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1.  Self-assembled Hybrid Nanoparticles for Targeted Co-delivery of Two Drugs into Cancer Cells 
A therapeutic aptamer-lipid-poly(lactide-co-glycolic acid) hybrid nanoparticle-based drug delivery system was prepared and characterized. The hybrid can co-deliver two different drugs with distinct solubility characteristics and different anticancer mechanisms to target cancer cells with high specificity and efficiency.
PMCID: PMC3973031  PMID: 24516863
2.  Reversible Phase Transfer of Nanoparticles Based on Photoswitchable Host–Guest Chemistry 
ACS Nano  2014;8(3):2555-2561.
An azobenzene-containing surfactant was synthesized for the phase transfer of α-cyclodextrin (α-CD)-capped gold nanoparticles between water and toluene phases by host–guest chemistry. With the use of the photoisomerization of azobenzene, the reversible phase transfer of gold nanoparticles was realized by irradiation with UV and visible light. Furthermore, the phase transfer scheme was applied for the quenching of a reaction catalyzed by gold nanoparticles, as well as the recovery and recycling of the gold nanoparticles from aqueous solutions. This work will have significant impact on materials transfer and recovery in catalysis and biotechnological applications.
PMCID: PMC4004314  PMID: 24524295
azobenzene; cyclodextrin; host−guest systems; phase transfer; photoresponsive systems
3.  Predictors of Percutaneous Catheter Drainage (PCD) after Abdominal Paracentesis Drainage (APD) in Patients with Moderately Severe or Severe Acute Pancreatitis along with Fluid Collections 
PLoS ONE  2015;10(2):e0115348.
Although we previously demonstrated abdominal paracentesis drainage (APD) preceding percutaneous catheter drainage (PCD) as the central step for treating patients with moderately severe (MSAP) or severe acute pancreatitis (SAP), the predictors leading to PCD after APD have not been studied.
Consecutive patients with MSAP or SAP were recruited between June 2011 and June 2013. As a step-up approach, all patients initially received medical management, later underwent ultrasound-guided APD before PCD, if necessary, followed by endoscopic necrosectomy through the path formed by PCD. APD primarily targeted fluid in the abdominal or pelvic cavities, whereas PCD aimed at (peri)pancreatic fluid.
Of the 92 enrolled patients, 40 were managed with APD alone and 52 received PCD after APD (14 required necrosectomy after initial PCD). The overall mortality was 6.5%. Univariate analysis showed that among the 20 selected parameters, 13 factors significantly affected PCD intervention after APD. Multivariate analysis revealed that infected (peri)pancreatic collections (P = -0.001), maximum extent of necrosis of more than 30% of the pancreas (P = -0.024), size of the largest necrotic peri(pancreatic) collection (P = -0.007), and reduction of (peri)pancreatic fluid collections by <50% after APD (P = -0.008) were all independent predictors of PCD.
Infected (peri)pancreatic collections, a largest necrotic peri(pancreatic) collection of more than 100 ml, and reduction of (peri)pancreatic fluid collections by <50% after APD could effectively predict the need for PCD in the early course of the disease.
PMCID: PMC4319763  PMID: 25659143
4.  Capture, Release and Culture of Circulating Tumor Cells from Pancreatic Cancer Patients using an Enhanced Mixing Chip 
Lab on a chip  2013;14(1):89-98.
Circulating tumor cells (CTCs) from peripheral blood hold important information for cancer diagnosis and disease monitoring. Analysis of this “liquid biopsy” holds the promise to usher in a new era of personalized therapeutic treatments and real-time monitoring for cancer patients. But the extreme rarity of CTCs in blood makes their isolation and characterization technologically challenging. This paper reports the development of a geometrically enhanced mixing (GEM) chip for high-efficiency and high-purity tumor cell capture. We also successfully demonstrated the release and culture of the captured tumor cells, as well as the isolation of CTCs from cancer patients. The high-performance microchip is based on geometrically optimized micromixer structures, which enhance the transverse flow and flow folding, maximizing the interaction between CTCs and antibody-coated surfaces. With the optimized channel geometry and flow rate, the capture efficiency reached >90% with a purity of >84% when capturing spiked tumor cells in buffer. The system was further validated by isolating a wide range of spiked tumor cells (50–50,000) in 1 mL of lysed blood and whole blood. With the combination of trypsinization and high flow rate washing, captured tumor cells were efficiently released. The released cells were viable and able to proliferate, and showed no difference compared with intact cells that were not subjected to the capture and release process. Furthermore, we applied the device for detecting CTCs from metastatic pancreatic cancer patients’ blood; and CTCs were found from 17 out of 18 samples (>94%). We also tested the potential utility of the device in monitoring the response to anti-cancer drug treatment in pancreatic cancer patients, and the CTC numbers correlated with the clinical computed tomograms (CT scans) of tumors. The presented technology shows great promise for accurate CTC enumeration, biological studies of CTCs and cancer metastasis, as well as for cancer diagnosis and treatment monitoring.
