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1.  Obesity and Risk of Thyroid Cancer: Evidence from a Meta-Analysis of 21 Observational Studies 
Background
Several studies have evaluated the association between obesity and thyroid cancer risk. However, the results remain uncertain. In this study, we conducted a meta-analysis to assess the association between obesity and thyroid cancer risk.
Material/Methods
Published literature from PubMed, EMBASE, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM) were retrieved before 10 August 2014. We included all studies that reported adjusted risk ratios (RRs), hazard ratios (HRs) or odds ratios (ORs), and 95% confidence intervals (CIs) of thyroid cancer risk.
Results
Thirty-two studies (n=12 620 676) were included in this meta-analysis. Obesity was associated with a significantly increased risk of thyroid cancer (adjusted RR=1.33; 95% CI, 1.24–1.42; I2=25%). In the subgroup analysis by study type, increased risk of thyroid cancer was found in cohort studies and case-control studies. In subgroup analysis by sex, both obese men and women were at significantly greater risk of thyroid cancer than non-obese subjects. When stratified by ethnicity, significantly elevated risk was observed in Caucasians and in Asians. In the age subgroup analysis, both young and old populations showed increased thyroid cancer risk. Subgroup analysis on smoking status showed that increased thyroid cancer risks were found in smokers and in non-smokers. In the histology subgroup analyses, increased risks of papillary thyroid cancer, follicular thyroid cancer, and anaplastic thyroid cancer were observed. However, obesity was associated with decreased risk of medullary thyroid cancer.
Conclusions
Our results indicate that obesity is associated with an increased thyroid cancer risk, except medullary thyroid cancer.
doi:10.12659/MSM.892035
PMCID: PMC4315628  PMID: 25612155
Meta-Analysis; Obesity; Thyroid Neoplasms
2.  Zoledronic Acid May Reduce Intraoperative Bleeding in Spinal Tumors: A Prospective Cohort Study 
BioMed Research International  2015;2015:936307.
Between June 2010 and June 2011, 176 patients were divided into 2 groups: a group with spinal metastasis of solid tumors (n = 157) and a group with multiple myeloma (n = 19). Both groups were further divided into 2 subgroups: a group receiving zoledronic acid before surgery and a control group. The zoledronic acid subgroup of the solid tumors group was group A (n = 81), the control subgroup of the solid tumors group was group B (n = 76), the zoledronic acid subgroup of the multiple myeloma group was group C (n = 10), and the control subgroup of the multiple myeloma group was group D (n = 9). The average intraoperative blood loss during spinal surgery was as follows: 1311 ± 691 mL in group A and 1752 ± 740 mL in group B (P = 0.000) and 1994 ± 810 mL in group C and 3134 ± 795 mL in group D (P = 0.000). Patients receiving zoledronic acid before surgery had significantly less intraoperative bleeding than those who did not receive it. Preoperative use of zoledronic acid can effectively reduce intraoperative bleeding during surgery for the treatment of spinal tumors.
doi:10.1155/2015/936307
PMCID: PMC4317594
3.  Culture medium of bone marrow-derived human mesenchymal stem cells effects lymphatic endothelial cells and tumor lymph vessel formation 
Oncology Letters  2015;9(3):1221-1226.
Human bone marrow mesenchymal stem cells (hBM-MSCs) favor tumor growth and metastasis in vivo and in vitro. Neovascularization is involved in several pathological conditions, including tumor growth and metastasis. Previous studies have demonstrated that human bone marrow MSC-derived conditioned medium (hBM-MSC-CM) can promote tumor growth by inducing the expression of vascular epidermal growth factor (VEGF) in tumor cells. However, the effect of BM-MSCs on tumor lymph vessel formation has yet to be elucidated. In the present study, the effect of BM-MSCs on processes involved in lymph vessel formation, including tube formation, migration and proliferation, was investigated in human-derived lymphatic endothelial cells (HDLECs). It was identified that hBM-MSC-CM promoted the tube formation and migration of HDLECs. In addition, tumor cells were revealed to participate in lymph vessel formation. In the present study, the SGC-7901, HGC-27 and GFP-MCF-7 cell lines were treated with hBM-MSC-CM. The results demonstrated that the expression of the lymph-associated markers, prospero homeobox protein 1 and VEGF receptor-3, were increased in the SGC-7901 and HGC-27 cell lines, but not in the GFP-MCF-7 cells. The tube formation assay demonstrated that the HGC-27 cells treated with hBM-MSC-CM for 20 days underwent tube formation. These findings indicate that hBM-MSC-CM can promote tube formation in HDLECs and HGC-27 cells, which may be associated with lymph vessel formation during tumor growth and metastasis.
doi:10.3892/ol.2015.2868
PMCID: PMC4315037  PMID: 25663886
mesenchymal stem cell; lymph vessel; tumor growth
4.  Digital PCR quantification of miRNAs in sputum for diagnosis of lung cancer 
Purpose
MicroRNAs (miRNAs) play important roles in the initiation and progression of lung cancer. Measuring miRNA expression levels in sputum could provide a potential approach for the diagnosis of lung cancer. The emerging digital PCR is a straightforward technique for precise, direct, and absolute quantification of nucleic acids. The objective of the study was to investigate whether digital PCR could be used to quantify miRNAs in sputum for lung cancer diagnosis.
