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1.  Chitinase 1 Is a Biomarker for and Therapeutic Target in Scleroderma-Associated Interstitial Lung Disease That Augments TGF-β1 Signaling 
Interstitial lung disease (ILD) with pulmonary fibrosis is an important manifestation in systemic sclerosis (SSc, scleroderma) where it portends a poor prognosis. However, biomarkers that predict the development and or severity of SSc-ILD have not been validated, and the pathogenetic mechanisms that engender this pulmonary response are poorly understood. In this study, we demonstrate in two different patient cohorts that the levels of chitotriosidase (Chit1) bioactivity and protein are significantly increased in the circulation and lungs of SSc patients compared with demographically matched controls. We also demonstrate that, compared with patients without lung involvement, patients with ILD show high levels of circulating Chit1 activity that correlate with disease severity. Murine modeling shows that in comparison with wild-type mice, bleomycin-induced pulmonary fibrosis was significantly reduced in Chit1−/− mice and significantly enhanced in lungs from Chit1 overexpressing transgenic animals. In vitro studies also demonstrated that Chit1 interacts with TGF-β1 to augment fibroblast TGF-β receptors 1 and 2 expression and TGF-β–induced Smad and MAPK/ERK activation. These studies indicate that Chit1 is potential biomarker for ILD in SSc and a therapeutic target in SSc-associated lung fibrosis and demonstrate that Chit1 augments TGF-β1 effects by increasing receptor expression and canonical and noncanonical TGF-β1 signaling.
PMCID: PMC4336775  PMID: 22826322
2.  Effect of bilateral supraclavicular postoperative radiotherapy in middle and lower thoracic esophageal carcinoma 
World Journal of Gastroenterology : WJG  2014;20(47):17970-17975.
AIM: To evaluate whether postoperative radiotherapy is an alternative to neck lymph node surgery and if it provides a survival benefit for those receiving two-field, chest and abdomen, lymphadenectomy.
METHODS: A total of 530 cases with middle and lower thoracic esophageal carcinoma in our hospital from January 2008 to April 2009 were selected and analyzed, of which 219 cases received right chest, upper abdominal incision Ivor-Lewis surgery and simultaneously underwent mediastinal and abdominal two-field lymphadenectomy. If regional lymph node metastasis occurred within the recurrent laryngeal nerve, the patients would receive bilateral supraclavicular radiotherapy (DT = 5000cGy) to be adopted at postoperative 4-5 wk (Group A) or cervical lymphadenectomy at postoperative 3-4 wk (Group B). If there were no regional lymph node metastases within the recurrent laryngeal nerve, the patients only underwent two-field, chest and abdomen, lymphadenectomy (Group C).
RESULTS: In 219 cases who underwent two-field lymphadenectomy, 91 cases were diagnosed with regional lymph node metastasis within the recurrent laryngeal nerve. Of them, 48 cases received cervical radiotherapy, and 43 cases underwent staging lymphadenectomy; 128 patients were not given the follow-up treatment of cervical radiotherapy because there was no regional lymph node metastasis within the recurrent laryngeal nerve. Five-year survival rates in group A and B were 47% and 50%, respectively, with no statistical difference between them, and the rate in group C was 58%.
CONCLUSION: For patients with middle and lower thoracic esophageal carcinoma combined with lymph node metastasis within the recurrent laryngeal nerve, cervical radiotherapy can be a substitute for surgery and provide benefit.
PMCID: PMC4273148  PMID: 25548496
Middle and lower thoracic esophageal carcinoma; Lymph node metastasis; Bilateral supraclavicular postoperative radiotherapy
3.  TGF-β1/Smad Signaling Pathway Regulates Epithelial-to-Mesenchymal Transition in Esophageal Squamous Cell Carcinoma: In Vitro and Clinical Analyses of Cell Lines and Nomadic Kazakh Patients from Northwest Xinjiang, China 
PLoS ONE  2014;9(12):e112300.
