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Find video protocols related to scientific articles indexed in Pubmed.
Reproducibility of thoracic and abdominal aortic wall measurements with three-dimensional, variable flip angle (SPACE) MRI.
J Magn Reson Imaging
PUBLISHED: 12-16-2014
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To evaluate the reproducibility and repeatability of high-resolution, isotropic thoracic and abdominal aortic wall measurements, and determine the implications they have on the number of subjects necessary for future clinical trials.
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Donor Activating KIR2DS1 in Leukemia.
N. Engl. J. Med.
PUBLISHED: 11-20-2014
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To the Editor: In our original report,(1) we used a method based on polymerase-chain-reaction (PCR) amplification developed in our laboratory to perform KIR genotyping.(2) We have retyped 1220 of the original 1277 donor samples using three separate published or commercial gene-typing methods (PCR-sequence-specific primers [SSP] and PCR-sequence-specific oligonucleotide probe [SSOP]), and we have repeated the analysis on the retyped cohort. For KIR2DS1, typing was confirmed in 1146 (94%) of the 1220 retested samples and corrected in 74 (6%) of the retested samples. For KIR3DS1, typing was confirmed in 1133 (93%) and corrected in 83 (7%). Differences in typing results came . . .
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A Pneumocyte-macrophage Paracrine Lipid Axis Drives the Lung Toward Fibrosis.
Am. J. Respir. Cell Mol. Biol.
PUBLISHED: 11-20-2014
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Lipid-laden macrophages "foam cells" are observed in the lungs of patients with fibrotic lung disease but their contribution to disease pathogenesis remains unexplored. Here, we demonstrate that fibrosis induced by bleomycin, silica dust, or thoracic radiation promotes early and sustained accumulation of foam cells in the lung. In the bleomycin model, we show that foam cells arise from neighboring alveolar epithelial type II cells (ATII), which respond to injury by dumping lipids into the distal airspaces of the lungs. We demonstrate that oxidized phospholipids accumulate within alveolar macrophages (AM) after bleomycin injury, and that murine and human AMs treated with oxidized phosphatidylcholine (OxPc) become polarized along an M2 phenotype and display enhanced production of TGF-?1. The direct instillation of OxPc into the mouse lung induces foam cell formation and triggers a severe fibrotic reaction. Further, we show that reducing pulmonary lipid clearance by targeted deletion of the lipid efflux transporter ABCG1 increases foam cell formation and worsens lung fibrosis after bleomycin. Conversely, we found that treatment with GM-CSF attenuates fibrotic responses, at least in part through its ability to decrease AM lipid accumulation. In summary, this work describes a novel mechanism leading to foam cell formation in the mouse lung and suggests that strategies aimed at blocking foam cell formation might be effective for treating fibrotic lung disorders.
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[Treatment of type 2 diabetic peripheral neuropathy patients of qi-yin deficiency complicated phlegm-dampness blocking collaterals syndrome by internal application of qigui mixture and external application of qigui huoxue lotion: a clinical study].
Zhongguo Zhong Xi Yi Jie He Za Zhi
PUBLISHED: 10-23-2014
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To evaluate the efficacy of internal application of Qigui Mixture (QM) and external application of Qigui Huoxue Lotion (QHL) in treating type 2 diabetic peripheral neuropathy (DNP) patients of qi-yin deficiency complicated phlegm-dampness blocking collaterals syndrome (QYD-PDBCS), and to primarily discuss its mechanism.
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Ghost marker detection and elimination in marker-based optical tracking systems for real-time tracking in stereotactic body radiotherapy.
Med Phys
PUBLISHED: 10-06-2014
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To propose a simple model to explain the origin of ghost markers in marker-based optical tracking systems (OTS) and to develop retrospective strategies to detect and eliminate ghost markers.
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Identification of Serine 348 on the Apelin Receptor as a Novel Regulatory Phosphorylation Site in Apelin-13-induced G Protein-independent Biased Signaling.
J. Biol. Chem.
PUBLISHED: 09-30-2014
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Phosphorylation plays vital roles in the regulation of G protein-coupled receptor (GPCR) functions. The apelin and apelin receptor (APJ) system is involved in the regulation of cardiovascular function and central control of body homeostasis. Here, using tandem mass spectrometry, we first identified phosphorylated serine residues in the C terminus of APJ. To determine the role of phosphorylation sites in APJ-mediated G protein-dependent and -independent signaling and function, we induced a mutation in the C-terminal serine residues and examined their effects on the interaction between APJ with G protein or GRK/?-arrestin and their downstream signaling. Mutation of serine 348 led to an elimination of both GRK and ?-arrestin recruitment to APJ induced by apelin-13. Moreover, APJ internalization and G protein-independent ERK signaling were also abolished by point mutation at serine 348. In contrast, this mutant at serine residues had no demonstrable impact on apelin-13-induced G protein activation and its intracellular signaling. These findings suggest that mutation of serine 348 resulted in inactive GRK/?-arrestin. However, there was no change in the active G protein thus, APJ conformation was biased. These results provide important information on the molecular interplay and impact of the APJ function, which may be extrapolated to design novel drugs for cardiac hypertrophy based on this biased signal pathway.
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Dynamics of apelin receptor/G protein coupling in living cells.
Exp. Cell Res.
PUBLISHED: 09-01-2014
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During our research on apelin receptor (APJ) signalling in living cells with BRET and FRET, we demonstrated that apelin-13 stimulation can lead to the activation of G?i2 or G?i3 through undergoing a molecular rearrangement rather than dissociation in HEK293 cells expressing APJ. Furthermore, G?o and G?q also showed involvement in APJ activation through a classical dissociation model. However, both FRET signal and BRET ratio between fluorescent G?i1 subunit and G?? subunits demonstrated little change after apelin-13 stimulation. These results demonstrated that stimulation of APJ with apelin-13 causes activation of G?i2, G?i3, G?o, G?q; among which G?i2, G?i3 were activated through a novel rearrangement process. These results provide helpful data for understanding APJ mediated G-protein signalling.
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Heterodimerization of apelin receptor and neurotensin receptor 1 induces phosphorylation of ERK1/2 and cell proliferation via G?q-mediated mechanism.
J. Cell. Mol. Med.
PUBLISHED: 08-28-2014
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Dimerization of G protein-coupled receptors (GPCRs) is crucial for receptor function including agonist affinity, efficacy, trafficking and specificity of signal transduction, including G protein coupling. Emerging data suggest that the cardiovascular system is the main target of apelin, which exerts an overall neuroprotective role, and is a positive regulator of angiotensin-converting enzyme 2 (ACE2) in heart failure. Moreover, ACE2 cleaves off C-terminal residues of vasoactive peptides including apelin-13, and neurotensin that activate the apelin receptor (APJ) and neurotensin receptor 1 (NTSR1) respectively, that belong to the A class of GPCRs. Therefore, based on the similar mode of modification by ACE2 at peptide level, the homology at amino acid level and the capability of forming dimers with other GPCRs, we have been suggested that APJ and NTSR1 can form a functional heterodimer. Using co-immunoprecipitation, BRET and FRET, we provided conclusive evidence of heterodimerization between APJ and NTSR1 in a constitutive and induced form. Upon agonist stimulation, hetrodimerization enhanced ERK1/2 activation and increased proliferation via activation of Gq ?-subunits. These novel data provide evidence for a physiological role of APJ/NTSR1 heterodimers in terms of ERK1/2 activation and increased intracellular calcium and induced cell proliferation and provide potential new pharmaceutical targets for cardiovascular disease.
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The composition and transmission of microbiome in hard tick, Ixodes persulcatus, during blood meal.
Ticks Tick Borne Dis
PUBLISHED: 08-20-2014
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The tick Ixodes persulcatus is the predominant tick species in Northeastern China, and it is a major vector in transmission of tick-borne diseases. By 16S rRNA Illumina sequencing, we investigated the microbiome of I. persulcatus and assessed the variation of the microbiome before and after blood feeding. The prolonged blood meal dramatically altered the composition of the microbiome but did not influence the bacterial diversity. Overall, 373 and 289 bacterial genera were assigned to unfed and fed ticks, respectively. To investigate microbes that were potentially transmitted to vertebrate hosts during a blood meal, we examined the microbiome in rat blood after tick bites. Our data showed that 237 bacterial genera were suspected to be pathogens of vertebrates because they were commonly detected in unfed ticks, fed ticks, and rat blood samples after tick bites. Additionally, the prevalence survey on Borrelia burgdorferi s.l., Ehrlichia chaffeensis, Anaplasma phagocytophilum and Yersinia pestis was performed. We found that B. garinii and B. afzelii are the predominant genospecies of the Lyme disease spirochete in I. persulcatus ticks. This is the first time that the microbial composition in this tick species and in rat blood transmitted via tick bites has been reported. These data may ultimately assist in identification of novel pathogens transmitted by I. persulcatus ticks.
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Construction of doxycycline-mediated BMP-2 transgene combining with APA microcapsules for bone repair.