PMCID: PMC3918168  PMID: 24220648
5.  Differentiation between Malignant and Benign Solitary Lesions in the Liver with 18FDG PET/CT: Accuracy of Age-related Diagnostic Standard 
Journal of Cancer  2015;6(1):40-47.
Objective: This study was to determine the reliability of age-stratified diagnostic index in differential diagnosis of malignant and benign solitary lesions in the liver using fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18FDG PET/CT).
Methods: The enrolled 272 patients with solitary lesions in the liver were divided into three age groups, younger group (under 50 years), middle-aged group (50-69 years), and elderly group (70 years and above). Patients' ages were compared, and the optimal cut-offs of the standard uptake value (SUV) ratio (tumor-to-non-tumor ratio of the SUV), as well as areas under the curves (AUC), were evaluated in terms of malignant and benign lesions in each age group by using receiver operating characteristic (ROC) analysis. Based on optimal cut-offs, the sensitivity, specificity, accuracy were calculated, and the diagnostic accordance rate was compared between each age group and all patients, supported by 18FDG PET/CT imaging data.
Results: There was a significant age difference between the malignant and benign groups (t=3.905 p=0.0001). ROC analysis showed that the optimal cut-off value in all patients, younger group, middle-aged group and elderly group was 1.25, 1.17, 1.45 and 1.25 for SUVratio, and 0.856, 0.962, 0.650, 0.973 for AUC. The chi-square test proved that diagnostic accordance rate of 18FDG PET/CT in younger group and elderly group were superior to that in all patients (χ2=13.352, P=0.0003) and (χ2=8.494, P=0.0036). Conversely, overall diagnostic accordance rate in all patient group was higher than that in middle-aged group (χ2=9.057, P=0.0026). Representative 18FDG PET/CT imaging findings are demonstrated.
Conclusion: This study indicates that diagnostic optimal cut-offs of SUVratio of liver solitary lesions of 18FDG PET/CT were different in each age group. In addition, the diagnostic performance of SUVratio was better in younger and elderly groups than that in all patients, and was poorer in middle-aged group than that in all patients. Therefore, age difference appears to be one of the important factors for discriminating malignant liver lesions from benign ones using 18 FDG PET/CT.
PMCID: PMC4278913  PMID: 25553087
Positron emission tomography/computed tomography (PET/CT); Standardized up take value (SUV); Solitary hepatic lesion; Age-related.
6.  Trichloroethylene-Induced Gene Expression and DNA Methylation Changes in B6C3F1 Mouse Liver 
PLoS ONE  2014;9(12):e116179.
Trichloroethylene (TCE), widely used as an organic solvent in the industry, is a common contaminant in air, soil, and water. Chronic TCE exposure induced hepatocellular carcinoma in mice, and occupational exposure in humans was suggested to be associated with liver cancer. To understand the role of non-genotoxic mechanism(s) for TCE action, we examined the gene expression and DNA methylation changes in the liver of B6C3F1 mice orally administered with TCE (0, 100, 500 and 1000 mg/kg b.w. per day) for 5 days. After 5 days TCE treatment at a dose level of 1000 mg/kg b.w., a total of 431 differentially expressed genes were identified in mouse liver by microarray, of which 291 were up-regulated and 140 down-regulated. The expression changed genes were involved in key signal pathways including PPAR, proliferation, apoptosis and homologous recombination. Notably, the expression level of a number of vital genes involved in the regulation of DNA methylation, such as Utrf1, Tet2, DNMT1, DNMT3a and DNMT3b, were dysregulated. Although global DNA methylation change was not detected in the liver of mice exposed to TCE, the promoter regions of Cdkn1a and Ihh were found to be hypo- and hypermethylated respectively, which correlated negatively with their mRNA expression changes. Furthermore, the gene expression and DNA methylation changes induced by TCE were dose dependent. The overall data indicate that TCE exposure leads to aberrant DNA methylation changes, which might alter the expression of genes involved in the TCE-induced liver tumorgenesis.
PMCID: PMC4280179  PMID: 25549359
7.  Glycyrrhizin Suppresses the Expressions of HMGB1 and Relieves the Severity of Traumatic Pancreatitis in Rats 
PLoS ONE  2014;9(12):e115982.
High mobility group box 1 (HMGB1) plays important roles in a large variety of diseases; glycyrrhizin (GL) is recognized as an HMGB1 inhibitor. However, few studies have focused on whether glycyrrhizin can potentially improve the outcome of traumatic pancreatitis (TP) by inhibiting HMGB1.
