and carbon dioxide (NH3-TPD and CO2-TPD). The catalytic performance over these ceria catalysts with different exposed planes were tested for dimethyl carbonate (DMC) synthesis from CO2 and methanol. The results showed that the spindle-like CeO2 showed the highest DMC yields, followed by nano-rods, nano-cubes and nano-octahedrons. A synergism among the exposed (111) plane, defect sites, and acid-basic sites was proposed to be crucial to obtaining the high reactivity of DMC formation.
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Loss of histone deacetylases 1 and 2 in hepatocytes impairs murine liver regeneration through Ki67 depletion.
Hepatology
PUBLISHED: 05-13-2013
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Histone deacetylases 1 and 2 (HDAC1 and HDAC2) are ubiquitously expressed in tissues, including the liver, and play critical roles in numerous physiopathological processes. Little is known regarding the role of HDAC1 and HDAC2 in liver regeneration. In this study we generated mice in which Hdac1, Hdac2 or both genes were selectively knocked out in hepatocytes to investigate the role of these genes in liver regeneration following hepatic injury induced by partial hepatectomy or carbon tetrachloride administration. The loss of HDAC1 and/or HDAC2 (HDAC1/2) protein resulted in impaired liver regeneration. HDAC1/2 inactivation did not decrease hepatocytic 5-bromo-2-deoxyuridine uptake or the expression of proliferating cell nuclear antigen, cyclins, or cyclin-dependent kinases. However, the levels of Ki67, a mitotic marker that is expressed from the mid-G1 phase to the end of mitosis and is closely involved in the regulation of mitotic progression, were greatly decreased, and abnormal mitosis lacking Ki67 expression was frequently observed in HDAC1/2-deficient livers. The down-regulation of either HDAC1/2 or Ki67 in the mouse liver cancer cell line Hepa1-6 resulted in similar mitotic defects. Finally, both HDAC1 and HDAC2 proteins were associated with the Ki67 gene mediated by CCAAT/enhancer-binding protein ?. Conclusion: Both HDAC1 and HDAC2 play crucial roles in the regulation of liver regeneration. The loss of HDAC1/2 inhibits Ki67 expression and results in defective hepatocyte mitosis and impaired liver regeneration. (Hepatology 2013; 58:2089-2098).
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Design, synthesis and biological evaluation of di-substituted cinnamic hydroxamic acids bearing urea/thiourea unit as potent histone deacetylase inhibitors.
Bioorg. Med. Chem. Lett.
PUBLISHED: 05-07-2013
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A novel class of di-substituted cinnamic hydroxamic acid derivatives containing urea or thiourea unit was designed, synthesized and evaluated as HDAC inhibitors. All tested compounds demonstrated significant HDAC inhibitory activities and anti-proliferative effects against diverse human tumor cell lines. Among them, 7l exhibited most potent pan-HDAC inhibitory activity, with an IC50 value of 130 nM. It also showed strong cellular inhibition against diverse cell lines including HCT-116, MCF-7, MDB-MB-435 and NCI-460, with GI50 values of 0.35, 0.22, 0.51 and 0.48 ?M, respectively.
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Diastereomeric spirooxindoles as highly potent and efficacious MDM2 inhibitors.
J. Am. Chem. Soc.
PUBLISHED: 05-03-2013
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Small-molecule inhibitors that block the MDM2-p53 protein-protein interaction (MDM2 inhibitors) are being intensely pursued as a new therapeutic strategy for cancer treatment. We previously published a series of spirooxindole-containing compounds as a new class of MDM2 small-molecule inhibitors. We report herein a reversible ring-opening-cyclization reaction for some of these spirooxindoles, which affords four diastereomers from a single compound. Our biochemical binding data showed that the stereochemistry in this class of compounds has a major effect on their binding affinities to MDM2, with >100-fold difference between the most potent and the least potent stereoisomers. Our study has led to the identification of a set of highly potent MDM2 inhibitors with a stereochemistry that is different from that of our previously reported compounds. The most potent compound (MI-888) binds to MDM2 with a Ki value of 0.44 nM and achieves complete and long-lasting tumor regression in an animal model of human cancer.
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Mammalian target of rapamycin complex 1 (mTORC1) enhances bortezomib-induced death in tuberous sclerosis complex (TSC)-null cells by a c-MYC-dependent induction of the unfolded protein response.
J. Biol. Chem.
PUBLISHED: 04-23-2013
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Many factors, including duration and intensity of the unfolded protein response (UPR), dictate whether cells will adapt to endoplasmic reticulum stress or undergo apoptosis. In tuberous sclerosis (TSC), elevation of mammalian target of rapamycin complex 1 (mTORC1) activity has been proposed to compound the induction of UPR transcription factors ATF4 and CHOP, suggesting that the UPR could be targeted to eradicate TSC1/2-null cells during patient therapy. Here we report that control of c-MYC translation by mTORC1 plays a key role in determining whether TSC2-null Elt3 rat leiomyoma cells apoptose in response to UPR induction by the proteasome inhibitor bortezomib. Although bortezomib induces eukaryotic initiating factor 2? phosphorylation, mTORC1 activity was also required for downstream induction of the UPR transcription factors ATF4 and CHOP by a mechanism involving increased expression of c-MYC. Although bortezomib-induced c-MYC transcription was resistant to rapamycin treatment, mTORC1 activity was required for efficient c-MYC translation. c-MYC subsequently bound to the ATF4 promoter, suggesting direct involvement of an mTORC1/c-MYC-driven signaling pathway in the activation of the UPR. Consistent with this notion, exogenously expressed c-MYC reversed the ability of rapamycin to prevent bortezomib-induced CHOP and ATF4 expression as well as apoptosis. These findings indicate that the induction of ATF4/CHOP expression occurs via mTORC1 regulation of c-MYC and that this signaling pathway is a major determinant in the ability of bortezomib to induce apoptosis.
