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1.  An Automatic Occlusion Device for Remote Control of Tumor Tissue Ischemia 
We developed an automatic occlusion device for remote control of tumor tissue ischemia. The device consists of a flexible cannula encasing a shape memory alloy wire with its distal end connected to surgical suture. Regional tissue occlusion was tested on both the benchtop and the animal models. In the benchtop test, the occlusion device introduced quantitative and reproducible changes of blood flow in a tissue simulating phantom embedding a vessel simulator. In the animal test, the device generated a cyclic pattern of reversible ischemia in the right hinder leg tissue of a black male C57BL/6 mouse. We also developed a multimodal detector that integrates near infrared spectroscopy and electron paramagnetic resonance spectroscopy for continuous monitoring of tumor tissue oxygenation, blood content, and oxygen tension changes. The multimodal detector was tested on a cancer xenograft nude mouse undergoing reversible tumor ischemia. The automatic occlusion device and the multi-modal detector can be potentially integrated for closed-loop feedback control of tumor tissue ischemia. Such an integrated occlusion device may be used in multiple clinical applications such as regional hypoperfusion control in tumor resection surgeries and thermal ablation processes. In addition, the proposed occlusion device can also be used as a research tool to understand tumor oxygen transport and hemodynamic characteristics.
PMCID: PMC4332819  PMID: 20082532
Occlusion; Reperfusion; Ischemia; Tumor; Oxygenation; Blood flow; Oxygen tension; Near infrared spectroscopy; Electron paramagnetic resonance spectroscopy; Shape memory alloy wire
2.  Draft Genome Sequence of Nocardia seriolae ZJ0503, a Fish Pathogen Isolated from Trachinotus ovatus in China 
Genome Announcements  2015;3(1):e01223-14.
Nocardia seriolae is a pathogen that causes nocardiosis in marine and freshwater fish. Here, we report the draft genome sequence of N. seriolae strain ZJ0503, which was isolated from Trachinotus ovatus in Guangdong, China.
PMCID: PMC4293623  PMID: 25555736
3.  Immunization interventions to interrupt hepatitis B virus mother-to-child transmission: a meta-analysis of randomized controlled trials 
BMC Pediatrics  2014;14(1):307.
This study aimed to determine the clinical efficacy of various immune interventions on mother-to-child transmission (MTCT) of hepatitis B virus (HBV).
We retrieved different immune strategies on how to prevent MTCT reported in the literature from Chinese and English electronic databases from the viewpoint of intrauterine and extrauterine prevention. Relative risk (RR) and 95% confidence interval (CI) methods were used.
Twenty-five articles on intrauterine prevention and 16 on extrauterine prevention were included in the analysis. Intrauterine prevention could reduce infants’ HBV infection rate (RR = 0.36, 95% CI: 0.28-0.45) and increase their anti-hepatitis B surface–positive rate (RR = 2.42, 95% CI: 1.46-4.01) at birth. Compared with passive immunization, passive-active immunization could reduce infants’ HBV infection rate (RR = 0.66, 95% CI: 0.52-0.84) at birth, even at more than 12 months of age (RR = 0.54, 95% CI: 0.42-0.69). Subgroup analysis demonstrated similar results except for pregnant women who were hepatitis B surface antigen–positive. Funnel plots and Egger’s tests showed publication bias mainly in intrauterine prevention not in extrauterine one.
The long-term protective effect of pregnant women injected with hepatitis B immunoglobulin during pregnancy should be further validated by large-scale randomized trials. Newborns of pregnant women who carried HBV should undergo a passive-active immunization strategy.
Electronic supplementary material
The online version of this article (doi:10.1186/s12887-014-0307-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4297423  PMID: 25526664
Hepatitis B immunoglobulin; Hepatitis B virus; Meta-analysis; Mother-to-child transmission
4.  Nonintubated anesthesia for thoracic surgery 
Journal of Thoracic Disease  2014;6(12):1868-1874.
Nonintubated thoracic surgery has been used in procedures including pleura, lungs and mediastinum. Appropriate anesthesia techniques with or without sedation allow thoracic surgery patients to avoid the potential risks of intubated general anesthesia, particularly for the high-risk patients. However, nonintubated anesthesia for thoracic surgery has some benefits as well as problems. In this review, the background, indication, perioperative anesthetic consideration and management, and advantages and disadvantages are discussed and summarized.
PMCID: PMC4283309  PMID: 25589994
Thoracic surgery; nonintubated anesthesia; epidural block; anesthesia technique
5.  Mechanisms of linezolid resistance in staphylococci and enterococci isolated from two teaching hospitals in Shanghai, China 
BMC Microbiology  2014;14(1):292.
Linezolid is one of the most effective treatments against Gram-positive pathogens. However, linezolid-resistant/intermediate strains have recently emerged in worldwide. The purpose of this study was to analyse the prevalence and resistance mechanisms of linezolid-resistant/intermediate staphylococci and enterococci in Shanghai, China.