Artif Cells Nanomed Biotechnol
PUBLISHED: 08-06-2014
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Objectives: The repairing of large segmental bone defects is difficult for clinical orthopedists at present. Gene therapy is regarded as a promising method for bone defects repair. The present study aimed to construct an effective and controllable Tet-On expression system for transferring hBMP-2 gene into bone marrow mesenchymal progenitor cells (BMSCs). Meanwhile, with combination of alginate-poly-L-lysine-alginate (APA) microencapsulation technology, we attempted to reduce the influence of immunologic rejection and examine the effect of the Tet-On expression system on osteogenesis of BMSCs. Methods: The adenovirus encoding hBMP-2 (ADV-hBMP2) was constructed using the means of molecular cloning. The ADV-hBMP2 and Adeno-X Tet-On virus was respectively transfected to the HEK293 for amplification and afterward BMSCs were co-infected with the virus of ADV-hBMP2 and the Adeno-X Tet-On. The expression of hBMP-2 was measured with induction by doxycycline (DOX) at different concentration by means of RT-PCR and ELISA. Combining Tet-On expression system and APA microcapsules with the use of the pulsed high-voltage electrostatic microcapsule instrument, we examined the expression level of hBMP-2 in APA microcapsules by ELISA as well as the osteogenesis by alizarin red S staining. Key findings: An effective Tet-On expression system for transferring hBMP-2 gene into BMSCs was constructed successfully. Also, the expression of hBMP-2 could be regulated by concentration of DOX. The data exhibited that BMSCs in APA microcapsules maintained the capability of proliferation and differentiation. The combination of Tet-On expression system and APA microcapsules could promote the osteogenesis of BMSCs. Conclusions: According to the results, microencapsulated Tet-On expression system showed the effective characteristics of secreting hBMP-2 and enhancing osteogenesis, which would provide a promising way for bone repair.
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Intrahepatic activation of naive CD4+ T cells by liver-resident phagocytic cells.
J. Immunol.
PUBLISHED: 07-28-2014
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Naive T cell activation is normally restricted to the lymphoid organs, in part because of their limited ability to migrate into the parenchyma of peripheral tissues. The liver vasculature is unique, however, and circulating leukocytes within the hepatic sinusoids have direct access to liver-resident cells, which include an abundant population of Kupffer cells. It is well accepted that recognition of cognate Ag within the liver leads to naive CD8(+) T cell activation in situ, but it is unclear whether the liver also supports naive CD4(+) T cell activation. In this study, we show that naive CD4(+) T cells can be activated to proliferate in the liver when cognate Ag expression is induced in hepatocytes by recombinant adeno-associated viral vectors. Ag-specific retention and activation of naive CD4(+) T cells within the liver are independent of lymphoid tissues but dependent on a clodronate liposome-sensitive population of liver-resident phagocytic cells. To our knowledge, this study provides the first unequivocal evidence that naive CD4(+) T cells can be activated in a nonlymphoid organ. It also gives critical insight into how CD4(+) T cells specific for Ag expressed in the liver are recruited to participate in protective or pathological responses during hepatotropic infections and autoimmune liver disease.
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Neuroprotective effects of apelin-13 on experimental ischemic stroke through suppression of inflammation.
Peptides
PUBLISHED: 07-13-2014
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Acute inflammation plays an important role in the pathogenic progression of post-ischemic neuronal damage. Apelin-13 has been investigated as a neuropeptide for various neurological disorders. The present study was performed to evaluate the effects of apelin-13 on the inflammation of cerebral ischemia/reperfusion (I/R) injury. Transient focal I/R model in male Wistar rats were induced by 2h middle cerebral artery occlusion (MCAO) followed by 24h reperfusion. Rats then received treatment with apelin-13 or vehicle after ischemia at the onset of reperfusion. The neurological deficit was evaluated and the infarct volume was measured by TTC staining. The activity of myeloperoxidase (MPO) was measured. The expression of pro-inflammatory cytokines including tumor necrosis factor-? (TNF-?), interleukin-1? (IL-1?), and intercellular adhesion molecule-1 (ICAM-1) were measured using real-time PCR. And the expression of apelin receptor (APJ), ionized calcium-binding adapter molecule-1 (Iba1), glial fibrillary acidic protein (GFAP) and high mobility group box 1 (HMGB1) were measured by immunohistochemistry and western blot. Our results demonstrated that treatment with apelin-13 in I/R rats markedly reduced neurological deficits and the infarct volume. The increase of MPO activity induced by I/R was inhibited by apelin-13 treatment. The real-time PCR showed that apelin-13 decreased the expression of inflammatory cytokines such as IL-1?, TNF-? and ICAM-1 in I/R rats. The expression of APJ in I/R rats was increased. And the expression of Iba1, GFAP and HMGB1 in I/R rats was decreased by apelin-13 treatment indicating the inhibition of microglia, astrocytes and other inflammatory cells. In conclusion, apelin-13 is neuroprotective for neurons against I/R through inhibiting the neuroinflammation.
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Miniscalpel-Needle versus Steroid Injection for Plantar Fasciitis: A Randomized Controlled Trial with a 12-Month Follow-Up.
Evid Based Complement Alternat Med
PUBLISHED: 07-08-2014
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Plantar fasciitis is the most common cause of heel pain in adults. A novel alternative medical instrument, the miniscalpel-needle (MSN), which is based on an acupuncture needle, has been recently developed in China. The objective of this study was to evaluate the effectiveness of the MSN release treatment versus that of traditional steroid injection for plantar fasciitis. Patients with plantar fasciitis were randomly assigned to 2 groups and followed up for 12 months, with 29 receiving MSN treatment and 25 receiving steroid injection treatment. The results showed that visual analog scale scores for morning pain, active pain, and overall heel pain all were decreased significantly in the MSN group from 1 to 12 months after treatment. In contrast, treatment with steroid injection showed a significant effect only at the 1-month follow-up but not at 6 or 12 months after treatment. Moreover, the MSN group achieved more rapid and sustained improvements than the steroid group throughout the duration of this study. No severe side effects were observed with MSN treatment. Our data suggest that the MSN release treatment is safe and has a significant benefit for plantar fasciitis compared to steroid injection.
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[Apoptosis-inducing effect of tetrandrine and imatinib on K562/G01 cells and its related mechanism].
Zhongguo Shi Yan Xue Ye Xue Za Zhi
PUBLISHED: 07-04-2014
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This study was purposed to explore the apoptosis-inducing effect of tetrandrine (Tet) and imatinib (IM) alone or both combined on K562/G01 cells and their mechanism. MTT assay was used to detect the inhibitory effect of drugs on cell growth, flow cytometry was used to detect the cell cycle and apoptosis rate. The expression of caspase-3/BCL-2 mRNA was determined by real time-PCR, and the expression of caspase-3/BCL-2 protein was assayed by Western blot. The results showed that after being treated by 1.0 µmol/L IM or 1.5 µmol/L Tet alone and combination of these two drugs for 48 h, the inhibitory rate was (22.74 ± 0.05)%, (20.34 ± 0.57)% and (44.28 ± 0.60)%, respectively, suggesting that inhibitory effect of two drug combination was more obvious. The arrest of cell cycle at G1/S phase could be observed after Tet treatment. Early apoptosis rate was (7.81 ± 0.16) %, (14.10 ± 0.28) % respectively after being treated by combination of 1.5 µmol/L and 3.0 µmol/L Tet with 1.0 µmol/L IM. After being treated with Tet alone, FQ-PCR and Western blot showed that the expressions of caspase-3 mRNA and caspase-3 protein were up-regulated, the expressions of BCL-2 mRNA and protein were down-regulated, the effect of both drug combination was more significant. It is concluded that IM or Tet alone can induce apoptosis of K562/G01. Combination of IM with Tet shows obvious synergistic effect, mechanism of which may associate with up-regulation of caspase-3 mRNA and protein expressions, and down-regulation of BCL-2 mRNA and protein expressions.
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Pressure-voltage trap for DNA near a solid-state nanopore.
ACS Nano
PUBLISHED: 06-20-2014
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We report the formation of a tunable single DNA molecule trap near a solid-state nanopore in an electrolyte solution under conditions where an electric force and a pressure-induced viscous flow force on the molecule are nearly balanced. Trapped molecules can enter the pore multiple times before escaping the trap by passing through the pore or by diffusing away. Statistical analysis of many individually trapped molecules yields a detailed picture of the fluctuation phenomena involved, which are successfully modeled by a one-dimensional first passage approach.
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Effects of parathyroid hormone on calcium ions in rat bone marrow mesenchymal stem cells.