A total of 60 male Wistar rats were randomly divided into three groups (n = 20 in each): Control group, TP group and TP-GL group. Pancreatic trauma was established with a custom-made biological impact machine-III, and GL was administered at 15 minutes after the accomplishment of operation. To determine survival rates during the first 7 days after injury, another 60 rats (n = 20 in each) were grouped and treated as mentioned above. At 24 hours of induction of TP, the histopathological changes in pancreas were evaluated and serum amylase levels were tested. Serum tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and HMGB1 were measured using enzyme linked immunosorbent assay. HMGB1 expressions in pancreas were measured using immunohistochemical staining, Western blot and Real-Time PCR analysis.
Serum levels of HMGB1, TNF-α and IL-6 were increased dramatically in TP group at 24 hours after induction of TP. However, these indicators were reduced significantly by GL administration in TP-GL group comparing with TP group (P<0.05). Meanwhile, survival analysis showed that the seven-day survival rate in TP-GL group was significantly higher than that in TP group (85% versus 65%, P<0.05). GL treatment significantly decreased the pancreatic protein and mRNA expressions of HMGB1 and ameliorated the pancreatic injury in rats with TP.
Glycyrrhizin might play an important role in improving survival rates and ameliorating pancreatic injury of TP by suppression of the expressions of HMGB1 and other proinflammatory cytokine.
PMCID: PMC4277455  PMID: 25541713
8.  Engineering of Serine-Deamination pathway, Entner-Doudoroff pathway and pyruvate dehydrogenase complex to improve poly(3-hydroxybutyrate) production in Escherichia coli 
Microbial Cell Factories  2014;13(1):172.
Poly(3-hydroxybutyrate) (PHB), a biodegradable bio-plastic, is one of the most common homopolymer of polyhydroxyalkanoates (PHAs). PHB is synthesized by a variety of microorganisms as intracellular carbon and energy storage compounds in response to environmental stresses. Bio-based production of PHB from renewable feedstock is a promising and sustainable alternative to the petroleum-based chemical synthesis of plastics. In this study, a novel strategy was applied to improve the PHB biosynthesis from different carbon sources.
In this research, we have constructed E. coli strains to produce PHB by engineering the Serine-Deamination (SD) pathway, the Entner-Doudoroff (ED) pathway, and the pyruvate dehydrogenase (PDH) complex. Firstly, co-overexpression of sdaA (encodes L-serine deaminase), L-serine biosynthesis genes and pgk (encodes phosphoglycerate kinase) activated the SD Pathway, and the resulting strain SD02 (pBHR68), harboring the PHB biosynthesis genes from Ralstonia eutropha, produced 4.86 g/L PHB using glucose as the sole carbon source, representing a 2.34-fold increase compared to the reference strain. In addition, activating the ED pathway together with overexpressing the PDH complex further increased the PHB production to 5.54 g/L with content of 81.1% CDW. The intracellular acetyl-CoA concentration and the [NADPH]/[NADP+] ratio were enhanced after the modification of SD pathway, ED pathway and the PDH complex. Meanwhile, these engineering strains also had a significant increase in PHB concentration and content when xylose or glycerol was used as carbon source.
Significant levels of PHB biosynthesis from different kinds of carbon sources can be achieved by engineering the Serine-Deamination pathway, Entner-Doudoroff pathway and pyruvate dehydrogenase complex in E. coli JM109 harboring the PHB biosynthesis genes from Ralstonia eutropha. This work demonstrates a novel strategy for improving PHB production in E. coli. The strategy reported here should be useful for the bio-based production of PHB from renewable resources.
PMCID: PMC4279783  PMID: 25510247
Escherichia coli; poly(3-hydroxybutyrate); L-serine deaminate; Entner-Doudoroff pathway; Pyruvate dehydrogenase complex
9.  The human constitutive androstane receptor promotes the differentiation and maturation of hepatic-like cells 
Developmental biology  2013;384(2):10.1016/j.ydbio.2013.10.012.
Expression of the constitutive androstane receptor (CAR, NR1I3) is enriched in the mature mammalian liver and increasingly recognized for its prominent role in regulating a myriad of processes including biotransformation, chemical transport, energy metabolism and lipid homeostasis. Previously, we demonstrated that CAR levels were markedly enhanced during the differentiation of hepatic-like cells derived from hESCs, prompting the hypothesis that CAR contributes a key functional role in directing human hepatogenesis. Here we demonstrate that over-expression of CAR in human embryonic stem cells (ESCs), transduced by a lentiviral vector, accelerates the maturation of hepatic-like cells, with CAR over-expressing cells exhibiting a 2.5-fold increase in albumin secretion by day 20 in culture differentiation, and significantly enhanced levels of mRNA expression of several liver-selective markers, including hepatic transcription factors, plasma proteins, biotransformation enzymes, and metabolic enzymes. CAR over-expressing cells also exhibited enhanced CITCO-inducible CYP3A7 enzymatic activity. Knockdown of CAR via siRNA attenuated the differentiation-dependent expression programs. In contrast, expression levels of the pregnane X receptor (PXR), a nuclear receptor most similar to CAR in primary sequence, were negligible in human fetal liver tissues or in the differentiating hESCs, and stable over-expression of PXR in hepatic-induced hESCs failed to enhance expression of hepatic phenotype markers. Together, these results define a novel role for human CAR in hepatic lineage commitment.