Thirty-two linezolid-resistant/intermediate strains, including 14 Staphylococcus capitis, three Staphylococcus aureus, 14 Enterococcus faecalis and one Enterococcus faecium clinical isolates, were collected in this study which displayed linezolid MICs of 8 to 512 μg/ml, 8–32 μg/ml, 4–8 μg/ml and 4 μg/ml, respectively. All linezolid-resistant S. capitis isolates had a novel C2131T mutation and a G2603T mutation in the 23S rRNA region, and some had a C316T (Arg106Cys) substitution in protein L4 and/or harboured cfr. Linezolid-resistant S. aureus isolates carried a C389G (Ala130Gly) substitution in protein L3, and/or harboured cfr. The cfr gene was flanked by two copies of the IS256-like element, with a downstream orf1 gene. Linezolid-resistant/intermediate enterococci lacked major resistance mechanisms. The semi-quantitative biofilm assay showed that 14 linezolid-resistant E. faecalis isolates produced a larger biofilm than linezolid-susceptible E. faecalis strains. Transmission electron microscopy showed the cell walls of linezolid-resistant/intermediate strains were thicker than linezolid-susceptible strains.
Our data indicated that major resistance mechanisms, such as mutations in 23S rRNA and ribosomal proteins L3 and L4, along with cfr acquisition, played an important role in linezolid resistance. Secondary resistance mechanisms, such as biofilm formation and cell wall thickness, should also be taken into account.
PMCID: PMC4245736  PMID: 25420718
Linezolid resistance; Mutations of 23S rRNA and ribosomal proteins; cfr; Biofilm production; Cell wall thickness
6.  Optimal single-dose epidural neostigmine for postoperative analgesia after partial hepatectomy 
Indian Journal of Pharmacology  2014;46(6):613-616.
Neostigmine can produce analgesia by acting on the spinal cord. This study was to determine the optimal single-dose of epidural neostigmine for postoperative analgesia after partial hepatectomy.
Patients and Methods:
Twenty-six patients undergoing elective partial hepatectomy under general anesthesia combined with epidural block were studied. The dose of epidural neostigmine was determined using Dixon's up-and-down method, starting from neostigmine 100 μg with an interval of 25 μg. Thirty minutes after skin incision, a predetermined dose of neostigmine was injected via the epidural catheter. Each patient received 0.125% bupivacaine and fentanyl 2 μg/ml for patient controlled epidural analgesia (PCEA) after the operation. Assessment of analgesia quality was performed at 8 h and 24 h after the operation.
The ED50 of epidural neostigmine in combination with PCEA for satisfactory analgesia was 226.78 ± 33.20 μg. Probit analysis showed that the ED50 and ED95 of epidural neostigmine were 228.63 μg (95% CI = 197.95–299.77 μg) and 300.12 μg (95% CI = 259.44–741.65 μg), respectively.
The ED50 and ED95 of epidural neostigmine in combination with PCEA for satisfactory analgesia after partial hepatectomy were 228.63 μg (95% CI = 197.95–299.77 μg) and 300.12 μg (95% CI = 259.44–741.65 μg).
PMCID: PMC4264076  PMID: 25538332
Dixon's up-and-down method; neostigmine; optimal dose; postoperative analgesia; patient controlled epidural analgesia
7.  The role of integrin-β/FAK in cyclic mechanical stimulation in MG-63 cells 
Objective: This study aims to explore the function of Integrin-β/FAK in the mechanical signal transduction and the connection with downstream ERK signal pathways. Methods: Human osteosarcoma MG63 cell lines were used in this study. The effects of mechanical strain on the Integrin-β1 expression, FAK and ERK signal pathway in Human osteosarcoma MG63 cells were detected using RT-PCR and Western-blotting methods. The localization of FAK in Human osteosarcoma MG63 cells were determined using immunofluorescent method. The interaction between Integrin-β1 and FAK were detected by using co-immunoprecipitation method. Results: The expression of Integrin-β1 shows a notable bimodel distribution, mechanical strain stimulation can promote Integrin-β1 expression and the phosphorylation of FAK and ERK, mechanical strain activated FAK and ERK mediated by Integrin-β1. Conclusion: Integrin-β1 may play an important role in osteoblast proliferation differentiation process, it might feel external strain stimulation through ECM composition and makes FAK phosphated through the interaction with FAK, thus causing a series of activation of signal molecules. Finally it reduces MAPK (ERK) activation and cellular responses to finish mechanical signal transduction.
PMCID: PMC4270589  PMID: 25550780
Integrin-β; human osteosarcoma MG63 cells; mechanical stimulation; focal adhesion kinase (FAK); ERK signal pathway
8.  Testing Stem Cell Therapy in a Rat Model of Inflammatory Bowel Disease: Role of Bone Marrow Stem Cells and Stem Cell Factor in Mucosal Regeneration 
PLoS ONE  2014;9(10):e107891.
