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1.  Axon guidance molecule semaphorin3A is a novel tumor suppressor in head and neck squamous cell carcinoma 
Oncotarget  2016;7(5):6048-6062.
Semaphorin3A (SEMA3A), an axon guidance molecule in the nervous system, plays an inhibitory role in oncogenesis. Here, we investigated the expression pattern and biological roles of SEMA3A in head and neck squamous cell carcinoma (HNSCC) by gain-of-function assays using adenovirus transfection and recombinant human SEMA3A protein. In addition, we explored the therapeutic efficacy of SEMA3A against HNSCC in vivo. We found that lower expression of SEMA3A correlated with shorter overall survival and had independent prognostic importance in patients with HNSCC. Both genetic and recombinant SEMA3A protein inhibited cell proliferation and colony formation and induced apoptosis, accompanied by decreased cyclin E, cyclin D, CDK2, CDK4 and CDK6 and increased P21, P27, activated caspase-5 and caspase-7. Moreover, over-expression of SEMA3A suppressed migration, invasion and epithelial-to-mesenchymal transition due in part to the inhibition of NF-κB and SNAI2 in HNSCC cell lines. Furthermore, intratumoral SEMA3A delivery significantly stagnated tumor growth in a xenograft model. Taken together, our results indicate that SEMA3A serves as a tumor suppressor during HNSCC tumorigenesis and a new target for the treatment of HNSCC.
PMCID: PMC4868739  PMID: 26755661
semaphorin3A; HNSCC; apoptosis; NF-kappaB; Snail
3.  Expression of Stanniocalcin-1 and Stanniocalcin-2 in Laryngeal Squamous Cell Carcinoma and Correlations with Clinical and Pathological Parameters 
PLoS ONE  2014;9(4):e95466.
Stanniocalcin-1 (STC1) and stanniocalcin-2 (STC2) are secreted glycoprotein hormones involved in various types of human malignancies. The roles of STC1 and STC2 in laryngeal squamous cell carcinoma (LSCC) remain unknown. We investigated correlations between STC1 and STC2 expression and clinicopathological or prognostic factors in LSCC.
Pre-surgical peripheral blood samples were collected between 2012 and 2013 from 62 patients with LSCC. Quantitative RT-PCR analysis was performed to examine mRNA levels of STC1 and STC2. Immunohistochemistry was performed to retrospectively analyze 90 paraffin-embedded LSCC tissue samples, which were obtained from patients who received surgery between 2006 and 2009. These patients did not have histories of treatment or malignancies. Univariate analysis of patient survival was performed by the Kaplan–Meier method. Multivariate analyses were performed with the Cox proportional hazards model.
The relative mRNA levels of STC1 and STC2 in peripheral blood were significantly greater in LSCC patients than those of healthy volunteers (both P<0.05). STC2 protein expression in tumor tissues was associated with invasion into the thyroid cartilage, T-Stage, lymphatic metastasis, clinical stage, and pathological differentiation (all P<0.05). In addition, STC2 protein expression was an independent prognostic factor for overall survival in patients with LSCC (P = 0.025). In contrast, STC1 expression only correlated with clinical stage (P = 0.026) and was not an independent or significant prognostic factor.
Circulating STC1 and STC2 mRNA are potentially useful blood markers for LSCC. Our results strongly suggest that the STC2 protein, but not STC1, may be a valuable biomarker for LSCC malignancies and a prognostic marker for poor outcome following surgery. Future studies should examine STC2 as a novel molecular target for the treatment of LSCC.
PMCID: PMC3990672  PMID: 24743310
4.  Prognostic Role of microRNA-155 in Various Carcinomas: Results from a Meta-Analysis 
Disease markers  2013;34(6):379-386.
BACKGROUND: Recent studies have shown that microRNAs (miRNA) have prognostic values in cancers. This meta-analysis seeks to summarize the global predicting role of miR-155 for survival in patients with a variety of carcinomas.
METHODS: Eligible studies were identified through multiple search strategies. Data were extracted from studies investigating the relationship between miR-155 expression and survival in cancer patients. Combined hazard ratios (HRs) of miR-155 for outcome were analyzed.
RESULTS: A total of 16 studies dealing with various carcinomas were included for this meta-analysis. For overall survival, higher miR-155 expression could significantly predict worse outcome with the pooled HR of 2.057 (95% CI: 1.392–3.039). For relapse or progress-free survival, elevated miR-155 was also a significant predictor, with a combined HR of 1.918 (95% CI: 1.311–2.806,). In addition, subgroup analysis showed that higher expression of miR-155 had the trends to predict worse outcome in lung cancer. However, the HRs did not reach the statistical significance.
CONCLUSION: Our findings suggest that miR-155 detection has a prognostic value in cancer patients. Regularly measuring miR-155 expression may be useful in clinical practice.
