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1.  Role of capecitabine in treating metastatic colorectal cancer in Chinese patients 
OncoTargets and therapy  2014;7:501-511.
The China Food and Drug Administration approved the use of capecitabine in patients with metastatic colorectal cancer (mCRC) in 2004. This paper reviews the available information of capecitabine in Chinese patients with mCRC, focusing on its effectiveness and safety against mCRC. Identification of all eligible studies was made by searching the PubMed and Wanfang database from 2000 to 2013. Published data examining various aspects of clinical response and tolerability with capecitabine alone or in combination with other chemotherapeutic or biological agents for first- and second-line mCRC were examined. Capecitabine and its combination displayed high efficacy in Chinese patients with mCRC. Toxicities are generally manageable, and elderly patients can tolerate capecitabine well.
PMCID: PMC3979786
capecitabine; metastatic colorectal cancer; Chinese
2.  S-1-Based Chemotherapy versus Capecitabine-Based Chemotherapy as First-Line Treatment for Advanced Gastric Carcinoma: A Meta-Analysis 
PLoS ONE  2013;8(12):e82798.
Although both oral fluoropyrimidines were reported effective and safe, doubts exist about whether S-1 or capecitabine is more advantageous in advanced gastric carcinoma (AGC). Herein, we performed a meta-analysis to comprehensively compare the efficacy and safety of S-1-based chemotherapy versus capecitabine-based chemotherapy as first-line treatment for AGC.
PubMed/Medline, EmBase, Cochrane library, and China National Knowledge Infrastructure databases were searched for articles comparing S-1-based chemotherapy to capecitabine-based chemotherapy for AGC. Primary outcomes were overall response rate (ORR), time to progression (TTP), overall survival (OS), progression-free probability, and survival probability. Secondary outcomes were toxicities. Fixed-effects model were used and all the results were confirmed by random-effects model.
Five randomized controlled trials and five cohort studies with 821 patients were included. We found equivalent ORR (38.3% vs. 39.1%, odds ratio [OR] 0.92, 95% confidence interval [CI] 0.69-1.24, P = 0.59), TTP (harzad ratio [HR] 0.98, 95% CI 0.82-1.16, P = 0.79), OS (HR 0.99, 95% CI 0.87-1.13, P = 0.91), progression-free probability (3-month OR 1.02, 95% CI 0.62-1.68, P = 0.94; 6-month OR 1.34, 95% CI 0.88-2.04, P = 0.18) and survival probability (0.5-year OR 0.90, 95% CI 0.61-1.31, P =0.57; 1-year OR 0.97, 95% CI 0.70- 1.33, P = 0.84; 2-year OR 1.15, 95% CI 0.61-2.17, P = 0.66). Equivalent grade 3 to 4 hematological and non-hematological toxicities were found except hand-foot syndrome was less prominent in S-1-based chemotherapy (0.3% vs. 5.9%, OR 0.19, 95% CI 0.06-0.56, P = 0.003). There’re no significant heterogeneity and publication bias. Cumulative analysis found stable time-dependent trend. Consistent results stratified by study design, age, regimen, cycle, country were observed.
S-1-based chemotherapy was associated with non-inferior antitumor efficacy and better safety profile, compared with capecitabine-based therapy. We recommended S-1 and capecitabine can be used interchangeably for AGC, at least in Asia.
PMCID: PMC3861463  PMID: 24349363
3.  The status of HBV infection influences metastatic pattern and survival in Chinese patients with pancreatic cancer 
It has been proved that hepatitis B virus (HBV) infection alters the metastatic pattern and affects survival in colorectal cancer (CRC) and hepatocellular carcinoma (HCC), while the influence of HBV infection on metastatic pattern and survival in patients with pancreatic cancer (PC) has not been investigated yet.
We conducted an investigation to evaluate the impact of HBV infection on metastatic pattern and overall survival in PC. We collected the data of 460 PC patients treated in our hospital from 1999 to 2010. Serum HBV markers were tested with enzyme-linked immunosorbent assay. The impact of HBV infection on metastatic pattern and overall survival was analyzed.
We found that the incidence of synchronous liver metastasis was significantly higher in patients with HBsAg positive than those with HBsAg negative (46.0% vs 32.0%, P < 0.05), and higher in chronic HBV infection (CHB) group than both non HBV infection and resolved HBV infection group (61.1% vs 33.9%, P < 0.05, and 61.1% vs 28.7%, P < 0.05, respectively). What’s more, Kaplan-Meier analysis showed that CHB, resolved HBV infection and non HBV infection group had significant longer overall survival (OS) compared with inactive HBsAg carriers (IC) group (P=0.037, P=0.009, and P=0.019 respectively). But, in the multivariate analysis, only the CHB and non HBV infection group had significant better overall survival compared with IC group (P=0.010 and P=0.018 respectively).
Our study found that HBV infection increased synchronous liver metastasis rate, and HBV infection status was an independent prognostic factor in PC patients.
PMCID: PMC3851713  PMID: 24099678
Hepatitis B virus; Pancreatic cancer; Liver metastasis; Survival
4.  Improvement of thermal stability of polypropylene using DOPO-immobilized silica nanoparticles 
Colloid and polymer science  2012;290(14):1371-1380.