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A copper-phyllosilicate core-sheath nanoreactor for carbon-oxygen hydrogenolysis reactions.
Nat Commun
PUBLISHED: 04-09-2013
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Hydrogenolysis of carbon-oxygen bonds is a versatile synthetic tool in organic synthesis. Copper-based catalysts have been intensively explored as the copper sites account for the highly selective hydrogenation of carbon-oxygen bonds. However, the inherent drawback of conventional copper-based catalysts is the deactivation by metal-particle growth and unstable surface Cu(0) and Cu(+) active species in the strongly reducing hydrogen and oxidizing carbon-oxygen atmosphere. Here we report the superior reactivity of a core (copper)-sheath (copper phyllosilicate) nanoreactor for carbon-oxygen hydrogenolysis of dimethyl oxalate with high efficiency (an ethanol yield of 91%) and steady performance (>300?h at 553?K). This nanoreactor, which possesses balanced and stable Cu(0) and Cu(+) active species, confinement effects, an intrinsically high surface area of Cu(0) and Cu(+) and a unique tunable tubular morphology, has potential applications in high-temperature hydrogenation reactions.
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[Meta analysis of efficacy and safety between mammotome minimally invasive operation and open excision for benign breast tumor].
Zhong Nan Da Xue Xue Bao Yi Xue Ban
PUBLISHED: 04-03-2013
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To compare the efficacy and safety between mammotome minimally invasive operation and conventional open excision for benign breast tumor.
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Design, synthesis and biological evaluation of indeno[1,2-d]thiazole derivatives as potent histone deacetylase inhibitors.
Bioorg. Med. Chem. Lett.
PUBLISHED: 03-22-2013
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Novel indeno[1,2-d]thiazole hydroxamic acids were designed, synthesized, and evaluated for histone deacetylases (HDACs) inhibition and antiproliferative activities on tumor cell lines. Most of the tested compounds exhibited HDAC inhibition and antiproliferative activity against both MCF7 and HCT116 cells with GI50 values in the sub-micromolar range. Among them, compound 6o showed good inhibitory activity against pan-HDAC with IC50 value of 0.14 ?M and significant growth inhibition on MCF7 and HCT116 cells with GI50 values of 0.869 and 0.535 ?M, respectively.
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Crosstalk between adaptive and innate immune cells leads to high quality immune protection at the mucosal borders.
Adv. Exp. Med. Biol.
PUBLISHED: 03-05-2013
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Mucosal effector memory CD8 T cells are located at the epithelium and have a heightened and immediate effector function. By contrast, central memory T cells reside within lymphoid tissues and require proliferation and differentiation to become effector cells that migrate to epithelial surfaces. The accumulation of effector memory T cells at the pathogen entry site(s) is essential for protective immunity, but the mechanisms that drive the differentiation of memory cell subsets are poorly understood. We recently showed that CD8??, induced selectively on the most highly activated primary CD8?? T cells, together with its ligand, the thymic leukemia (TL) antigen, induced on mucosal antigen-presenting cells and constitutively expressed on intestinal epithelial cells (IEC), serve as key components to mediate the selective accumulation of the fittest effector cells to form mucosal effector memory T cells. Therefore, the generation of mucosal effector memory is controlled by an innate-adaptive crosstalk that provides for host defense at the bodys largest interface.
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Hypoxia induces epithelial-mesenchymal transition via activation of SNAI1 by hypoxia-inducible factor -1? in hepatocellular carcinoma.
BMC Cancer
PUBLISHED: 02-25-2013
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High invasion and metastasis are the primary factors causing poor prognosis of patients with hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying these biological behaviors have not been completely elucidated. In this study, we investigate the molecular mechanism by which hypoxia promotes HCC invasion and metastasis through inducing epithelial-mesenchymal transition (EMT).
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Role of integrin ?v?6 in the pathogenesis of ischemia-related biliary fibrosis after liver transplantation.
Transplantation
PUBLISHED: 02-21-2013
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Biliary fibrosis has been referred to as the "final common pathway" of acute and chronic bile duct injury after orthotopic liver transplantation (OLT). We studied the role of integrin ?v?6 in the pathogenesis of ischemia-related biliary fibrosis after OLT.
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Protection of chickens against infectious bronchitis virus with a multivalent DNA vaccine and boosting with an inactivated vaccine.
J. Vet. Sci.
PUBLISHED: 02-05-2013
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The protective efficacy of DNA plasmids encoding avian infectious bronchitis virus (IBV) S1, N, or M protein was investigated in chickens. Chickens were inoculated monovalently (with plasmid pVAX1-16S1, pVAX1-16M, or pVAX1-16N alone) or multivalently (combination of the three different plasmids, pVAX1-16S1/M/N). A prime-boost immunization protocol against IBV was developed. Chickens were immunized with the multivalent DNA vaccine twice and then boosted with an inactivated vaccine once. Antibody titers of the chickens immunized with pVAX1-16S1/M/N were much higher than those of the monovalent groups (p < 0.01). A protective rate up to 90% was observed in the pVAX1-16S1/M/N group. The serum antibody titers in the prime-boost birds were significantly higher than those of the multivalent DNA vaccine group (p < 0.01) but not significantly different compared to the inactivated vaccine group at 49 days of age. Additionally, the prime-boost group also showed the highest level of IBV-specific cellular proliferation compared to the monovalent groups (p < 0.01) but no significant difference was found compared to the multivalent DNA vaccine group, and the prime-boost group completely protected from followed viral challenge.
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