PMCID: PMC3810250  PMID: 23481631
miR-155; cancer; prognosis; clinical
5.  Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies 
Abnet, Christian C. | Wang, Zhaoming | Song, Xin | Hu, Nan | Zhou, Fu-You | Freedman, Neal D. | Li, Xue-Min | Yu, Kai | Shu, Xiao-Ou | Yuan, Jian-Min | Zheng, Wei | Dawsey, Sanford M. | Liao, Linda M. | Lee, Maxwell P. | Ding, Ti | Qiao, You-Lin | Gao, Yu-Tang | Koh, Woon-Puay | Xiang, Yong-Bing | Tang, Ze-Zhong | Fan, Jin-Hu | Chung, Charles C. | Wang, Chaoyu | Wheeler, William | Yeager, Meredith | Yuenger, Jeff | Hutchinson, Amy | Jacobs, Kevin B. | Giffen, Carol A. | Burdett, Laurie | Fraumeni, Joseph F. | Tucker, Margaret A. | Chow, Wong-Ho | Zhao, Xue-Ke | Li, Jiang-Man | Li, Ai-Li | Sun, Liang-Dan | Wei, Wu | Li, Ji-Lin | Zhang, Peng | Li, Hong-Lei | Cui, Wen-Yan | Wang, Wei-Peng | Liu, Zhi-Cai | Yang, Xia | Fu, Wen-Jing | Cui, Ji-Li | Lin, Hong-Li | Zhu, Wen-Liang | Liu, Min | Chen, Xi | Chen, Jie | Guo, Li | Han, Jing-Jing | Zhou, Sheng-Li | Huang, Jia | Wu, Yue | Yuan, Chao | Huang, Jing | Ji, Ai-Fang | Kul, Jian-Wei | Fan, Zhong-Min | Wang, Jian-Po | Zhang, Dong-Yun | Zhang, Lian-Qun | Zhang, Wei | Chen, Yuan-Fang | Ren, Jing-Li | Li, Xiu-Min | Dong, Jin-Cheng | Xing, Guo-Lan | Guo, Zhi-Gang | Yang, Jian-Xue | Mao, Yi-Ming | Yuan, Yuan | Guo, Er-Tao | Zhang, Wei | Hou, Zhi-Chao | Liu, Jing | Li, Yan | Tang, Sa | Chang, Jia | Peng, Xiu-Qin | Han, Min | Yin, Wan-Li | Liu, Ya-Li | Hu, Yan-Long | Liu, Yu | Yang, Liu-Qin | Zhu, Fu-Guo | Yang, Xiu-Feng | Feng, Xiao-Shan | Wang, Zhou | Li, Yin | Gao, She-Gan | Liu, Hai-Lin | Yuan, Ling | Jin, Yan | Zhang, Yan-Rui | Sheyhidin, Ilyar | Li, Feng | Chen, Bao-Ping | Ren, Shu-Wei | Liu, Bin | Li, Dan | Zhang, Gao-Fu | Yue, Wen-Bin | Feng, Chang-Wei | Qige, Qirenwang | Zhao, Jian-Ting | Yang, Wen-Jun | Lei, Guang-Yan | Chen, Long-Qi | Li, En-Min | Xu, Li-Yan | Wu, Zhi-Yong | Bao, Zhi-Qin | Chen, Ji-Li | Li, Xian-Chang | Zhuang, Xiang | Zhou, Ying-Fa | Zuo, Xian-Bo | Dong, Zi-Ming | Wang, Lu-Wen | Fan, Xue-Pin | Wang, Jin | Zhou, Qi | Ma, Guo-Shun | Zhang, Qin-Xian | Liu, Hai | Jian, Xin-Ying | Lian, Sin-Yong | Wang, Jin-Sheng | Chang, Fu-Bao | Lu, Chang-Dong | Miao, Jian-Jun | Chen, Zhi-Guo | Wang, Ran | Guo, Ming | Fan, Zeng-Lin | Tao, Ping | Liu, Tai-Jing | Wei, Jin-Chang | Kong, Qing-Peng | Fan, Lei | Wang, Xian-Zeng | Gao, Fu-Sheng | Wang, Tian-Yun | Xie, Dong | Wang, Li | Chen, Shu-Qing | Yang, Wan-Cai | Hong, Jun-Yan | Wang, Liang | Qiu, Song-Liang | Goldstein, Alisa M. | Yuan, Zhi-Qing | Chanock, Stephen J. | Zhang, Xue-Jun | Taylor, Philip R. | Wang, Li-Dong
Human Molecular Genetics  2012;21(9):2132-2141.
Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P< 5 × 10−8, and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) of 1.29 (1.19–1.40) and P= 7.63 × 10−10. An imputation analysis of 4304 SNPs at 2q33 suggested a single association signal, and the strongest imputed SNP associations were similar to those from the genotyped SNPs. We conducted an ancestral recombination graph analysis with 53 SNPs to identify one or more haplotypes that harbor the variants directly responsible for the detected association signal. This showed that the five SNPs exist in a single haplotype along with 45 imputed SNPs in strong linkage disequilibrium, and the strongest candidate was rs10201587, one of the genotyped SNPs. Our meta-analysis found genome-wide significant SNPs at 2q33 that map to the CASP8/ALS2CR12/TRAK2 gene region. Variants in CASP8 have been extensively studied across a spectrum of cancers with mixed results. The locus we identified appears to be distinct from the widely studied rs3834129 and rs1045485 SNPs in CASP8. Future studies of esophageal and other cancers should focus on comprehensive sequencing of this 2q33 locus and functional analysis of rs13016963 and rs10201587 and other strongly correlated variants.
PMCID: PMC3315211  PMID: 22323360
6.  The Epithelial–Mesenchymal Transition Promotes Transdifferentiation of Subcutaneously Implanted Hepatic Oval Cells Into Mesenchymal Tumor Tissue 
Stem Cells and Development  2009;18(9):1293-1298.