The gastrointestinal (GI) mucosal cells turnover regularly under physiological conditions, which may be stimulated in various pathological situations including inflammation. Local epithelial stem cells appear to play a major role in such mucosal renewal or pathological regeneration. Less is clear about the involvement of multipotent stem cells from blood in GI repair. We attempted to explore a role of bone marrow mesenchymal stromal cells (BMMSCs) and soluble stem cell factor (SCF) in GI mucosa regeneration in a rat model of inflammatory bowel diseases (IBD).
BMMSCs labelled with the fluorescent dye PKH26 from donor rats were transfused into rats suffering indomethacin-induced GI injury. Experimental effects by BMMSCs transplant and SCF were determined by morphometry of intestinal mucosa, double labeling of PKH26 positive BMMSCs with endogenous proliferative and intestinal cell markers, and western blot and PCR analyses of the above molecular markers in the recipient rats relative to controls.
PKH26 positive BMMSCs were found in the recipient mucosa, partially colocalizing with the proliferating cell nuclear antigen (PCNA), Lgr5, Musashi-1 and ephrin-B3. mRNA and protein levels of PCNA, Lgr5, Musashi-1 and ephrin-B3 were elevated in the intestine in BMMSCs-treated rats, most prominent in the BMMSCs-SCF co-treatment group. The mucosal layer and the crypt layer of the small intestine were thicker in BMMSCs-treated rats, more evident in the BMMSCs-SCF co-treatment group.
BMMSCs and SCF participate in but may play a synergistic role in mucosal cell regeneration following experimentally induced intestinal injury. Bone marrow stem cell therapy and SCF administration may be of therapeutic value in IBD.
PMCID: PMC4195572  PMID: 25309991
9.  Effects of Astragaloside IV combined with the active components of Panax notoginseng on oxidative stress injury and nuclear factor-erythroid 2-related factor 2/heme oxygenase-1 signaling pathway after cerebral ischemia-reperfusion in mice 
Pharmacognosy Magazine  2014;10(40):402-409.
Astragalus and Panax notoginseng are traditional Chinese Medicines used for the treatments of ischemic cerebrovascular disease, being often combined together in China and achieving a good effect.
The objective of this study is to investigate the effects of astragaloside-IV (AST-IV) (the effective component of Astragalus) combined with ginsenoside Rg1, ginsenoside Rb1, notoginsenoside R1 (the effective components of P. notoginseng) on oxidative stress injury after cerebral ischemia-reperfusion in mice, and to explore the mechanisms through nuclear factor-erythroid 2-related factor-2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway.
Materials and Methods:
C57BL/6 mice were randomly grouped after treated for 3 days, the model of cerebral ischemia-reperfusion injury was established, and the brain tissues were detected.
AST-IV combined with ginsenoside Rg1, ginsenoside Rb1, notoginsenoside R1 could increase significantly the survival rate of nerve cell; decrease the contents of malondialdehyde, nitric oxide, increase the activity of superoxide dismutase and the level of glutathione; Nrf2 was down-regulated in the cytoplasm while up-regulated in nucleus, nuclear translocation rate raised as well as HO-1 messenger ribonucleic acid and protein expressions increased. The effects of four active components combination were better than those of the active components alone.
Active components of Astragalus and P. notoginseng had the effects against cerebral ischemia-reperfusion injury, which were related to the antioxidative stress after cerebral ischemia-reperfusion. AST-IV combined with ginsenoside Rg1, ginsenoside Rb1, notoginsenoside R1 could strengthen the antagonism effects on ischemia-reperfusion and oxidative stress injury, the mechanism underlying might be associated with jointly activating Nrf2/HO-1 signaling pathway after cerebral ischemia-reperfusion.
PMCID: PMC4239715  PMID: 25422538
Astragaloside IV; combination; ginsenoside Rb1; ginsenoside Rg1; notoginsenoside R1; nuclear factor-erythroid 2-related factor-2/heme oxygenase
10.  Contribution of β-Lactamases and Porin Proteins OmpK35 and OmpK36 to Carbapenem Resistance in Clinical Isolates of KPC-2-Producing Klebsiella pneumoniae 
Fifty-seven carbapenem-resistant Klebsiella pneumoniae isolates belonging to ST11 (50 isolates), ST423 (5 isolates), and two other sequence types were studied. All were positive for blaKPC-2, blaTEM-1, and blaCTX-M-14. SDS-PAGE analysis of six representative isolates demonstrated varied porin expression. Nevertheless, when blaKPC-2 was deleted, carbapenem resistance was markedly reduced. Additionally, SHV-12, DHA-1, and/or VIM-1 appeared to contribute to accessory carbapenemase activity. In contrast, OmpK35 and/or OmpK36 deficiency seemed to serve only as a minor cooperative factor.