Biomed Res Int
PUBLISHED: 06-18-2014
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The present study was conducted in order to explore the mechanisms whereby parathyroid hormone (PTH) maintains in vitro proliferation of bone marrow mesenchymal stem cells (BMSCs). Bone marrow was isolated from Sprague Dawley (SD) rat femurs, cultured in vitro, and passaged using a cell adherent culture method. The BMSC proliferation was evaluated by the methyl thiazolyl tetrazolium (MTT) assay and the fluorescence intensity of calcium ions in BMSCs was analyzed by laser scanning confocal microscopy (LSCM). Our results show that BMSC proliferation in the experimental group treated with PTH was more significant than controls. The calcium ion fluorescence intensity in BMSCs was significantly higher for the experimental group as compared to the control group. For each group, there was significant difference in the fluorescence intensity of calcium ions in BMSCs between 7?d and 14?d. In conclusion, parathyroid hormone increased the fluorescence intensity of calcium ions in BMSCs, which might represent a key mechanism whereby BMSC proliferation is maintained.
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NVP-BEZ-235 enhances radiosensitization via blockade of the PI3K/mTOR pathway in cisplatin-resistant non-small cell lung carcinoma.
Genes Cancer
PUBLISHED: 06-13-2014
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Most drug resistant cancer cells also develop resistance to radiation therapy. In this study, we hypothesized that the dual inhibitor of phosphatidylinositol-3 kinase/mammalian target of rapamycin, NVP-BEZ-235, could potentially enhance radiosensitization in cisplatin-resistance (CDDP-R) non-small cell lung cancer (NSCLC) cells by disabling autophagy as a mechanism of self-preservation.
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[Triptolide affect the methylation status of HL-60cells].
Zhonghua Xue Ye Xue Za Zhi
PUBLISHED: 05-27-2014
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To study the effect of triptolide (TP) on the methylation status of human promyelocytic leukemia cells (HL-60) and explore a preliminary demethylation mechanism.
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Intra-periaqueductal gray infusion of zeta inhibitory peptide attenuates pain-conditioned place avoidance in rats.
Brain Res.
PUBLISHED: 05-23-2014
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Pain is a complex experience that made up of sensory, emotional and cognitive dimensions, and the emotional factors have an important influence on intensity of pain perception. The role of periaqueductal gray (PAG) in sensory component of pain has been extensively studied, while data about pain affect are quite limited. Using formalin-induced conditioned place avoidance (F-CPA) test and inflammatory pain model, present study investigated the effect of intra-PAG infusion of zeta inhibitory peptide (ZIP) on noxious stimulation induced aversion, and the sensory component of pain. Intra-PAG injection of ZIP is sufficient to disrupt pain-induced aversion, but the ZIP infusion did not change inflammation induced pain hypersensitivity in rats. These findings suggest that PAG contributes to pain-related aversion in rats, and the mechanism of pain emotion encoding in PAG may attribute to the activation of targets of ZIP.
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[Effectiveness of total hip arthroplasty for severe developmental dysplasia of hip in adults].
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi
PUBLISHED: 05-22-2014
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To evaluate the effectiveness of the total hip arthroplasty (THA) for severe development dysplasia of the hip (DDH) in adults.
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Mechanisms of behavior modification in clinical behavioral medicine in China.
Int J Behav Med
PUBLISHED: 05-21-2014
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Behavior modification, as the core of clinical behavioral medicine, is often used in clinical settings.
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Surface modification of solid-state nanopores for sticky-free translocation of single-stranded DNA.
Small
PUBLISHED: 04-21-2014
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Nanopore technology is one of the most promising approaches for fast and low-cost DNA sequencing application. Single-stranded DNA detection is primary objective in such device, while solid-state nanopores remain less explored than their biological counterparts due to bio-molecule clogging issue caused by surface interaction between DNA and nanopore wall. By surface coating a layer of polyethylene glycol (PEG), solid-state nanopore can achieve long lifetime for single-stranded DNA sticky-free translocation at pH 11.5. Associated with elimination of non-specific binding of molecule, PEG coated nanopore presents new surface characteristic as less hydrophility, lower 1/f noise, and passivated surface charge responsiveness on pH. Meanwhile, conductance blockage of single-stranded DNA is found to be deeper than double-stranded DNA, which can be well described by a string of blobs model for a quasi-equilibrium state polymer in constraint space.
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A novel melphalan polymeric prodrug: preparation and property study.
Carbohydr Polym
PUBLISHED: 04-15-2014
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The clinical application of melphalan (Me), an anticancer drug for the treatment of hematologic malignancies, has been limited due to its poor water solubility, rapid elimination and lack of target specificity. To solve these problems, O,N-carboxymethyl chitosan-peptide-melphalan conjugates were synthesized and characterized. All polymeric prodrugs showed satisfactory water solubility. It was found that the molecular weight of O,N-carboxymethyl chitosan (O,N-CMCS) and the peptide spacer played a crucial role in controlling the drug content, diameter and drug release properties of O,N-carboxymethyl chitosan-peptide-melphalan conjugates. The studies of in vitro drug release and cell cytotoxicity by MTT assay revealed that, employing the polymeric conjugation strategy and using the peptides glycylglycine (Gly-Gly) as a spacer, the conjugates have good cathepsin X-sensitivity and lower toxicity and the drug release behavior improved remarkably. In conclusion, O,N-carboxymethyl chitosan-peptide-melphalan conjugates could be promising prodrugs for anticancer application.
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Microdevice-based cell therapy for age-related macular degeneration.
Dev Ophthalmol
PUBLISHED: 04-10-2014
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This chapter reports the application of a micromachined parylene-C device as an artificial Bruch's membrane for the stem cell-based therapy of age-related macular degeneration. The feasibility of parylene-C as a substitute substrate material is demonstrated by evaluating the permeability of membranes of submicron thicknesses. It has been found that parylene-C membranes thinner than 0.3 µm possess similar molecular weight exclusion limit and nutrient diffusion flux to that of the healthy human Bruch's membrane. This conclusion is further validated by the in vitro perfusion cell viability test. Since the submicron parylene-C itself is difficult to handle, we design a mesh-supported submicron parylene membrane (MSPM) to provide sufficient mechanical support. This MSPM can support the growth of retinal pigment epithelial (RPE) cells in a monolayer with well-polarized morphology. Human embryonic stem cell-derived H9-RPE cells are cultured in vitro on the MSPM for one month before the implantation of the MSPM into the rat's retina. To facilitate the surgical implantation, a parylene-C/SU-8 hybrid microfluidic device is designed as an inserter. Histological studies with hematoxylin-eosin staining and immunofluorescence staining show that the implanted RPE cells adhere well to the artificial Bruch's membrane and are able to maintain high viability and normal morphology in vivo.
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Molecular markers to predict clinical outcome and radiation induced toxicity in lung cancer.
J Thorac Dis
PUBLISHED: 04-02-2014
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The elucidation of driver mutations involved in the molecular pathogenesis of cancer has led to a surge in the application of novel targeted therapeutics in lung cancer. Novel oncologic research continues to lead investigators towards targeting personalized tumor characteristics rather than applying targeted therapy to broad patient populations. Several driver genes, in particular epidermal growth factor receptor (EGFR) and ALK fusions, are the earliest to have made their way into clinical trials. The avant-garde role of genomic profiling has led to important clinical challenges when adapting current standard treatments to personalized oncologic care. This new frontier of medicine requires newer biomarkers for toxicity that will identify patients at risk, as well as, new molecular markers to predict and assess clinical outcomes. Thus far, several signature genes have been developed to predict outcome as well as genetic factors related to inflammation to predict toxicity.
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Even mildly elevated TSH is associated with an atherogenic lipid profile in postmenopausal women with subclinical hypothyroidism.
Endocr. Res.
PUBLISHED: 04-01-2014
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Abstract Postmenopausal women, a population with increased risk of atherosclerosis, also have an appreciable risk of subclinical hypothyroidism (SCH). The current study sought an association between serum thyrotropin (TSH), the biomarker of SCH and atherosclerosis lipid profile changes. A total of 45 postmenopausal women with SCH and 27 healthy women matched by age and body mass index were enrolled in this observational study. Serum lipid profiles and thyroid function were assessed. Compared with healthy controls, the serum levels of TC, TG, LDL-c and oxidized LDL (oxLDL) in SCH were increased by ?22.8%, 29.6%, 30.5% and 23.2%, respectively. TSH was positively correlated with TC, LDL-c and oxLDL in all of the study subjects after adjusting for age and BMI. In particular, the positive correlation remained significant after adjusting for serum FT3 and FT4. When further stratified by TSH levels, both the subgroup of mildly elevated TSH (4.78-9.99?mU/L) and overtly elevated TSH (>10.00?mU/L) exhibited significantly higher serum levels of TC, TG, LDL-c and oxLDL compared to the normal TSH subgroup. Path analysis revealed that the total effects of TSH on TC (total effectsTC,TSH?=?0.4323) included a significant direct effect (direct effectTC,TSH?=?0.4932) and an indirect effect via an intermediary variable (FT3, FT4). Furthermore, TC exhibited a direct effect on LDL-c, as did LDL-c on oxLDL. In conclusion, even with a mild elevation of serum TSH, SCH is associated with atherogenic lipid profiles in postmenopausal women independent of thyroid hormones.