Hepatic oval cells are thought to represent facultative hepatic epithelial stem cells in liver in which damage inhibits hepatocyte proliferation and liver regeneration. The LE/6 hepatic stem cell line was derived from the liver of male Sprague-Dawley rats fed a choline-deficient diet containing 0.1% ethionine. They are histochemically characterized by their expression of hepatocytic (hepPar1), cholangiocytic cytokeratin (CK19), hepatic progenitor cell (OV-6), and hematopoietic stem cell (c-kit) markers. In this study, we transplanted LE/6 cells by subcutaneous injection into adult female nude mice, and examined their engraftment and differentiation potential in the subcutaneous microenvironment in vivo. Our results demonstrated that following subcutaneous transplantation, differentiation of LE/6 cells into mesenchymal tumor tissue (MTT) was associated with reduced E-cadherin expression, upregulation of E-cadherin repressor molecules (Snail proteins), and increased expression of vimentin and N-cadherin, all of these events are characteristic of the epithelial–mesenchymal transition (EMT).
PMCID: PMC3156617  PMID: 19226223
7.  Major complications after radiofrequency ablation for liver tumors: Analysis of 255 patients 
AIM: To investigate the major complications after radiofrequency ablation (RFA) for the treatment of liver tumors and analyze possible risk factors that precipitate these complications.
METHODS: From March 2001 to April 2008, 255 patients with liver tumors (205 male, 50 female; age range, 18-89 years; mean age, 56.0 years) who received RFA were enrolled in this study. Of these patients, 212 had hepatocellular carcinoma, 39 had metastatic liver tumors and four had cholangiocellular carcinoma. One hundred and forty eight patients had a single tumor, and 107 had multiple tumors. Maximum diameter of the tumors ranged 1.3-20 cm (mean, 5.1 cm). All patients were treated with a cooled-tip perfusion electrode attached to a radiofrequency generator (Radionics, Burlington, MA, USA). RFA was performed via the percutaneous approach (n = 257), laparoscopy (n = 7), or open surgical treatment (n = 86). The major complications related to RFA were recorded. The resultant data were analyzed to determine risk factors associated these complications.
RESULTS: Among the 255 patients, 425 liver tumors were treated and 350 RFA sessions were performed. Thirty-seven (10%) major complications were observed which included 13 cases of liver failure, 10 cases of hydrothorax requiring drainage, three cases of tumor seeding, one case of upper gastrointestinal bleeding, one case of intrahepatic abscess, one case of bile duct injury, one case of cardiac arrest, and five cases of hyperglycemia. Seven patients had more than two complications. Liver failure was the most severe complication and was associated with the highest mortality. Eleven patients died due to worsening liver decompensation. Child-Pugh classification (P = 0.001) and choice of approach (P = 0.045) were related to post-treatment liver failure, whereas patient age, tumor size and number were not significant factors precipitating this complication.
CONCLUSION: RFA can be accepted as a relatively safe procedure for the treatment of liver tumors. However, attention should be paid to possible complications even though the incidences of these complications are rare. Careful patient selection and the best approach choice (percutaneous, laparoscopy, or laparotomy) will help to minimize the incidence and morbidity rate of complications which occur after RFA.
PMCID: PMC2691498  PMID: 19496197
Complication; Hepatocellular carcinoma; Metastatic liver tumor; Radiofrequency ablation; Liver failure
8.  Effect of SLCO1B1 genetic polymorphism on the pharmacokinetics of nateglinide 
Nateglinide is a meglitinide analogue with antidiabetic action. A recent study showed that SLCO1B1 (which codes the OATP1B1 gene, also known as OATP-C, OATP2) is a major determinant which markedly affects the pharmacokinetics of repaglinide. Our objective was to assess the association between single nucleotide polymorphisms (SNPs) of SLCO1B1 and the pharmacokinetics of nateglinide.
Seventeen healthy volunteers with different SLCO1B1 genotypes (11 with 521TT, four with 521TC and two with 521CC) were enrolled in this study. Each was given a single oral dose of 90 mg nateglinide. Plasma concentrations of nateglinide were measured up to 8 h by HPLC.
The Cmax and AUC(0,∞) of nateglinide were 83% (P = 0.002) and 82% (P = 0.001) higher in the SLCO1B 1521TC subjects (n = 4), and 76% (P = 0.016) and 108% (P = 0.001) higher in the SLCO1B1521CC subjects (n = 2) than in the SLCO1B1521TT subjects (n = 11), respectively. The t1/2 of nateglinide in SLCO1B1521CC subjects was 78% longer than that in 521TT subjects (P = 0.036). The difference in tmax values among the three genotypic groups was not statistically significant.
Our results suggest that OATP1B1-mediated hepatic uptake of nateglinide may be the prior step for its metabolism and elimination. SLCO1B1521T > C SNP might play an important role in the pharmacokinetics of nateglinide.
PMCID: PMC1885174  PMID: 16796707
nateglinide; pharmacokinetics; SLCO1B1 polymorphism
9.  Skp2 is required for Aurora B activation in cell mitosis and spindle checkpoint 
Cell Cycle  2015;14(24):3877-3884.
