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author:("Li, maijuna")
1.  MicroRNA-153 acts as a prognostic marker in gastric cancer and its role in cell migration and invasion 
OncoTargets and therapy  2015;8:357-364.
MicroRNA (miRNA)-153 (miR-153) has been considered as a novel tumor-related miRNA and is found to be significantly deregulated in human cancers. In this study, we found that the expression levels of miR-153 were obviously lower in gastric cancer tissues than those in matched adjacent nontumor tissues. Otherwise, miR-153 was expressed at significantly lower levels in aggressive tumor tissues. Clinical association analysis indicated that low expression of miR-153 was prominently correlated with poor prognostic features in gastric cancer. Furthermore, we demonstrated that the low expression of miR-153 was correlated with short 5-year survival of gastric cancer patients. Multivariate Cox regression analysis indicated that miR-153 was an independent prognostic marker in gastric cancer. Our in vitro studies showed that upregulation of miR-153 reduced cell migration and invasion in MKN-45 cells. Meanwhile, downregulation of miR-153 promoted SGC-7901 cell migration and invasion. An inverse correlation between miR-153 and SNAI1 expression was observed in gastric cancer tissues. In addition, upregulation of miR-153 reduced SNAI1 expression and subsequently suppressed epithelial–mesenchymal transition (EMT) with elevated expression of E-cadherin and reduced expression of vimentin in MKN-45 cells. Furthermore, downregulation of miR-153 increased SNAI1 expression and promoted EMT in SGC-7901 cells. In conclusion, miR-153 is an independent prognostic marker for predicting survival of gastric cancer patients and may promote gastric cancer cell migration and invasion, by inhibiting SNAI1-induced EMT.
PMCID: PMC4322869
miR-153; prognosis; SNAI1; EMT; tumor metastasis
2.  Modeling and Simulation of a Parametrically Resonant Micromirror With Duty-Cycled Excitation 
High frequency large scanning angle electrostatically actuated microelectromechanical systems (MEMS) mirrors are used in a variety of applications involving fast optical scanning. A 1-D parametrically resonant torsional micromirror for use in biomedical imaging is analyzed here with respect to operation by duty-cycled square waves. Duty-cycled square wave excitation can have significant advantages for practical mirror regulation and/or control. The mirror’s nonlinear dynamics under such excitation is analyzed in a Hill’s equation form. This form is used to predict stability regions (the voltage-frequency relationship) of parametric resonance behavior over large scanning angles using iterative approximations for nonlinear capacitance behavior of the mirror. Numerical simulations are also performed to obtain the mirror’s frequency response over several voltages for various duty cycles. Frequency sweeps, stability results, and duty cycle trends from both analytical and simulation methods are compared with experimental results. Both analytical models and simulations show good agreement with experimental results over the range of duty cycled excitations tested. This paper discusses the implications of changing amplitude and phase with duty cycle for robust open-loop operation and future closed-loop operating strategies.
PMCID: PMC4262121  PMID: 25506188
MEMS; micro-mirror; parametric resonance; Hill’s equation; nonlinear dynamics
3.  Delineation of Early and Later Adult Onset Depression by Diffusion Tensor Imaging 
PLoS ONE  2014;9(11):e112307.
Due to a lack of evidence, there is no consistent age of onset to define early onset (EO) versus later onset (LO) major depressive disorder (MDD). Fractional anisotropy (FA), derived from diffusion tensor imaging (DTI), has been widely used to study neuropsychiatric disorders by providing information about the brain circuitry, abnormalities of which might facilitate the delineation of EO versus LO MDD.
In this study, 61 pairs of untreated, non-elderly, first-episode MDD patients and healthy controls (HCs) aged 18–45 years old received DTI scans. The voxel-based analysis method (VBM), classification analysis, using the Statistical Package for the Social Sciences (SPSS), and regression analyses were used to determine abnormal FA clusters and their correlations with age of onset and clinical symptoms.