PMCID: PMC3910872  PMID: 24277031
11.  A potential therapeutic effect of CYP2C8 overexpression on anti-TNF-α activity 
Epoxyeicosatrienoic acids (EETs) are generated from arachidonic acid catalysed by cytochrome P450 (CYP) epoxygenases. In addition to regulating vascular tone EETs may alleviate inflammation and ROS. The present study was conducted to determine whether CYP2C8 gene overexpression was able to increase the level of EETs, and subsequently prevent TNF-α induced inflammation and reactive oxygen species (ROS) in human umbilical vein endothelial cells (HUVECs) and macrophages. Peroxisome proliferator-activated receptor γ (PPARγ) activation, nuclear factor-κB (NF-κB) activation, endothelial nitric oxide synthase (eNOS) activation, gp-91 activation, and inflammatory cytokine expression were detected by western blot analysis or enzyme-linked immunosorbent assay. Intracellular reactive oxygen species (ROS) was measured by flow cytometry, while the migration of vascular smooth muscle cells (VSMCs) was detected by Transwell assay. pCMV-mediated CYP2C8 overexpression and its metabolites, EETs, markedly suppressed TNF-α induced inflammatory cytokines IL-6 and MCP-1 expression via the activation of NF-κB and degradation of IκBα. Moreover, pretreatment with 11,12-EET significantly blocked TNF-α-induced ROS production. CYP2C8-derived EETs also effectively alleviated the migration of VSMCs and improved the function of endothelial cells through the upregulation of eNOS, which was significantly decreased under the stimulation of TNF-α. Furthermore, these protective effects observed were mediated by PPARγ activation. To the best of our knowledge, the results of the present study demonstrated for the first time that CYP2C8-derived EETs exerted antivascular inflammatory and anti-oxidative effects, at least in part, through the activation of PPARγ. Thus, the CYP2C8 gene may be useful in the prevention and treatment of vascular inflammatory diseases.
PMCID: PMC4121355  PMID: 25017038
CYP2C8; epoxyeicosatrienoic acids; inflammation; reactive oxygen species; nuclear factor-κB; atherosclerosis
12.  Left Ventricular Myocardial Function in Hemodialysis and Nondialysis Uremia Patients: A Three-Dimensional Speckle-Tracking Echocardiography Study 
PLoS ONE  2014;9(6):e100265.
Several studies have demonstrated that uremic patients who have preserved left ventricular ejection fraction (LVEF) could still have the potential for systolic dysfunction. The aim of this study was to assess the differences between the left ventricular (LV) myocardial function in hemodialysis and nondialysis uremic patients based on three-dimensional speckle-tracking echocardiography.
The study population consisted of 35 maintenance hemodialysis patients (the hemodialysis group), 30 uremic patients who were hospitalized for the creation of a primary arteriovenous fistula (the nondialysis group), and 32 healthy volunteers. All of the patients had normal left ventricular ejection fractions (i.e., 55% or greater). Three-dimensional speckle tracking echocardiography was performed to assess the left ventricle's global three-dimensional strain, regional longitudinal strain, circumferential strain, and radial strain.
The left ventricular regional longitudinal strain, radial strain, circumferential strain, and global three-dimensional strain were significantly decreased in the nondialysis patients compared with the other two groups (all, P<0.001). However, the three-dimensional strain and the regional longitudinal strain were lower in the hemodialysis patients than in the controls (P<0.01). In the hemodialysis patients and the control group, the longitudinal strain, circumferential strain, and radial strain were higher at the apical level than they were at the basal level and midlevels. A multivariate linear regression analysis showed that the blood urea nitrogen and creatinine levels were independently associated with the values of the global three-dimensional strain (β = −0.217, P = 0.000; β = −0.243, P = 0.011, respectively) and the longitudinal strain (β = −0.154, P = 0.032; β = −0.188, P = 0.029, respectively).
Three-dimensional speckle-tracking echocardiography may detect myocardial dysfunction in patients with uremia who have preserved LVEF. The global three-dimensional strain and the regional longitudinal strain appear to be superior in hemodialysis patients compared with nondialysis patients.
PMCID: PMC4069011  PMID: 24959903
13.  Population pharmacokinetics of trastuzumab emtansine (T-DM1), a HER2-targeted antibody–drug conjugate, in patients with HER2-positive metastatic breast cancer: clinical implications of the effect of covariates 
Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising the humanized monoclonal antibody trastuzumab linked to DM1, a highly potent cytotoxic agent. A population pharmacokinetic (PK) analysis was performed to estimate typical values and interindividual variability of T-DM1 PK parameters and the effects of clinically relevant covariates.