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Hemodiafiltration combined with resin-mediated absorption as a therapy for hyperlipidemic acute pancreatitis.
Cell Biochem. Biophys.
PUBLISHED: 03-28-2014
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The aim of this study is to investigate whether hemodiafiltration combined with resin-mediated absorption is a better therapy for hyperlipidemic acute pancreatitis. Patients (n = 67) with acute pancreatitis treated in ICU from January 2009 to December 2012 were included in this study. Seven of these 67 cases were diagnosed hyperlipidemic acute pancreatitis (HLAP). All the 7 HLAP patients went through fast, gastrointestinal decompression, anti-shock treatment, inhibition of pancreatic secretion, antiseptic treatments, and hemoperfusion (HP) combined with continuous veno venous hemodiafiltration (CVVHDF). After one round of treatment by resin adsorption, there was a significant decrease in serum triglycerides (TG) (29.78 %) and total cholesterol (TC) (24.02 %) levels (p < 0.01). TG and TC levels dropped by 49.02 and 37.66 %, respectively, after 1-day treatment of HP + CVVHDF; by 62.81 and 47.37 % on day 2 post-treatment; and by 69.57 and 49.47 % on day 3 post-treatment. All the 7 patients survived. The average time spent in the ICU was 7 ± 3.8 days, and the average duration of hospitalization was 19 ± 15.1 days. Our results show that hemoperfusion combined with hemodiafiltration is an efficient treatment as this approach can reduce plasma lipid levels effectively and reduce the risk of acute pancreatitis due to hyperlipidemia.
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Assessment of accuracy of robotically assisted unicompartmental arthroplasty.
Knee Surg Sports Traumatol Arthrosc
PUBLISHED: 03-26-2014
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The purpose of this study was to analyse the accuracy of component placement during unicompartmental knee arthroplasty (UKA) using a robotic-assisted system.
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Neuroprotection of microRNA in neurological disorders (Review).
Biomed Rep
PUBLISHED: 03-25-2014
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MicroRNAs (miRNAs) are small, endogenous, non-coding RNA molecules that function as post-transcriptional regulators of gene expression by imperfect base-pairing with the 3'-untranslated regions of their target mRNAs. Altered expression of numerous miRNAs has been shown to be extensively involved in the pathogenesis of various diseases and cancers. Additionally, the specific expression of miRNAs in the nervous system has indicated that miRNAs are critical for the occurrence and development of neurological diseases. Increasing evidence has shown that specific miRNAs target the expression of particular proteins that are significant in the disease pathogenesis. Therefore, miRNA-mediated regulation may be important in the occurrence and development of neurological diseases and may function as a novel biomarker and tool for clinical therapy. In the present study, the significance of miRNAs is reviewed in a number of neurological disorders and the possibility of their use in therapeutic interventions is evaluated.
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Identification of Conserved and Novel microRNAs in Cerebral Ischemia-Reperfusion Injury of Rat Using Deep Sequencing.
J. Mol. Neurosci.
PUBLISHED: 03-24-2014
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MicroRNAs are a class of noncoding small RNAs that regulate gene expression by inhibiting target genes at post-transcriptional levels. MicroRNAs have been highlighted in many organs and tissues, including the brain. To identify special microRNAs involved in ischemia-reperfusion injury, we performed a comprehensive small RNA profiling in rat model and the control using Illumina high-throughput sequencing. A total of 9,444,562 and 10,290,391 clean reads were sequenced from two small RNA libraries constructed, respectively. Three hundred fifty-eight known microRNAs were identified, in which 78 microRNAs exhibited significantly differential expression between model and control. In addition, 62 and 68 novel miRNAs were found in model and control, respectively. Comparative analysis showed that 24 novel microRNAs were differentially expressed with greater than six-fold change. The GO annotation suggested that predicted targets of microRNAs were enriched into the category of metabolic process, cell part, cell-extracellular communications, and so on. KEGG pathway analysis suggested that these genes were involved in many important pathways, mainly including signaling transduction, MAPK signaling pathway, NF-?B signaling pathway, and neurotrophin signaling pathway. Our findings provided a deeper understanding to the regulatory mechanism of microRNAs underlying cerebral ischemia, therefore benefitting the improvement of the protection and treatment strategies of this disease.
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Heterodimerization of human apelin and bradykinin 1 receptors: novel signal transduction characteristics.
Cell. Signal.
PUBLISHED: 02-28-2014
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Apelin receptor (APJ) and bradykinin 1 receptor (B1R) are involved in a variety of important physiological processes, which share many similar characteristics in distribution and functions in the cardiovascular system. This study explored the possibility of heterodimerization between APJ and B1R, and investigated the impact of heterodimer on the signal transduction characteristics and the physiological functions in human endothelial cells after stimulation with their agonists. We first identified the endogenous expression of APJ and B1R in HUVECs and their co-localization on HEK293 membrane. The constitutive heterodimerization between the APJ and B1R was then demonstrated by BRET and FRET assays. Stimulation with Apelin-13 and des -Arg(9)-BK enhanced the phosphorylation of eNOS in HUVECs, which could be dampened by the knockdown of APJ or B1R, indicating the co-existence of APJ and B1R is critical for eNOS phosphorylation in HUVECs. Furthermore, APJ/B1R heterodimers were found to enhance the activity of PKC signaling pathway and increase intracellular Ca(2+) concentration in HEK293 cells, which might be the mechanism of APJ/B1R heterodimers promoting the phosphorylation of eNOS and leads to increased G?q, PKC signal pathway activities and a significant increase in cell proliferation. The results provide a new theoretical and experimental base for revealed intracellular molecular mechanisms of physiological function involved in the APJ and B1R and provide potential new targets for the development of drugs and treating cardiovascular disease.
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Endoplasmic reticulum stress in cerebral ischemia.
Neurochem. Int.
PUBLISHED: 02-03-2014
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The endoplasmic reticulum (ER) stress is an essential step in the progression of brain ischemia/reperfusion (I/R) injury. It is possible that the timing of events for ER stress signaling regulation is important for the balance of life and death such that ER stress is initially protective, aiming to restore ER homeostasis, whereas prolonged periods of ER stress can be deleterious and damaging. Nevertheless, modulation of ER stress exerts a remarkable protective effect on the ischemic brain and offers the prospect of new stroke therapies. As ER stress is not devoid of deleterious side effects, a better understanding of the reciprocal interaction between the ER and the ischemic brain is essential to harness the full therapeutic potential of ischemic stroke.
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Combined use of non-biological artificial liver treatments for patients with acute liver failure complicated by multiple organ dysfunction syndrome.
World J Emerg Med
PUBLISHED: 01-11-2014
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Acute liver failure (ALF) caused by viral and non-viral hepatitis is often accompanied with severe metabolic disorders, the accumulation of toxic substances and continuous release and accumulation of a large number of endogenous toxins and inflammatory mediators. The present study aimed to investigate the effects of various combined non-biological artificial liver treatments for patients with acute liver failure (ALF) complicated by multiple organ dysfunction syndrome (MODS).
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Edaravone protected PC12 cells against MPP(+)-cytoxicity via inhibiting oxidative stress and up-regulating heme oxygenase-1 expression.
J. Neurol. Sci.
PUBLISHED: 01-03-2014
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Oxidative stress is involved in the pathogenesis of Parkinson's disease (PD). Edaravone has been shown to have a neuroprotective effect. In the present work, we investigated the effect of edaravone on 1-methyl-4-phenylpyridinium (MPP(+))-treated PC12 cells. Edaravone inhibited the decrease of cell viability and apoptosis induced by MPP(+) in PC12 cells. In addition, edaravone alleviated intracellular reactive oxygen species (ROS) production. MPP(+) induced heme oxygenase-1 (HO-1) expression, which was further enhanced by edaravone. The inhibitor of HO-1 zinc protoporphyrin-IX attenuated the neuroprotection of edaravone. So edaravone protected PC12 cells against MPP(+)-cytoxicity via inhibiting oxidative stress and up-regulating HO-1 expression. The data showed that edaravone was neuroprotective and could be potentially therapeutics for PD in future.
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Modeling the overall survival of patients with advanced-stage non-small cell lung cancer using data of routine laboratory tests.
Int. J. Cancer
PUBLISHED: 01-02-2014
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Cancer patients undergo routine clinical monitoring with an array of blood tests that may carry long-term prognostic information. We aimed to develop a new prognostic model predicting survival for patients with advanced non-small cell lung cancer (NSCLC), based on laboratory tests commonly performed in clinical practice. A cohort of 1,161 stage IIIB or IV NSCLC patients was divided into training (n?=?773) and testing (n?=?388) cohorts. We analyzed the associations of 32 commonly tested laboratory variables with patient survival in the training cohort. We developed a model based on those significant laboratory variables, together with important clinical variables. The model was then evaluated in the testing cohort. Five variables, including albumin, total protein, alkaline phosphatase, blood urea nitrogen and international normalized ratio, were significantly associated with patient survival after stepwise selection. A model incorporating these variables classified patients into low-, medium- and high-risk groups with median survival of 16.9, 7.2 and 2.1 months, respectively (p?