Classification analysis suggested in the best model that there were two subgroups of MDD patients, delineated by an age of onset of 30 years old, by which MDD patients could be divided into EO (18–29 years old) and LO (30–45 years old) groups. LO MDD was characterized by decreased FA, especially in the white matter (WM) of the fronto-occipital fasciculus and posterior limb of internal capsule, with a negative correlation with the severity of depressive symptoms; in marked contrast, EO MDD showed increased FA, especially in the WM of the corpus callosum, corticospinal midbrain and inferior fronto-occipital fasciculus, while FA of the WM near the midbrain had a positive correlation with the severity of depressive symptoms.
Specific abnormalities of the brain circuitry in EO vs. LO MDD were delineated by an age of onset of 30 years old, as demonstrated by distinct abnormal FA clusters with opposite correlations with clinical symptoms. This DTI study supported the evidence of an exact age for the delineation of MDD, which could have broad multidisciplinary importance.
Trial Registration NCT00703742
PMCID: PMC4231105  PMID: 25393297
4.  Cross-linking of CD81 by HCV-E2 protein inhibits human intrahepatic plasmacytoid dendritic cells response to CpG-ODN 
Cellular immunology  2013;284(0):98-103.
Plasmacytoid dendritic cells (pDCs) are reported to be defective in HCV-infected patients, the mechanisms of which remain poorly understood. We isolated liver derived mononuclear cells (LMNCs) and pDCs from normal liver tissues of benign tumor dissections and liver transplant donors. Isolated pDCs and LMNCs were cultured with precoated HCV envelop protein E2 (HCV-E2) or anti-CD81 mAb in the presence of CpG-ODN. Our results show that cross-linking of CD81 by either HCV-E2 or anti-CD81 mAb inhibits IFN-α secretion in CpG-induced pDCs; down-regulates HLA-DR, CD80 and CD86 expression in pDCs; and suppresses CpG-ODN induced proliferation and survival of pDCs. The blockade of CD81 by soluble anti-CD81 antibody restores pDCs response to CpG-ODN. These results suggest that HCV E2 protein interacts with CD81 to inhibit pDC maturation, activation, and IFN-α production, and may thereby contribute to the impaired innate anti-viral immune response in HCV infection.
PMCID: PMC3979323  PMID: 23954883
Plasmacytoid dendritic cells (pDCs); Hepatitis C virus envelop protein (HCV-E); CpG oligodeoxynucleotides (CpG-ODN); Toll-like receptor 9 (TLR9); Cross-linking
5.  Association between ischemic stroke and migraine in elderly Chinese: a case–control study 
BMC Geriatrics  2013;13:126.
Recent observations suggest that migraine and cerebrovascular disease are comorbid conditions. However, the association of migraine with cerebrovascular disease in the population of elderly Chinese has not been established. This prospective case–control study aimed to investigate the prevalence and lesion characteristics of migraine in elderly Chinese patients with acute cerebral infarction (ACI).
A total of 968 ACI patients aged 55–70 years and 1024 sex- and age-matched control subjects were recruited between January, 2003 and July, 2009. Migraine was determined based on the International Headache Society’s Classification of Headache Disorders, together with past medical records and admission examination results, following an initial questionnaire screening at the first hospital visit. Prevalence rates of overall migraine, migraine with aura and migraine without aura in both ACI patients and control subjects, the stroke subtypes classified according to the Chinese Ischemic Stroke Subclassification (CISS) system and brain locations of the ischemic lesions in ACI patients were analyzed.
The overall prevalence rate of migraine was 17.15% (166/968) in patients with ACI but only 3.9% (40/1024) in control subjects (P < 0.01). In both subject groups, over 80% of migraine cases were migraine without aura. In the 166 ACI patients with comorbid migraine, large artery atherosclerosis was the most frequent subtype of ischemic lesion (65.06%), followed by cardiogenic stroke (23.50%), and all other lesion subtypes were each less than 10%. Ischemic infarctions were located predominantly in the anterior circulation in the brain in both ACI patients with and without migraine.