Methods
We first determined and compared dynamic ranges of digital PCR and conventional quantitative reverse transcriptase PCR (qRT-PCR) for miRNA quantification using RNA isolated from sputum of five healthy individuals. We then used digital PCR to quantify copy number of two lung cancer-associated miRNAs (miR-31 and miR-210) in 35 lung cancer patients and 40 cancer-free controls.
Results
Copy number of the miRNAs measured by digital PCR displayed a linear response to input cDNA amount in a twofold dilution series over seven orders of magnitude. miRNA quantification determined by digital PCR assay was in good agreement with that obtained from qRT-PCR analysis in sputum. Furthermore, combined quantification of miR-31 and miR-210 copy number by using digital PCR in sputum of the cases and controls provided 65.71 % sensitivity and 85.00 % specificity for lung cancer diagnosis.
Conclusion
As digital PCR becomes more established, it would be a robust tool for quantitative assessment of miRNA copy number in sputum for lung cancer diagnosis.
doi:10.1007/s00432-013-1555-5
PMCID: PMC3898839  PMID: 24281335
Digital PCR; miRNAs; Sputum; Diagnosis; Lung cancer
5.  Th17/Treg Cells Imbalance and GITRL Profile in Patients with Hashimoto’s Thyroiditis 
Hashimoto’s thyroiditis (HT) is an organ-specific immune disease characterized by the presence of lymphocytic infiltration and serum autoantibodies. Previous studies have confirmed the critical role of Th17 cells in the pathopoiesis of HT patients. Additionally, regulatory T cells (Treg) display a dysregulatory function in autoimmune disease. The purpose of this study is to investigate the alteration of Th17 and Treg cells in HT patients and explore contributing factors. We found there was an increased ratio of Th17/Treg in HT patients and a positive correlation with autoantibodies (anti-TgAb). In addition, there was an increased level of GITRL, which has been demonstrated to be correlated with the increassement of Th17 cells in the serum and thyroid glands of HT patients; the upregulated serum level of GITRL has a positive correlation with the percentage of Th17 cells in HT patients. In summary, an increase in GITRL may impair the balance of Th17/Treg, and contribute to the pathopoiesis of Hashimoto’s thyroiditis.
doi:10.3390/ijms151221674
PMCID: PMC4284671  PMID: 25429429
Hashimoto’s thyroiditis; Th17 cells; Treg cells; GITRL
6.  Non-small cell lung cancer with EML4-ALK translocation in Chinese male never-smokers is characterized with early-onset 
BMC Cancer  2014;14(1):834.
Background
The translocations of the anaplastic lymphoma kinase (ALK) gene with the echinoderm microtubule-associated protein-like 4 (EML4) gene on chromosome 2p have been identified in non-small-cell lung cancers (NSCLCs) as oncogenic driver mutations. It has been suggested that EML4-ALK fusion is associated with the resistance in NSCLCs to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), such as gefitinib and erlotinib. In contrast, ALK tyrosine kinase inhibitor (ALK TKI) crizotinib has shown superior effects in combating NSCLCs with EML4-ALK. Thus, characterization of EML4-ALK fusion genes and clinical features of resulting carcinomas would be a great benefit to disease diagnosis and designing customized treatment plans. Studies have suggested that EML4-ALK translocation occurs more frequently in never-smokers with NSCLC, especially in female patients. However, it is not clear whether this is the case in male patients, too. In this study, we have determined the frequency of EML4-ALK translocation in male never-smokers with NSCLC in a cohort of Chinese patients. The clinical features associated with EML4-ALK translocation were also investigated.
Methods
A cohort of 95 Chinese male never-smokers with NSCLC was enrolled in this study. EML4-ALK fusion genes were detected using one-step real time RT-PCR and DNA sequencing. We further determined the expression levels of ALK mRNA by RT-PCR and ALK protein by immunohistochemistry in these specimens. The clinical features of EML4-ALK–positive carcinomas were also determined.
Results
We have identified EML4-ALK fusion genes in 8 out of 95 carcinoma cases, accounting for 8.42% in Chinese male never-smokers with NSCLC. It is significantly higher than that in all Chinese male patients (3.44%) regardless smoking habit. It is also significantly higher than that in all Chinese smokers (8/356 or 2.25%) or in smokers worldwide (2.9%) by comparing to published data. Interestingly, EML4-ALK fusion genes are more frequently found in younger patients and associated with less-differentiated carcinomas.