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Association of single nucleotide polymorphisms of nucleotide excision repair genes with laryngeal cancer risk and interaction with cigarette smoking and alcohol drinking.
Tumour Biol.
PUBLISHED: 01-02-2014
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We investigated the potential association of 12 single nucleotide polymorphisms (SNPs) of nucleotide excision repair (NER) genes with risk of laryngeal cancer. A ratio of 1:1 matched case-control study was conducted. Conditional regression analysis indicated that subjects with ERCC1 rs11615 CC and C allele had an increased risk of laryngeal cancer compared with the TT genotype. Individuals with the ERCC5 rs17655 GG and G allele had a moderately increased risk of laryngeal cancer when compared with the CC genotype. By stratified analysis, ERCC1 rs11615 CC genotype and C allele were significantly associated with greatly increased risk of laryngeal cancer in ever smokers. ERCC1 rs11615 and ERCC5 rs17655 polymorphisms were associated with a moderately increased risk of this cancer in ever drinkers. In summary, we suggest that genetic variations in ERCC1 rs11615 and ERCC5 rs17655 are associated with laryngeal cancer risk in a Chinese population, especially in ever smokers and drinkers. Our finding could be helpful in identifying people at high risk for the disease for early intervention.
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Low Serum Cartonectin/CTRP3 Concentrations in Newly Diagnosed Type 2 Diabetes Mellitus: In Vivo Regulation of Cartonectin by Glucose.
PLoS ONE
PUBLISHED: 01-01-2014
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Cartonectin is a novel adipokine of the C1q complement/TNF-related protein (CTRP) superfamily, with glucose lowering effects, anti-inflammatory and cardio-protective properties. We sought to investigate circulating cartonectin concentrations in subjects with type 2 diabetes mellitus (T2DM) as well as age and BMI matched control subjects. We also examined the effects of a 2 hour 75 g oral glucose tolerance test (OGTT) on serum cartonectin concentrations in T2DM subjects.
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Lavage with allicin in combination with vancomycin inhibits biofilm formation by Staphylococcus epidermidis in a rabbit model of prosthetic joint infection.
PLoS ONE
PUBLISHED: 01-01-2014
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The present anti-infection strategy for prosthetic joint infections (PJI) includes the use of antibiotics and surgical treatments, but the bacterial eradication rates are still low. One of the major challenges is the formation of biofilm causing poor bacterial eradication. Recently it has been reported that allicin (diallyl thiosulphinate), an antibacterial principle of garlic, can inhibit bacteria adherence and prevent biofilm formation in vitro. However, whether allicin could inhibit biofilm formation in vivo is unknown. The aim of this study was to investigate the effects of allicin on biofilm formation, and whether allicin could potentiate the bactericidal effect of vancomycin in a rabbit PJI model.
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Incidence of adverse events in an integrated US healthcare system: a retrospective observational study of 82,784 surgical hospitalizations.
Patient Saf Surg
PUBLISHED: 01-01-2014
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Many health care facilities have developed electronic reporting systems for identifying and reporting adverse events (AEs), so that measures can be taken to improve patient safety. Although several studies have examined AEs in surgical settings, there has not previously been a systematic assessment of the variations in adverse event rates among different types of surgery, nor an identification of the particular types of AEs that are most common within each surgical category. Additionally, this study will identify the AE severity level associated with each of the AE category types.
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Meat consumption and risk of oral cavity and oropharynx cancer: a meta-analysis of observational studies.
PLoS ONE
PUBLISHED: 01-01-2014
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High meat consumption, especially red and processed meat consumption is associated with an increased risk of several cancers, however, evidence for oral cavity and oropharynx cancer is limited. Thus, we performed this meta-analysis to determine the association between intakes of total meat, processed meat, red meat, and white meat, and the risk of oral cavity and oropharynx cancer.
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Assessment of M867, a selective caspase-3 inhibitor, in an orthotopic mouse model for non-small cell lung carcinoma.
Am J Cancer Res
PUBLISHED: 01-01-2014
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Radiation-induced lung injury (RILI) is a significant dose limiting complication of thoracic radiation for lung, breast, and esophageal cancer. Strategies for increasing the therapeutic index of radiation involve the use of radiosensitizing agents. We investigated the potential of M867 to sensitize non-small cell lung cancer (NSCLC) to radiation in vivo, while assessing its protective effects in normal lung parenchyma. H460-Luc2 cells were implanted into the mediastinum of athymic nude mice, which were separated into four treatment groups: control, M867, radiation therapy (RT) or combination. H460-Luc2 cell cultures were treated in parallel. Tumor growth was followed using bioluminescence imaging. Immunohistochemistry staining was used to detect phospho-Smad2/3 and cleaved caspase-3 expression. Western blot was done for the detection of cleaved caspase-3 and phospho-Smad2/3. TUNEL assays were used to measure apoptosis. M867+RT group had significantly increased tumor growth inhibition relative to either treatment alone (p=0.02). M867+RT was associated with increased levels of apoptosis (p<0.01), but combination treatment was associated with a decrease in caspase-dependent apoptosis relative to RT alone (p<0.01). We found that this increase in apoptosis in the M867+RT group was due to caspase-independent cell death. Based on early biomarker analyses of phospho-Smad 2/3 and cleaved caspase-3, M867+RT had a radio-protective effect on normal lung parenchyma. M867 may increase the therapeutic ratio of RT by enhancing the radiosensitivity of NSCLC while mitigating RILI. Further research is warranted to examine the late effects of lung injury and to study differences in the mechanism of action of M867 on lung cancer and normal tissue.
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Constitutive activation of AMPK ?1 in vascular endothelium promotes high-fat diet-induced fatty liver injury: role of COX-2 induction.
Br. J. Pharmacol.
PUBLISHED: 01-01-2014
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AMP-activated protein kinase (AMPK), an important regulator of energy metabolism, comprises three (?, ? and ?) subunits, each with a unique tissue distribution. As AMPK has a wide range of protein and gene targets, defining its role has been difficult. Here, we have studied a transgenic mouse model overexpressing the constitutively active ?1 subunit of AMPK in endothelial cells (EC-AMPK) to elucidate its role in energy homeostasis.
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[Role of the CX3CR1/ERK5 pathway in spinal microglia for the development of neuropathic pain].
Zhonghua Yi Xue Za Zhi
PUBLISHED: 10-31-2013
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To explore the role of spinal microglial CX3CR1/ERK5 pathway in the development of neuropathic pain.
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Comprehensive treatment for gas gangrene of the limbs in earthquakes.
Chin. Med. J.
PUBLISHED: 10-26-2013
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Mortality rates for patients with gas gangrene from trauma or surgery are as high as 25%, but they increase to 50%-80% for patients injured in natural hazards. Early diagnosis and treatment are essential for these patients.
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[Triptolide Inhibits Proliferation and Iuduces Apoptosis of Imatinib Resistant K562/G01 cells].
Zhongguo Shi Yan Xue Ye Xue Za Zhi
PUBLISHED: 10-26-2013
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This study was aimed to explore the inhibitory effect of triptolide on proliferation and inducing apoptosis effect of K562/G01 cells and their possible mechanism. MTT assay was used to detect the effect of imatinib or triptolide alone and their combination on K562/G01 proliferation; the cell cycle, apoptosis rate, P-gp protein expression were detected by folw cytometry (FCM); the expression of P-gp was assessed by Western blot; the BCR/ABL gene expression was assayed by real time guantitative PCR. The results showed that triptolide could enhance the effect of imatinib on proliferation inhibition and apoptosis of K562/G01, arrested the cell cycle in G1 phase, down-regulated the expression of BCR/ABL gene and P-gp protein. It is concluded that triptolide induces K562/G01 cell proliferation inhibition and apoptosis, the mechanism may be related to cell cycle arrest, decrease of P-gp protein expression, inhibition of BCR/ABL gene expression.
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A further investigation of the centroid-to-centroid method for stereotactic lung radiotherapy: a phantom study.
Med Phys
PUBLISHED: 10-05-2013
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Our previous study [B. Lu et al., "A patient alignment solution for lung SBRT setups based on a deformable registration technique," Med. Phys. 39(12), 7379-7389 (2012)] proposed a deformable-registration-based patient setup strategy called the centroid-to-centroid (CTC) method, which can perform an accurate alignment of internal-target-volume (ITV) centroids between averaged four-dimensional computed tomography and cone-beam computed tomography (CBCT) images. Scenarios with variations between CBCT and simulation CT caused by irregular breathing and/or tumor change were not specifically considered in the patient study [B. Lu et al., "A patient alignment solution for lung SBRT setups based on a deformable registration technique," Med. Phys. 39(12), 7379-7389 (2012)] due to the lack of both a sufficiently large patient data sample and a method of tumor tracking. The aim of this study is to thoroughly investigate and compare the impacts of breathing pattern and tumor change on both the CTC and the translation-only (T-only) gray-value mode strategies by employing a four-dimensional (4D) lung phantom.