The prevalence rate of migraine is significantly higher in ACI patients than non-ACI subjects in the population of elderly Chinese. Migraine without aura is the major form of migraine in both ACI patients and non-ACI subjects. In ACI patients, regardless of migraine, infarction lesions were predominantly located in the anterior cerebral circulation.
PMCID: PMC3835862  PMID: 24245875
Migraine; Acute cerebral infarction; Elderly Chinese; Aura
6.  Concomitant Targeting of Multiple Key Transcription Factors Effectively Disrupts Cancer Stem Cells Enriched in Side Population of Human Pancreatic Cancer Cells 
PLoS ONE  2013;8(9):e73942.
A major challenge in the treatment of pancreatic ductal adenocarcinoma is the failure of chemotherapy, which is likely due to the presence of the cancer stem cells (CSCs).
To identify side population (SP) cells and characterize s-like properties in human pancreatic cancer cell lines (h-PCCLs) and to exploit the efficacy of concomitant targeting of multiple key transcription factors governing the stemness of pancreatic CSCs in suppressing CSC-like phenotypes.
Flow cytometry and Hoechst 33342 DNA-binding dye efflux assay were used to sort SP and non-SP (NSP) cells from three h-PCCLs: PANC-1, SW1990, and BxPc-3. The self-renewal ability, invasiveness, migration and drug resistance of SP cells were evaluated. Expression of CSC marker genes was analyzed. Tumorigenicity was assessed using a xenograft model in nude mice. Effects of a complex decoy oligonucleotide (cdODN-SCO) designed to simultaneously targeting Sox2, Oct4 and c-Myc were assessed.
CSCs were enriched in the side proportion (SP) cells contained in the h-PCCLs and they possessed aggressive growth, invasion, migration and drug-resistance properties, compared with NSP cells. SP cells overexpressed stem cell markers CD133 and ALDH1, pluripotency maintaining factors Nanog, Sox2 and Oct4, oncogenic transcription factor c-Myc, signaling molecule Notch1, and drug resistant gene ABCG2. Moreover, SP cells consistently demonstrated significantly greater tumorigenicity than NSP cells in xenograft model of nude mice. CdODN–SOC efficiently suppressed all CSC properties and phenotypes, and minimized the tumorigenic capability of the SP cells and the resistance to chemotherapy. By comparison, the negative control failed to do so.
The findings indicate that targeting the key genes conferring the stemness of CSCs can efficiently eliminate CSC-like phenotypes, and thus may be considered a new approach for cancer therapy. Specifically, the present study establishes the combination of Sox2/Oct4/c-Myc targeting as a potential anti-pancreatic cancer agent worthy of further studies in preclinical settings.
PMCID: PMC3770686  PMID: 24040121
7.  Abnormal Resting-State Activities and Functional Connectivities of the Anterior and the Posterior Cortexes in Medication-Naïve Patients with Obsessive-Compulsive Disorder 
PLoS ONE  2013;8(6):e67478.
Obsessive-compulsive disorder (OCD) is a mental illness characterized by the loss of control. Because the cingulate cortex is believed to be important in executive functions, such as inhibition, we used functional magnetic resonance imaging (fMRI) techniques to examine whether and how activity and functional connectivity (FC) of the cingulate cortex were altered in drug-naïve OCD patients.
Twenty-three medication-naïve OCD patients and 23 well-matched healthy controls received fMRI scans in a resting state. Functional connectivities of the anterior cingulate (ACC) and the posterior cingulate (PCC) to the whole brain were analyzed using correlation analyses based on regions of interest (ROI) identified by the fractional amplitude of low-frequency fluctuation (fALFF). Independent Component Analysis (ICA) was used to identify the resting-state sub-networks.
fALFF analysis found that regional activity was increased in the ACC and decreased in the PCC in OCD patients when compared to controls. FC of the ACC and the PCC also showed different patterns. The ACC and the PCC were found to belong to different resting-state sub-networks in ICA analysis and showed abnormal FC, as well as contrasting correlations with the severity of OCD symptoms.