PMCID: PMC3872969  PMID: 24144921
CAR; PXR; Hepatic differentiation; Lentivirus; siRNA; hESCs; Drug metabolism
10.  Epidermal growth factor receptor pathway polymorphisms and the prognosis of hepatocellular carcinoma 
The EGFR signaling pathway is important in the control of vital processes in the carcinogenesis of hepatocellular carcinoma (HCC), including cell survival, cell cycle progression, tumor invasion and angiogenesis. In the current study, we aim to assess if genetic variants in the genes of the EGFR signaling pathway are associated with the prognosis of HCC. We genotyped 36 single nucleotide polymorphisms (SNP) in four core genes (EGF, EGFR, VEGF, and VEGFR2) by using DNA from blood samples of 363 HCC patients with surgical resection. The associations between genotypes and overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method. Hazard ratios (HRs) and 95% confident intervals (CIs) were estimated for the multivariate survival analyses by Cox proportional hazards regression models, adjusting for age, gender, family history, HBsAg and AFP. We found that five SNPs in the VEGFR2 gene were significantly associated with clinical outcomes of HCC patients. Among them, four SNPs (rs7692791, rs2305948, rs13109660, rs6838752) were associated with OS (p=0.035, 0.038, 0.029 and 0.028, respectively), and two SNPs (rs7692791 and rs2034965) were associated with DFS (p=0.039 and 0.017, respectively). Particularly, rs7692791 TT genotype was associated with both reduced OS (p=0.037) and DFS (p=0.043). However, only one SNP rs2034965 with the AA genotype was shown to be an independent effect on DFS (p=0.009) in the multivariate analysis. None of the other 31 polymorphisms or 9 haplotypes attained from the four genes was significantly associated with OS or DFS. Our results illustrated the potential use of VEGFR2 polymorphisms as prognostic markers for HCC patients.
PMCID: PMC4300692  PMID: 25628948
Hepatocellular carcinoma; survival; EGF; EGFR; VEGF; VEGFR2; genetic polymorphisms
11.  Building a Multifunctional Aptamer-Based DNA Nanoassembly for Targeted Cancer Therapy 
Journal of the American Chemical Society  2013;135(49):18644-18650.
The ability to self-assemble one-dimensional DNA building blocks into two- and three-dimensional nanostructures via DNA/RNA nanotechnology has led to broad applications in bioimaging, basic biological mechanism studies, disease diagnosis and drug delivery. However, the cellular uptake of most nucleic acid nanostructures is dependent on passive delivery or the enhanced permeability and retention effect, which may not be suitable for certain types of cancers, especially for treatment in vivo. To meet this need, we have constructed a multifunctional aptamer-based DNA nanoassembly (AptNA) for targeted cancer therapy. In particular, we first designed various Y-shaped functional DNA domains through predesigned base pair hybridization, including targeting aptamers, intercalated anticancer drugs and therapeutic antisense oligonucleotides. Then these functional DNA domains were linked to an X-shaped DNA core connector, termed a building unit, through the complementary sequences in the arms of functional domains and connector. Finally, hundreds (~100–200) of these basic building units with 5′-modification of acrydite groups were further photocrosslinked into a multifunctional and programmable aptamer-based nanoassembly structure able to take advantage of facile modular design and assembly, high programmability, excellent biostability and biocompatibility, as well as selective recognition and transportation. With these properties, AptNAs were demonstrated to have specific cytotoxic effect against leukemia cells. Moreover, the incorporation of therapeutic antisense oligonucleotides resulted in the inhibition of P-gp expression (a drug efflux pump to increase excretion of anticancer drugs), as well as a decrease in drug resistance. Therefore, these multifunctional and programmable aptamer-based DNA nanoassemblies show promise as candidates for targeted drug delivery and cancer therapy.