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Cell biology in neuroscience: RNA-based mechanisms underlying axon guidance.
J. Cell Biol.
PUBLISHED: 10-02-2013
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Axon guidance plays a key role in establishing neuronal circuitry. The motile tips of growing axons, the growth cones, navigate by responding directionally to guidance cues that pattern the embryonic neural pathways via receptor-mediated signaling. Evidence in vitro in the last decade supports the notion that RNA-based mechanisms contribute to cue-directed steering during axon guidance. Different cues trigger translation of distinct subsets of mRNAs and localized translation provides precise spatiotemporal control over the growth cone proteome in response to localized receptor activation. Recent evidence has now demonstrated a role for localized translational control in axon guidance decisions in vivo.
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Reuse of hazardous calcium fluoride sludge from the integrated circuit industry.
Waste Manag Res
PUBLISHED: 09-11-2013
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The Chinese integrated circuit industry has been transformed from a small state-owned sector into a global competitor, but chip manufacturing produces large amounts of calcium fluoride sludges (CFS). In China, landfill is a current option for treating CFS. In order to solve the problem of unavailable landfill sites and prevent fluorine from dissolved CFS polluting water sources, CFS was tested as a component for a ceramic product made with sodium borate, sodium phosphate and waste alumina using a low-temperature sintering technology, and the effects of various factors on characteristics of the ceramic were investigated to optimize the process. The best sintering temperature was controlled at 700°C, and the optimal raw material ratio of the ceramic was 11% sodium borate, 54% sodium phosphate, 30% CFS and 5% waste alumina. The CFS ceramic was characterized by a morphological structure and X-ray diffraction. The results indicated that CFS was transformed into Na2Ca(PO4)F as an inert and a main crystalline phase in the ceramic, which was enclosed by the borophosphate glass. Toxicity characteristic leaching procedure, corrosion resistance and compressive strength tests verified CFS ceramic as a qualified construction ceramic material, and the fluorine from CFS was solidified in the inert crystalline phase, which would not be released to cause secondary pollution. This novel technology not only avoids the CFS hydrolyzing reaction forming harmful hydrofluoric acid gas at 800°C and above, but also produces high-performance ceramics as a construction material, in accordance with the concept of sustainable development.
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AKIP1, a cardiac hypertrophy induced protein that stimulates cardiomyocyte growth via the Akt pathway.
Int J Mol Sci
PUBLISHED: 08-09-2013
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Cardiac adaptation to unremitting physiological stress typically involves hypertrophic growth of cardiomyocytes, a compensatory response that often fails and causes heart disease. Gene array analysis identified AKIP1 (A Kinase Interacting Protein 1) as a hypertrophic gene and we therefore hypothesized a potential role in the hypertrophic response. We show for the first time that both AKIP1 mRNA and protein levels increased in hypertrophic cardiomyocytes under conditions of sustained cardiac stress, including pressure overload and after myocardial infarction and in vitro in phenylephrine (PE) stimulated neonatal rat ventricular cardiomyocytes (NRVCs). AKIP1 overexpression in NRVCs markedly stimulated hypertrophic growth responses, including significantly increased cell size, augmented cytoskeletal organization and protein synthesis. Although, AKIP1 was not essential for PE induced hypertrophy in NRVCs, it did potentiate neurohormonal induced protein synthesis. AKIP1 did, however, not induce expression of pathological marker genes like ANP and ?-MHC. ERK and Akt kinase signaling pathways have been linked to hypertrophy and AKIP1 specifically induced phosphorylation of Akt. This phosphorylation of Akt was essential for activation of ribosomal rpS6 and translation elongation factor eEF2 and this readily explains the increased protein synthesis. Akt inhibition fully blocked AKIP1 induced hypertrophy, showing that this pathway is critically involved. In conclusion, our results show that AKIP1 is induced in hypertrophic hearts and can stimulate adaptive cardiomyocyte growth, which involves Akt signaling.
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Identification of a KRAS mutation in a patient with non-small cell lung cancer treated with chemoradiotherapy and panitumumab.
Cancer Biol. Ther.
PUBLISHED: 08-02-2013
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RTOG 0839 is a Phase II study of pre-operative chemoradiotherapy with or without panitumumab in potentially operable locally advanced non-small cell lung cancer (NSCLC). The investigational agent, panitumumab, is an anti-epithelial growth factor receptor (EGFR) antibody that improves progression-free survival in chemorefractory metastatic colorectal cancer (mCRC). Recently, both KRAS mutational status (i.e., mutated or not) and subtype (i.e., activating or inactivating) have been shown to be predictive of response to anti-EGFR therapy in mCRC. However, in NSCLC, it is unknown if KRAS mutational status or subtype predict benefit to anti-EGFR therapies because of unique genetic and epigenetic factors unique to each cancer. We present a patient with stage III NSCLC containing a KRAS G12D activating mutation who had a partial pathologic response, with disappearance of a minor KRAS mutant clone. This case suggests possible eradication of the G12D KRAS lung cancer clones by concurrent chemoradiation with panitumumab.
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[The pharmacological effect of allosteric regulation at GPCR heterodimer].
Sheng Li Ke Xue Jin Zhan
PUBLISHED: 07-16-2013
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Traditionally GPCR can exist as monomer, and its function is linear. The signal is transduced when the ligand binds to the orthosteric site. It has been reported that GPCR can form homodimer or heterodimer. In the dimers, allosteric sites will form when ligand binds to one monomer and then regulates of another monomer. Therefore the signaling pathway and the function of the receptor will be changed. Compared to orthosteric agonists, allosteric modulators have a number of potential advantages, which make allosteric modulators as a drug discovery candidate for GPCR. Herein, we introduce the concept of allosteric regulation at GPCR dimers, and its impact on the function of the receptor. We also introduce the drug screening methods of allosteric regulator, and those will contribute to drug discovery for GPCR.
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Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 07-11-2013
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A growing number of agents targeting ligand-induced Wnt/?-catenin signaling are being developed for cancer therapy. However, clinical development of these molecules is challenging because of the lack of a genetic strategy to identify human tumors dependent on ligand-induced Wnt/?-catenin signaling. Ubiquitin E3 ligase ring finger 43 (RNF43) has been suggested as a negative regulator of Wnt signaling, and mutations of RNF43 have been identified in various tumors, including cystic pancreatic tumors. However, loss of function study of RNF43 in cell culture has not been conducted, and the functional significance of RNF43 mutations in cancer is unknown. Here, we show that RNF43 inhibits Wnt/?-catenin signaling by reducing the membrane level of Frizzled in pancreatic cancer cells, serving as a negative feedback mechanism. Inhibition of endogenous Wnt/?-catenin signaling increased the cell surface level of Frizzled. A panel of 39 pancreatic cancer cell lines was tested for Wnt dependency using LGK974, a selective Porcupine inhibitor being examined in a phase 1 clinical trial. Strikingly, all LGK974-sensitive lines carried inactivating mutations of RNF43. Inhibition of Wnt secretion, depletion of ?-catenin, or expression of wild-type RNF43 blocked proliferation of RNF43 mutant but not RNF43-wild-type pancreatic cancer cells. LGK974 inhibited proliferation and induced differentiation of RNF43-mutant pancreatic adenocarcinoma xenograft models. Our data suggest that mutational inactivation of RNF43 in pancreatic adenocarcinoma confers Wnt dependency, and the presence of RNF43 mutations could be used as a predictive biomarker for patient selection supporting the clinical development of Wnt inhibitors in subtypes of cancer.
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Pressure-Controlled Motion of Single Polymers through Solid-State Nanopores.
Nano Lett.
PUBLISHED: 06-28-2013
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Voltage-biased solid-state nanopores are well established in their ability to detect and characterize single polymers, such as DNA, in electrolytes. The addition of a pressure gradient across the nanopore yields a second molecular driving force that provides new freedom for studying molecules in nanopores. In this work, we show that opposing pressure and voltage bias enables nanopores to detect and resolve very short DNA molecules, as well as to detect near-neutral polymers.
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Interaction with both ZNRF3 and LGR4 is required for the signalling activity of R-spondin.
EMBO Rep.
PUBLISHED: 06-18-2013
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R-spondin proteins sensitize cells to Wnt signalling and act as potent stem cell growth factors. Various membrane proteins have been proposed as potential receptors of R-spondin, including LGR4/5, membrane E3 ubiquitin ligases ZNRF3/RNF43 and several others proteins. Here, we show that R-spondin interacts with ZNRF3/RNF43 and LGR4 through distinct motifs. Both LGR4 and ZNRF3 binding motifs are required for R-spondin-induced LGR4/ZNRF3 interaction, membrane clearance of ZNRF3 and activation of Wnt signalling. Importantly, Wnt-inhibitory activity of ZNRF3, but not of a ZNRF3 mutant with reduced affinity to R-spondin, can be strongly suppressed by R-spondin, suggesting that R-spondin primarily functions by binding and inhibiting ZNRF3. Together, our results support a dual receptor model of R-spondin action, where LGR4/5 serve as the engagement receptor whereas ZNRF3/RNF43 function as the effector receptor.
