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1.  Typing of Blood-Group Antigens on Neutral Oligosaccharides by Negative-Ion Electrospray Ionization Tandem Mass Spectrometry 
Analytical chemistry  2013;85(12):10.1021/ac400700e.
Blood-group antigens, such as those containing fucose and bearing the ABO(H)- and Lewis-type determinants expressed on the carbohydrate chains of glycoproteins and glycolipids, and also on unconjugated free oligosaccharides in human milk and other secretions, are associated with various biological functions. We have previously shown the utility of negative-ion electrospay ionization tandem mass spectrometry with collision-induced dissociation (ESI-CID-MS/MS) for typing of Lewis (Le) determinants, e.g. Lea, Lex, Leb, and Ley on neutral and sialylated oligosaccharide chains. In the present report we extended the strategy to characterization of blood-group A-, B- and H-determinants on type 1 and type 2, and also on type 4 globoside chains to provide a high sensitivity method for typing of all the major blood-group antigens, including the A, B, H, Lea, Lex, Leb, and Ley determinants, present in oligosaccharides. Using the principles established we identified two minor unknown oligosaccharide components present in the products of enzymatic synthesis by bacterial fermentation. We also demonstrated that the unique fragmentations derived from the D- and 0,2A-type cleavages observed in ESI-CID-MS/MS, which are important for assigning blood-group and chain types, only occur under the negative-ion conditions for reducing sugars but not for reduced alditols or under positive-ion conditions.
PMCID: PMC3856363  PMID: 23692402
2.  Transcriptional analysis of the titin cap gene 
Mutations in titin cap (Tcap), also known as telethonin, cause limb-girdle muscular dystrophy type 2G (LGMD2G). Tcap is one of the titin interacting Z-disc proteins involved in the regulation and development of normal sarcomeric structure. Given the essential role of Tcap in establishing and maintaining normal skeletal muscle architecture, we were interested in determining the regulatory elements required for expression of this gene in myoblasts. We have defined a highly conserved 421 bp promoter proximal promoter fragment that contains two E boxes and multiple putative Mef2 binding sequences. This promoter can be activated by MyoD and myogenin in NIH3T3 fibroblast cells, and maintains the differentiated cell-specific expression pattern of the endogenous Tcap in C2C12 cells. We find that while both E boxes are required for full activation by MyoD or myogenin in NIH3T3 cells, the promoter proximal E box has a greater contribution to activation of this promoter in C2C12 cells and to activation by MyoD in NIH3T3 cells. Together, the data suggest an important role for MyoD in activating Tcap expression through the promoter proximal E box. We also show that myogenin is required for normal expression in vivo and physically binds to the Tcap promoter during embryogenesis.
PMCID: PMC4059767  PMID: 21305318
Titin cap; Myogenin; MyoD; E box
3.  Polyclonal rabbit anti-human ovarian cancer globulins inhibit tumor growth through apoptosis involving the caspase signaling 
Scientific Reports  2014;4:4984.
Most women with ovarian cancer are diagnosed at an advanced stage and there are few therapeutic options. Recently, monoclonal antibody therapies have had limited success, thus more effective antibodies are needed to improve long-term survival. In this report, we prepared polyclonal rabbit anti-ovarian cancer antibody (Poly Ab) by immunizing rabbits with the human ovarian cancer cell line SKOV3. The Poly Ab bound to SKOV3 and inhibited the cancer cells proliferation. Western blot analysis was conducted, which indicated that Poly Ab inhibited cancer cells through apoptosis involving the caspase signaling pathway including caspase-3 and caspase-9. Finally, compared with the control antibody, administration of Poly Ab reached 64% and 72% tumor inhibition in the subcutaneous and intraperitoneal xenograft mouse model, respectively. Our findings suggest that Poly Ab is an effective agent for apoptosis induction and may be useful as a safe anticancer agent for ovarian cancer therapy.
PMCID: PMC4021334  PMID: 24828460
4.  Immunosuppressive Activity of Daphnetin, One of Coumarin Derivatives, Is Mediated through Suppression of NF-κB and NFAT Signaling Pathways in Mouse T Cells 
PLoS ONE  2014;9(5):e96502.