After the surface silylation with 3-methacryloxypropyltrimethoxysilane, silica nanoparticles were further modified by 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide (DOPO). The immobilization of DOPO on silica nanoparticles was confirmed by Fourier transform infrared spectroscopy, UV–visible spectroscopy, magic angle spinning nuclear magnetic resonance, and thermogravimetric analysis. By incorporating the DOPO-immobilized silica nanoparticles (5 wt%) into polypropylene matrix, the thermal oxidative stability exhibited an improvement of 62 °C for the half weight loss temperature, while that was only 26 °C increment with incorporation of virgin silica nanoparticles (5 wt%). Apparent activation energies of the polymer nanocomposites were estimated via Flynn–Wall–Ozawa method. It was found that the incorporation of DOPO-immobilized silica nanoparticles improved activation energies of the degradation reaction. Based on the results, it was speculated that DOPO-immobilized silica nanoparticles could inhibit the degradation of polypropylene and catalyze the formation of carbonaceous char on the surface. Thus, thermal stability was significantly improved.
PMCID: PMC3981559
Polypropylene; DOPO; Silica; Nanocomposites; Kinetic
5.  Melatonin Improves the Quality of In Vitro Produced (IVP) Bovine Embryos: Implications for Blastocyst Development, Cryotolerance, and Modifications of Relevant Gene Expression 
PLoS ONE  2014;9(4):e93641.
To evaluate the potential effects of melatonin on the kinetics of embryo development and quality of blastocyst during the process of in vitro bovine embryo culture. Bovine cumulus–oocyte complexes (COCs) were fertilized after in vitro maturation. The presumed zygotes were cultured in in vitro culture medium supplemented with or without 10−7 M melatonin. The cleavage rate, 8-cell rate and blastocyst rate were examined to identify the kinetics of embryo development. The hatched blastocyst rate, mortality rate after thawing and the relevant transcript abundance were measured to evaluate the quality of blastocyst. The results showed that melatonin significantly promoted the cleavage rate and 8-cell embryo yield of in vitro produced bovine embryo. In addition, significantly more blastocysts were observed by Day 7 of embryo culture at the presence of melatonin. These results indicated that melatonin accelerated the development of in vitro produced bovine embryos. Following vitrification at Day 7 of embryo culture, melatonin (10−7 M) significantly increased the hatched blastocyst rate from 24 h to 72 h and decreased the mortality rate from 48 h to 72 h after thawing. The presence of melatonin during the embryo culture resulted in a significant increase in the gene expressions of DNMT3A, OCC, CDH1 and decrease in that of AQP3 after thawing. In conclusion, melatonin not only promoted blastocyst yield and accelerated in vitro bovine embryo development, but also improved the quality of blastocysts which was indexed by an elevated cryotolerance and the up-regulated expressions of developmentally important genes.
PMCID: PMC3973586  PMID: 24695534
6.  Restoring Eelgrass (Zostera marina L.) Habitats Using a Simple and Effective Transplanting Technique 
PLoS ONE  2014;9(4):e92982.
Eelgrass beds in coastal waters of China have declined substantially over the past 30 years. In this study, a simple new transplanting technique was developed for eelgrass (Zostera marina L.) restoration. To assist in anchoring single shoots, several rhizomes of rooted shoots were bound to a small elongate stone (50–150 g) with biodegradable thread (cotton or hemp), and then the bound packet was buried at an angle in the sediments at a depth of 2–4 cm. This stone anchoring method was used to transplant eelgrass in early November 2009 and late May 2010 in Huiquan Bay, Qingdao. The method led to high success. Three month survivorship of the transplanted shoots at the two transplant sites was >95%. From April 20 to November 19, 2012, the following characteristics of the 2009 and 2010 transplanted eelgrass beds were monitored: morphological changes, shoot density, shoot height, leaf biomass, and sediment particle size. Results showed that the sexual reproduction period of the planted eelgrass was from April to August, and vegetative reproduction reached its peak in autumn. Maximum shoot height and biomass were observed in June and July. After becoming established, the transplanted eelgrass beds were statistically equal to natural eelgrass beds nearby in terms of shoot height, biomass, and seasonal variations. This indicates that the transplant technique is effective for eelgrass restoration in coastal waters.
PMCID: PMC3973628  PMID: 24695414
7.  A Polycarbonate/Magnesium Oxide Nanocomposite with High Flame Retardancy 
Journal of applied polymer science  2012;123(2):1085-1093.
A new flame retardant polycarbonate/magnesium oxide (PC/MgO) nanocomposite, with high flame retardancy was developed by melt compounding. The effect of MgO to the flame retardancy, thermal property, and thermal degradation kinetics were investigated. Limited oxygen index (LOI) test revealed that a little amount of MgO (2 wt %) led to significant enhancement (LOI = 36.8) in flame retardancy. Thermogravimetric analysis results demonstrated that the onset temperature of degradation and temperature of maximum degradation rate decreased in both air and N2 atmosphere. Apparent activation energy was estimated via Flynn–Wall–Ozawa method. Three steps in the thermal degradation kinetics were observed after incorporation of MgO into the matrix and the additive raised activation energies of the composite in the full range except the initial stage. It was interpreted that the flame retardancy of PC was influenced by MgO through the following two aspects: on the one hand, MgO catalyzed the thermal-oxidative degradation and accelerated a thermal protection/mass loss barrier at burning surface; on the other hand, the filler decreased activation energies in the initial step and improved thermal stability in the final period.
PMCID: PMC3970200
polycarbonates; flame retardance; thermal properties; activation energy
8.  Epidemiologic characterization of 30 confirmed cases of human infection with avian influenza A(H7N9) virus in Hangzhou, China 
BMC Infectious Diseases  2014;14:175.