The Aurora B kinase plays a critical role in cell mitosis and spindle checkpoint. Here, we showed that the ubiquitin E3-ligase protein Skp2, also as a cell-cycle regulatory protein, was required for the activation of Aurora B and its downstream protein. When we restored Skp2 knockdown Hela cells with Skp2 and Skp2-LRR E3 ligase dead mutant we found that Skp2 could rescue the defect in the activation of Aurora B, but the mutant failed to do so. Furthermore, we discovered that Skp2 could interact with Aurora B and trigger Aurora B Lysine (K) 63-linked ubiquitination. Finally, we demonstrated the essential role of Skp2 in cell mitosis progression and spindle checkpoint, which was Aurora B dependent. Our results identified a novel ubiquitinated substrate of Skp2, and also indicated that Aurora B ubiquitination might serve as an important event for Aurora B activation in cell mitosis and spindle checkpoint.
PMCID: PMC4825700  PMID: 26697838
Aurora B; cell mitosis; genomic stability; Skp2; spindle checkpoint; tumorigenesis; ubiquitination
10.  Least Squares Regression Methods for Clustered ROC Data with Discrete Covariates 
The receiver operating characteristic (ROC) curve is a popular tool to evaluate and compare the accuracy of diagnostic tests to distinguish the diseased group from the non-diseased group when test results from tests are continuous or ordinal. A complicated data setting occurs when multiple tests are measured on abnormal and normal locations from the same subject and the measurements are clustered within the subject. Although least squares regression methods can be used for the estimation of ROC curve from correlated data, how to develop the least squares methods to estimate the ROC curve from the clustered data has not been studied. Also, the statistical properties of the least squares methods under the clustering setting are unknown. In this article, we develop the least squares ROC methods to allow the baseline and link functions to differ, and more importantly, to accommodate clustered data with discrete covariates. The methods can generate smooth ROC curves which satisfy the inherent continuous property of the true underlying curve. The least squares methods are shown to be more efficient than the existing nonparametric ROC methods under appropriate model assumptions in simulation studies. We apply the methods to a real example in the detection of glaucomatous deterioration. We also derive the asymptotic properties of the proposed methods.
PMCID: PMC5178105  PMID: 26848938
11.  PTP1B regulates non-mitochondrial oxygen consumption via RNF213 to promote tumour survival during hypoxia 
Nature cell biology  2016;18(7):803-813.
Tumours exist in a hypoxic microenvironment and must limit excessive oxygen consumption. Hypoxia-inducible factor controls mitochondrial oxygen consumption, but how/if tumours regulate non-mitochondrial oxygen consumption (NMOC) is unknown. Protein-Tyrosine Phosphatase-1B (PTP1B) is required for Her2/Neu-driven breast cancer (BC) in mice, though the underlying mechanism and human relevance remain unclear. We found that PTP1B-deficient HER2+ xenografts have increased hypoxia, necrosis and impaired growth. In vitro, PTP1B deficiency sensitizes HER2+ BC lines to hypoxia by increasing NMOC by α-KG-dependent dioxygenases (α-KGDDs). The Moyamoya disease gene product RNF213 , an E3 ligase, is negatively regulated by PTP1B in HER2+ BC cells. RNF213 knockdown reverses the effects of PTP1B-deficiency on α-KGDDs, NMOC and hypoxia-induced death of HER2+ BC cells, and partially restores tumourigenicity. We conclude that PTP1B acts via RNF213 to suppress α-KGDD activity and NMOC. This PTP1B/RNF213/α-KGDD pathway is critical for survival of HER2+ BC, and possibly other malignancies, in the hypoxic tumour microenvironment.
PMCID: PMC4936519  PMID: 27323329
12.  Rapamycin rescues vascular, metabolic and learning deficits in apolipoprotein E4 transgenic mice with pre-symptomatic Alzheimer’s disease 
Apolipoprotein E ɛ4 allele is a common susceptibility gene for late-onset Alzheimer's disease. Brain vascular and metabolic deficits can occur in cognitively normal apolipoprotein E ɛ4 carriers decades before the onset of Alzheimer's disease. The goal of this study was to determine whether early intervention using rapamycin could restore neurovascular and neurometabolic functions, and thus impede pathological progression of Alzheimer's disease-like symptoms in pre-symptomatic Apolipoprotein E ɛ4 transgenic mice. Using in vivo, multimodal neuroimaging, we found that apolipoprotein E ɛ4 mice treated with rapamycin had restored cerebral blood flow, blood–brain barrier integrity and glucose metabolism, compared to age- and gender-matched wild-type controls. The preserved vasculature and metabolism were associated with amelioration of incipient learning deficits. We also found that rapamycin restored the levels of the proinflammatory cyclophilin A in vasculature, which may contribute to the preservation of cerebrovascular function in the apolipoprotein E ɛ4 transgenics. Our results show that rapamycin improves functional outcomes in this mouse model and may have potential as an effective intervention to block progression of vascular, metabolic and early cognitive deficits in human Apolipoprotein E ɛ4 carriers. As rapamycin is FDA-approved and neuroimaging is readily used in humans, the results of the present study may provide the basis for future Alzheimer's disease intervention studies in human subjects.
PMCID: PMC5167110  PMID: 26721390
Brain imaging; rapamycin; APOE4; cerebral blood flow; cerebral glucose metabolism; cognition; blood–brain barrier; inflammation; Alzheimer’s disease
13.  High Expression of Derlin-1 Is Associated with the Malignancy of Bladder Cancer in a Chinese Han Population 
PLoS ONE  2016;11(12):e0168351.