Conclusions
The frequency of EML4-ALK translocation is strongly associated with smoking habits in Chinese male patients with higher frequency in male never-smokers. EML4-ALK translocation is associated with early-onset and less-differentiated carcinomas.
doi:10.1186/1471-2407-14-834
PMCID: PMC4240865  PMID: 25407901
Non-small-cell lung cancers (NSCLCs); Anaplastic lymphoma kinase (ALK); Echinoderm microtubule-associated protein-like 4 (EML4); Tyrosine kinase inhibitors (TKIs); Never-smokers; Adenocarcinoma
7.  Esophageal Adenocarcinoma and Its Rare Association with Barrett’s Esophagus in Henan, China 
PLoS ONE  2014;9(10):e110348.
Incidence of esophageal adenocarcinoma (EAC) has increased sharply in Western Europe and United States over the past three decades. Nearly all cases of EAC in the west are thought to be associated with Barrett’s esophagus (BE) at the time of diagnosis. Regions in the Henan province of China have one of world’s highest incidences of esophageal cancer, yet recent temporal trends in the relative rates of EAC with respect to esophageal squamous-cell carcinoma (ESCC), as well as its association with Barrett’s esophagus (BE), have not been reported. In this report, we present large-scale longitudinal clinical and histological data on 5401 esophageal cancers (EC) patients diagnosed during the recent 10-year period (2002–2011) at Henan Cancer Hospital, China. All 217 esophageal adenocarcinoma (EAC) patients from these 5401 EC patients were examined to better understand the relationship between Barrett’s esophagus (BE) and EAC. We found that EAC was relatively rare and accounted for approximately 5% of all esophageal cancers each year during 2002–2011. There is no evidence of significant temporal trends in the rate of EAC relative to ESCC. Only 10 out of 217 (4.6%) EAC cases were detected to have any evidence of Barrett’s esophagus. This result raises the possibility of a different etiological basis for EAC in China motivating more detailed epidemiological, clinical and molecular characterization of EAC in China in order to better understand the neoplastic development of EAC.
doi:10.1371/journal.pone.0110348
PMCID: PMC4198241  PMID: 25333822
8.  A Novel Bradykinin-Related Dodecapeptide (RVALPPGFTPLR) from the Skin Secretion of the Fujian Large-Headed Frog (Limnonectes fujianensis) Exhibiting Unusual Structural and Functional Features 
Toxins  2014;6(10):2886-2898.
Bradykinin-related peptides (BRPs) are significant components of the defensive skin secretions of many anuran amphibians, and these secretions represent the source of the most diverse spectrum of such peptides so far encountered in nature. Of the many families of bioactive peptides that have been identified from this source, the BRPs uniquely appear to represent homologues of counterparts that have specific distributions and receptor targets within discrete vertebrate taxa, ranging from fishes through mammals. Their broad spectra of actions, including pain and inflammation induction and smooth muscle effects, make these peptides ideal weapons in predator deterrence. Here, we describe a novel 12-mer BRP (RVALPPGFTPLR-RVAL-(L1, T6, L8)-bradykinin) from the skin secretion of the Fujian large-headed frog (Limnonectes fujianensis). The C-terminal 9 residues of this BRP (-LPPGFTPLR) exhibit three amino acid substitutions (L/R at Position 1, T/S at Position 6 and L/F at Position 8) when compared to canonical mammalian bradykinin (BK), but are identical to the kinin sequence present within the cloned kininogen-2 from the Chinese soft-shelled turtle (Pelodiscus sinensis) and differ from that encoded by kininogen-2 of the Tibetan ground tit (Pseudopodoces humilis) at just a single site (F/L at Position 8). These data would imply that the novel BRP is an amphibian defensive agent against predation by sympatric turtles and also that the primary structure of the avian BK, ornithokinin (RPPGFTPLR), is not invariant within this taxon. Synthetic RVAL-(L1, T6, L8)-bradykinin was found to be an antagonist of BK-induced rat tail artery smooth muscle relaxation acting via the B2-receptor.
doi:10.3390/toxins6102886
PMCID: PMC4210874  PMID: 25268979
amphibian; skin secretion; molecular cloning; bradykinin; smooth muscle
9.  Mild hypothermia combined with neural stem cell transplantation for hypoxic-ischemic encephalopathy: neuroprotective effects of combined therapy 
Neural Regeneration Research  2014;9(19):1745-1752.
Neural stem cell transplantation is a useful treatment for ischemic stroke, but apoptosis often occurs in the hypoxic-ischemic environment of the brain after cell transplantation. In this study, we determined if mild hypothermia (27–28°C) can increase the survival rate of neural stem cells (1.0 × 105/μL) transplanted into neonatal mice with hypoxic-ischemic encephalopathy. Long-term effects on neurological functioning of the mice were also examined. After mild hypothermia combined with neural stem cell transplantation, we observed decreased expression levels of inflammatory factor nuclear factor-kappa B and apoptotic factor caspase-3, reduced cerebral infarct volumes, increased survival rate of transplanted cells, and marked improvements in neurological function. Thus, the neuroprotective effects of mild hypothermia combined with neural stem cell transplantation are superior to those of monotherapy. Moreover, our findings suggest that the neuroprotective effects of mild hypothermia combined with neural stem cell transplantation on hypoxic-ischemic encephalopathy are achieved by anti-inflammatory and anti-apoptotic mechanisms.