We examined the clinical and epidemiological characteristics of 30 cases of human infection with avian influenza A(H7N9) virus in Hangzhou and investigated their external environments to provide evidence for contact tracing and disease prevention and control.
The cases confirmed from April 1 through May 1, 2013 were studied. Field epidemiologic surveys were conducted to collect the clinical and epidemiologic data. Case-related and environmental specimens were collected for etiologic detection.
Thirty cases of human infection with avian influenza A(H7N9) virus were confirmed in Hangzhou from April 1 through May 1, 2013, including one pregnant woman and three deaths. The median age of the patients was 62 years (range: 38–86 years). Twenty-three of the patients were men (76.67%). The median duration between disease onset and occurrence of respiratory failure and confirmed diagnosis was 5 and 6 days, respectively. Maximum medical observation of 666 close contacts of the patients revealed no irregularity. Of 314 external environmental specimens, the overall positive detection rate of H7N9 nucleic acid was 28.98%. Eight districts of Hangzhou city had positive detections in the external environments, the highest rate being in Yuhang District (78.13%). Statistical analysis of the specimen collection locations indicates a significant difference between the case-linked locations and the non-case locations (χ 2  = 16.563, p < 0.05) in terms of H7N9 viral nucleic acid detection rate. No epidemiologic link has been found among the 30 cases.
Most of the infected were retired individuals aged 60 years or older. Men made the majority. The cases are sporadic at present, with no evidence of human-to-human transmission. Exposures to poultry and live poultry markets may be important sources of infection.
PMCID: PMC3977889  PMID: 24678603
Human avian influenza; H7N9 subtype; Epidemiologic characteristics; External environmental detection
9.  JMJD6 Promotes Colon Carcinogenesis through Negative Regulation of p53 by Hydroxylation 
PLoS Biology  2014;12(3):e1001819.
p53 hydroxylation by JMJD6 represents a novel post-translational modification for p53. JMJD6-mediated hydroxylation regulates p53's transcriptional activity and the p53-dependent control of colon cancer.
Jumonji domain-containing 6 (JMJD6) is a member of the Jumonji C domain-containing family of proteins. Compared to other members of the family, the cellular activity of JMJD6 is still not clearly defined and its biological function is still largely unexplored. Here we report that JMJD6 is physically associated with the tumor suppressor p53. We demonstrated that JMJD6 acts as an α-ketoglutarate– and Fe(II)-dependent lysyl hydroxylase to catalyze p53 hydroxylation. We found that p53 indeed exists as a hydroxylated protein in vivo and that the hydroxylation occurs mainly on lysine 382 of p53. We showed that JMJD6 antagonizes p53 acetylation, promotes the association of p53 with its negative regulator MDMX, and represses transcriptional activity of p53. Depletion of JMJD6 enhances p53 transcriptional activity, arrests cells in the G1 phase, promotes cell apoptosis, and sensitizes cells to DNA damaging agent-induced cell death. Importantly, knockdown of JMJD6 represses p53-dependent colon cell proliferation and tumorigenesis in vivo, and significantly, the expression of JMJD6 is markedly up-regulated in various types of human cancer especially in colon cancer, and high nuclear JMJD6 protein is strongly correlated with aggressive clinical behaviors of colon adenocarcinomas. Our results reveal a novel posttranslational modification for p53 and support the pursuit of JMJD6 as a potential biomarker for colon cancer aggressiveness and a potential target for colon cancer intervention.
Author Summary
JMJD6 belongs to the Jumonji C domain-containing family of proteins. The majority of this family are histone demethylases implicated in chromatin-associated events, but there have also been some reports of lysyl hydroxylase activity for JMJD6. Here we report a new posttranslational modification for the tumor suppressor protein p53 that is mediated by JMJD6. Via a physical associations with p53, JMJD6 catalyzes the hydroxylation of p53, thereby repressing its transcriptional activity. Depletion of JMJD6 promotes cell apoptosis, arrests cells in the G1 phase, sensitizes cells to DNA damaging agent-induced cell death, and represses p53-dependent colon cell proliferation and tumorigenesis. Significantly, the expression of JMJD6 is markedly up-regulated in various types of human cancer especially in colon cancer, and high nuclear JMJD6 protein is strongly correlated with aggressive clinical behaviors of colon adenocarcinomas. Our results support the pursuit of JMJD6 as a potential biomarker for colon cancer aggressiveness and a potential target for colon cancer intervention.
PMCID: PMC3965384  PMID: 24667498
10.  Selection of Suitable Reference Genes for qPCR Normalization under Abiotic Stresses in Oenanthe javanica (BI.) DC 
PLoS ONE  2014;9(3):e92262.
Accurate normalization of gene expression data is an absolute prerequisite to obtain reliable results in qPCR analysis. Oenanthe javanica, an aquatic perennial herb, belongs to the Oenanthe genus in Apiaceae family, with known medicinal properties. In the current study, O. javanica was subjected to hormone stimuli (gibberellin, salicylic acid, methyl jasmonate, and abscisic acid) and abiotic stresses (heat, cold, salt, and drought), and the expression of nine candidate reference genes (eIF-4α, ACT7, TIP41, GAPDH, SAND, EF-1α, PP2A, TBP, and TUB) was evaluated. Stability of the genes was assessed using geNorm, NormFinder and BestKeeper. All the genes presented distinct expression profiles under the experimental conditions analyzed. Under abiotic stress conditions, ACT7 and PP2A genes displayed the maximum stability; PP2A and SAND were the most stable genes under hormone stimuli. Even though PP2A gene was most stable across all the samples, individual analysis revealed changes in expression profile. To further validate the suitability of the reference genes identified in this study, the expression level of M6PR gene under salt treatment was studied. Based on our data, we propose that it is essential to normalize the target gene expression with specific reference genes under different experimental conditions for most accurate results. To our knowledge, this is the first systematic analysis for reference genes under abiotic stress and hormone stimuli conditions in O. javanica. This will be beneficial for future studies on O. javanica and other plants in Apiaceae family at molecular level.