PMCID: PMC3891927  PMID: 24245521
Multifunctionality; Aptamer-based nanostructure; Self-assembly; Targeted cancer therapy
12.  Genetic Variations rs11892031 and rs401681 Are Associated with Bladder Cancer Risk in a Chinese Population 
Genome-wide association studies (GWAS) have identified a number of genetic variants associated with risk of bladder cancer in populations of European descent. Here, we assessed association of two of these variants, rs11892031 (2q37.1 region) and rs401681 (5p15.33 region) in a Chinese case-control study, which included 367 bladder cancer cases and 420 controls. We found that the AC genotype of rs11892031 was associated with remarkably decreased risk of bladder cancer (adjusted odds ratio (OR), 0.27; 95% confidence interval (CI), 0.09–0.81; p = 0.019), compared with the AA genotype of rs11892031; and that CT/CC genotypes of rs401681 were associated with significantly increased risk of bladder cancer (adjusted OR, 1.79; 95% CI, 1.10–2.91; p = 0.02), compared with the TT genotype of rs401681. We further conducted stratification analysis to examine the correlation between single nucleotide polymorphism (SNP) rs11892031/rs401681 and tumor grade/stage. Results showed that heterogeneity in ORs of tumor categories was not significant for either rs11892031 or rs401681 (p > 0.05), indicating that the two SNPs seemingly do not associate with tumor grade and stage of bladder cancer in our study population. The present study suggests that the SNPs rs11892031 and rs401681 are associated with bladder cancer risk in a Chinese population. Future analyses will be conducted with more participants recruited in a case-control study.
PMCID: PMC4264113  PMID: 25347272
bladder cancer; genetic variations; polymorphism; genome-wide association studies
13.  Inhibitory effects of transcription factor Ikaros on the expression of liver cancer stem cell marker CD133 in hepatocellular carcinoma 
Oncotarget  2014;5(21):10621-10635.
CD133 is a cellular surface glycoprotein that has been reported as a marker for the enrichment of cancer stem cells (CSCs). However, the regulatory mechanism of CD133 remains unknown. CSCs have been proposed to contribute to radioresistance and multi-drug resistance. The elucidation of key regulators of CD133 and CSCs is critical for the development of CSC-targeted therapy. In this study, we showed that Ikarosinhibited the expression of CD133 via direct binding to the CD133 P1 promoter and repressed the tumorigenic and self-renewal capacity of CD133+ cancer stem-like cells in hepatocellular carcinoma (HCC). We found that Ikaros interacted with CtBP as a transcription repressor complex, which inhibited CD133 expression in HCC. We also demonstrated that Ikaros expression was up-regulated by ETS1 which activity was regulated by MAPKs pathway. Furthermore, decreased expression of Ikaroswas significantly associated with poor survival in HCC patients. Overall, our study identifies that Ikaros plays a role as a transcription repressor in HCC and is a new reactivated therapeutic target for the treatment of HCC. Meanwhile, our findings provide evidence that Ikaros could be an attractive inhibitor of the target gene CD133, which reactivates anticancer mechanisms in targeted CSC therapy.
PMCID: PMC4279398  PMID: 25301737
Ikaros; CD133; hepatocellular carcinoma; cancer stem cells
14.  Postsynaptic insertion of AMPA receptor onto cortical pyramidal neurons in the anterior cingulate cortex after peripheral nerve injury 
Molecular Brain  2014;7(1):76.
Long-term potentiation (LTP) is the key cellular mechanism for physiological learning and pathological chronic pain. Postsynaptic accumulation of AMPA receptor (AMPAR) GluA1 plays an important role for injury-related cortical LTP. However, there is no direct evidence for postsynaptic GluA1 insertion or accumulation after peripheral injury. Here we report nerve injury increased the postsynaptic expression of AMPAR GluA1 in pyramidal neurons in the layer V of the anterior cingulate cortex (ACC), including the corticospinal projecting neurons. Electrophysiological recordings show that potentiation of postsynaptic responses was reversed by Ca2+ permeable AMPAR antagonist NASPM. Finally, behavioral studies show that microinjection of NASPM into the ACC inhibited behavioral sensitization caused by nerve injury. Our findings provide direct evidence that peripheral nerve injury induces postsynaptic GluA1 accumulation in cingulate cortical neurons, and inhibits postsynaptic GluA1 accumulation which may serve as a novel target for treating neuropathic pain.
PMCID: PMC4221704  PMID: 25359681
15.  Data access for the 1,000 Plants (1KP) project 
GigaScience  2014;3:17.
The 1,000 plants (1KP) project is an international multi-disciplinary consortium that has generated transcriptome data from over 1,000 plant species, with exemplars for all of the major lineages across the Viridiplantae (green plants) clade. Here, we describe how to access the data used in a phylogenomics analysis of the first 85 species, and how to visualize our gene and species trees. Users can develop computational pipelines to analyse these data, in conjunction with data of their own that they can upload. Computationally estimated protein-protein interactions and biochemical pathways can be visualized at another site. Finally, we comment on our future plans and how they fit within this scalable system for the dissemination, visualization, and analysis of large multi-species data sets.
PMCID: PMC4306014  PMID: 25625010
Viridiplantae; Biodiversity; Transcriptomes; Phylogenomics; Interactions; Pathways
16.  Nanotechnology in Plant Disease Management: DNA-Directed Silver Nanoparticles on Graphene Oxide as an Antibacterial Against Xanthomonas Perforans 
ACS nano  2013;7(10):10.1021/nn4034794.