Daphnetin, a plant-derived dihydroxylated derivative of coumarin, is an effective compound extracted from a plant called Daphne Korean Nakai. Coumarin derivates were known for their antithrombotic, anti-inflammatory, and antioxidant activities. The present study was aimed to determine the immunosuppressive effects and the underlying mechanisms of daphnetin on concanavalin A (ConA) induced T lymphocytes in mice. We showed that, in vitro, daphnetin suppressed ConA-induced splenocyte proliferation, influenced production of the cytokines and inhibited cell cycle progression through the G0/G1 transition. The data also revealed that daphnetin could down-regulate activation of ConA induced NF-κB and NFAT signal transduction pathways in mouse T lymphocyte. In vivo, daphnetin treatment significantly inhibited the 2, 4- dinitrofluorobenzene (DNFB) -induced delayed type hypersensitivity (DTH) reactions in mice. Collectively, daphnetin had strong immunosuppressive activity both in vitro and in vivo, suggesting a potential role for daphnetin as an immunosuppressive agent, and established the groundwork for further research on daphnetin.
PMCID: PMC4011761  PMID: 24800925
5.  Change in Hepatitis B Virus Large Surface Antigen Variant Prevalence 13 Years after Implementation of a Universal Vaccination Program in China 
Journal of Virology  2013;87(22):12196-12206.
A nationwide hepatitis B virus (HBV) vaccination program was implemented in China starting in 1992. To study the change in HBV variant prevalence with massive immunization, large HBV surface protein (LHBs) genes from HBV surface antigen (HBsAg)-positive sera were amplified and sequenced. The prevalences of LHBs mutants were compared between the 1992 and 2005 surveys in child and adult groups. The prevalence of “α” determinant mutants in the children increased from 6.5% in 1992 to 14.8% in 2005, where the G145R mutant occurred most frequently. In contrast, mutation frequencies showed little difference between 1992 (9.4%) and 2005 (9.9%) in adults. Moreover, compared to the 1992 survey, the child group surface (S) protein mutation frequency specifically increased (P = 0.005) in the 2005 survey, but the pre-S region mutation frequency did not show a significant difference (P > 0.05). However, the mutation frequency in the adult group increased in both the pre-S and S regions. Furthermore, the frequencies of the disease-related pre-S2 deletion and start codon mutations were significantly higher in the adult groups than in the child groups in both the 1992 and 2005 surveys (P < 0.01). Massive immunization enhances the HBV S protein mutation; the prevalence of LHBs mutants, particularly disease-related mutants, tends to increase with patient age.
PMCID: PMC3807931  PMID: 24006443
6.  Marked tumor response to crizotinib after 4 years of maintenance pemetrexed in a patient with anaplastic lymphoma kinase-positive non-small-cell lung cancer 
Molecular and Clinical Oncology  2014;2(4):567-570.
Maintenance therapy with pemetrexed is well tolerated and achieves prolonged progression-free and overall survival in patients with advanced lung adenocarcinoma. The echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) is a recently identified fusion oncogene that exists in ~5% of non-small-cell lung cancers (NSCLCs). It was demonstrated that ALK-positive NSCLCs exhibit a high response rate to the ALK inhibitor crizotinib. This is the case report of a patient with NSCLC harboring EML4-ALK rearrangement, who experienced slowly progressive disease within 4 years of maintenance treatment with pemetrexed and later exhibited a marked response to crizotinib. The sustained clinical benefits suggest further investigations on anticancer agent administration.
PMCID: PMC4051572  PMID: 24940496
anaplastic lymphoma kinase-positive non-small-cell lung cancer; adenocarcinoma; crizotinib; pemetrexed
7.  Enhanced efficacy of combination therapy with adeno-associated virus-delivered pigment epithelium-derived factor and cisplatin in a mouse model of Lewis lung carcinoma 
Molecular Medicine Reports  2014;9(6):2069-2076.
Pigment epithelium-derived factor (PEDF) is a potent inhibitor of angiogenesis, and the antitumor effect of adeno-associated virus (AAV)-mediated PEDF expression has been demonstrated in a range of animal models. The combined treatment of low-dose chemotherapy and gene therapy inhibits the growth of solid tumors more effectively than current traditional therapies or gene therapy alone. In the present study, the effect of treatment with an AAV2 vector harboring the human PEDF (hPEDF) gene in combination with low-dose cisplatin on the growth of Lewis lung carcinoma (LLC) in mice was assessed. LLC cells were infected with AAV-enhanced green fluorescent protein (EGFP) in the presence or absence of cisplatin, and then the effect of cisplatin on AAV-mediated gene expression was evaluated by image and flow cytometric analysis. Tumor growth, survival time, vascular endothelial growth factor (VEGF) expression, microvessel density (MVD) and apoptotic index were analyzed in C57BL/6 mice treated with AAV-hPEDF, cisplatin or cisplatin plus AAV-hPEDF. The results of the present study provide evidence that cisplatin treatment is able to enhance AAV-mediated gene expression in LLC cells. In addition, the combined treatment of cisplatin plus AAV-hPEDF markedly prolonged the survival time of the mice and inhibited tumor growth, resulting in significant suppression of tumor angiogenesis and induction of tumor apoptosis in vivo, and also protected against cisplatin-related toxicity. These findings suggest that combination of AAV-hPEDF and cisplatin has potential as a novel therapeutic strategy for lung cancer.