PMCID: PMC3961309  PMID: 24651080
11.  Transcriptomic Analysis of the Rice White Tip Nematode, Aphelenchoides besseyi (Nematoda: Aphelenchoididae) 
PLoS ONE  2014;9(3):e91591.
The rice white tip nematode Aphelenchoides besseyi, a devastating nematode whose genome has not been sequenced, is distributed widely throughout almost all the rice-growing regions of the world. The aims of the present study were to define the transcriptome of A. besseyi and to identify parasite-related, mortality-related or host resistance-overcoming genes in this nematode.
Methodology and Principal Findings
Using Solexa/Illumina sequencing, we profiled the transcriptome of mixed-stage populations of A. besseyi. A total of 51,270 transcripts without gaps were produced based on high-quality clean reads. Of all the A. besseyi transcripts, 9,132 KEGG Orthology assignments were annotated. Carbohydrate-active enzymes of glycoside hydrolases (GHs), glycosyltransferases (GTs), carbohydrate esterases (CEs) and carbohydrate-binding modules (CBMs) were identified. The presence of the A. besseyi GH45 cellulase gene was verified by in situ hybridization. Given that 13 unique A. besseyi potential effector genes were identified from 41 candidate effector homologs, further studies of these homologs are merited. Finally, comparative analyses were conducted between A. besseyi contigs and Caenorhabditis elegans genes to look for orthologs of RNAi phenotypes, neuropeptides and peptidases.
Conclusions and Significance
The present results provide comprehensive insight into the genetic makeup of A. besseyi. Many of this species' genes are parasite related, nematode mortality-related or necessary to overcome host resistance. The generated transcriptome dataset of A. besseyi reported here lays the foundation for further studies of the molecular mechanisms related to parasitism and facilitates the development of new control strategies for this species.
PMCID: PMC3956754  PMID: 24637831
12.  Patients with Old Age or Proximal Tumors Benefit from Metabolic Syndrome in Early Stage Gastric Cancer 
PLoS ONE  2014;9(3):e89965.
Metabolic syndrome and/or its components have been demonstrated to be risk factors for several cancers. They are also found to influence survival in breast, colon and prostate cancer, but the prognostic value of metabolic syndrome in gastric cancer has not been investigated.
Clinical data and pre-treatment information of metabolic syndrome of 587 patients diagnosed with early stage gastric cancer were retrospectively collected. The associations of metabolic syndrome and/or its components with clinical characteristics and overall survival in early stage gastric cancer were analyzed.
Metabolic syndrome was identified to be associated with a higher tumor cell differentiation (P = 0.036). Metabolic syndrome was also demonstrated to be a significant and independent predictor for better survival in patients aged >50 years old (P = 0.009 in multivariate analysis) or patients with proximal gastric cancer (P = 0.047 in multivariate analysis). No association was found between single metabolic syndrome component and overall survival in early stage gastric cancer. In addition, patients with hypertension might have a trend of better survival through a good control of blood pressure (P = 0.052 in univariate analysis).
Metabolic syndrome was associated with a better tumor cell differentiation in patients with early stage gastric cancer. Moreover, metabolic syndrome was a significant and independent predictor for better survival in patients with old age or proximal tumors.
PMCID: PMC3943843  PMID: 24599168
13.  Effect of Age-Related Cartilage Turnover on Serum C-Telopeptide of Collagen Type II and Osteocalcin Levels in Growing Rabbits with and without Surgically Induced Osteoarthritis 
BioMed Research International  2014;2014:284784.
This study aims to determine the effect of age-related cartilage turnover on the serum C-telopeptide of type II collagen (CTX-II) and osteocalcin (OC) levels in growing rabbits with and without surgically induced osteoarthritis. Twenty-four New Zealand male 3-month-old rabbits were randomized into three operated groups (n = 6 per group, with surgically induced osteroarthritis in the right knee; after blood sampling, the knees were harvested following euthanization at 2, 3, and 6 months after surgery) and a control group (n = 6, blood samples were obtained monthly between 3 and 15 months). Histomorphologically, the medial femoral condyles, particularly the central parts, harbored the most severe osteoarthritic changes among the operated rabbits. The serum levels of CTX-II and OC decreased in the controls from 3 to 11 months and then remained stable. No significant differences in the serum CTX-II and OC levels between the osteoarthritic rabbits and controls were observed. The osteoarthritic-to-normal ratios (ONRs, the ratios of serum CTX-II or OC levels in osteoarthritic rabbits to those of the controls at same ages) enabled an overall assessment of osteoarthritis and age-related cartilage turnover. Elevated CTX-II ONRs were observed in rabbits with mild to advanced osteoarthritis. However, the OC ONRs were unhelpful in assessing osteoarthritic growing rabbits.