Derlin-1 is overexpressed in various types of solid tumors and has an important function in cancer progression. However, its expression pattern in and association with the clinicopathological characteristics of human bladder cancer remain unclear. In the present study, 3 pairs of fresh samples of bladder cancer tissue and paracancerous tissue were first detected by liquid chromatography tandem mass spectrometry (UPLC-MS/MS) to screen for differentially expressed proteins. Following bioinformatics analysis and assessments by qRT-PCR and western blotting, Derlin-1 was selected as a candidate protein and was then validated in samples from patients with bladder cancer by immunohistochemistry and western blotting. The results showed that the bladder cancer tissues exhibited higher levels of Derlin-1 expression than the paracancerous tissues (P < 0.05). Positive expression of Derlin-1 was significantly correlated with tumor stage, histological grade, and lymph node metastasis (P < 0.001) but was not correlated with other clinicopathological parameters including patient age (P = 0.758) and gender (P = 0.831). Besides, Derlin-1 was highly expressed in BC cell lines (um-uc-3 and T24), and the interference of Derlin-1 could reverse EMT progression, inhibit the tumor migration and invasion in T24 cells. Further, patients with positive Derlin-1 expression had shorter overall survival than those with negative expression (P < 0.001). Taken together, our results demonstrated that Derlin-1 was overexpressed in bladder cancer and was associated with the malignancy of bladder cancer.
PMCID: PMC5158059  PMID: 27977784
14.  Metrics of brain network architecture capture the impact of disease in children with epilepsy 
NeuroImage : Clinical  2016;13:201-208.
Background and objective
Epilepsy is associated with alterations in the structural framework of the cerebral network. The aim of this study was to measure the potential of global metrics of network architecture derived from resting state functional MRI to capture the impact of epilepsy on the developing brain.
Pediatric patients were retrospectively identified with: 1. Focal epilepsy; 2. Brain MRI at 3 Tesla, including resting state functional MRI; 3. Full scale IQ measured by a pediatric neuropsychologist. The cerebral cortex was parcellated into approximately 700 gray matter network nodes. The strength of a connection between two nodes was defined as the correlation between their resting BOLD signal time series. The following global network metrics were then calculated: clustering coefficient, transitivity, modularity, path length, and global efficiency. Epilepsy duration was used as an index for the cumulative impact of epilepsy on the brain.
45 patients met criteria (age: 4–19 years). After accounting for age of epilepsy onset, epilepsy duration was inversely related to IQ (p: 0.01). Epilepsy duration predicted by a machine learning algorithm on the basis of the five global network metrics was highly correlated with actual epilepsy duration (r: 0.95; p: 0.0001). Specifically, modularity and to a lesser extent path length and global efficiency were independently associated with epilepsy duration.
We observed that a machine learning algorithm accurately predicted epilepsy duration based on global metrics of network architecture derived from resting state fMRI. These findings suggest that network metrics have the potential to form the basis for statistical models that translate quantitative imaging data into patient-level markers of cognitive deterioration.
•Brain network architecture was measured using resting state functional MRI.•Global intelligence declined with increasing duration of epilepsy.•A machine learning algorithm accurately predicted the neurologic impact of epilepsy.•Network architecture was highly associated with the impact of epilepsy on the brain.
PMCID: PMC5157798  PMID: 28003958
FSL, FMRIB Software Library; ICA, independent components analysis; IQ, intelligence quotient; Network; Graph theory; Epilepsy; Brain; Intelligence
15.  Combined Oral and Intravenous Immunization Stimulates Strong IgA Responses in Both Systemic and Mucosal Compartments 
PLoS ONE  2016;11(12):e0168037.
To investigate the influence of immunization routes onIgG, IgA and IgM production in systemic and mucosal compartments, we immunized mice with keyhole limpet hemocyanin (KLH) via oral, intranasal (i.n.) or subcutaneous (s.c.) routes alone or combined with the intravenous (i.v.) route. We found that administering antigen intravenously could affect antibody production and formation of antibody secreting cells (ASCs) depending on the immunization route previously used. Combined oral/i.v. immunization but not s.c./i.v. immunization caused a great increase of IgA ASCs in the spleen and enhanced IgA production in the small intestine and serum. Combined i.n./i.v. immunization could also increase IgA ASCs in the spleen and enhance IgA production in serum but had no effect on IgA production in the small intestine. Oral/i.v. immunization caused increase of IgG ASCs in both the spleen and bone marrow. In comparison, combined i.n./i.v. and s.c./i.v. immunization could increase IgG ASCs in the spleen but not in bone marrow. Intravenous administration of KLH in mice that had been immunized via oral, i.n. or s.c. routes caused some increase of IgM ASCs in the spleen but not in bone marrow. In conclusion, combined oral and i.v. administration of an antigen can induce fast and strong immune responses, especially for IgA, in both systemic and mucosal compartments.
PMCID: PMC5148103  PMID: 27936222
16.  Cerebrospinal Fluid IL-10 and IL-10/IL-6 as Accurate Diagnostic Biomarkers for Primary Central Nervous System Large B-cell Lymphoma 
Scientific Reports  2016;6:38671.