Serum samples were collected from 671 patients with human epidermal growth factor receptor 2-positive locally advanced or metastatic breast cancer (MBC) who received single-agent T-DM1 in five phase I to phase III studies. Nonlinear mixed-effects modeling with the first-order conditional estimation method was used.
A linear two-compartment model with first-order elimination from the central compartment described T-DM1 PKs in the clinical dose range. T-DM1 elimination clearance was 0.676 L/day, volume of distribution in the central compartment (Vc) was 3.127 L, and terminal elimination half-life was 3.94 days. Age, race, region, and renal function did not influence T-DM1 PK. Given the low-to-moderate effect of all statistically significant covariates on T-DM1 exposure, none of these covariates is expected to result in a clinically meaningful change in T-DM1 exposure.
T-DM1 PK properties are consistent and predictable in patients. A further refinement of dose based on baseline covariates other than body weight for the current 3.6 mg/kg regimen would not yield clinically meaningful reductions in interindividual PK variability in patients with MBC.
Electronic supplementary material
The online version of this article (doi:10.1007/s00280-014-2500-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4112050  PMID: 24939213
Ado-trastuzumab emtansine; T-DM1; HER2; Pharmacokinetics; Metastatic breast cancer
14.  Dlx6 Regulates Molecular Properties of the Striatum and Central Nucleus of the Amygdala 
The Journal of comparative neurology  2011;519(12):2320-2334.
We describe here the prenatal telencephalic expression of Dlx6 RNA and β-galactosidase driven from a mutant Dlx6 locus. The mutant Dlx6 allele, which we believe is either a null or severe hypomorph, has an IRES-lacZ-neomycin resistance cassette inserted into the Dlx6 homeobox coding sequence (Dlx6LacZ). We compared expression from the Dlx6-lacZ (Dlx6LacZ) allele in heterozygotes (Dlx6LacZ/+), with the expression of Dlx1, Dlx2, Dlx5 and Dlx6 RNA. Like these wild-type alleles, Dlx6LacZ is expressed in the developing ganglionic eminences, and their derivatives. Unlike the other Dlx genes, Dlx6 and Dlx6LacZ expression is not readily observed in tangentially migrating interneurons. In addition to Dlx6’s expression at later stages of differentiation of many basal ganglia nuclei, it shows particularly robust expression in the central nucleus of the amygdala. Histological analysis of Dlx6 mutants (Dlx6LacZ/LacZ) shows that this homeobox transcription factor is required for molecular properties of the striatum, nucleus accumbens, olfactory tubercle, and central nucleus of the amygdala. For instance, we observed reduced of Golf, RXRγ, and Tiam2 expression in the striatum, and reduced Dlx5 expression in the central nucleus of the amygdala. RNA expression array analysis of the E18.5 striatum was useful in identifying the transcription factors that are expressed in this tissue, but did not identify major changes in gene expression in the Dlx6LacZ/LacZ mutant.
PMCID: PMC4019376  PMID: 21452241
Dlx; striatum; amygdala; mouse; development
15.  Extracts from Curcuma zedoaria Inhibit Proliferation of Human Breast Cancer Cell MDA-MB-231 In Vitro 
Objective. To evaluate the effect of petroleum ether extracts of Curcuma zedoaria on the proliferation of human triple negative breast cancer cell line MDA-MB-231. Methods. The reagents were isolated from Curcuma zedoaria by petroleum ether fraction. It was assayed by CCK8 for MDA-MB-231 cellular viability with various concentrations and days, cell cycle analyses, Western Blot analysis, and Realtime Reverse Transcriptase PCR analyses for chemokines molecules including E-cadherin, and E-selectin, and adhesion molecules including CCR7, SLC, SDF-1, and CXCR4. Epirubicin was used as control in the study. Results. MDA-MB-231 cells were inhibited by petroleum ether extracts of Curcuma zedoaria (P < 0.05), and the inhibition rate was dependent on concentrations and time. Petroleum ether extracts of Curcuma zedoaria as well as Epirubicin produce a significant G0/G1 cell cycle arrest. The level of expression of proteins E-cadherin and E-cadherin mRNA was significantly increased, while proteins SDF-1, CCR7, and CXCR4 mRNA were decreased after being incubated with petroleum ether extracts of Curcuma zedoaria at the concentrations of 300 μg/mL than control (P < 0.05). The differences were that the protein CXCR4 mRNA expression level was higher than vehicle. Conclusions. MDA-MB-231 cells were inhibited by petroleum ether extracts of Curcuma zedoaria.