PMCID: PMC4055432  PMID: 24714917
adeno-associated virus-pigment epithelium-derived factor; cisplatin; combination; tumor; apoptosis; angiogenesis
8.  Pretreatment with chemotherapeutics for enhanced nanoparticles accumulation in tumor: the potential role of G2 cycle retention effect 
Scientific Reports  2014;4:4492.
Ligands were anchored onto nanoparticles (NPs) to improve the cell internalization and tumor localization of chemotherapeutics. However, the clinical application was shadowed by the complex preparation procedure and the immunogenicity and poor selectivity and stability of ligands. In this study, a novel strategy was developed to elevate the tumor cellular uptake and tumor localization of NPs utilizing the G2/M phase retention effect of docetaxel, one of the most common chemotherapeutics. Results showed pretreatment with docetaxel could effectively arrest cells in G2/M phase, leading to an enhanced cell uptake of NPs, which may be caused by the facilitated endocytosis of NPs. In vivo imaging and slice distribution also demonstrated the pretreatment with docetaxel improved the localization of NPs in tumor. This strategy can be easily transferred to clinical for cancer management. Combination chemotherapeutics injections with commercial nano-drugs may result in better antitumor effect than the administration of a single drug.
PMCID: PMC3967147  PMID: 24670376
9.  The Membrane-Associated Transcription Factor NAC089 Controls ER-Stress-Induced Programmed Cell Death in Plants 
PLoS Genetics  2014;10(3):e1004243.
The unfolded protein response (UPR) is activated to sustain cell survival by reducing misfolded protein accumulation in the endoplasmic reticulum (ER). The UPR also promotes programmed cell death (PCD) when the ER stress is severe; however, the underlying molecular mechanisms are less understood, especially in plants. Previously, two membrane-associated transcriptions factors (MTFs), bZIP28 and bZIP60, were identified as the key regulators for cell survival in the plant ER stress response. Here, we report the identification of another MTF, NAC089, as an important PCD regulator in Arabidopsis (Arabidopsis thaliana) plants. NAC089 relocates from the ER membrane to the nucleus under ER stress conditions. Inducible expression of a truncated form of NAC089, in which the transmembrane domain is deleted, induces PCD with increased caspase 3/7-like activity and DNA fragmentation. Knock-down NAC089 in Arabidopsis confers ER stress tolerance and impairs ER-stress-induced caspase-like activity. Transcriptional regulation analysis and ChIP-qPCR reveal that NAC089 plays important role in regulating downstream genes involved in PCD, such as NAC094, MC5 and BAG6. Furthermore, NAC089 is up-regulated by ER stress, which is directly controlled by bZIP28 and bZIP60. These results show that nuclear relocation of NAC089 promotes ER-stress-induced PCD, and both pro-survival and pro-death signals are elicited by bZIP28 and bZIP60 during plant ER stress response.
Author Summary
Protein folding is fundamentally important for development and responses to environmental stresses in eukaryotes. When excess misfolded proteins are accumulated in the endoplasmic reticulum (ER), the unfolded protein response (UPR) is triggered to promote cell survival through optimizing protein folding, and also promote programmed cell death (PCD) when the stress is severe. However, the link from ER-stress-sensing to PCD is largely unknown. Here, we report the identification of one membrane-associated transcription factor NAC089 as an important regulator of ER stress-induced PCD in plants. We have established a previously unrecognized molecular connection between ER stress sensors and PCD regulators. We have shown that organelle-to-organelle translocation of a transcription factor is important for its function in transcriptional regulation. Our results have provided novel insights into the molecular mechanisms of PCD in plants, especially under ER stress conditions.
PMCID: PMC3967986  PMID: 24675811
10.  Estrogen receptor α-coupled Bmi1 regulation pathway in breast cancer and its clinical implications 
BMC Cancer  2014;14:122.
Bmi1 has been identified as an important regulator in breast cancer, but its relationship with other signaling molecules such as ERα and HER2 is undetermined.
The expression of Bmi1 and its correlation with ERα, PR, Ki-67, HER2, p16INK4a, cyclin D1 and pRB was evaluated by immunohistochemistry in a collection of 92 cases of breast cancer and statistically analyzed. Stimulation of Bmi1 expression by ERα or 17β-estradiol (E2) was analyzed in cell lines including MCF-7, MDA-MB-231, ERα-restored MDA-MB-231 and ERα-knockdown MCF-7 cells. Luciferase reporter and chromatin immunoprecipitation assays were also performed.