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[Significance of carbonic anhydrase IX protein expression in molecular subtyping of breast cancers].
Zhonghua Bing Li Xue Za Zhi
PUBLISHED: 06-18-2013
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To study the expression of carbonic anhydrase (CA) IX and its significance in molecular subtyping of breast carcinomas. METHODL MaxVision immunohistochemical staining was used to examine the expression of ER, PR, HER2, CK5/6, EGFR, and CA IX in 117 cases of breast invasive ductal carcinomas.
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Secure encapsulation and publication of biological services in the cloud computing environment.
Biomed Res Int
PUBLISHED: 06-05-2013
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Secure encapsulation and publication for bioinformatics software products based on web service are presented, and the basic function of biological information is realized in the cloud computing environment. In the encapsulation phase, the workflow and function of bioinformatics software are conducted, the encapsulation interfaces are designed, and the runtime interaction between users and computers is simulated. In the publication phase, the execution and management mechanisms and principles of the GRAM components are analyzed. The functions such as remote user job submission and job status query are implemented by using the GRAM components. The services of bioinformatics software are published to remote users. Finally the basic prototype system of the biological cloud is achieved.
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A study of IMRT planning parameters on planning efficiency, delivery efficiency, and plan quality.
Med Phys
PUBLISHED: 05-31-2013
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To improve planning and delivery efficiency of head and neck IMRT without compromising planning quality through the evaluation of inverse planning parameters.
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Differential migration of passenger leukocytes and rapid deletion of naive alloreactive CD8 T cells after mouse liver transplantation.
Liver Transpl.
PUBLISHED: 05-28-2013
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Donor passenger leukocytes (PLs) from transplanted livers migrate to recipient lymphoid tissues, where they are thought to induce the deletion of donor-specific T cells and tolerance. Difficulties in tracking alloreactive T cells and PLs in rats and in performing this complex surgery in mice have limited progress in identifying the contribution of PL subsets and sites and the kinetics of T cell deletion. Here we developed a mouse liver transplant model in which PLs, recipient cells, and a reporter population of transgenic CD8 T cells specific for the graft could be easily distinguished and quantified in allografts and recipient organs by flow cytometry. All PL subsets circulated rapidly via the blood as soon as 1.5 hours after transplantation. By 24 hours, PLs were distributed differently in the lymph nodes and spleen, whereas donor natural killer and natural killer T cells remained in the liver and blood. Reporter T cells were activated in both liver and lymphoid tissues, but their numbers dramatically decreased within the first 48 hours. These results provide the first unequivocal demonstration of the differential recirculation of liver PL subsets after transplantation, and show that alloreactive CD8 T cells are deleted more rapidly than initially reported. This model will be useful for dissecting early events leading to the spontaneous acceptance of liver transplants. Liver Transpl, 2013. © 2013 AASLD.
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Prevention of gross setup errors in radiotherapy with an efficient automatic patient safety system.
J Appl Clin Med Phys
PUBLISHED: 05-22-2013
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Treatment of the wrong body part due to incorrect setup is among the leading types of errors in radiotherapy. The purpose of this paper is to report an efficient automatic patient safety system (PSS) to prevent gross setup errors. The system consists of a pair of charge-coupled device (CCD) cameras mounted in treatment room, a single infrared reflective marker (IRRM) affixed on patient or immobilization device, and a set of in-house developed software. Patients are CT scanned with a CT BB placed over their surface close to intended treatment site. Coordinates of the CT BB relative to treatment isocenter are used as reference for tracking. The CT BB is replaced with an IRRM before treatment starts. PSS evaluates setup accuracy by comparing real-time IRRM position with reference position. To automate system workflow, PSS synchronizes with the record-and-verify (R&V) system in real time and automatically loads in reference data for patient under treatment. Special IRRMs, which can permanently stick to patient face mask or body mold throughout the course of treatment, were designed to minimize therapists workload. Accuracy of the system was examined on an anthropomorphic phantom with a designed end-to-end test. Its performance was also evaluated on head and neck as well as abdominalpelvic patients using cone-beam CT (CBCT) as standard. The PSS system achieved a seamless clinic workflow by synchronizing with the R&V system. By permanently mounting specially designed IRRMs on patient immobilization devices, therapist intervention is eliminated or minimized. Overall results showed that the PSS system has sufficient accuracy to catch gross setup errors greater than 1 cm in real time. An efficient automatic PSS with sufficient accuracy has been developed to prevent gross setup errors in radiotherapy. The system can be applied to all treatment sites for independent positioning verification. It can be an ideal complement to complex image-guidance systems due to its advantages of continuous tracking ability, no radiation dose, and fully automated clinic workflow.
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Bias associated with using the estimated propensity score as a regression covariate.
Stat Med
PUBLISHED: 05-22-2013
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The use of propensity score methods to adjust for selection bias in observational studies has become increasingly popular in public health and medical research. A substantial portion of studies using propensity score adjustment treat the propensity score as a conventional regression predictor. Through a Monte Carlo simulation study, Austin and colleagues. investigated the bias associated with treatment effect estimation when the propensity score is used as a covariate in nonlinear regression models, such as logistic regression and Cox proportional hazards models. We show that the bias exists even in a linear regression model when the estimated propensity score is used and derive the explicit form of the bias. We also conduct an extensive simulation study to compare the performance of such covariate adjustment with propensity score stratification, propensity score matching, inverse probability of treatment weighted method, and nonparametric functional estimation using splines. The simulation scenarios are designed to reflect real data analysis practice. Instead of specifying a known parametric propensity score model, we generate the data by considering various degrees of overlap of the covariate distributions between treated and control groups. Propensity score matching excels when the treated group is contained within a larger control pool, while the model-based adjustment may have an edge when treated and control groups do not have too much overlap. Overall, adjusting for the propensity score through stratification or matching followed by regression or using splines, appears to be a good practical strategy. Copyright © 2013 John Wiley & Sons, Ltd.
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Aliskiren effect on plaque progression in established atherosclerosis using high resolution 3D MRI (ALPINE): a double-blind placebo-controlled trial.
J Am Heart Assoc
PUBLISHED: 05-21-2013
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The renin-angiotensin system is well recognized as a mediator of pathophysiological events in atherosclerosis. The benefits of renin inhibition in atherosclerosis, especially when used in combination with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) are currently not known. We hypothesized that treatment with the renin inhibitor aliskiren in patients with established cardiovascular disease will prevent the progression of atherosclerosis as determined by high-resolution magnetic resonance imaging (MRI) measurements of arterial wall volume in the thoracic and abdominal aortas of high-risk patients with preexisting cardiovascular disease.
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Everolimus enhances the cytotoxicity of bendamustine in multiple myeloma cells through a network of pro-apoptotic and cell-cycle-progression regulatory proteins.
Acta Biochim. Biophys. Sin. (Shanghai)
PUBLISHED: 05-20-2013
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Bendamustine is a bifunctional alkylating agent with some efficacy in the treatment of newly diagnosed and relapsed/refractory multiple myeloma (MM). Everolimus, an mammalian target of rapamycin (mTOR) inhibitor, is a additional promising chemotherapeutic agent that has efficacy in a variety of cancers. We investigated the individual and combinational cytotoxic effects of these drugs in MM cell lines (RPMI8226 and MM1.S) and primary MM cells. Our results demonstrated a synergistic effect of these drugs, which was effective for both p53-wild-type and p-53-deleted MM cells, but was minimal in mononuclear cells from a healthy donor. Combination treatment with the two agents inhibited proliferation and promoted cytotoxicity and apoptosis as assessed by Annexin-V/PI staining, caspase-3 degradation, and PARP cleavage. Cell death was associated with the up-regulation of the pro-apoptotic protein Bax and the down-regulation of the anti-apoptotic proteins Mcl-1 and survivin. The combination drug treatment also promoted a decrease in the levels of the downstream target proteins of the mTOR pathway, p70s6k, and 4EBP-1, as well as an increase in the level of phosphorylation of the tumor suppressor protein p53 in MM1.S cells. p21 was also down-regulated upon treatment with the two drugs, suggesting a mechanism of sensitization through the release of cell cycle arrest. Our results demonstrate a network of regulatory factors that may contribute to the synergistic cytotoxicity of everolimus and bendamustine, and provide a rationale for application for the combinatorial treatment of MM with alkylating agents and mTOR inhibitors in future clinical practice.
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Loss-of-SIRT1 function during vascular ageing: Hyperphosphorylation mediated by cyclin-dependent kinase 5.
Trends Cardiovasc. Med.