Early diagnosis of primary central nervous system lymphoma (PCNSL) represents a challenge, and cerebrospinal fluid (CSF) cytokines may be diagnostic biomarkers for PCNSL. We used an electrochemiluminescence immunoassay to measure interleukin (IL)-10, IL-6, IL-8 and tumor necrosis factor α (TNF-α) in the CSF of 22 B cell PCNSL patients and 80 patients with other CNS diseases. CSF IL-10 was significantly higher in PCNSL patients than in the control group (median 74.7 pg/ml vs < 5.0 pg/ml, P < 0.000). Using a CSF IL-10 cutoff value of 8.2 pg/ml, the diagnostic sensitivity and specificity were 95.5% and 96.1%, respectively (AUC, 0.957; 95% CI, 0.901–1.000). For a CSF IL-10/IL-6 cutoff value of 0.72, the sensitivity was 95.5%, and the specificity was 100.0% (AUC, 0.976; 95% CI, 0.929–1.000). An increased CSF IL-10 level at diagnosis and post-treatment was associated with poor Progression free survival (PFS) for patients with PCNSL (P = 0.0181 and P = 0.0002, respectively). A low diagnostic value for PCNSL was found with CSF IL-8 or TNF-α. In conclusion, increased CSF IL-10 was a reliable diagnostic biomarker for large B cell PCNSL, and an IL-10/IL-6 ratio facilitates differentiation from other conditions, especially a CNS infection.
PMCID: PMC5141427  PMID: 27924864
17.  Molecular Structure and Dynamics of Water on Pristine and Strained Phosphorene: Wetting and Diffusion at Nanoscale 
Scientific Reports  2016;6:38327.
Phosphorene, a newly fabricated two-dimensional (2D) nanomaterial, has emerged as a promising material for biomedical applications with great potential. Nonetheless, understanding the wetting and diffusive properties of bio-fluids on phosphorene which are of fundamental importance to these applications remains elusive. In this work, using molecular dynamics (MD) simulations, we investigated the structural and dynamic properties of water on both pristine and strained phosphorene. Our simulations indicate that the diffusion of water molecules on the phosphorene surface is anisotropic, with strain-enhanced diffusion clearly present, which arises from strain-induced smoothing of the energy landscape. The contact angle of water droplet on phosphorene exhibits a non-monotonic variation with the transverse strain. The structure of water on transverse stretched phosphorene is demonstrated to be different from that on longitudinal stretched phosphorene. Moreover, the contact angle of water on strained phosphorene is proportional to the quotient of the longitudinal and transverse diffusion coefficients of the interfacial water. These findings thereby offer helpful insights into the mechanism of the wetting and transport of water at nanoscale, and provide a better foundation for future biomedical applications of phosphorene.
PMCID: PMC5138611  PMID: 27922072
18.  Application of Ultrasound-Guided Ilioinguinal/Iliohypogastric Nerve Block in Pediatric Same-Day Surgery 
The Indian Journal of Surgery  2015;77(6):512-516.
The aim of this study was to evaluate the safety and efficacy of ultrasound-guided ilioinguinal/iliohypogastric nerve block (IINB) in pediatric patients undergoing same-day inguinal region surgery. Ninety patients aged 4–6 years, ASA levels I–II, were randomly divided into three groups: U, T, or C (n = 30 each). After basic anesthesia, patients in group U underwent ultrasound-guided IINB, those in group T underwent traditional Schulte-Steinberg IINB, and those in group C (controls) received intravenous anesthesia (ketamine-propofol) only. Patients who remained sensitive to intraoperative stimuli received additional intravenous doses of 1 mg/kg ketamine. Heart rate (HR), mean arterial pressure (MAP), and oxygen saturation (SPO2) were recorded upon entering the operating room (T0), at skin incision (T1), while pulling the hernia sac (T2), during skin closing (T3), and upon awakening (T4) at recovery. HR and MAP at T1, T2, and T4 were higher in group C than those in the other two groups, and recovery time in group C was significantly prolonged (P < 0.05). Group U required significantly lower quantities and frequency of ketamine injection, and pain scores in group U during awakening were lower than those in the other two groups (P < 0.05). Ultrasound-guided IINB provided an improved nerve block effect and postoperative analgesia, reduced the amount of local anesthetic required, facilitated more rapid postoperative recovery, and was a safe and effective method of anesthesia.
PMCID: PMC4744206  PMID: 26884660
Ultrasonography; Ilioinguinal/iliohypogastric nerve; Nerve block; Daytime surgery
19.  Predictive Factors for Surgical Intervention in Patients over the Age of 80 with Adhensive Small-Bowel Obstruction 
The Indian Journal of Surgery  2015;77(Suppl 3):1280-1284.