Immunostaining revealed strong correlation of Bmi1 and ERα expression status in breast cancer. Expression of Bmi1 was stimulated by 17β-estradiol in ERα-positive MCF-7 cells but not in ERα-negative MDA-MB-231 cells, while the expression of Bmi1 did not alter expression of ERα. As expected, stimulation of Bmi1 expression could also be achieved in ERα-restored MDA-MB-231 cells, and at the same time depletion of ERα decreased expression of Bmi1. The proximal promoter region of Bmi1 was transcriptionally activated with co-transfection of ERα in luciferase assays, and the interaction of the Bmi1 promoter with ERα was confirmed by chromatin immunoprecipitation. Moreover, in breast cancer tissues activation of the ERα-coupled Bmi1 pathway generally correlated with high levels of cyclin D1, while loss of its activity resulted in aberrant expression of p16INK4a and a high Ki-67 index, which implied a more aggressive phenotype of breast cancer.
Expression of Bmi1 is influenced by ERα, and the activity of the ERα-coupled Bmi1 signature impacts p16INK4a and cyclin D1 status and thus correlates with the tumor molecular subtype and biologic behavior. This demonstrates the important role which is played by ERα-coupled Bmi1 in human breast cancer.
PMCID: PMC3939403  PMID: 24559156
Bmi1; Estrogen receptor α; p16INK4a; Cyclin D1; Breast cancer
11.  Determination of 16 Selected Trace Elements in Children Plasma from China Economical Developed Rural Areas Using High Resolution Magnetic Sector Inductively Coupled Mass Spectrometry 
A rapid, accurate, and high performance method of high resolution sector field inductively coupled plasma mass spectrometry (HR-ICP-MS) combined with a small-size sample (0.1 mL) preparation was established. The method was validated and applied for the determination of 16 selected plasma trace elements (Fe, Cu, Zn, Rb, B, Al, Se, Sr, V, Cr, Mn, Co, As, Mo, Cd, and Pb). The linear working ranges were over three intervals, 0-1 μg/L, 0–10 μg/L and 0–100 μg/L. Correlation coefficients (R2) ranged from 0.9957 to 0.9999 and the limits of quantification (LOQ) ranged from 0.02 μg/L (Rb) to 1.89 μg/L (Se). The trueness (or recovery) spanned from 89.82% (Al) to 119.15% (Se) and precision expressed by the relative standard deviation (RSD %) for intra-day ranging from 1.1% (Zn) to 9.0% (Se), while ranged from 3.7% (Fe) to 12.7% (Al) for interday. A total of 440 plasma samples were collected from Chinese National Nutrition and Health Survey Project 2002 (CNNHS 2002), which represented the status of plasma trace elements for the children aged 3–12 years from China economical developed rural areas. The concentrations of 16 trace elements were summarized and compared by age groups and gender, which can be used as one of the basic components for the formulation of the baseline reference values of trace elements for the children in 2002.
PMCID: PMC3950582  PMID: 24701366
12.  Cellular immunotherapy using irradiated lung cancer cell vaccine co-expressing GM-CSF and IL-18 can induce significant antitumor effects 
BMC Cancer  2014;14:48.
Although the whole tumor cell vaccine can provide the best source of immunizing antigens, there is still a limitation that most tumors are not naturally immunogenic. Tumor cells genetically modified to secrete immune activating cytokines have been proved to be more immunogenic. IL-18 could augment proliferation of T cells and cytotoxicity of NK cells. GM-CSF could stimulate dendritic cells, macrophages and enhance presentation of tumor antigens. In our study, we used mouse GM-CSF combined with IL-18 to modify Lewis lung cancer LL/2, then investigated whether vaccination could suppress tumor growth and promote survival.
The Lewis lung cancer LL/2 was transfected with co-expressing mouse GM-CSF and IL-18 plasmid by cationic liposome, then irradiated with a sublethal dose X ray (100 Gy) to prepare vaccines. Mice were subcutaneously immunized with this inactivated vaccine and then inoculated with autologous LL/2 to estimate the antitumor efficacy.
The studies reported here showed that LL/2 tumor cell vaccine modified by a co-expressing mouse GM-CSF and IL-18 plasmid could significantly inhibit tumor growth and increased survival of the mice bearing LL/2 tumor whether prophylactic or adoptive immunotherapy in vivo. A significant reduction of proliferation and increase of apoptosis were also observed in the tumor treated with vaccine of co-expressing GM-CSF and IL-18. The potent antitumor effect correlated with higher secretion levels of pro-inflammatory cytokines such as IL-18, GM-CSF, interferon-γ in serum, the proliferation of CD4+ IFN-γ+, CD8+ IFN-γ+ T lymphocytes in spleen and the infiltration of CD4+, CD8+ T in tumor. Furthermore, the mechanism of tumor-specific immune response was further proved by 51Cr cytotoxicity assay in vitro and depletion of CD4, CD8, NK immune cell subsets in vivo. The results suggested that the antitumor mechanism was mainly depended on CD4+, CD8+ T lymphocytes.