Invasion and metastasis are the major causes of death in patients with esophageal squamous cell carcinoma (ESCC). Epithelial-mesenchymal transition (EMT) is a critical step in tumor progression and transforming growth factor-β1 (TGF-β1) signaling has been shown to play an important role in EMT. In this study, we investigated how TGF-β1 signaling pathways contributed to EMT in three ESCC cell lines as well as 100 patients of nomadic ethnic Kazakhs residing in northwest Xinjiang Province of China. In vitro analyses included Western blotting to detect the expression of TGF-β1/Smad and EMT-associated proteins in Eca109, EC9706 and KYSE150 cell lines following stimulation with recombinant TGF-β1 and SB431542, a potent inhibitor of ALK5 that also inhibits TGF-β type II receptor. TGF-β-activated Smad2/3 signaling in EMT was significantly upregulated as indicated by mesenchymal markers of N-cadherin and Vimentin, and in the meantime, epithelial marker, E-cadherin, was markedly downregulated. In contrast, SB431542 addition downregulated the expression of N-cadherin and Vimentin, but upregulated the expression of E-cadherin. Moreover, the TGF-β1-induced EMT promoted invasion capability of Eca109 cells. Tumor cells undergoing EMT acquire fibroblastoid-like phenotype. Expressed levels of TGF-β1/Smad signaling molecules and EMT-associated proteins were examined using immunohistochemical analyses in 100 ESCC tissues of Kazakh patients and 58 matched noncancerous adjacent tissues. The results showed that ESCC tissues exhibited upregulated expression of TGF-β1/Smad. We also analyzed the relationship between the above proteins and the patients' clinicopathological characteristics. The TGF-β1/Smad signaling pathway in human Eca109 ESCC cells may carry similar features as in Kazakh ESCC patients, suggesting that TGF-β1/Smad signaling pathway may be involved in the regulation of EMT in ethnic Kazakh patients with ESCC from Xinjiang, China.
PMCID: PMC4251902  PMID: 25464508
4.  Interaction between fatty acid synthase and human epidermal growth receptor 2 (HER2) in osteosarcoma cells 
Elevated expression of fatty acid synthase (FASN) and human epidermal growth factor receptor-2 (HER2) are observed in human osteosarcoma (OS). The aim in this study is to investigate a possible connection between FASN expression and the activity of HER2. The immunohistochemistry staining was conducted on 24 OS specimens from patients, which revealed a significant positive correlation between FASN and HER2 as well as p-HER2 protein expression. Furthermore, the human OS cell lines MG-63 and U2-OS were treated with FASN-specific RNAi Plasmid or Lapatinib (an inhibitor of HER2). The mRNA of HER2 and FASN was measured using RT-PCR. Western blot was performed to detect the protein expression of HER2, p-HER2 and FASN. The results demonstrated that HER2 modulates FASN expression, inhibition of FASN resulted in down-regulation of HER2 and p-HER2 protein in OS cells. Our findings suggested that there was positive feedback regulation between FASN and HER2 expression and phosphorylation in OS cells.
PMCID: PMC4313995
Osteosarcoma; FASN; HER2; positive feedback regulation
5.  De Novo Assembly and Characterization of the Transcriptome of Seagrass Zostera marina Using Illumina Paired-End Sequencing 
PLoS ONE  2014;9(11):e112245.
The seagrass Zostera marina is a monocotyledonous angiosperm belonging to a polyphyletic group of plants that can live submerged in marine habitats. Zostera marina L. is one of the most common seagrasses and is considered a cornerstone of marine plant molecular ecology research and comparative studies. However, the mechanisms underlying its adaptation to the marine environment still remain poorly understood due to limited transcriptomic and genomic data.