doi:10.4103/1673-5374.143417
PMCID: PMC4238162  PMID: 25422635
nerve regeneration; brain injury; hypoxic-ischemic encephalopathy; neural precursor cells; hypothermia; neural stem cells; cell transplantation; hippocampus; neuron; cell apoptosis; astrocytes; oligodendrocytes; neuroprotection; NSFC grants; neural regeneration
10.  Inhibition of protein phosphatase 2A with a small molecule LB100 radiosensitizes nasopharyngeal carcinoma xenografts by inducing mitotic catastrophe and blocking DNA damage repair 
Oncotarget  2014;5(17):7512-7524.
Nasopharyngeal carcinoma (NPC), while uncommon worldwide, is a major health problem in China. Although local radiation and surgery provide good control of NPC, better treatments that permit reductions in radiation dosing are needed. Inhibition of protein phosphatase 2A (PP2A), a ubiquitous multifunctional enzyme with critical roles in cell cycle regulation and DNA-damage response, reportedly sensitizes cancer cells to radiation and chemotherapy. We studied PP2A inhibition with LB100, a small molecule currently in a Phase I clinical trial, on radiosensitization of two human nasopharyngeal cell lines: CNE1, which is reportedly radioresistant, and CNE2. In both cell lines, LB100 exposure increased intracellular p-Plk1, TCTP, and Cdk1 and decreased p53, changes associated with cell cycle arrest, mitotic catastrophe and radio-inhibition of cell proliferation. Mice bearing subcutaneous xenografts of either cell line were administered 1.5 mg/kg LB100 daily for three days and a single dose of 20 Gy radiation (day 3), which produced marked and prolonged tumor mass regression (dose enhancement factors of 2.98 and 2.27 for CNE1 and CNE2 xenografts, respectively). Treatment with either LB100 or radiation alone only transiently inhibited xenograft growth. Our results support further exploration of PP2A inhibition as part of radiotherapy regimens for NPC and potentially other solid tumors.
PMCID: PMC4202140  PMID: 25245035
LB100; Radiosensitization; Protein phosphatase 2A; Nasopharyngeal Carcinoma
11.  Hydrogen-Rich Saline Inhibits NLRP3 Inflammasome Activation and Attenuates Experimental Acute Pancreatitis in Mice 
Mediators of Inflammation  2014;2014:930894.
Increasing evidence has demonstrated that reactive oxygen species (ROS) induces oxidative stress and plays a crucial role in the pathogenesis of acute pancreatitis (AP). Hydrogen-rich saline (HRS), a well-known ROS scavenger, has been shown to possess therapeutic benefit on AP in many animal experiments. Recent findings have indicated that the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome, an intracellular multiprotein complex required for the maturation of interleukin- (IL-) 1β, may probably be a potential target of HRS in the treatment of AP. Therefore, in this study, we evaluated the activation of NLRP3 inflammasome and meanwhile assessed the degree of oxidative stress and inflammatory cascades, as well as the histological alterations in mice suffering from cerulein-induced AP after the treatment of HRS. The results showed that the activation of NLRP3 inflammasome in AP mice was substantially inhibited following the administration of HRS, which was paralleled with the decreased NF-κB activity and cytokines production, attenuated oxidative stress and the amelioration of pancreatic tissue damage. In conclusion, our study has, for the first time, revealed that inhibition of the activation of NLRP3 inflammasome probably contributed to the therapeutic potential of HRS in AP.
doi:10.1155/2014/930894
PMCID: PMC4158121  PMID: 25214720
12.  Up-Regulation of MicroRNA-145 Associates with Lymph Node Metastasis in Colorectal Cancer 
PLoS ONE  2014;9(7):e102017.
Metastasis is the main cause of mortality in patients with solid tumours. Identifying the exact molecules associated with CRC metastasis may be crucial to understand the process, which might also be translated to the diagnosis and treatment of CRC. In this study, we investigate the association of microRNA expression patterns with the lymph node metastasis of colorectal cancer. Among these candidate miRNAs, the expression of miRNA-145 was significantly related to lymph node metastasis of CRC. Both in vitro and in vivo study demonstrated that up-regulation of miR-145 could improve the ability of migration and invasion of colorectal cancer cell, while no effect on proliferation was observed. The mechanism of this promotion is associated with the stabilization of Hsp-27, a protein which plays an important role in the promotion of metastasis. These results may be crucial to understanding CRC metastasis and may be translated to the diagnosis and treatment of CRC.