PMCID: PMC3963374
14.  Measles virus nucleocapsid protein, a key contributor to Paget’s disease, increases IL-6 expression via down-regulation of FoxO3/Sirt1signaling 
Bone  2012;53(1):269-276.
Measles virus plays an important role as an environmental factor in the pathogenesis of Paget’s disease (PD). Previous studies have shown that IL-6 is increased in the bone marrow of Paget’s patients and that measles virus nucleocapsid protein (MVNP) induces IL-6 secretion by pagetic osteoclasts. Further, IL-6 plays a critical role in the development of pagetic osteoclasts and bone lesions induced by PD, but the mechanisms regulating IL-6 production by MVNP remain unclear. Our current studies revealed that MVNP expression in osteoclast precursors down-regulated Sirt1 mRNA and protein, a negative regulator of NF-κB activity, which is a key factor for IL-6 expression. MVNP expression in NIH3T3 cells also elevated Il-6 transcription and impaired the expression of Sirt1 mRNA both under basal conditions and upon activation of the Sirt1 upstream regulator FoxO3 by LY294002 (a PI3K/AKT inhibitor). Luciferase activity assays showed that constitutively active FoxO3 abolished the repressive effect of MVNP on reporters driven by either FoxO3 response elements or the Sirt1 promoter. Further, protein stability assays revealed that FoxO3 was degraded more rapidly in MVNP-expressing cells than in control cells following the addition of cycloheximide. Similarly, co-transfection of MVNP and FoxO3 into HEK293 cells demonstrated that MVNP decreased the protein levels of over-expressed FoxO3 in a dose-dependent manner. Treatment with the proteasome inhibitor, MG132, blocked the MVNP-triggered decrease of FoxO3, and the treatment with the serine/threonine phosphatase inhibitor, Calyculin A, revealed that MVNP increased phosphorylation of FoxO3. Further, over-expression of Sirt1 or treatment with the Sirt1 activator resveratrol blocked the increase in Il-6 transcription by MVNP. Finally, resveratrol reduced the numbers of TRAP positive multi-nuclear cells in bone marrow cultures from TRAP-MVNP transgenic mice to wild type levels. These results indicate that MVNP decreases FoxO3/Sirt1 signaling to enhance the levels of IL-6, which in part mediate MVNP’s contribution to the development of Paget’s disease.
PMCID: PMC3552041  PMID: 23262029
MVNP; FoxO3; Sirt1; Il-6; Paget’s disease; NF-κB
15.  Positive effects of porcine IL-2 and IL-4 on virus-specific immune responses induced by the porcine reproductive and respiratory syndrome virus (PRRSV) ORF5 DNA vaccine in swine 
Journal of Veterinary Science  2014;15(1):99-109.
The purpose of this study was to investigate the effects of porcine interleukin (IL)-2 and IL-4 genes on enhancing the immunogenicity of a porcine reproductive and respiratory syndrome virus ORF5 DNA vaccine in piglets. Eukaryotic expression plasmids pcDNA-ORF5, pcDNA-IL-2, and pcDNA-IL-4 were constructed and then expressed in Marc-145 cells. The effects of these genes were detected using an indirect immunofluorescent assay and reverse transcription polymerase chain reaction (RT-PCR). Characteristic fluorescence was observed at different times after pcDNA-ORF5 was expressed in the Marc-145 cells, and PCR products corresponding to ORF5, IL-2, and IL-4 genes were detected at 48 h. Based on these data, healthy piglets were injected intramuscularly with different combinations of the purified plasmids: pcDNA-ORF5 alone, pcDNA-ORF5 + pcDNA-IL-2, pcDNA-ORF5 + pcDNA-IL-4, and pcDNA-ORF5 + pcDNAIL-4 + pcDNA-IL-2. The ensuing humoral immune responses, percentages of CD4+ and CD8+ T lymphocytes, proliferation indices, and interferon-γ expression were analyzed. Results revealed that the piglets co-immunized with pcDNA-ORF5 + pcDNA-IL-4 + pcDNA-IL-2 plasmids developed significantly higher antibody titers and neutralizing antibody levels, had significantly increased levels of specific T lymphocyte proliferation, elevated percentages of CD4+ and CD8+ T lymphocytes, and significantly higher IFN-γ production than the other inoculated pigs (p < 0.05).
PMCID: PMC3973771  PMID: 24136204
IL-2; IL-4; immunogenicity; ORF5 DNA vaccine; porcine reproductive and respiratory syndrome virus
16.  CMTM3 Inhibits Human Testicular Cancer Cell Growth through Inducing Cell-Cycle Arrest and Apoptosis 
PLoS ONE  2014;9(2):e88965.
Human CMTM3 has been proposed as a putative tumor suppressor gene. The loss of CMTM3 has been found in several carcinomas. However, the regulation of CMTM3 expression and its function in tumor progression remain largely unknown. Here, we investigated the regulation of CMTM3 expression, function and molecular mechanism in human testicular cancer cells. CMTM3 was frequently downregulated or silenced in testicular cancer cell lines and tumor tissues but highly expressed in normal testis tissues. The re-expression of CMTM3 significantly suppressed the colony formation, proliferation, and migration capacity of testicular cancer cells by inducing a G2 cell cycle arrest and apoptosis. Moreover, the re-expression of CMTM3 activated the transcription of p53, induced p53 accumulation, up-regulated the expression of p21, and increased the cleavage of caspase 9, 8, 3, and PARP. The downregulation of CMTM3 in clinical tumor tissues was associated with the methylation of a single CpG site located within the Sp1/Sp3-responsive region of the core promoter. These results indicate that CMTM3 can function as tumor suppressor through the induction of a G2 cell cycle arrest and apoptosis. CMTM3 is thus involved in testicular cancer pathogenesis, and it is frequently at least partially silenced by the methylation of a single, specific CpG site in tumor tissues.