Bacterial spot caused by Xanthomonas perforans is a major disease of tomatoes, leading to reduction in production by 10–50%. While copper (Cu)-based bactericides have been used for disease management, most of the X. perforans strains isolated from tomatoes in Florida and other locations worldwide are Cu-resistant. We have developed DNA-directed silver (Ag) nanoparticles (NPs) grown on graphene oxide (GO). These Ag@dsDNA@GO composites effectively decrease X. perforans cell viability in culture and on plants. At the very low concentration of 16 ppm of Ag@dsDNA@GO, composites show excellent antibacterial capability in culture with significant advantages in improved stability, enhanced antibacterial activity and stronger adsorption properties. Application of Ag@dsDNA@GO at 100 ppm on tomato transplants in a greenhouse experiment significantly reduced the severity of bacterial spot disease compared to untreated plants, giving results similar to those of the current grower standard treatment, with no phytotoxicity.
PMCID: PMC3830795  PMID: 24016217
Ag NPs; graphene oxide; Ag@dsDNA@GO composites; dsDNA; bacteria; tomato
17.  Adenylyl cyclase subtype 1 is essential for late-phase long term potentiation and spatial propagation of synaptic responses in the anterior cingulate cortex of adult mice 
Molecular Pain  2014;10(1):65.
Long-term potentiation (LTP) is a key cellular mechanism for pathological pain in the central nervous system. LTP contains at least two different phases: early-phase LTP (E-LTP) and late-phase LTP (L-LTP). Among several major cortical areas, the anterior cingulate cortex (ACC) is a critical brain region for pain perception and its related emotional changes. Periphery tissue or nerve injuries cause LTP of excitatory synaptic transmission in the ACC. Our previous studies have demonstrated that genetic deletion of calcium-stimulated adenylyl cyclase 1 (AC1) or pharmacological application of a selective AC1 inhibitor NB001 blocked E-LTP in the ACC. However, the effect of AC1 on L-LTP, which requires new protein synthesis and is important for the process of chronic pain, has not been investigated. Here we tested the effects of NB001 on the ACC L-LTP and found that bath application of NB001 (0.1 μM) totally blocked the induction of L-LTP and recruitment of cortical circuitry without affecting basal excitatory transmission. In contrast, gabapentin, a widely used analgesic drug for neuropathic pain, did not block the induction of L-LTP and circuitry recruitment even at a high concentration (100 μM). Gabapentin non-selectively decreased basal synaptic transmission. Our results provide strong evidence that the selective AC1 inhibitor NB001 can be used to inhibit pain-related cortical L-LTP without affecting basal synaptic transmission. It also provides basic mechanisms for possible side effects of gabapentin in the central nervous system and its ineffectiveness in some patients with neuropathic pain.
PMCID: PMC4198686  PMID: 25304256
Adenylyl cyclase 1; Gabapentin; Anterior cingulate cortex; LTP; Chronic pain
18.  Easy quantitative assessment of genome editing by sequence trace decomposition 
Nucleic Acids Research  2014;42(22):e168.
The efficacy and the mutation spectrum of genome editing methods can vary substantially depending on the targeted sequence. A simple, quick assay to accurately characterize and quantify the induced mutations is therefore needed. Here we present TIDE, a method for this purpose that requires only a pair of PCR reactions and two standard capillary sequencing runs. The sequence traces are then analyzed by a specially developed decomposition algorithm that identifies the major induced mutations in the projected editing site and accurately determines their frequency in a cell population. This method is cost-effective and quick, and it provides much more detailed information than current enzyme-based assays. An interactive web tool for automated decomposition of the sequence traces is available. TIDE greatly facilitates the testing and rational design of genome editing strategies.
PMCID: PMC4267669  PMID: 25300484
19.  Maternal Parity and the Risk of Congenital Heart Defects in Offspring: A Dose-Response Meta-Analysis of Epidemiological Observational Studies 
PLoS ONE  2014;9(10):e108944.
Epidemiological studies have reported conflicting results regarding maternal parity and the risk of congenital heart defects (CHDs). However, a meta-analysis of the association between maternal parity and CHDs in offspring has not been conducted.
We searched MEDLINE and EMBASE for articles catalogued between their inception and March 8, 2014; we identified relevant published studies that assessed the association between maternal parity and CHD risk. Two authors independently assessed the eligibility of the retrieved articles and extracted data from them. Study-specific relative risk estimates were pooled by random-effects or fixed-effects models. From the 11272 references, a total of 16 case-control studies and 3 cohort studies were enrolled in this meta-analysis.