These results provide a new insight into therapeutic mechanisms of IL-18 plus GM-CSF modified tumor cell vaccine and provide a potential clinical cancer immunotherapeutic agent for improved antitumor immunity.
PMCID: PMC3922726  PMID: 24475975
Cancer immunotherapy; IL-18; GM-CSF; Cell vaccine; Apoptosis
13.  The downregulation of PRDM1/Blimp-1 is associated with aberrant expression of miR-223 in extranodal NK/T-cell lymphoma, nasal type 
The mechanism for inactivation of positive regulatory domain containing I (PRDM1), a newly identified tumour suppressor gene in extranodal NK/T-cell lymphoma, nasal type (EN-NK/T-NT) has not been well defined. The aim of the present study was to investigate the expression of PRDM1 in EN-NK/T-NT and analyse its downregulation by miRNAs.
PRDM1 and miRNA expression were evaluated in EN-NK/T-NT samples by immunohistochemical analysis, qRT-PCR, and in situ hybridisation. Luciferase assays were performed to verify the direct binding of miR-223 to the 3′-untranslated region of PRDM1 mRNA. In addition, the effect of miR-223 on PRDM1 expression was assessed in NK/T lymphoma cell lines by transfecting a miR-223 mimic or inhibitor to increase or decrease the effective expression of miR-223. Overall survival and failure-free survival in EN-NK/T-NT patients were analysed using Kaplan-Meier single-factor analysis and the log-rank test.
Investigation of the downregulation of PRDM1 in EN-NK/T-NT cases revealed that PRDM1-positive staining might be a favourable predictor of overall survival and failure-free survival in EN-NK/T-NT patients. However, the negative staining of PRDM1 usually presented transcripts, suggesting a possible post-transcriptional regulation. miR-223 and its putative target gene, PRDM1, exhibited opposite patterns of expression in EN-NK/T-NT tissues and cell lines. Moreover, PRDM1 was identified as a direct target gene of miR-223 by luciferase assays. The ectopic expression of miR-223 led to the downregulation of the PRDM1 protein in the NK/T-cell lymphoma cell line, whereas a decrease in miR-223 restored the level of PRDM1 protein.
Our findings reveal that the downregulation of the tumour suppressor PRDM1 in EN-NK/T-NT samples is mediated by miR-223 and that PRDM1-positive staining might have prognostic value for evaluating the clinical outcome of EN-NK/T-NT patients.
PMCID: PMC3898819  PMID: 24438193
Extranodal NK/T-cell lymphoma; Nasal type; PRDM1; miR-223
14.  Fast and robust reconstruction for fluorescence molecular tomography via a sparsity adaptive subspace pursuit method 
Biomedical Optics Express  2014;5(2):387-406.
Fluorescence molecular tomography (FMT), as a promising imaging modality, can three-dimensionally locate the specific tumor position in small animals. However, it remains challenging for effective and robust reconstruction of fluorescent probe distribution in animals. In this paper, we present a novel method based on sparsity adaptive subspace pursuit (SASP) for FMT reconstruction. Some innovative strategies including subspace projection, the bottom-up sparsity adaptive approach, and backtracking technique are associated with the SASP method, which guarantees the accuracy, efficiency, and robustness for FMT reconstruction. Three numerical experiments based on a mouse-mimicking heterogeneous phantom have been performed to validate the feasibility of the SASP method. The results show that the proposed SASP method can achieve satisfactory source localization with a bias less than 1mm; the efficiency of the method is much faster than mainstream reconstruction methods; and this approach is robust even under quite ill-posed condition. Furthermore, we have applied this method to an in vivo mouse model, and the results demonstrate the feasibility of the practical FMT application with the SASP method.
PMCID: PMC3920871  PMID: 24575335
(100.3010) Image reconstruction techniques; (100.3190) Inverse problems; (110.6955) Tomographic imaging; (170.3660) Light propagation in tissues; (170.3880) Medical and biological imaging; (290.1990) Diffusion; (290.7050) Turbid media
15.  Cytoprotective effects of urinary trypsin inhibitor on astrocytes injured by sustained compression 
Molecular Biology Reports  2014;41:1311-1316.