PMCID: PMC4026840  PMID: 24883070
16.  Surface-Enhanced Raman Scattering Study on Graphene-Coated Metallic Nanostructure Substrates 
Graphene, which has a linear electronic band structure, is widely considered as a semimetal. In the present study, we combine graphene with conventional metallic surface-enhanced Raman scattering (SERS) substrates to achieve higher sensitivity of SERS detection. We synthesize high-quality, single-layer graphene sheets by chemical vapor deposition (CVD) and transfer them from copper foils to gold nanostructures, i.e., nanoparticle or nanohole arrays. SERS measurements are carried out on methylene blue (MB) molecules. The combined graphene nanostructure substrates show about threefold or ninefold enhancement in the Raman signal of MB, compared with the bare nanohole or nanoparticle substrates, respectively. The difference in the enhancement factors is explained by the different morphologies of graphene on the two substrates with the aid of numerical simulations. Our study indicates that applying graphene to SERS substrates can be an effective way to improve the sensitivity of conventional metallic SERS substrates.
PMCID: PMC3998773  PMID: 24772200
Graphene; SERS; Plasmonics; Nanostructure
17.  JNK-mediated phosphorylation of DLK suppresses its ubiquitination to promote neuronal apoptosis 
The Journal of Cell Biology  2013;202(5):747-763.
Neuronal injury induces JNK phosphorylation of DLK, which reduces DLK ubiquitination and creates a positive feedback loop to enhance JNK signaling and increase apoptosis.
Neurons are highly polarized cells that often project axons a considerable distance. To respond to axonal damage, neurons must transmit a retrograde signal to the nucleus to enable a transcriptional stress response. Here we describe a mechanism by which this signal is propagated through injury-induced stabilization of dual leucine zipper-bearing kinase (DLK/MAP3K12). After neuronal insult, specific sites throughout the length of DLK underwent phosphorylation by c-Jun N-terminal kinases (JNKs), which have been shown to be downstream targets of DLK pathway activity. These phosphorylation events resulted in increased DLK abundance via reduction of DLK ubiquitination, which was mediated by the E3 ubiquitin ligase PHR1 and the de-ubiquitinating enzyme USP9X. Abundance of DLK in turn controlled the levels of downstream JNK signaling and apoptosis. Through this feedback mechanism, the ubiquitin–proteasome system is able to provide an additional layer of regulation of retrograde stress signaling to generate a global cellular response to localized external insults.
PMCID: PMC3760612  PMID: 23979718
18.  Enrichment and Purging of Human Embryonic Stem Cells by Detection of Cell Surface Antigens Using the Monoclonal Antibodies TG30 and GCTM-2 
Human embryonic stem cells (hESC) can self-renew indefinitely in vitro, and with the appropriate cues can be induced to differentiate into potentially all somatic cell lineages. Differentiated hESC derivatives can potentially be used in transplantation therapies to treat a variety of cell-degenerative diseases. However, hESC differentiation protocols usually yield a mixture of differentiated target and off-target cell types as well as residual undifferentiated cells. For the translation of differentiated hESC-derivatives from the laboratory to the clinic, it is important to be able to discriminate between undifferentiated (pluripotent) and differentiated cells, and generate methods to separate these populations. Safe application of hESC-derived somatic cell types can only be accomplished with pluripotent stem cell-free populations, as residual hESCs could induce tumors known as teratomas following transplantation. Towards this end, here we describe a methodology to detect pluripotency associated cell surface antigens with the monoclonal antibodies TG30 (CD9) and GCTM-2 via fluorescence activated cell sorting (FACS) for the identification of pluripotent TG30Hi-GCTM-2Hi hESCs using positive selection. Using negative selection with our TG30/GCTM-2 FACS methodology, we were able to detect and purge undifferentiated hESCs in populations undergoing very early-stage differentiation (TG30Neg-GCTM-2Neg). In a further study, pluripotent stem cell-free samples of differentiated TG30Neg-GCTM-2Neg cells selected using our TG30/GCTM-2 FACS protocol did not form teratomas once transplanted into immune-compromised mice, supporting the robustness of our protocol. On the other hand, TG30/GCTM-2 FACS-mediated consecutive passaging of enriched pluripotent TG30Hi-GCTM-2Hi hESCs did not affect their ability to self-renew in vitro or their intrinsic pluripotency. Therefore, the characteristics of our TG30/GCTM-2 FACS methodology provide a sensitive assay to obtain highly enriched populations of hPSC as inputs for differentiation assays and to rid potentially tumorigenic (or residual) hESC from derivative cell populations.
PMCID: PMC4044978  PMID: 24335647
Stem Cell Biology; Issue 82; Stem cells; cell surface antigens; antibodies; FACS; purging stem cells; differentiation; pluripotency; teratoma; human embryonic stem cells (hESC)
19.  Impaired Spatial Learning and Memory after Sevoflurane–Nitrous Oxide Anesthesia in Aged Rats Is Associated with Down-Regulated cAMP/CREB Signaling 
PLoS ONE  2013;8(11):e79408.