doi:10.1371/journal.pone.0102017
PMCID: PMC4096587  PMID: 25019299
13.  Genetically determined ABCB5 functionality correlates with pigmentation phenotype and melanoma risk 
ABCB5 is a multidrug resistance (MDR) member of the ATP-binding cassette (ABC) superfamily of active transporters and represents a marker for chemoresistant malignant melanoma-initiating cells. ABCB5 expression is closely linked to tumorigenicity and progression of diverse human malignancies, including melanoma, and is functionally required for tumor growth. Here, we genotyped 585 melanoma cases and 605 age-matched controls for 44 ABCB5 tagging single nucleotide polymorphisms (SNPs) to span a region covering 108.2kb of the gene on the 7p21.1 locus. We identified three SNPs that were associated with decreased melanoma risk in additive models: rs10231520 (OR: 0.83, 95% CI: 0.70–0.98), rs17817117 (OR: 0.82, 95% CI: 0.68–0.98), and rs2301641 (OR: 0.83, 95% CI: 0.69–0.98). Additionally, the rs2301641 SNP was associated with non-red compared to red hair color (OR: 0.38, 95% CI: 0.14–1.03) in controls. Twelve human melanoma cell lines were genotyped for the rs2301641 SNP, which encodes a non-synonymous ABCB5 amino acid change (K115E). Functional studies revealed that the E form associated with lower melanoma risk correlated significantly with decreased ABCB5 transport capacity (P<0.01) and increased melanin production (P<0.05). Our results identify novel associations of the ABCB5 K115E polymorphism with human pigmentation phenotype and melanoma risk and point to potential functional roles of ABCB5 in melanomagenesis. Moreover, they provide a first example that functional variation in a prospective cancer stem cell marker can be associated with disease risk for the corresponding malignancy.
doi:10.1016/j.bbrc.2013.06.006
PMCID: PMC3756469  PMID: 23770371
ABCB5; single nucleotide polymorphism; genotype; melanoma; cancer; cancer stem cells; pigmentation; case-controlled study; humans
14.  Ficus carica Polysaccharides Promote the Maturation and Function of Dendritic Cells 
Various polysaccharides purified from plants are considered to be biological response modifiers and have been shown to enhance immune responses. Ficus carica L. is a Chinese traditional plant and has been widely used in Asian countries for its anti-tumor properties. Ficus carica polysaccharides (FCPS), one of the most essential and effective components in Ficus carica L., have been considered to be a beneficial immunomodulator and may be used in immunotherapy. However, the immunologic mechanism of FCPS is still unclear. Dectin-1 is a non-toll-like pattern recognition receptor, predominately expressed on dendritic cells (DCs). Activation of DCs through dectin-1 signaling can lead to the maturation of DC, thus inducing both innate and adaptive immune responses against tumor development and microbial infection. In our study, we found that FCPS could effectively stimulate DCs, partially through the dectin-1/Syk pathway, and promote their maturation, as shown by the up-regulation of CD40, CD80, CD86, and major histocompatibility complex II (MHCII). FCPS also enhanced the production of cytokines by DCs, including IL-12, IFN-γ, IL-6, and IL-23. Moreover, FCPS-treated DCs showed an enhanced capability to stimulate T cells and promote T cell proliferation. Altogether, these results demonstrate that FCPS are able to activate and maturate DCs, thereby up-regulating the immunostimulatory capacity of DCs, which leads to enhanced T cell responses.
doi:10.3390/ijms150712469
PMCID: PMC4139854  PMID: 25026176
polysaccharide; dendritic cells; dectin-1; Syk; immunomodulators
15.  Adsorption of tetracycline from aqueous solutions onto multi-walled carbon nanotubes with different oxygen contents 
Scientific Reports  2014;4:5326.
Oxidized multi-walled carbon nanotubes (MWCNTs) with different oxygen contents were investigated for the adsorption of tetracycline (TC) from aqueous solutions. As the surface oxygen content of the MWCNTs increased, the maximum adsorption capacity and adsorption coefficient of TC increased to the largest values and then decreased. The relation can be attributed to the interplay between the nanotubes' dispersibility and the water cluster formation upon TC adsorption. The overall adsorption kinetics of TC onto CNTs-3.2%O might be dependent on both intra-particle diffusion and boundary layer diffusion. The maximum adsorption capacity of TC on CNTs-3.2%O was achieved in the pH range of 3.3–8.0 due to formation of water clusters or H-bonds. Furthermore, the presence of Cu2+ could significantly enhanced TC adsorption at pH of 5.0. However, the solution ionic strength did not exhibit remarkable effect on TC adsorption. In addition, when pH is beyond the range (3.3–8.0), the electrostatic interactions caused the decrease of TC adsorption capacity. Our results indicate that surface properties and aqueous solution chemistry play important roles in TC adsorption on MWCNTs.
doi:10.1038/srep05326
PMCID: PMC4060509  PMID: 24937315
16.  Synchronous primary triple carcinoma of thyroid and kidney accompanied by solitary fibrous tumor of the kidney: a unique case report 
Thyroid cancers coexisted with kidney cancer in a patient is an unusual event. Here, we described a case of 35-year-old woman with synchronous occurrence of primary papillary carcinoma and follicular carcinoma of the thyroid, accompanied by renal cell carcinoma and solitary fibrous tumor of the kidney, which has not been reported in literature to our best knowledge. Its clinical and pathological features, as well as the possible pathogenic factors were discussed.