PUBLISHED: 05-15-2013
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The longevity regulator SIRT1 is an enzyme catalyzing the deacetylation of protein substrates, in turn modulating their biological functions. In endothelial cells, downregulation of SIRT1 evokes cellular senescence. In aged arteries, SIRT1 expression and activity is blunted, which contributes to the development of atherosclerosis and abnormal vascular responses. A recent study suggests that cyclin-dependent kinase 5 (CDK5) is responsible for the phosphorylation of SIRT1 at the serine 47 residue. This modification blocks the anti-senescence activity of SIRT1 and plays a critical role in the loss-of-SIRT1 function during vascular ageing. Thus, by inhibiting CDK5, SIRT1 function can be improved, in turn preventing the development of atherosclerosis and slowing down the process of vascular ageing.
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A novel three-dimensional AgI coordination polymer based on mixed naphthalene-1,5-disulfonate and aminoacetate ligands.
Acta Crystallogr C
PUBLISHED: 05-03-2013
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The three-dimensional coordination polymer poly[[bis(??-2-aminoacetato)di-?-aqua-??-(naphthalene-1,5-disulfonato)-hexasilver(I)] dihydrate], {[Ag?(C??H?O?S?)(C?H?NO?)?(H?O)?]·2H?O}n, based on mixed naphthalene-1,5-disulfonate (L1) and 2-aminoacetate (L2) ligands, contains two Ag(I) centres (Ag1 and Ag4) in general positions, and another two (Ag2 and Ag3) on inversion centres. Ag1 is five-coordinated by three O atoms from one L1 anion, one L2 anion and one water molecule, one N atom from one L2 anion and one AgI cation in a distorted trigonal-bipyramidal coordination geometry. Ag2 is surrounded by four O atoms from two L2 anions and two water molecules, and two AgI cations in a slightly octahedral coordination geometry. Ag3 is four-coordinated by two O atoms from two L2 anions and two AgI cations in a slightly distorted square geometry, while Ag4 is also four-coordinated by two O atoms from one L1 and one L2 ligand, one N atom from another L2 anion, and one AgI cation, exhibiting a distorted tetrahedral coordination geometry. In the crystal structure, there are two one-dimensional chains nearly perpendicular to one another (interchain angle = 87.0°). The chains are connected by water molecules to give a two-dimensional layer, and the layers are further bridged by L1 anions to generate a novel three-dimensional framework. Moreover, hydrogen-bonding interactions consolidate the network.
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NK cell tolerance of self-specific activating receptor KIR2DS1 in individuals with cognate HLA-C2 ligand.
J. Immunol.
PUBLISHED: 04-03-2013
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NK cells are regulated by inhibiting and activating cell surface receptors. Most inhibitory receptors recognize MHC class I Ags and protect healthy cells from NK cell-mediated autoaggression. However, certain activating receptors, including the human activating killer cell Ig-like receptor (KIR) 2DS1, also recognize MHC class I. This fact raises the question of how NK cells expressing such activating receptors are tolerized to host tissues. We investigated whether the presence of HLA-C2, the cognate ligand for 2DS1, induces tolerance in 2DS1-expressing NK cells. Anti-HLA-C2 activity could be detected in vitro in some 2DS1 positive NK clones irrespective of the presence or absence of HLA-C2 ligand in the donor. The frequency of anti-HLA-C2 reactivity was high in donors homozygous for HLA-C1. Surprisingly, no significant difference was seen in the frequency of anti-HLA-C2 cytotoxicity in donors heterozygous for HLA-C2 and donors without HLA-C2 ligand. However, donors homozygous for HLA-C2, compared with all other donors, had significantly reduced frequency of anti-HLA-C2 reactive clones. The 2DS1 positive clones that express inhibitory KIR for self-HLA class I were commonly noncytotoxic, and anti-HLA-C2 cytotoxicity was nearly exclusively restricted to 2DS1 single positive clones lacking inhibitory KIR. 2DS1 single positive NK clones with anti-HLA-C2 reactivity were also present posttransplantation in HLA-C2 positive recipients of hematopoietic stem cell transplants from 2DS1 positive donors. These results demonstrate that many NK cells with anti-HLA-C2 reactivity are present in HLA-C1 homozygous and heterozygous donors with 2DS1. In contrast, 2DS1 positive clones from HLA-C2 homozygous donors are frequently tolerant to HLA-C2.
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Preparation, characterization, and in vitro efficacy of O-carboxymethyl chitosan conjugate of melphalan.
Carbohydr Polym
PUBLISHED: 03-25-2013
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A series of melphalan-O-carboxymethyl chitosan (Mel-OCM-chitosan) conjugates with different spacers were prepared and structurally characterized. All conjugates showed satisfactory water-solubility (160-217 times of Mel solubility). In vitro drug release behaviors by both chemical and enzymatic hydrolysis were investigated. The prodrugs released Mel rapidly within papain and lysosomal enzymes of about 40-75%, while released only about 4-5% in buffer and plasma, which suggested that the conjugates have good plasma stability and the hydrolysis in both papain and lysosomes occurs mostly via enzymolysis. It was found that the spacers have important effect on the drug content, water solubility, drug release properties and cytotoxicity of Mel-OCM-chitosan conjugates. Cytotoxicity studies by MTT assay demonstrated that these conjugates had 52-70% of cytotoxicity against RPMI8226 cells in vitro as compared with free Mel, indicating the conjugates did not lose anti-cancer activity of Mel. Overall these studies indicated Mel-OCM-chitosan conjugates as potential prodrugs for cancer treatment.
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Boron nitride nanopores: highly sensitive DNA single-molecule detectors.
Adv. Mater. Weinheim
PUBLISHED: 03-25-2013
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The first electronic measurement of DNA translocation through ultrathin BN nanopores is demonstrated. BN nanopores show much higher detection sensitivity compared with SiN nanopores. BN has a spatial resolution as graphene. The ultrathin BN nanopores provide substantial opportunities in realizing high-spatial-sensitivity nanopore electrical devices for various applications.
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Effect of arthritis in other compartment after unicompartmental arthroplasty.
Eur J Orthop Surg Traumatol
PUBLISHED: 03-08-2013
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The purpose of this study is to evaluate the outcome of robotic-assisted (MAKO Surgical Corp.) unicondylar replacement in the treatment for knee osteoarthritis after the initial surgical insult is worn off to evaluate the impact of residual patellofemoral and lateral osteoarthritis on the outcome of medial unicompartmental knee replacement. One hundred and thirty-four patients who underwent uncomplicated 144 robotic-assisted medial unicondylar replacements for knee arthritis were identified and studied. Original radiographs were used to classify severity of patellofemoral and lateral compartmental osteoarthritis in these patients. Severity of patellofemoral and lateral compartmental osteoarthritis was analyzed against Oxford and Knee Society scores and amount of ipsilateral residual knee symptoms at 6 months postoperative period. Preoperative Oxford and Knee Society scores, other comorbidities and long-term disability were studied as confounding variables. We found significant improvement in symptoms and scores in spite of other compartment diseases. Poorer outcome was seen in association with comorbidities and long-term disability but not when radiographic signs of arthritis in the other compartments were present. Six patients required revision of which three had (lateral facet) patellofemoral disease in the original X-rays. In conclusion, there is a higher amount of postoperative retained symptoms, but similar outcome when there is radiographic disease in the other compartments. However, when symptoms are severe enough to necessitate revision, this is due to the lateral facet of patellofemoral compartment and not lateral compartment disease.
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Silibinin induced the apoptosis of Hep-2 cells via oxidative stress and down-regulating survivin expression.
Eur Arch Otorhinolaryngol
PUBLISHED: 03-08-2013
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Silibinin is an anticancer and chemopreventive natural compound, which is extracted from milk thistle (Silybum marianum). It is reported that silibinin has anticancer efficacy in many malignant tumors. Laryngeal carcinoma is the second most common head and neck squamous carcinoma. In the present work, we investigated the effects of silibinin on laryngeal squamous cell carcinoma (LSCC) cell line Hep-2 cells. We found that silibinin induced the decrease of cell viability in Hep-2 cells with a concentration- and time-dependent manner. Moreover, silibinin resulted in the apoptosis of Hep-2 cells and had synergy effects with arsenic trioxide. Intracellular reactive oxygen species (ROS) accumulation increased because of silibinin exposure. ROS scavenger NAC alleviated the cytotoxicity of silibinin to Hep-2 cells. The mitochondrial membrane potential (MMP) was lost in Hep-2 cells treated with silibinin. Subsequently, silibinin induced the activation of caspase-3 in Hep-2 cells and caspase inhibitor Z-VAD-FMK inhibited the cytotoxicity of silibinin in Hep-2 cells. The survivin expression decreased after Hep-2 cells were treated with silibinin. In conclusion, silibinin induced the apoptosis of Hep-2 cells via oxidative stress and down-regulating survivin expression. Therefore, silibinin is a potential therapeutical agent against LSCC in future.
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