Activity of the ACC and the PCC were increased and decreased, respectively, in the medication-naïve OCD patients compared to controls. Different patterns in FC were also found between the ACC and the PCC with respect to these two groups. These findings implied that the cardinal feature of OCD, the loss of control, may be attributed to abnormal activities and FC of the ACC and the PCC.
PMCID: PMC3696097  PMID: 23840714
8.  Replication-Competent Infectious Hepatitis B Virus Vectors Carrying Substantially Sized Transgenes by Redesigned Viral Polymerase Translation 
PLoS ONE  2013;8(4):e60306.
Viral vectors are engineered virus variants able to deliver nonviral genetic information into cells, usually by the same routes as the parental viruses. For several virus families, replication-competent vectors carrying reporter genes have become invaluable tools for easy and quantitative monitoring of replication and infection, and thus also for identifying antivirals and virus susceptible cells. For hepatitis B virus (HBV), a small enveloped DNA virus causing B-type hepatitis, such vectors are not available because insertions into its tiny 3.2 kb genome almost inevitably affect essential replication elements. HBV replicates by reverse transcription of the pregenomic (pg) RNA which is also required as bicistronic mRNA for the capsid (core) protein and the reverse transcriptase (Pol); their open reading frames (ORFs) overlap by some 150 basepairs. Translation of the downstream Pol ORF does not involve a conventional internal ribosome entry site (IRES). We reasoned that duplicating the overlap region and providing artificial IRES control for translation of both Pol and an in-between inserted transgene might yield a functional tricistronic pgRNA, without interfering with envelope protein expression. As IRESs we used a 22 nucleotide element termed Rbm3 IRES to minimize genome size increase. Model plasmids confirmed its activity even in tricistronic arrangements. Analogous plasmids for complete HBV genomes carrying 399 bp and 720 bp transgenes for blasticidin resistance (BsdR) and humanized Renilla green fluorescent protein (hrGFP) produced core and envelope proteins like wild-type HBV; while the hrGFP vector replicated poorly, the BsdR vector generated around 40% as much replicative DNA as wild-type HBV. Both vectors, however, formed enveloped virions which were infectious for HBV-susceptible HepaRG cells. Because numerous reporter and effector genes with sizes of around 500 bp or less are available, the new HBV vectors should become highly useful tools to better understand, and combat, this important pathogen.
PMCID: PMC3615001  PMID: 23589756
9.  XRCC1 codon 399Gln polymorphism is associated with radiotherapy-induced acute dermatitis and mucositis in nasopharyngeal carcinoma patients 
To evaluate the association between single nucleotide polymorphisms (SNPs) at the 194 and 399 codons of XRCC1, and the risk of severe acute skin and oral mucosa reactions in nasopharyngeal carcinoma patients in China.
114 patients with nasopharyngeal carcinoma were sequentially recruited in this study. Heparinized peripheral blood samples were taken for SNPs analysis before the start of radiation treatment. SNPs in XRCC1 (194Arg/Trp and 399Arg/Gln) gene were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Dermatitis at upper neck and oral mucositis were clinically recorded according to the Common Terminology Criteria for Adverse Events v.3.0.
The variant allele frequencies were 0.289 for XRCC1 194Trp and 0.263 for XRCC1 399Gln. Of the 114 patients, 24 experienced grade 3 acute dermatitis and 48 had grade 3 acute mucositis. The XRCC1 399Arg/Gln was significantly associated with the development of grade 3 dermatitis (Odds Ratio, 2.65; 95% CI, 1.04–6.73; p = 0.037, χ2 = 4.357). In addition, it was also associated with higher incidence of grade 3 mucositis with a borderline statistical significance (Odds Ratio, 2.11; 95% CI, 0.951–4.66; p = 0.065, χ2 = 3.411). The relationship between XRCC1 194Arg/Trp and acute dermatitis, and mucositis was not found.