PMCID: PMC4129043  PMID: 25120808
Follicular carcinoma; papillary carcinoma; renal cell carcinoma; thyroid; kidney; solitary fibrous tumor
17.  A Chimeric Dengue Virus Vaccine using Japanese Encephalitis Virus Vaccine Strain SA14-14-2 as Backbone Is Immunogenic and Protective against Either Parental Virus in Mice and Nonhuman Primates 
Journal of Virology  2013;87(24):13694-13705.
The development of a safe and efficient dengue vaccine represents a global challenge in public health. Chimeric dengue viruses (DENV) based on an attenuated flavivirus have been well developed as vaccine candidates by using reverse genetics. In this study, based on the full-length infectious cDNA clone of the well-known Japanese encephalitis virus live vaccine strain SA14-14-2 as a backbone, a novel chimeric dengue virus (named ChinDENV) was rationally designed and constructed by replacement with the premembrane and envelope genes of dengue 2 virus. The recovered chimeric virus showed growth and plaque properties similar to those of the parental DENV in mammalian and mosquito cells. ChinDENV was highly attenuated in mice, and no viremia was induced in rhesus monkeys upon subcutaneous inoculation. ChinDENV retained its genetic stability and attenuation phenotype after serial 15 passages in cultured cells. A single immunization with various doses of ChinDENV elicited strong neutralizing antibodies in a dose-dependent manner. When vaccinated monkeys were challenged with wild-type DENV, all animals except one that received the lower dose were protected against the development of viremia. Furthermore, immunization with ChinDENV conferred efficient cross protection against lethal JEV challenge in mice in association with robust cellular immunity induced by the replicating nonstructural proteins. Taken together, the results of this preclinical study well demonstrate the great potential of ChinDENV for further development as a dengue vaccine candidate, and this kind of chimeric flavivirus based on JE vaccine virus represents a powerful tool to deliver foreign antigens.
doi:10.1128/JVI.00931-13
PMCID: PMC3838253  PMID: 24109223
18.  Wavelength-Versatile Graphene-Gold Film Saturable Absorber Mirror for Ultra-Broadband Mode-Locking of Bulk Lasers 
Scientific Reports  2014;4:5016.
An ultra-broadband graphene-gold film saturable absorber mirror (GG-SAM) with a spectral coverage exceeding 1300 nm is experimentally demonstrated for mode-locking of bulk solid-state lasers. Owing to the p-type doping effect caused by graphene-gold film interaction, the graphene on gold-film substrate shows a remarkably lower light absorption relative to pristine graphene, which is very helpful to achieve continuous-wave mode-locking in low-gain bulk lasers. Using the GG-SAM sample, stable mode-locking is realized in a Yb:YCOB bulk laser near 1 μm, a Tm:CLNGG bulk laser near 2 μm and a Cr:ZnSe bulk laser near 2.4 μm. The saturable absorption is characterised at an intermediate wavelength of 1.56 μm by pump-probe measurements. The as-fabricated GG-SAM with ultra-broad bandwidth, ultrafast recovery time, low absorption, and low cost has great potential as a universal saturable absorber mirror for mode-locking of various bulk lasers with unprecedented spectral coverage.
doi:10.1038/srep05016
PMCID: PMC4031483  PMID: 24853072
19.  Selection of a Novel DNA Aptamer for Assay of Intracellular Interferon-Gamma 
PLoS ONE  2014;9(5):e98214.
Interferon-gamma (IFN-γ) is a glycoprotein generated by lymphocytes that possesses anti-tumor, antiviral and immunomodulatory functions. IFN-γ assays are broadly employed in immunological research and clinical diagnostic tests. Intracellular IFN-γ staining, in particular, is an important immune assay that allows simultaneous determination of cellular phenotype and antigen-specific T cell response. Aptamers have great potential for molecule detection and can bind to target molecules with high affinity and specificity. In this study, a novel 59-mer DNA aptamer (B1–4) was developed for assay of intracellular IFN-γ. The selected aptamer bound to IFN-γ with a Kd of 74.5 nM, with minimal cross-reactivity to albumin. The aptamer was also found capable of binding with paraformaldehyde-fixed IFN-γ. Moreover, B1–4 could enter permeated and paraformaldehyde-fixed lymphocytes, and bound to intracellular IFN-γ produced by these cells. When FITC-labeled B1–4 was used to stain a group of lymphocytes, the average fluorescence of the cells was positively correlated with the number of PMA-stimulated lymphocytes within the group. A standard curve could thus be established for assessing the fraction of IFN-γ-producing cells in a cluster of lymphocytes. The selected aptamer hence provides a novel approach for assaying intracellular IFN-γ generated by a group of lymphocytes, and may have application potential in both scientific research and clinical laboratory test.
doi:10.1371/journal.pone.0098214
PMCID: PMC4029989  PMID: 24849390
20.  Recombinant tandem multi-linear neutralizing epitopes of human enterovirus 71 elicited protective immunity in mice 
Virology Journal  2014;11:79.