Decreased cell membrane integrity is a primary pathological change observed in traumatic brain injury (TBI) that activates a number of complex intercellular and intracellular pathological events, leading to further neural injury. In this paper, we assessed the effects of urinary trypsin inhibitor (UTI) on astrocyte membrane integrity by determining the percentage of lactate dehydrogenase (LDH) released after sustained compression injury using a hydrostatic pressure model of mechanical-like TBI. Astrocytes isolated from SD rat pups were injured by sustained compression. At a pressure of 0.3 MPa for 5 min, a significant increase in LDH release was observed compared with control samples. Astrocytes displayed extensive structural disruption of mitochondrial cristae reflected in their swelling. Based on our initial results, injured astrocytes were treated with UTI at a final concentration of 500, 1,000, 3,000 or 5,000 U/ml for 24 h. The percentage of LDH released from injured astrocytes was significantly decreased when 1,000 and 3,000 U/ml of UTI were used. In a separate experiment, astrocytes were treated with UTI at a final concentration of 1,000 U/ml immediately, or at 30 min, 2, 6, or 24 h after sustained compression. The percentage of LDH release was significantly reduced (P < 0.05) when astrocytes were treated with UTI immediately or 30 min later. Together, our results suggest that UTI may have protective effects on astrocytes injured by sustained compression injury. Furthermore, the early administration (<2 h after injury) of UTI may result in a better outcome compared with delayed administration.
PMCID: PMC3933746  PMID: 24385305
Astrocytes; Compression injury; LDH release; UTI; Cytoprotection
16.  Molecular Epidemiology of Coxsackievirus A16: Intratype and Prevalent Intertype Recombination Identified 
PLoS ONE  2013;8(12):e82861.
Coxsackievirus A16 (CVA16) is responsible for nearly 50% of all the confirmed hand, foot, and mouth disease (HFMD) cases in mainland China, sometimes it could also cause severe complications, and even death. To clarify the genetic characteristics and the epidemic patterns of CVA16 in mainland China, comprehensive bioinfomatics analyses were performed by using 35 CVA16 whole genome sequences from 1998 to 2011, 593 complete CVA16 VP1 sequences from 1981 to 2011, and prototype strains of human enterovirus species A (EV-A). Analysis on complete VP1 sequences revealed that subgenotypes B1a and B1b were prevalent strains and have been co-circulating in many Asian countries since 2000, especially in mainland China for at least 13 years. While the prevalence of subgenotype B1c (totally 20 strains) was much limited, only found in Malaysia from 2005 to 2007 and in France in 2010. Genotype B2 only caused epidemic in Japan and Malaysia from 1981 to 2000. Both subgenotypes B1a and B1b were potential recombinant viruses containing sequences from other EV-A donors in the 5’-untranslated region and P2, P3 non-structural protein encoding regions.
PMCID: PMC3858299  PMID: 24340064
17.  Rectal adenocarcinoma metastatic to the tonsil; PET-CT observations with pathological confirmation: A case report 
Oncology Letters  2013;7(1):153-155.
Metastasis of rectal adenocarcinoma develops by lymphatic or hematogenous spread. The usual sites of metastasis from rectal adenocarcinoma include local and distant lymph nodes, the liver and the lungs. The current case report presents a unique case of a mass that was identified in the tonsil by positron emission tomography-computed tomography (PET-CT), indicating a metastasis from rectal adenocarcinoma. Metastatic tumor to the tonsil is extremely rare and to the best of our knowledge, no previous studies have reported a case of tonsil metastasis from rectal adenocarcinoma. PET-CT scanners represent an important evolution in technology that is helping to bring anatomical imaging togeother with functional imaging in cancer diagnosis and therapy. Written informed consent was obtained from the patient.
PMCID: PMC3861609  PMID: 24348839
tonsil; metastasis; rectal adenocarcinoma
18.  Ligand modified nanoparticles increases cell uptake, alters endocytosis and elevates glioma distribution and internalization 
Scientific Reports  2013;3:2534.
Nanoparticles (NPs) were widely used in drugs/probes delivery for improved disease diagnosis and/or treatment. Targeted delivery to cancer cells is a highly attractive application of NPs. However, few studies have been performed on the targeting mechanisms of these ligand-modified delivery systems. Additional studies are needed to understand the transport of nanoparticles in the cancer site, the interactions between nanoparticles and cancer cells, the intracellular trafficking of nanoparticles within the cancer cells and the subcellular destiny and potential toxicity. Interleukin 13 (IL-13) peptide can specifically bind IL-13Rα2, a receptor that is highly expressed on glioma cells but is expressed at low levels on other normal cells. It was shown that the nanoparticels modification with the IL-13 peptide could improve glioma treatment by selectively increasing cellular uptake, facilitating cell internalization, altering the uptake pathway and increasing glioma localization.