Principal Findings
Here we explored the transcriptome of Z. marina leaves under different environmental conditions using Illumina paired-end sequencing. Approximately 55 million sequencing reads were obtained, representing 58,457 transcripts that correspond to 24,216 unigenes. A total of 14,389 (59.41%) unigenes were annotated by blast searches against the NCBI non-redundant protein database. 45.18% and 46.91% of the unigenes had significant similarity with proteins in the Swiss-Prot database and Pfam database, respectively. Among these, 13,897 unigenes were assigned to 57 Gene Ontology (GO) terms and 4,745 unigenes were identified and mapped to 233 pathways via functional annotation against the Kyoto Encyclopedia of Genes and Genomes pathway database (KEGG). We compared the orthologous gene family of the Z. marina transcriptome to Oryza sativa and Pyropia yezoensis and 11,667 orthologous gene families are specific to Z. marina. Furthermore, we identified the photoreceptors sensing red/far-red light and blue light. Also, we identified a large number of genes that are involved in ion transporters and channels including Na+ efflux, K+ uptake, Cl− channels, and H+ pumping.
Our study contains an extensive sequencing and gene-annotation analysis of Z. marina. This information represents a genetic resource for the discovery of genes related to light sensing and salt tolerance in this species. Our transcriptome can be further utilized in future studies on molecular adaptation to abiotic stress in Z. marina.
PMCID: PMC4244107  PMID: 25423588
6.  Recurrent genetic alterations in hepatitis C-associated hepatocellular carcinoma detected by genomic microarray: a genetic, clinical and pathological correlation study 
Molecular Cytogenetics  2014;7(1):81.
In the US, approximately 50% of hepatocellular carcinoma (HCC) is caused by hepatitis-C virus (HCV) infection. The molecular mechanism of a malignant transformation of hepatocyte induced by HCV infection is still largely unclear. There are several clinical and pathological staging systems for HCC, but none of them include biological parameters as predictors for prognosis and there has not been a standardized molecular classification of HCC. To understand the underlying pathogenic genetic alterations in HCV-associated HCC and aid in molecular classification of HCC and patient prognosis, microarray analysis of DNA copy number alterations in HCC were conducted using whole genome microarray with DNA from formalin-fixed paraffin-embedded (FFPE) specimens of both cancer tissues and paired nearby cirrhotic non-neoplastic tissues.
Our results show that the most common chromosomal aberrations (>5 Mb) observed in HCC were chromosomal gains of 1q (80%), 8q (60%), 7q (40%), 5p (33%), 7p (33%), Xq (33%), 5q (27%), and Xp (20%), as well as chromosome losses of 17p (40%), 4q21.21-q26 (33%), 8p (33%), 1p36.11-pter (20%), and 9p (20%). Statistically significant smaller copy number alterations (3.9 kb to 644 kb) were identified using STAC algorithm, including losses of FGFR3, RECQL4, NOTCH1, PTEN, TSC2, and/or ASPSCR1 and gains of ETV1and/or MAF. Correlation analysis between genetic data and pathological data showed that gain of 1q21.1-q23.2 and gain of 8q11.1q13.1 are significantly associated with grade 2–4 and moderately or poorly differentiated HCCs, and gain of chromosome 5q was significantly associated with HCCs with vascular invasion, while gain of chromosome 7q is significantly associated with stage I HCCs.
This study has provided a detailed map of genomic aberrations occurring in HCV-associated HCC and has suggested candidate genes. In addition, gene enrichment analysis on the recurrent abnormal regions indicated NF- kappaB and BMP signaling pathways in HCC development and progression. This study demonstrated that genomic microarray test can be used to distinguish HCC from non- neoplastic cirrhotic nodules and to identify prognostic factors associated with HCC progression using pathologically characterized FFPE samples. Our data support the utility of genomic microarray test for the diagnosis, risk stratification, and pathogenic studies of HCC.