Background
Human Enterovirus 71 (EV71) has emerged as the leading cause of viral encephalitis in children, especially in the Asia-Pacific regions. EV71 vaccine development is of high priority at present, and neutralization antibodies have been documented to play critical roles during in vitro and in vivo protection against EV71 infection.
Results
In this study, a novel strategy to produce EV71 vaccine candidate based on recombinant multiple tandem linear neutralizing epitopes (mTLNE) was proposed. The three well identified EV71 linear neutralizing epitopes in capsid proteins, VP1-SP55, VP1-SP70 and VP2-SP28, were sequentially linked by a Gly-Ser linker ((G4S)3), and expressed in E.coli in fusion with the Trx and His tag at either terminal. The recombinant protein mTLNE was soluble and could be purified by standard affinity chromatography. Following three dosage of immunization in adult mice, EV71-specific IgG and neutralization antibodies were readily induced by recombinant mTLNE. IgG subtyping demonstrated that lgG1 antibodies dominated the mTLNE-induced humoral immune response. Especially, cytokine profiling in spleen cells from the mTLNE-immunized mice revealed high production of IL-4 and IL-6. Finally, in vivo challenge experiments showed that passive transfer with anti-mTLNE sera conferred full protection against lethal EV71 challenge in neonatal mice.
Conclusion
Our results demonstrated that this rational designed recombinant mTLNE might have the potential to be further developed as an EV71 vaccine in the future.
doi:10.1186/1743-422X-11-79
PMCID: PMC4030048  PMID: 24885030
Enterovirus 71; Vaccine; Linear neutralizing epitopes
21.  Deep mRNA sequencing reveals stage-specific transcriptome alterations during microsclerotia development in the smoke tree vascular wilt pathogen, Verticillium dahliae 
BMC Genomics  2014;15(1):324.
Background
Verticillium dahliae is a soil-borne fungus that causes vascular wilt diseases in a wide range of plant hosts. V. dahliae produces multicelled, melanized resting bodies, also known as microsclerotia (MS) that can survive for years in the soil. The MS are the primary source of infection of the Verticillium disease cycle. Thus, MS formation marks an important event in the disease cycle of V. dahliae.
Results
In this study, next generation sequencing technology of RNA-Seq was employed to investigate the global transcriptomic dynamics of MS development to identify differential gene expression at several stages of MS formation in strain XS11 of V. dahliae, isolated from smoke tree. We observed large-scale changes in gene expression during MS formation, such as increased expression of genes involved in protein metabolism and carbohydrate metabolism. Genes involved in glycolytic pathway and melanin biosynthesis were dramatically up-regulated in MS. Cluster analyses revealed increased expression of genes encoding products involved in primary metabolism and stress responses throughout MS development. Differential expression of ubiquitin-dependent protein catabolism and cell death-associated genes during MS development were revealed. Homologs of genes located in the lineage-specific (LS) regions of V. dahliae strain VdLs.17, were either not expressed or showed low expression. Furthermore, alternative splicing (AS) events were analyzed, revealing that over 95.0% AS events involve retention of introns (RI).
Conclusions
These data reveal the dynamics of transcriptional regulation during MS formation and were used to construct a comprehensive high-resolution gene expression map. This map provides a key resource for understanding the biology and molecular basis of MS development of V. dahliae.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-324) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2164-15-324
PMCID: PMC4035056  PMID: 24884698
Verticillium dahliae; Microsclerotia development; RNA-Seq; Transcriptome; Gene expression; Alternative splicing
22.  Wen-Dan Decoction Improves Negative Emotions in Sleep-Deprived Rats by Regulating Orexin-A and Leptin Expression 
Wen-Dan Decoction (WDD), a formula of traditional Chinese medicine, has been clinically used for treating insomnia for approximately 800 years. However, the therapeutic mechanisms of WDD remain unclear. Orexin-A plays a key role in the sleep-wake cycle, while leptin function is opposite to orexin-A. Thus, orexin-A and leptin may be important factors in sleep disorders. In this study, 48 rats were divided into control, model, WDD-treated, and diazepam-treated groups. The model of insomnia was produced by sleep deprivation (SD) for 14 days. The expressions of orexin-A, leptin, and their receptors in blood serum, prefrontal cortex, and hypothalamus were detected by enzyme-linked immunosorbent assay, immunohistochemistry, and real time PCR. Open field tests showed that SD increased both crossing movement (Cm) and rearing-movement (Rm) times. Orexin-A and leptin levels in blood serum increased after SD but decreased in brain compared to the control group. mRNA expressions of orexin receptor 1 and leptin receptor after SD were decreased in the prefrontal cortex but were increased in hypothalamus. WDD treatment normalized the behavior and upregulated orexin-A, leptin, orexin receptor 1 and leptin receptor in brain. The findings suggest that WDD treatment may regulate SD-induced negative emotions by regulating orexin-A and leptin expression.
doi:10.1155/2014/872547
PMCID: PMC4016855  PMID: 24864160
23.  Mechanical Stress Stimulates the Osteo/Odontoblastic Differentiation of Human Stem Cells from Apical Papilla via ERK 1/2 and JNK MAPK Pathways 
BioMed Research International  2014;2014:494378.