PMCID: PMC3755284  PMID: 23982586
19.  Correction: Viral Etiology of Acute Respiratory Infection in Gansu Province, China, 2011 
PLoS ONE  2013;8(7):10.1371/annotation/91d141f8-549c-475c-891a-5d8b4e5f91fd.
PMCID: PMC3728372
21.  Genome-Wide Identification and Evolutionary and Expression Analyses of MYB-Related Genes in Land Plants 
MYB proteins constitute one of the largest transcription factor families in plants. Recent evidence revealed that MYB-related genes play crucial roles in plants. However, compared with the R2R3-MYB type, little is known about the complex evolutionary history of MYB-related proteins in plants. Here, we present a genome-wide analysis of MYB-related proteins from 16 species of flowering plants, moss, Selaginella, and algae. We identified many MYB-related proteins in angiosperms, but few in algae. Phylogenetic analysis classified MYB-related proteins into five distinct subgroups, a result supported by highly conserved intron patterns, consensus motifs, and protein domain architecture. Phylogenetic and functional analyses revealed that the Circadian Clock Associated 1-like/R-R and Telomeric DNA-binding protein-like subgroups are >1 billion yrs old, whereas the I-box-binding factor-like and CAPRICE-like subgroups appear to be newly derived in angiosperms. We further demonstrated that the MYB-like domain has evolved under strong purifying selection, indicating the conservation of MYB-related proteins. Expression analysis revealed that the MYB-related gene family has a wide expression profile in maize and soybean development and plays important roles in development and stress responses. We hypothesize that MYB-related proteins initially diversified through three major expansions and domain shuffling, but remained relatively conserved throughout the subsequent plant evolution.
PMCID: PMC3789555  PMID: 23690543
MYB-related transcription factors; classification; evolution; phylogenetic analysis; expression profile analysis
22.  Viral Etiology of Acute Respiratory Infection in Gansu Province, China, 2011 
PLoS ONE  2013;8(5):e64254.
Acute respiratory infections (ARIs) are the leading cause of children and their leading killer. ARIs are responsible for at least six percent of the world's disability and death. Viruses are one of the most common agents causing ARIs. Few studies on the viral etiology and clinical characteristics of ARIs have been performed in the northwest region of China, including Gansu Province.
Clinical and demographic information and throat swabs were collected from 279 patients from January 1st to December 30st, 2011. Multiplex RT-PCR was performed to detect 16 respiratory viral pathogens.
279 patients were admitted for ARIs. The patients aged from 1 month to 12 years, with the median age of 2 years. Of which, 105 (37.6%) were positive for at least one pathogen. A total of 136 respiratory viral pathogens were identified from the 105 patients. Respiratory syncytial virus (RSV) was the most frequently detected pathogen (26.5%, 36/136), followed by parainfluenza virus (PIV) 1–3 (22.1%, 30/136), human rhinovirus (HRV) (21.3%, 29/136), human coronavirus (CoV) (10.3%, 14/136) and human adenovirus (HAdV) (9.6%, 13/136). Influenza A (Flu A), human metapneumovirus (hMPV) and human bocavirus (BoCA) were found 4.4%, 3.7% and 2.2%, respectively. Influenza B (Flu B) and seasonal influenza A H1N1(sH1N1) were not detected. Single-infections were detected in 30.5% (85/279) of cases. RSV was the most common pathogens in patients under 1 year and showed seasonal variation with peaks during winter and spring.
This paper presents data on the epidemiology of viral pathogens associated with ARIs among children in Gansu Province, China. RSV is most frequently detected in our study. The findings could serve as a reference for local CDC in drawing up further plans to prevent and control ARIs.
PMCID: PMC3653869  PMID: 23691184
23.  Fucoidan Inhibits the Growth of Hepatocellular Carcinoma Independent of Angiogenesis 
Some sulphated polysaccharides can bind bFGF but are unable to present bFGF to its high-affinity receptors. Fucoidan, a sulphated polysaccharide purified from brown algae, which has been used as an anticancer drug in traditional Chinese medicine for hundreds of years, exhibits a variety of anticancer effects, including the induction of the apoptosis and autophagy of cancer cells, the inhibition of the growth of cancer cells, the induction of angiogenesis, and the improvement of antitumour immunity. Our research shows that fucoidan dose not inhibit the expressions of VEGF, bFGF, IL-8, and heparanase in HCC cells and/or tumour tissues. Moreover, fucoidan exhibited low affinity for bFGF and could not block the binding of bFGF to heparan sulphated. Although fucoidan had no effect on angiogenesis and apoptosis in vivo, this drug significantly inhibited the tumour growth and the expression of PCNA. These results suggest that fucoidan exhibits an anticancer effect in vivo at least partly through inhibition of the proliferation of HCC cells, although it is unable to suppress the angiogenesis induced by HCC.