PMCID: PMC3938458  PMID: 24586462
17.  Regulation of Drosophila Eye Development by the Transcription Factor Sine oculis 
PLoS ONE  2014;9(2):e89695.
Homeodomain transcription factors of the Sine oculis (SIX) family direct multiple regulatory processes throughout the metazoans. Sine oculis (So) was first characterized in the fruit fly Drosophila melanogaster, where it is both necessary and sufficient for eye development, regulating cell survival, proliferation, and differentiation. Despite its key role in development, only a few direct targets of So have been described previously. In the current study, we aim to expand our knowledge of So-mediated transcriptional regulation in the developing Drosophila eye using ChIP-seq to map So binding regions throughout the genome. We find 7,566 So enriched regions (peaks), estimated to map to 5,952 genes. Using overlap between the So ChIP-seq peak set and genes that are differentially regulated in response to loss or gain of so, we identify putative direct targets of So. We find So binding enrichment in genes not previously known to be regulated by So, including genes that encode cell junction proteins and signaling pathway components. In addition, we analyze a subset of So-bound novel genes in the eye, and find eight genes that have previously uncharacterized eye phenotypes and may be novel direct targets of So. Our study presents a greatly expanded list of candidate So targets and serves as basis for future studies of So-mediated gene regulation in the eye.
PMCID: PMC3934907  PMID: 24586968
18.  Escherichia coli and Candida albicans Induced Macrophage Extracellular Trap-Like Structures with Limited Microbicidal Activity 
PLoS ONE  2014;9(2):e90042.
The formation of extracellular traps (ETs) has recently been recognized as a novel defense mechanism in several types of innate immune cells. It has been suggested that these structures are toxic to microbes and contribute significantly to killing several pathogens. However, the role of ETs formed by macrophages (METs) in defense against microbes remains little known. In this study, we demonstrated that a subset of murine J774A.1 macrophage cell line (8% to 17%) and peritoneal macrophages (8.5% to 15%) form METs-like structures (METs-LS) in response to Escherichia coli and Candida albicans challenge. We found only a portion of murine METs-LS, which are released by dying macrophages, showed detectable killing effects on trapped E. coli but not C. albicans. Fluorescence and scanning electron microscopy analyses revealed that, in vitro, both microorganisms were entrapped in J774A.1 METs-LS composed of DNA and microbicidal proteins such as histone, myeloperoxidase and lysozyme. DNA components of both nucleus and mitochondrion origins were detectable in these structures. Additionally, METs-LS formation occurred independently of ROS produced by NADPH oxidase, and this process did not result in cell lysis. In summary, our results emphasized that microbes induced METs-LS in murine macrophage cells and that the microbicidal activity of these METs-LS differs greatly. We propose the function of METs-LS is to contain invading microbes at the infection site, thereby preventing the systemic diffusion of them, rather than significantly killing them.
PMCID: PMC3934966  PMID: 24587206
19.  Comprehensive molecular diagnosis of 179 Leber congenital amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing 
Journal of medical genetics  2013;50(10):674-688.
Leber congenital amaurosis (LCA) and juvenile retinitis pigmentosa (RP) are inherited retinal diseases that cause early onset severe visual impairment. An accurate molecular diagnosis can refine the clinical diagnosis and allow gene specific treatments.
We developed a capture panel that enriches the exonic DNA of 163 known retinal disease genes. Using this panel, we performed targeted next generation sequencing (NGS) for a large cohort of 179 unrelated and prescreened patients with the clinical diagnosis of LCA or juvenile RP. Systematic NGS data analysis, Sanger sequencing validation, and segregation analysis were utilised to identify the pathogenic mutations. Patients were revisited to examine the potential phenotypic ambiguity at the time of initial diagnosis.
Pathogenic mutations for 72 patients (40%) were identified, including 45 novel mutations. Of these 72 patients, 58 carried mutations in known LCA or juvenile RP genes and exhibited corresponding phenotypes, while 14 carried mutations in retinal disease genes that were not consistent with their initial clinical diagnosis. We revisited patients in the latter case and found that homozygous mutations in PRPH2 can cause LCA/juvenile RP. Guided by the molecular diagnosis, we reclassified the clinical diagnosis in two patients.
We have identified a novel gene and a large number of novel mutations that are associated with LCA/juvenile RP. Our results highlight the importance of molecular diagnosis as an integral part of clinical diagnosis.
PMCID: PMC3932025  PMID: 23847139
20.  Massage Therapy for Fibromyalgia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2014;9(2):e89304.
Although some studies evaluated the effectiveness of massage therapy for fibromyalgia (FM), the role of massage therapy in the management of FM remained controversial.
The purpose of this systematic review is to evaluate the evidence of massage therapy for patients with FM.
Electronic databases (up to June 2013) were searched to identify relevant studies. The main outcome measures were pain, anxiety, depression, and sleep disturbance. Two reviewers independently abstracted data and appraised risk of bias. The risk of bias of eligible studies was assessed based on Cochrane tools. Standardised mean difference (SMD) and 95% confidence intervals (CI) were calculated by more conservative random-effects model. And heterogeneity was assessed based on the I2 statistic.