Our investigation shows, for the first time, that patients with the XRCC1 399Arg/Gln genotype were more likely to experience severe acute dermatitis and oral mucositis. With further validation, the information can be used to determine personalized radiotherapy strategy.
PMCID: PMC3570437  PMID: 23375119
Single nucleotide polymorphisms (SNPs); X-ray cross-complementing group 1 (XRCC1); Nasopharyngeal carcinoma (NPC); Radiotherapy; Acute skin reactions; Acute mucosa reactions
10.  Truncated Active Human Matrix Metalloproteinase-8 Delivered by a Chimeric Adenovirus-Hepatitis B Virus Vector Ameliorates Rat Liver Cirrhosis 
PLoS ONE  2013;8(1):e53392.
Liver cirrhosis is a potentially life-threatening disease caused by progressive displacement of functional hepatocytes by fibrous tissue. The underlying fibrosis is often driven by chronic infection with hepatitis B virus (HBV). Matrix metalloproteinases including MMP-8 are crucial for excess collagen degradation. In a rat model of liver cirrhosis, MMP-8 delivery by an adenovirus (Ad) vector achieved significant amelioration of fibrosis but application of Ad vectors in humans is subject to various issues, including a lack of intrinsic liver specificity.
HBV is highly liver-specific and its principal suitability as liver-specific gene transfer vector is established. HBV vectors have a limited insertion capacity and are replication-defective. Conversely, in an HBV infected cell vector replication may be rescued in trans by the resident virus, allowing conditional vector amplification and spreading. Capitalizing on a resident pathogen to help in its elimination and/or in treating its pathogenic consequences would provide a novel strategy. However, resident HBV may also reduce susceptibility to HBV vector superinfection. Thus a size-compatible truncated MMP-8 (tMMP8) gene was cloned into an HBV vector which was then used to generate a chimeric Ad-HBV shuttle vector that is not subject to superinfection exclusion. Rats with thioacetamide-induced liver cirrhosis were injected with the chimera to evaluate therapeutic efficacy.
Our data demonstrate that infectious HBV vector particles can be obtained via trans-complementation by wild-type virus, and that the tMMP8 HBV vector can efficiently be shuttled by an Ad vector into cirrhotic rat livers. There it exerted a comparable beneficial effect on fibrosis and hepatocyte proliferation markers as a conventional full-length MMP-8Ad vector.
Though the rat cirrhosis model does not allow assessing in vivo HBV vector amplification these results advocate the further development of Ad-HBV vectors for liver-specific gene therapy, including and perhaps particularly for HBV-related disease.
PMCID: PMC3536652  PMID: 23301066
11.  Modulation of ovine SBD-1 expression by 17beta-estradiol in ovine oviduct epithelial cells 
Mucosal epithelia, including those of the oviduct, secrete antimicrobial innate immune molecules (AIIMS). These have bactericidal/bacteriostatic functions against a variety of pathogens. Among the AIIMs, sheep β-defensin-1 (SBD-1) is one of the most potent. Even though the SBD-1 is an important AIIM and it is regulated closely by estrogenic hormone, the regulation mechanism of 17β-estradiol has not been clearly established. We investigated the effects of E2 and agonist or inhibitor on ovine oviduct epithelial cells in regard to SBD-1 expression using reverse transcription quantitative PCR (RT-qPCR). In addition, three different pathways were inhibited separately or simultaneously to confirm the effect of different inhibitors in the regulation mechanism.