Neurocognitive deficits arising from anesthetic exposure have recently been debated, while studies have shown that the phosphorylation of cyclic AMP response element-binding protein (CREB) in the hippocampus is critical for long-term memory. To better understand the neural effects of inhalational anesthetics, we studied the behavioral and biochemical changes in aged rats that were exposed to sevoflurane (Sev) and nitrous oxide (N2O) for 4 h. Eighteen-month-old rats were randomly assigned to receive 1.3% sevoflurane and 50% nitrous oxide/50% oxygen or 50% oxygen for 4 h. Spatial learning and memory were tested with the Morris water maze 48 h after exposure, and the results showed that sevoflurane–nitrous oxide exposure induced a significant deficit in spatial learning acquisition and memory retention. Experiments revealed that the cAMP and pCREB levels in the dorsal hippocampus were decreased in rats with anesthetic exposure in comparison with control rats 48 h after anesthesia as well as 15 min after the probe trial, but there were no significant differences in CREB expression. Besides these, the current study also found the DG neurogenesis significantly decreased as well as neuronal loss and neuronal apoptosis increased in the hippocampus of rats exposed to Sev+N2O. The current study demonstrated that down-regulation of cAMP/CREB signaling, decrease of CREB-dependent neurogenesis and neuronal survival in the hippocampus contributed to the neurotoxicity and cognitive dysfunction induced by general anesthesia with sevoflurane–nitrous oxide.
PMCID: PMC3829840  PMID: 24260214
20.  Expression of NgBR Is Highly Associated with Estrogen Receptor Alpha and Survivin in Breast Cancer 
PLoS ONE  2013;8(11):e78083.
NgBR is a type I receptor with a single transmembrane domain and was identified as a specific receptor for Nogo-B. Our recent findings demonstrated that NgBR binds farnesylated Ras and recruits Ras to the plasma membrane, which is a critical step required for the activation of Ras signaling in human breast cancer cells and tumorigenesis. Here, we first use immunohistochemistry and real-time PCR approaches to examine the expression patterns of Nogo-B and NgBR in both normal and breast tumor tissues. Then, we examine the relationship between NgBR expression and molecular subtypes of breast cancer, and the roles of NgBR in estrogen-dependent survivin signaling pathway. Results showed that NgBR and Nogo-B protein were detected in both normal and breast tumor tissues. However, the expression of Nogo-B and NgBR in breast tumor tissue was much stronger than in normal breast tissue. The statistical analysis demonstrated that NgBR is highly associated with ER-positive/HER2-negative breast cancer. We also found that the expression of NgBR has a strong correlation with the expression of survivin, which is a well-known apoptosis inhibitor. The correlation between NgBR and survivin gene expression was further confirmed by real-time PCR. In vitro results also demonstrated that estradiol induces the expression of survivin in ER-positive T47D breast tumor cells but not in ER-negative MDA-MB-468 breast tumor cells. NgBR knockdown with siRNA abolishes estradiol-induced survivin expression in ER-positive T47D cells but not in ER-negative MDA-MB-468 cells. In addition, estradiol increases the expression of survivin and cell growth in ER-positive MCF-7 and T47D cells whereas knockdown of NgBR with siRNA reduces estradiol-induced survivin expression and cell growth. In summary, these results indicate that NgBR is a new molecular marker for breast cancer. The data suggest that the expression of NgBR may be essential in promoting ER-positive tumor cell proliferation via survivin induction in breast cancer.
PMCID: PMC3817177  PMID: 24223763
21.  Helios Transcription Factor Expression Depends on Gsx2 and Dlx1&2 Function in Developing Striatal Matrix Neurons 
Stem Cells and Development  2011;21(12):2239-2251.
Development of the nervous system is finely regulated by consecutive expression of cell-specific transcription factors. Here we show that Helios, a member of the Ikaros transcription factor family, is expressed in ectodermal and neuroectodermal-derived tissues. During embryonic development, Helios is expressed by several brain structures including the lateral ganglionic eminence (LGE, the striatal anlage); the cingulated, insular and retrosplenial cortex; the hippocampus; and the accessory olfactory bulb. Moreover, Helios is also expressed by Purkinje neurons during postnatal cerebellar development. Within the LGE, Helios expression follows a dynamic spatio-temporal pattern starting at embryonic stages (E14.5), peaking at E18.5, and completely disappearing during postnatal development. Helios is expressed by a small population of nestin-positive neural progenitor cells located in the subventricular zone as well as by a larger population of immature neurons distributed throughout the mantle zone. In the later, Helios is preferentially expressed in the matrix compartment, where it colocalizes with Bcl11b and Foxp1, well-known markers of striatal projection neurons. In addition, we observed that Helios expression is not detected in Dlx1/2 and Gsx2 null mutants, while its expression is maintained in Ascl1 mutants. These findings allow us to introduce a new transcription factor in the cascade of events that take part of striatal development postulating the existence of at least 4 different neural progenitors in the LGE. An Ascl1-independent but Gsx2- & Dlx1/2-dependent precursor will express Helios defining a new lineage for a subset of matrix striatal neurons.