The overall relative risk of CHD in parous versus nulliparous women was 1.01 (95% CI, 0.97–1.06; Q = 32.34; P = 0.006; I2 = 53.6%). Furthermore, we observed a significant association between the highest versus lowest parity number, with an overall RR = 1.20 (95% CI, 1.10–1.31; (Q = 74.61, P<0.001, I2 = 82.6%). A dose–response analysis also indicated a positive effect of maternal parity on CHD risk, and the overall increase in relative risk per one live birth was 1.06 (95% CI, 1.02–1.09); Q = 68.09; P<0.001; I2 = 80.9%). We conducted stratified and meta-regression analyses to identify the origin of the heterogeneity among studies. A Galbraith plot was created to graphically assess the sources of heterogeneity.
In summary, this meta-analysis provided a robust estimate of the positive association between maternal parity and risk of CHD.
PMCID: PMC4189919  PMID: 25295723
20.  Novel approach to identifying the hepatitis B virus pre-S deletions associated with hepatocellular carcinoma 
World Journal of Gastroenterology : WJG  2014;20(37):13573-13581.
AIM: To develop a novel non-sequencing method for the detection of hepatitis B virus (HBV) pre-S deletion mutants in HBV carriers.
METHODS: The entire region of HBV pre-S1 and pre-S2 was amplified by polymerase chain reaction (PCR). The size of PCR products was subsequently determined by capillary gel electrophoresis (CGE). CGE were carried out in a PACE-MDQ instrument equipped with a UV detector set at 254 nm. The samples were separated in 50 μm ID eCAP Neutral Coated Capillaries using a voltage of 6 kV for 30 min. Data acquisition and analysis were performed using the 32 Karat Software. A total of 114 DNA clones containing different sizes of the HBV pre-S gene were used to determine the accuracy of the CGE method. One hundred and fifty seven hepatocellular carcinoma (HCC) and 160 non-HCC patients were recruited into the study to assess the association between HBV pre-S deletion and HCC by using the newly-established CGE method. Nine HCC cases with HBV pre-S deletion at the diagnosis year were selected to conduct a longitudinal observation using serial serum samples collected 2-9 years prior to HCC diagnosis.
RESULTS: CGE allowed the separation of PCR products differing in size > 3 bp and was able to identify 10% of the deleted DNA in a background of wild-type DNA. The accuracy rate of CGE-based analysis was 99.1% compared with the clone sequencing results. Using this assay, pre-S deletion was more frequently found in HCC patients than in non-HCC controls (47.1% vs 28.1%, P < 0.001). Interestingly, the increased risk of HCC was mainly contributed by the short deletion of pre-S. While the deletion ≤ 99 bp was associated with a 2.971-fold increased risk of HCC (95%CI: 1.723-5.122, P < 0.001), large deletion (> 99 bp) did not show any association with HCC (P = 0.918, OR = 0.966, 95%CI: 0.501-1.863). Of the 9 patients who carried pre-S deletions at the stage of HCC, 88.9% (8/9) had deletions 2-5 years prior to HCC, while only 44.4%4 (4/9) contained such deletions 6-9 years prior to HCC.
CONCLUSION: CGE is a sensitive approach for HBV pre-S deletion analysis. Pre-S deletion, especially for short DNA fragment deletion, is a useful predictive marker for HCC.
PMCID: PMC4188909  PMID: 25309088
Hepatitis B virus; Pre-S deletion; Capillary gel electrophoresis; Sequence analysis; Hepatocellular carcinoma
21.  Dielectrophoresis for Bioparticle Manipulation 
As an ideal method to manipulate biological particles, the dielectrophoresis (DEP) technique has been widely used in clinical diagnosis, disease treatment, drug development, immunoassays, cell sorting, etc. This review summarizes the research in the field of bioparticle manipulation based on DEP techniques. Firstly, the basic principle of DEP and its classical theories are introduced in brief; Secondly, a detailed introduction on the DEP technique used for bioparticle manipulation is presented, in which the applications are classified into five fields: capturing bioparticles to specific regions, focusing bioparticles in the sample, characterizing biomolecular interaction and detecting microorganism, pairing cells for electrofusion and separating different kinds of bioparticles; Thirdly, the effect of DEP on bioparticle viability is analyzed; Finally, the DEP techniques are summarized and future trends in bioparticle manipulation are suggested.
PMCID: PMC4227216  PMID: 25310652
dielectrophoresis; lab-on-a-chip; bioparticle; trapping; detection; focusing; pairing; separation
22.  Endoscopic retrieval of an 18-cm long chopstick embedded for ten months post-automutilation in the esophagus of a patient with psychosis 
Foreign body ingestion is an emergency or acute situation that commonly occurs in children or adults and involves the ingestion of one or more objects. Moreover, once the discovery of swallowed foreign bodies has been made, families are typically very anxious to have the patient see a doctor. If the foreign object becomes embedded in the digestive tract, it must be removed; in emergencies, this is done by endoscopy or surgery. This case report presents the successful endoscopic retrieval of a chopstick with both sides embedded 4 cm into the esophageal wall for > 10 mo in a male patient following automutilation in an attempt to be released from a psychiatric hospital. Hot hemostatic forceps were used to open the distal esophageal mucosa in which the chopstick was embedded. The procedure was performed under intravenous general anesthesia and took approximately 7 h.