17beta-estradiol (E2) induced release of SBD-1 in ovine oviduct epithelial cells. SBD-1 expression was mediated through G-protein-coupled receptor 30 (GPR30) and Estrogen Receptors (ERs) activation in ovine oviduct epithelial cell. Inhibition of gene expression of protein kinase A (PKA), protein kinase C (PKC), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) led to a decreased SBD-1 expression.
Taken together, E2-induced up-regulation of SBD-1 expressions were GPR30-dependent during prophase and ERs-dependent during later-stage in ovine oviduct epithelial cells, and we assume that the effect was completed by the PKA, PKC, and NF-κB pathways simultaneous.
PMCID: PMC3487956  PMID: 22920556
Sheep; Oviduct epithelial; SBD-1; Modulation; Signaling pathway
12.  Effects of propranolol in combination with radiation on apoptosis and survival of gastric cancer cells in vitro 
The National Comprehensive Cancer Network (NCCN) guidelines recommend radiotherapy as a standard treatment for patients with a high risk of recurrence in gastric cancer. Because gastric cancer demonstrates limited sensitivity to radiotherapy, a radiosensitizer might therefore be useful to enhance the radiosensitivity of patients with advanced gastric carcinoma. In this study, we evaluated if propranolol, a β-adrenoceptor (β-AR) antagonist, could enhance radiosensitivity and explored its precise molecular mechanism in gastric cancer cells.
Human gastric adenocarcinoma cell lines (SGC-7901 and BGC-823) were treated with or without propranolol and exposed to radiation. Cell viability and clonogenic survival assays were performed, and cell apoptosis was evaluated with flow cytometry. In addition, the expression of nuclear factor κB (NF-κB), vascular endothelial growth factor (VEGF), cyclooxygenase 2 (COX-2), and epidermal growth factor receptor (EGFR) were detected by western blot and real-time reverse transcription polymerase chain reaction (PCR).
Propranolol combined with radiation decreased cell viability and clonogenic survivability. Furthermore, it also induced apoptosis in both cell lines tested, as determined by Annexin V staining. In addition, treatment with propranolol decreased the level of NF-κB and, subsequently, down-regulated VEGF, COX-2, and EGFR expression.
Taken together, these results suggested that propranolol enhanced the sensitivity of gastric cancer cells to radiation through the inhibition of β-ARs and the downstream NF-κB-VEGF/EGFR/COX-2 pathway.
PMCID: PMC2974742  PMID: 20977754
13.  Lack of association of two polymorphisms of IRF5 with Behcet’s disease 
Molecular Vision  2009;15:2018-2021.
Interferon regulation factor 5 (IRF5) is a member of the IRF family of transcription factors that control the transactivation of type I interferon system-related genes as well as the expression of several other genes involved in immune response. Here, we investigated its association with Behcet’s disease (BD) in a well defined group of Chinese Han patients.
A total of 152 unrelated Chinese patients with BD and 149 healthy blood donors were genotyped for IRF5 rs2280714 and rs752637 polymorphisms. Genomic DNA was isolated from peripheral blood mononuclear cells. Genotyping of each single nucleotide polymorphism (SNPs) was performed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Allele and genotype frequencies of IRF5 rs2280714 and rs752637 polymorphisms were compared between patients and controls using a two-sided χ2 test.
The results showed no significant difference concerning the frequency of the allele of rs2280714 and rs752637 polymorphisms between BD patients and the normal controls (p=0.647 and p=0.105, respectively). The frequencies of the genotype of rs2280714 and rs752637 were not different between BD patients and the normal controls (p=0.233 and, p=0.266, respectively). Clinical manifestation stratification analysis did not show any association of IRF5 polymorphisms with BD patients (p>0.05).
Our study revealed that the rs2280714 and rs752637 SNPs were not associated with the susceptibility to BD. There was no association between the two polymorphisms of IRF5 and any extraocular clinical manifestations in BD.
PMCID: PMC2759328  PMID: 19816589

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