Background Information. Stem cells from apical papilla (SCAPs) are a potent candidate for the apexogenesis/apexification due to their multiple differentiation capacity. During the orthodontic treatment of developing teeth, SCAPs in vivo are usually subjected to the cyclic stress induced by compression forces. However, it remains unclear whether mechanical stress can affect the proliferation and differentiation of human SCAPs. Results. Human SCAPs were isolated and stimulated by 200 g mechanical stimuli for 30 min and their proliferation and differentiation capacity were evaluated in vitro at different time points. MTT and FCM results demonstrated that cell proliferation was enhanced, while TEM findings showed the morphological and ultrastructural changes in stress-treated SCAPs. ALP activity and mineralization capacity of stress-treated SCAPs were upregulated . In the meantime, higher odontogenic and osteogenic differentiation were found in stress-treated SCAPs by real-time RT-PCR and Western blot, as indicated by the expression of related markers at both mRNA and protein levels. Moreover, the protein expressions of pJNK and pERK MAPK pathways were upregulated. Conclusion. Together, these findings suggest that mechanical stress is an important factor affecting the proliferation and differentiation of SCAPs via the activation of ERK and JNK signaling pathway.
doi:10.1155/2014/494378
PMCID: PMC4009119  PMID: 24826377
24.  Ranakinestatin-PPF from the Skin Secretion of the Fukien Gold-Striped Pond Frog, Pelophylax plancyi fukienensis: A Prototype of a Novel Class of Bradykinin B2 Receptor Antagonist Peptide from Ranid Frogs 
The Scientific World Journal  2014;2014:564839.
The defensive skin secretions of many amphibians are a rich source of bradykinins and bradykinin-related peptides (BRPs). Members of this peptide group are also common components of reptile and arthropod venoms due to their multiple biological functions that include induction of pain, effects on many smooth muscle types, and lowering systemic blood pressure. While most BRPs are bradykinin receptor agonists, some have curiously been found to be exquisite antagonists, such as the maximakinin gene-related peptide, kinestatin—a specific bradykinin B2-receptor antagonist from the skin of the giant fire-bellied toad, Bombina maxima. Here, we describe the identification, structural and functional characterization of a heptadecapeptide (DYTIRTRLHQGLSRKIV), named ranakinestatin-PPF, from the skin of the Chinese ranid frog, Pelophylax plancyi fukienensis, representing a prototype of a novel class of bradykinin B2-receptor specific antagonist. Using a preconstricted preparation of rat tail arterial smooth muscle, a single dose of 10−6 M of the peptide effectively inhibited the dose-dependent relaxation effect of bradykinin between 10−11 M and 10−5 M and subsequently, this effect was pharmacologically-characterized using specific bradykinin B1- (desArg-HOE140) and B2-receptor (HOE140) antagonists; the data from which demonstrated that the antagonism of the novel peptide was mediated through B2-receptors. Ranakinestatin—PPF—thus represents a prototype of an amphibian skin peptide family that functions as a bradykinin B2-receptor antagonist herein demonstrated using mammalian vascular smooth muscle.
doi:10.1155/2014/564839
PMCID: PMC4000668  PMID: 25161395
25.  Identification of Duplication Downstream of BMP2 in a Chinese Family with Brachydactyly Type A2 (BDA2) 
PLoS ONE  2014;9(4):e94201.
Brachydactyly type A2 (BDA2, MIM 112600) is characterized by the deviation and shortening of the middle phalange of the index finger and the second toe. Using genome-wide linkage analysis in a Chinese BDA2 family, we mapped the maximum candidate interval of BDA2 to a ∼1.5 Mb region between D20S194 and D20S115 within chromosome 20p12.3 and found that the pairwise logarithm of the odds score was highest for marker D20S156 (Zmax = 6.09 at θ = 0). Based on functional and positional perspectives, the bone morphogenetic protein 2 (BMP2) gene was identified as the causal gene for BDA2 in this region, even though no point mutation was detected in BMP2. Through further investigation, we identified a 4,671 bp (Chr20: 6,809,218–6,813,888) genomic duplication downstream of BMP2. This duplication was located within the linked region, co-segregated with the BDA2 phenotype in this family, and was not found in the unaffected family members and the unrelated control individuals. Compared with the previously reported duplications, the duplication in this family has a different breakpoint flanked by the microhomologous sequence GATCA and a slightly different length. Some other microhomologous nucleotides were also found in the duplicated region. In summary, our findings support the conclusions that BMP2 is the causing gene for BDA2, that the genomic location corresponding to the duplication region is prone to structural changes associated with malformation of the digits, and that this tendency is probably caused by the abundance of microhomologous sequences in the region.
doi:10.1371/journal.pone.0094201
PMCID: PMC3978006  PMID: 24710560

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