PMCID: PMC3666199  PMID: 23737842
24.  A Positive Feedback Loop Involving Gcm1 and Fzd5 Directs Chorionic Branching Morphogenesis in the Placenta 
PLoS Biology  2013;11(4):e1001536.
Placenta formation during pregnancy requires chorioallantoic branching morphogenesis that involves establishing an amplifying feedback loop between Frizzled5 and Gcm1 to regulate branching initiation and trophoblast differentiation.
Chorioallantoic branching morphogenesis is a key milestone during placental development, creating the large surface area for nutrient and gas exchange, and is therefore critical for the success of term pregnancy. Several Wnt pathway molecules have been shown to regulate placental development. However, it remains largely unknown how Wnt-Frizzled (Fzd) signaling spatiotemporally interacts with other essential regulators, ensuring chorionic branching morphogenesis and angiogenesis during placental development. Employing global and trophoblast-specific Fzd5-null and Gcm1-deficient mouse models, combining trophoblast stem cell lines and tetraploid aggregation assay, we demonstrate here that an amplifying signaling loop between Gcm1 and Fzd5 is essential for normal initiation of branching in the chorionic plate. While Gcm1 upregulates Fzd5 specifically at sites where branching initiates in the basal chorion, this elevated Fzd5 expression via nuclear β-catenin signaling in turn maintains expression of Gcm1. Moreover, we show that Fzd5-mediated signaling induces the disassociation of cell junctions for branching initiation via downregulating ZO-1, claudin 4, and claudin 7 expressions in trophoblast cells at the base of the chorion. In addition, Fzd5-mediated signaling is also important for upregulation of Vegf expression in chorion trophoblast cells. Finally, we demonstrate that Fzd5-Gcm1 signaling cascade is operative during human trophoblast differentiation. These data indicate that Gcm1 and Fzd5 function in an evolutionary conserved positive feedback loop that regulates trophoblast differentiation and sites of chorionic branching morphogenesis.
Author Summary
Abnormal placental development during pregnancy is associated with conditions such as preeclampsia, intrauterine growth restriction, and even fetal death in humans. Here we focus on the earliest steps of placenta formation, which involves the development of the labyrinthine layer, a specialized epithelium that sits between the maternal blood and fetal blood vessels and facilitates the exchange of nutrients, gases, and wastes between the mother and fetus. Pivotal to the development of a functional labyrinth layer are the processes of folding and branching of a flat sheet of trophoblast cells (originally the outer layer of the blastocyst), and of trophoblast cell differentiation. Here, we show in mice that Frizzled5, a receptor component of the Wnt signaling pathway, and Gcm1, an important transcription factor for labyrinth development, form a positive feedback loop that directs normal placental development. We find that Gcm1 up-regulates Fzd5 specifically at branching sites and that elevated Fzd5 expression in turn maintains expression of Gcm1. Moreover, Fzd5-mediated signaling is required for the disassociation of cell junctions and for the up-regulation of Vegf expression in trophoblast cells. Finally, with implications for human disease, we demonstrate that the FZD5-GCM1 signaling cascade operates in primary cultures of human trophoblasts undergoing differentiation.
PMCID: PMC3627642  PMID: 23610556
25.  Identification and Function of Leucine-Rich Repeat Flightless-I-Interacting Protein 2 (LRRFIP2) in Litopenaeus vannamei 
PLoS ONE  2013;8(2):e57456.
Leucine-rich repeat flightless-I-interacting protein 2 (LRRFIP2) is a myeloid differentiation factor 88-interacting protein with a positive regulatory function in toll-like receptor signaling. In this study, seven LRRFIP2 protein variants (LvLRRFIP2A-G) were identified in Litopenaeus vannamei. All the seven LvLRRFIP2 protein variants encode proteins with a DUF2051 domain. LvLRRFIP2s were upregulated in hemocytes after challenged with lipopolysaccharide, poly I:C, CpG-ODN2006, Vibrio parahaemolyticus, Staphylococcus aureus, and white spot syndrome virus (WSSV). Dual-luciferase reporter assays in Drosophila Schneider 2 cells revealed that LvLRRFIP2 activates the promoters of Drosophila and shrimp AMP genes. The knockdown of LvLRRFIP2 by RNA interference resulted in higher cumulative mortality of L. vannamei upon V. parahaemolyticus but not S. aureus and WSSV infections. The expression of L. vannamei AMP genes were reduced by dsLvLRRFIP2 interference. These results indicate that LvLRRFIP2 has an important function in antibacterials via the regulation of AMP gene expression.
PMCID: PMC3585381  PMID: 23468989

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