Nine randomized controlled trials involving 404 patients met the inclusion criteria. The meta-analyses showed that massage therapy with duration ≥5 weeks significantly improved pain (SMD, 0.62; 95% CI 0.05 to 1.20; p = 0.03), anxiety (SMD, 0.44; 95% CI 0.09 to 0.78; p = 0.01), and depression (SMD, 0.49; 95% CI 0.15 to 0.84; p = 0.005) in patients with FM, but not on sleep disturbance (SMD, 0.19; 95% CI −0.38 to 0.75; p = 0.52).
Massage therapy with duration ≥5 weeks had beneficial immediate effects on improving pain, anxiety, and depression in patients with FM. Massage therapy should be one of the viable complementary and alternative treatments for FM. However, given fewer eligible studies in subgroup meta-analyses and no evidence on follow-up effects, large-scale randomized controlled trials with long follow-up are warrant to confirm the current findings.
PMCID: PMC3930706  PMID: 24586677
21.  A Genetic Variant in Vitamin B12 Metabolic Genes That Reduces the Risk of Congenital Heart Disease in Han Chinese Populations 
PLoS ONE  2014;9(2):e88332.
Genome-wide association studies on components of the one-carbon metabolic pathway revealed that human vitamin B12 levels could be significantly influenced by variationsinthefucosyltransferase 2 (FUT2), cubilin (CUBN), and transcobalamin-I (TCN1) genes. An altered vitamin B12 level is an important factor that disturbs the homeostasis of the folate metabolism pathway, which in turn can potentially lead to the development of congenital heart disease (CHD). Therefore, we investigated the association between the variants of vitamin B12-related genes and CHD in Han Chinese populations.
Methods and Results
Six variants of the vitamin B12-related genes were selected for analysis in two independent case-control studies, with a total of 868 CHD patients and 931 controls. The variant rs11254363 of the CUBN gene was associated with a decreased risk of developing CHD in both the separate and combined case-control studies. Combined samples from the two cohorts had a significant decrease in CHD risk for the G allele (OR = 0.48, P = 1.7×10−5) and AG+GG genotypes (OR = 0.49, P = 4×10−5), compared with the wild-type A allele and AA genotype, respectively.
Considering the G allele of variant rs11254363 of the CUBN gene was associated with an increased level of circulating vitamin B12. This result suggested that the carriers of the G allele would benefit from the protection offered by the high vitamin B12 concentration during critical heart development stages. This finding shed light on the unexpected role of CUBN in CHD development and highlighted the interplay of diet, genetics, and human birth defects.
PMCID: PMC3922769  PMID: 24533076
22.  Expression of granulocyte colony-stimulating factor receptor in rectal cancer 
AIM: To evaluate whether granulocyte colony-stimulating factor receptor (G-CSFR) expression before preoperative irradiation can predict the radiosensitivity of rectal cancer.
METHODS: The expression of G-CSFR was examined, using immunohistochemistry, in biopsy specimens from 126 patients with locally advanced rectal adenocarcinoma before preoperative irradiation. Radiosensitivity was then evaluated according to the Rectal Cancer Regression Grading. Endoscopic inspection was used to detect the tumor area in each patient. General patient information, such as age, gender, lymph node status, tumor size and degree of differentiation was recorded. A statistical analysis was then performed to evaluate the correlation between clinical or pathological parameters and G-CSFR expression in tumors.
RESULTS: According to endoscopic inspection, the tumor area ranged from 4 to 48 cm2 (median, 15 cm2). Positive G-CSFR immunoreactions (G-CSFR+) were observed in 85 specimens, and negative (G-CSFR-) in 41. No significant differences were found in age, gender, tumor invasion, lymph node status and tumor size between G-CSFR+ and G-CSFR- patients. G-CSFR expression was positively correlated with poor radiotherapy response (58.8% vs 75.6%, P = 0.014, r = 0.219). The proportion of well-differentiated tumors in G-CSFR+ and G-CSFR- patients was 24.7% and 36.6%, respectively. Sphincter preservation was observed in 57.6% of G-CSFR+ patients and 78.5% of G-CSFR- patients. Significant correlations were found between G-CSFR expression and tumor differentiation (24.7% vs 36.6%, P = 0.019, r = 0.210), as well as sphincter preservation (57.6% vs 78.5%, P = 0.044, r = 0.180).
CONCLUSION: The expression of G-CSFR before preoperative irradiation may predict the radiosensitivity of rectal cancer.
PMCID: PMC3921532  PMID: 24574781
Radiotherapy; Rectal cancer; Radiosensitivity; Predictive factor; Tumor
23.  Adjuvant chemotherapy, p53, carcinoembryonic antigen expression and prognosis after D2 gastrectomy for gastric adenocarcinoma 
AIM: To investigate adjuvant chemotherapy, p53 and carcinoembryonic antigen (CEA) expression and prognosis after D2 gastrectomy for stage II/III gastric adenocarcinoma.
METHODS: A total of 286 patients with stage II or III gastric adenocarcinoma who underwent D2 radical gastrectomy between May 2007 and December 2010 were enrolled into this study. One hundred and sixty-nine of these patients received surgery plus adjuvant chemotherapy, and 117 patients received surgery alone. Tumor expression of p53 and CEA proteins in all patients was evaluated immunohistochemically and correlated with clinicopathological parameters. The Kaplan-Meier curves for overall survival (OS) and disease-free survival (DFS) with log-rank testing were used to compare the survival difference. A Cox proportional hazard regression model was used for multivariate analysis.