Adhensive small-bowel obstruction (SBO) remains a common cause of admission to surgical wards around the world. Given the growing elderly population, the number of elderly patients with adhensive SBO can be expected to increase substantially. Timely and appropriate treatment would improve morbidity and mortality rates in elderly patients with adhensive SBO. However, accurately determining which patients should undergo surgical treatment during the hospitalization remains difficult. The aim of this study was to identify predictive factors for surgical intervention in patients aged over 80 years presenting with SBO due to postoperative adhesions. A clinical and radiological data for the assessment of patients presenting with adhensive SBO were collected. A logistic regression model was applied to identify risk factors that would predict the need of surgical intervention. A total of 21 patients (13 males, 8 females) were treated during a 3.5-year period. The mean age was 85.5 ± 4.7 years, ranging from 80 to 97 years. There is no significant difference in age (group 1 87.6 ± 5.9 years vs. group 2 84.8 ± 4.3 years, p = 0.262) between two groups. Serious coexisting diseases were noted in 13 (61.9 %, 13/21) patients. Primary hypertension, cardiac diseases, and diabetes mellitus were common coexisting conditions. However, there is no significant difference in comorbidities (40 vs. 68.8 %, p = 0.325) between group 1 and group 2. Adhensive SBO was successfully treated with conservative treatment in 16 patients (76.2 %, 16/21, group 2), whereas conservative treatment failed in 5 patients (23.8 %, 5/21, group 1), who subsequently underwent laparotomy. Postoperative complication rate was 14.3 % (wound infection, 1/5) and mortality was 0 % (0/5) in group 1. One patient death was recorded in group 2 (1/16, 6.3 %). The overall mean hospital stay was 10.0 ± 5.9 days (range 3–27 days). Group 1 had a longer hospital stay than group 2. However, the difference did not reach the significant level (12.8 ± 8.2 vs. 9.1 ± 5.9 days, p = 0.274). On univariate analysis, the need for surgical intervention was significantly associated with granulocyte percentage (2.768, 0.961–7.975, p = 0.059), CT findings of free intraabdominal fluid (28.000, 1.988–394.405, p = 0.014), and level of albumin (0.265, 0.073–0.970, p = 0.045). On multivariate analysis, the predictive factor was free intraabdominal fluid (28.000, 1.988–394.405, p = 0.014). Conservative treatment remains a major consideration in patients over the age of 80. Although major cases of adhensive SBO are successfully treated with conservative methods, some fail to respond, and the independent risk factor for surgical indication is free intraabdominal fluid.
PMCID: PMC4775599  PMID: 27011551
Small-bowel obstruction; Surgery; Risk factors; Adhesion; The elderly
20.  Human Cartilage-Derived Progenitor Cells From Committed Chondrocytes for Efficient Cartilage Repair and Regeneration 
A population of cartilage stem/progenitor cells can be derived from fully differentiated chondrocytes that have the potential to reassume their chondrocytic phenotype for efficient cartilage regeneration. This novel concept supports the possibility of using in vitro amplified chondrocyte-derived progenitor cells for joint repair.
Articular cartilage is not a physiologically self-renewing tissue. Injury of cartilage often progresses from the articular surface to the subchondral bone, leading to pathogenesis of tissue degenerative diseases, such as osteoarthritis. Therapies to treat cartilage defects using autologous chondrocyte-based tissue engineering have been developed and used for more than 20 years; however, the challenge of chondrocyte expansion in vitro remains. A promising cell source, cartilage stem/progenitor cells (CSPCs), has attracted recent attention. Because their origin and identity are still unclear, the application potential of CSPCs is under active investigation. Here we have captured the emergence of a group of stem/progenitor cells derived from adult human chondrocytes, highlighted by dynamic changes in expression of the mature chondrocyte marker, COL2, and mesenchymal stromal/stem cell (MSC) marker, CD146. These cells are termed chondrocyte-derived progenitor cells (CDPCs). The stem cell-like potency and differentiation status of CDPCs were determined by physical and biochemical cues during culture. A low-density, low-glucose 2-dimensional culture condition (2DLL) was critical for the emergence and proliferation enhancement of CDPCs. CDPCs showed similar phenotype as bone marrow mesenchymal stromal/stem cells but exhibited greater chondrogenic potential. Moreover, the 2DLL-cultured CDPCs proved efficient in cartilage formation both in vitro and in vivo and in repairing large knee cartilage defects (6–13 cm2) in 15 patients. These findings suggest a phenotype conversion between chondrocytes and CDPCs and provide conditions that promote the conversion. These insights expand our understanding of cartilage biology and may enhance the success of chondrocyte-based therapies.
Injury of cartilage, a non-self-repairing tissue, often progresses to pathogenesis of degenerative joint diseases, such as osteoarthritis. Although tissue-derived stem cells have been shown to contribute to tissue renewal and homeostasis, the derivation, biological function, and application potential of stem/progenitor cells found in adult human articular cartilage are incompletely understood. This study reports the derivation of a population of cartilage stem/progenitor cells from fully differentiated chondrocytes under specific culture conditions, which have the potential to reassume their chondrocytic phenotype for efficient cartilage regeneration. These findings support the possibility of using in vitro amplified chondrocyte-derived progenitor cells for joint cartilage repair.
PMCID: PMC4878331  PMID: 27130221
Stem and progenitor cells; Chondrocytes; Cartilage repair; Tissue regeneration; Osteoarthritis; Dedifferentiation; Stemness; Stem cell markers; Cell transplantation
22.  Transcriptome analysis reveals the genetic basis underlying the seasonal development of keratinized nuptial spines in Leptobrachium boringii 
BMC Genomics  2016;17:978.
The expression of sexually selected traits often varies with populations’ breeding cycles in many animals. The elucidation of mechanisms underlying the expression of such traits is a research topic in evolutionary biology; however, the genetic basis of the seasonal development of their expression remains unknown. Male Leptobrachium boringii develop keratinized nuptial spines on their upper jaw during the breeding season that fall off when the breeding season ends. To illuminate the genetic basis for the expression of this trait and its seasonal development, we assessed the de novo transcriptome for L. boringii using brain, testis and upper jaw skin and compared gene expression profiles of these tissues between two critical periods of the spine growth cycle.