PMCID: PMC3411368  PMID: 22142223
22.  Application of CRT-D in a Marfan syndrome patient with chronic heart failure accompanied by ventricular tachycardia and ventricular fibrillation 
Marfan syndrome is a systemic connective tissue disease that could affect the cardiovascular system and eventually lead to heart enlargement and heart failure with high mortality, mainly due to progressive heart failure and/or sudden cardiac death caused by malignant arrhythmia. Here we report that a patient received a cardiac resynchronization therapy-defibrillator (CRT-D) with a pre-monitor function for heart failure and experienced obvious improvements in his cardiac function. Postoperative follow-up showed that the patient had reduced morbidity and hospitalization for heart failure, and also experienced improved quality of life.
PMCID: PMC3735978  PMID: 23897797
23.  Differentiation of Breast Cancer from Fibroadenoma with Dual-Echo Dynamic Contrast-Enhanced MRI 
PLoS ONE  2013;8(7):e67731.
Dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) of the breast is a routinely used imaging method which is highly sensitive for detecting breast malignancy. Specificity, though, remains suboptimal. Dynamic susceptibility contrast magnetic resonance imaging (DSC MRI), an alternative dynamic contrast imaging technique, evaluates perfusion-related parameters unique from DCE MRI. Previous work has shown that the combination of DSC MRI with DCE MRI can improve diagnostic specificity, though an additional administration of intravenous contrast is required. Dual-echo MRI can measure both T1W DCE MRI and T2*W DSC MRI parameters with a single contrast bolus, but has not been previously implemented in breast imaging. We have developed a dual-echo gradient-echo sequence to perform such simultaneous measurements in the breast, and use it to calculate the semi-quantitative T1W and T2*W related parameters such as peak enhancement ratio, time of maximal enhancement, regional blood flow, and regional blood volume in 20 malignant lesions and 10 benign fibroadenomas in 38 patients. Imaging parameters were compared to surgical or biopsy obtained tissue samples. Receiver operating characteristic (ROC) curves and area under the ROC curves were calculated for each parameter and combination of parameters. The time of maximal enhancement derived from DCE MRI had a 90% sensitivity and 69% specificity for predicting malignancy. When combined with DSC MRI derived regional blood flow and volume parameters, sensitivity remained unchanged at 90% but specificity increased to 80%. In conclusion, we show that dual-echo MRI with a single administration of contrast agent can simultaneously measure both T1W and T2*W related perfusion and kinetic parameters in the breast and the combination of DCE MRI and DSC MRI parameters improves the diagnostic performance of breast MRI to differentiate breast cancer from benign fibroadenomas.
PMCID: PMC3699626  PMID: 23844077
24.  Draft Genome Sequence of the Fish Pathogen Vibrio harveyi Strain ZJ0603 
Journal of Bacteriology  2012;194(23):6644-6645.
Vibrio harveyi is an important pathogen that causes vibriosis in various aquatic organisms. Here, we announce the draft genome sequence of V. harveyi strain ZJ0603, which was isolated from diseased Orange-spotted grouper (Epinephelus coioides) in Guangdong, China.
PMCID: PMC3497516  PMID: 23144396
25.  Adiponectin-11377CG Gene Polymorphism and Type 2 Diabetes Mellitus in the Chinese Population: A Meta-Analysis of 6425 Subjects 
PLoS ONE  2013;8(4):e61153.
Although adiponectin −11377CG gene polymorphism is implied to be associated with increased type 2 diabetes mellitus (T2DM) risk, results of individual studies are inconsistent.
Objective and Methods
A meta-analysis consisting of 12 individual studies, including a total of 6425 participants, was carried out in order to investigate the association of adiponectin −11377CG gene polymorphism with T2DM. The pooled odds ratio (OR) and its corresponding confidence interval (CI) at 95% were assessed through the random- or fixed- effect model.
A significant relationship was observed between adiponectin −11377CG gene polymorphism and T2DM under allelic (OR: 1.150, 95% CI: 1.060 to 1.250, P = 0.001), recessive (OR: 1.450, 95% CI: 1.180–1.770, P = 0.0004), dominant (OR: 1.071, 95% CI: 1.013–1.131, P = 0.015), additive (OR: 1.280, 95% CI: 1.090–1.510, P = 0.002), and homozygous genetic models (OR: 1.620, 95% CI: 1.310–1.990, P<0.00001). No significant association was found between them under the heterozygous genetic model (OR: 1.640, 95% CI: 0.850–3.170, P = 0.140).
Adiponectin −11377CG gene polymorphism was significantly associated with T2DM risk susceptibility. G allele carriers are predisposed to T2DM risk.
PMCID: PMC3621968  PMID: 23585875

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