RESULTS: Patients with adjuvant chemotherapy had a significantly better median OS (50.87 mo vs 30.73 mo, P = 0.000) and median DFS (36.30 mo vs 25.60 mo, P = 0.001) than patients with surgery alone in the entire cohort. Consistent results with the entire cohort were found in stage II (P = 0.006 and P = 0.047), stage III (P = 0.005 and P = 0.030), and stage IIIB/IIIC patients (P = 0.000 and P = 0.001). The median OS and DFS advantages were confirmed by multivariate analysis (P = 0.000 and P = 0.008) and maintained when the analyses were restricted to fluoropyrimidine monotherapy (P = 0.003 and P = 0.001) and fluoropyrimidine plus platinum regimen (P = 0.001 and P = 0.007), however, not the fluoropyrimidine plus taxane (P = 0.198 and P = 0.777) or platinum plus taxane (P = 0.666 and P = 0.687) regimens. Median OS and median DFS did not differ significantly between the patients with p53(+) and p53(-) tumors (P = 0.608 and P = 0.064), or between patients with CEA(+) and CEA(-) tumors (P = 0.052 and P = 0.989), which were maintained when the analyses were restricted to surgery alone (p53: P = 0.864 and P = 0.431; CEA: P = 0.142 and P = 0.948), adjuvant chemotherapy (p53: P = 0.802 and P = 0.091; CEA: P = 0.223 and P = 0.946) and even different chemotherapy regimens (P > 0.05).
CONCLUSION: Patients after D2 gastrectomy for stage II/III gastric adenocarcinoma had significantly better survival after fluoropyrimidine monotherapy and fluoropyrimidine plus platinum. p53 and CEA were not prognostic.
PMCID: PMC3886018  PMID: 24415881
Gastric adenocarcinoma; Adjuvant chemotherapy; p53; Carcinoembryonic antigen; Immunohistochemistry
24.  Layer-specific BOLD activation in awake monkey V1 revealed by ultra-high spatial resolution functional magnetic resonance imaging 
NeuroImage  2012;64:147-155.
The laminar structure of the cortex has previously been explored both in non-human primates and human subjects using high-resolution functional magnetic resonance imaging (fMRI). However, whether the spatial specificity of the blood-oxygenation-level-dependent (BOLD) fMRI is sufficiently high to reveal lamina specific organization in the cortex reliably is still unclear. In this study we demonstrate for the first time the detection of such layer-specific activation in awake monkeys at the spatial resolution of 200×200×1000 µm3 in a vertical 4.7T scanner. Results collected in trained monkeys are high in contrast-to-noise ratio and low in motion artifacts. Isolation of laminar activation was aided by choosing the optimal slice orientation and thickness using a novel pial vein pattern analysis derived from optical imaging. We found the percent change of GE-BOLD signal is the highest at a depth corresponding to layer IV. Changes in the middle layers (layer IV) were 30% greater than changes in the top layers (layers I–III), and 32% greater than the bottom layers (layers V/VI). The laminar distribution of BOLD signal correlates well with neural activity reported in the literature. Our results suggest the high intrinsic spatial resolution of GE-BOLD signal is sufficient for mapping sub-millimeter functional structures in awake monkeys. This degree of spatial specificity will be useful for mapping both laminar activations and columnar structures in the cerebral cortex.
PMCID: PMC3508288  PMID: 22960152
BOLD spatial resolution; Cortical layers; Functional MRI; Non-human primate; Visual cortex
25.  Controlling fibrous capsule formation through long-term down-regulation of collagen type I (COL1A1) expression by nanofiber-mediated siRNA gene silencing 
Acta biomaterialia  2012;9(1):4513-4524.
The foreign body reaction often interferes with the long-term functionality and performance of implanted biomedical devices through fibrous capsule formation. While many implant modification techniques have been adopted in attempts to control fibrous encapsulation, the outcomes remained sub-optimal. Nanofiber scaffold-mediated RNA interference may serve as an alternative approach through the localized and sustained delivery of siRNA at implant sites. In this study, we investigated the efficacy of siRNA-PCLEEP (poly(caprolactone-co-ethylethylene phosphate) nanofibers in controlling fibrous capsule formation through the down-regulation of Collagen type I (COL1A1) in vitro and in vivo. By encapsulating complexes of COL1A1 siRNA with a transfection reagent (Transit TKO) or cell penetrating peptides (CPPs), CADY or MPG, within the nanofibers (550–650 nm in diameter), a sustained release of siRNA was obtained for at least 28 days (loading efficiency ~ 60–67%). Scaffold-mediated transfection significantly enhanced cellular uptake of oligonucleotides and prolonged in vitro gene silencing duration by at least 2–3 times as compared to conventional bolus delivery of siRNA (14 days vs 5–7 days by bolus delivery). In vivo subcutaneous implantation of siRNA scaffolds revealed a significant decrease in fibrous capsule thickness at weeks 2 and 4 as compared to plain nanofibers (p < 0.05). Taken together, the results demonstrated the efficacy of scaffold-mediated siRNA gene-silencing in providing effective long-term control of fibrous capsule formation.
PMCID: PMC3523808  PMID: 23036951
RNA interference; Gene knockdown; Scaffold-mediated transfection; Cell penetrating peptides; Electrospinning

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