PMCID: PMC4163728  PMID: 25228948
Foreign body; Esophagus; Endoscopy; Chopstick; Gastroscope; Hot hemostatic forceps
23.  A Targeted, Self-delivered and Photocontrolled Molecular Beacon for mRNA Detection in Living Cells 
Journal of the American Chemical Society  2013;135(35):12952-12955.
Messenger RNA (mRNA) is, by its nature, transient, beginning with transcription and ending with degradation, but with a period of processing and transport in between. As such, the spatiotemporal dynamics of specific mRNA molecules are difficult to image and detect inside living cells, and this has been a significant challenge for the chemical and biomedical communities. To solve this problem, we have developed a targeted, self-delivered, and photocontrolled aptamer-based molecular beacon (MB) for intracellular mRNA analysis. An internalizing aptamer connected via a double-stranded DNA structure is used as a carrier probe (CP) for cell-specific delivery of the MB designed to signal target mRNA. A light activation strategy was employed by inserting two photolabile groups in the CP sequence, enabling control over the MB's intracellular function. After being guided to their target cells via specific binding of aptamer AS1411 to nucleolin on the cell membrane, light illumination releases the MB for mRNA monitoring. Consequently, the MB is able to perform live-cell mRNA imaging with precise spatiotemporal control, while the CP acts as both a tracer for intracellular distribution of the MB before photoinitiation, and an internal reference for mRNA ratiometric detection.
PMCID: PMC3791631  PMID: 23931073
24.  FDG PET-CT combined with TBNA for the diagnosis of atypical relapsing polychondritis: report of 2 cases and a literature review 
Journal of Thoracic Disease  2014;6(9):1285-1292.
To explore the value of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) combined with transbronchial needle aspiration (TBNA) in diagnosing atypical relapsing polychondritis (RP).
Data from two patients with atypical RP, which had been diagnosed in our hospital using FDG PET-CT combined with TBNA, were retrospectively analyzed. A review of the relevant literature was also performed.
Consistent with the previously reported 20 cases of RP that had been diagnosed using FDG PET-CT, the two patients in the present study showed the involvement of multiple organs, including the nose, throat, trachea, bronchi, costicartilage and joint cartilages, and increased FDG uptake was found in these areas. The mean value of SUVmax was 5.14. PET-CT revealed that 86.4% of the patients with RP had airway involvement. TBNA technique was used for biopsy of the hypermetabolic lesions, and pathologic examinations confirmed the diagnosis of RP. The time to diagnosis in these two patients and the 20 cases reported previously was about 6.9 months, significantly shorter than the average diagnosis time (20 months).
FDG PET-CT has several advantages for diagnosing RP, especially atypical RP. TBNA is a minimally invasive and safe technique for obtaining airway cartilage. Combining PET-CT with TBNA may play an important role in shortening the time to diagnosis in patients with RP involvement of airway.
PMCID: PMC4178094  PMID: 25276371
Relapsing polychondritis (RP); positron emission tomography-computed tomography (PET-CT); transbronchial needle aspiration (TBNA); cartilage; fluorodeoxyglucose (FDG); standard uptake value (SUV)
25.  Engineering microorganisms based on molecular evolutionary analysis: a succinate production case study 
Evolutionary Applications  2014;7(8):913-920.
Evolution has resulted in thousands of species possessing similar metabolic enzymes with identical functions that are, however, regulated by different mechanisms. It is thus difficult to select optimal gene to engineer novel or manipulated metabolic pathways. Here, we tested the ability of molecular evolutionary analysis to identify appropriate genes from various species. We calculated the fraction of synonymous substitution and the effective number of codons (ENC) for nine genes stemming from glycolysis. Our research indicated that an enzyme gene with a stronger selective constraint in synonymous sites would mainly regulate corresponding reaction flux through altering the concentration of the protein, whereas those with a more relaxed selective constraint would primarily affect corresponding reaction flux by changing kinetic properties of the enzyme. Further, molecular evolutionary analysis was investigated for three types of genes involved in succinate precursor supply by catalysis of pyruvate. In this model, overexpression of Corynebacterium glutamicum pyc should result in greater conversion of pyruvate. Succinate yields in two Escherichia coli strains that overexpressed each of the three types of genes supported the molecular evolutionary analysis. This approach may thus provide an alternative strategy for selecting genes from different species for metabolic engineering and synthetic biology.
PMCID: PMC4211721  PMID: 25469170
metabolic engineering; molecular evolution; succinate; synonymous substitution; synthetic biology

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