We identified 94,900 unigenes in our transcriptome. Among them, 2,131 genes were differentially expressed between the breeding period when the spines developed and the post-breeding period when the spines were sloughed. An increased number of differentially expressed genes (DEGs) were identified in the upper jaw skin compared with the testis and brain. In the upper jaw skin, DEGs were mainly enriched in cytosolic part, peptidase inhibitor activity and peptidase regulator activity based on GO enrichment analysis and in glycolysis/gluconeogenesis, ribosome biogenesis in eukaryotes and retinol metabolism based on KEGG enrichment analysis. In the other two tissues, DEGs were primarily involved in the cell cycle, DNA replication and melatonin production. Specifically, insulin/insulin-like growth factor and sex steroid hormone-related DEGs were identified in the upper jaw skin, indicating . The expression variation of IGF2 and estrogen-related genes may be the main factors regulating the seasonal development of the spines.
Our study provides a list of potential genes involved in the regulation of seasonal development of nuptial spines in L. boringii. This is the first transcriptome survey of seasonally developed sexually selected traits for non-model amphibian species, and candidate genes provided here may provide valuable information for further studies of L. boringii.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-016-3295-9) contains supplementary material, which is available to authorized users.
PMCID: PMC5126826  PMID: 27894252
Leptobrachium boringii; Nuptial spine; Transcriptome; Estrogen; Insulin growth factor; Sexually selected traits
23.  Suprapedicular Foraminal Endoscopic Approach to Lumbar Lateral Recess Decompression Surgery to Treat Degenerative Lumbar Spinal Stenosis 
To discuss the strategy of suprapedicular foraminal endoscopic approach to lumbar lateral recess decompression and evaluate the safety and effectiveness of this strategy.
Complete clinical information of 52 cases of lumbar lateral recess decompression with therapy of suprapedicular foraminal endoscopic approach were analyzed during the period from February 2010 to April 2014 in the Third Hospital of Hebei. All patients were followed up for 24 months, and VAS, JOA, ODI, and LRD were compared between preoperative and postoperative therapy and changes of FA. Intraoperative and postoperative complications were recorded and the safety of the surgery was evaluated. The surgical “excellent” and “good” rates were evaluated using MacNab score.
VAS scores for lumbago and leg pain at 3, 6, 12, and 24 months after surgery were significantly lower than before surgery (p<0.05). JOA scores at 12 and 24 months after surgery were significantly higher than before surgery (p<0.05). ODI at 12 and 24 months after surgery were significantly lower than before surgery (p<0.05). LRD after surgery was higher (p<0.05), and FA was lower than before surgery.
Use of the suprapedicular foraminal endoscopic approach to lumbar lateral recess decompression is safe and effective, and this minimally invasive treatment can achieve satisfactory results, especially for elderly patients with complicated underlying diseases.
PMCID: PMC5142585  PMID: 27890911
Lumbar Vertebrae; Spinal Puncture; Spine
24.  Isolation and characterization of adenoviruses infecting endangered golden snub-nosed monkeys (Rhinopithecus roxellana) 
Virology Journal  2016;13:190.
Adenoviruses are important pathogens with the potential for interspecies transmission between humans and non-human primates. Although many adenoviruses have been identified in monkeys, the knowledge of these viruses from the Colobinae members is quite limited.
We conducted a surveillance of viral infection in endangered golden snub-nosed monkeys (Rhinopithecus roxellana) in the subfamily Colobinae in China, and found that 5.1% of sampled individuals were positive for adenovirus. One of the adenoviruses (SAdV-WIV19) was successfully isolated and its full-length genome was sequenced. The full-length genome of WIV19 is 33,562 bp in size, has a G + C content of 56.2%, and encodes 35 putative genes. Sequence analysis revealed that this virus represents a novel species in the genus Mastadenovirus. Diverse cell lines, including those of human origin, were susceptible to WIV19.
We report the first time the isolation and full-length genomic characterization of an adenovirus from the subfamily Colobinae.
Electronic supplementary material
The online version of this article (doi:10.1186/s12985-016-0648-6) contains supplementary material, which is available to authorized users.
PMCID: PMC5123214  PMID: 27884154
Mastadenovirus; Simian adenovirus; Golden snub-nosed monkey
25.  Hydrogen Sulfide and/or Ammonia Reduces Spermatozoa Motility through AMPK/AKT Related Pathways 
Scientific Reports  2016;6:37884.
A number of emerging studies suggest that air pollutants such as hydrogen sulfide (H2S) and ammonia (NH3) may cause a decline in spermatozoa motility. The impact and underlying mechanisms are currently unknown. Boar spermatozoa (in vitro) and peripubertal male mice (in vivo) were exposed to H2S and/or NH3 to evaluate the impact on spermatozoa motility. Na2S and/or NH4Cl reduced the motility of boar spermatozoa in vitro. Na2S and/or NH4Cl disrupted multiple signaling pathways including decreasing Na+/K+ ATPase activity and protein kinase B (AKT) levels, activating Adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) and phosphatase and tensin homolog deleted on chromosome ten (PTEN), and increasing reactive oxygen species (ROS) to diminish boar spermatozoa motility. The increase in ROS might have activated PTEN, which in turn diminished AKT activation. The ATP deficiency (indicated by reduction in Na+/K+ ATPase activity), transforming growth factor (TGFβ) activated kinase-1 (TAK1) activation, and AKT deactivation stimulated AMPK, which caused a decline in boar spermatozoa motility. Simultaneously, the deactivation of AKT might play some role in the reduction of boar spermatozoa motility. Furthermore, Na2S and/or NH4Cl declined the motility of mouse spermatozoa without affecting mouse body weight gain in vivo. Findings of the present study suggest that H2S and/or NH3 are adversely associated with spermatozoa motility.
PMCID: PMC5121643  PMID: 27883089

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