PMCID: PMC4251858  PMID: 25469175
Hepatocellular carcinoma; Hepatitis-C virus; Copy number aberration; Copy number variants; Genomic microarray; Prognosis; Pathological correlation
7.  Effect of cold adaptation on activities of relevant enzymes and antioxidant system in rats 
Exercise in cold environments can cause significant metabolic regulation and antioxidant behavior. For discussing enzymatic responses towards cold adaptation, we investigated enzyme activities of adenylate cyclase (AC) and phosphodiesterase (PDE) in liver, skeletal muscle, and brown adipose tissue (BAT), as well as Na+·K+ ATPase and Na+/K+ ratio in blood. Malondialdehyde (MDA) and superoxide dismutase (SOD) activity in blood were also studied to address the effect of cold adaptation on oxidative damage and antioxidant system. Experimental results indicated that enzyme activities in liver, skeletal muscle and BAT maintained relatively constant for the control group. For the cold adaptation group, enzyme activities in liver and skeletal muscle were in high levels at the beginning, and then gradually decreased to similar values with the control group. However, enzyme activities in BAT performed an increasing trend and significantly higher than the control at the end. In addition, decreased oxidative damage and activated antioxidant system was observed along with the cold adaptation process.
PMCID: PMC4276194  PMID: 25550936
Cold adaptation; adenylate cyclase; phosphodiesterase; Na+·K+ ATPase; malondialdehyde; superoxide dismutase
8.  Type 3 muscarinic acetylcholine receptor stimulation is a determinant of endothelial barrier function and adherens junctions integrity: role of protein-tyrosine phosphatase 1B 
BMB Reports  2014;47(10):552-557.
The main purpose of this study was to investigate whether type 3 muscarinic acetylcholine receptor (M3R) dysfunction induced vascular hyperpermeability. Transwell system analysis showed that M3R inhibition by selective antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) and small interfering RNA both increased endothelial permeability. Using coimmunoprecipitation and Western blot assay, we found that M3R inhibition increased VE-cadherin and β-catenin tyrosine phosphorylation without affecting their expression. Using PTP1B siRNA, we found that PTP1B was required for maintaining VE-cadherin and β-catenin protein dephosphorylation. In addition, 4-DAMP suppressed PTP1B activity by reducing cyclic adenosine monophosphate (cAMP), but not protein kinase Cα (PKCα). These data indicate that M3R preserves the endothelial barrier function through a mechanism potentially maintaining PTP1B activity, keeping the adherens junction proteins (AJPs) dephosphorylation. [BMB Reports 2014; 47(10): 552-557]
PMCID: PMC4261512  PMID: 24393526
β-catenin; M3R; PTP1B; VE-cadherin
9.  Magnolin Protects against Contrast-Induced Nephropathy in Rats via Antioxidation and Antiapoptosis 
Background. Magnolin is the major active ingredient of the herb Magnolia fargesii which has anti-inflammatory and antioxidative effects. Oxidative stress and apoptosis are involved in the pathogenesis of contrast-induced nephropathy (CIN). We hypothesize that Magnolin could protect against CIN through antioxidative and antiapoptotic properties. Methods. To test whether Magnolin could attenuate CIN, oxidative stress and apoptosis, in vivo and in vitro, we utilized a rat model of ioversol-induced CIN and a cell model of oxidative stress in which HK2 cells were treated with H2O2. Rats were assigned to 4 groups (n = 6 per group): control group, ioversol group (ioversol-induced CIN), vehicle group (CIN rats pretreated with vehicle), and Magnolin group (CIN rats pretreated with 1 mg/kg Magnolin). Results. The results showed that magnolin ameliorated the renal tubular necrosis, apoptosis, and the deterioration of renal function (P < 0.05). Furthermore, Magnolin reduced the renal oxidative stress, suppressed caspase-3 activity, and increased Bcl-2 expression in vivo and in vitro. Conclusion. Magnolin might protect CIN in rats through antioxidation and antiapoptosis.
PMCID: PMC4221873  PMID: 25400863
10.  Circulating MiR-133a as a Biomarker Predicts Cardiac Hypertrophy in Chronic Hemodialysis Patients 
PLoS ONE  2014;9(10):e103079.
MicroRNAs (miRNAs) are small ribonucleotides regulating gene expression. MicroRNAs are present in the blood in a remarkably stable form and have emerged as potential diagnostic markers in patients with cardiovascular disease. Our study aimed to assess circulating miR-133a levels in MHD patients and the relation of miR-133a to cardiac hypertrophy.
We profiled miRNAs using RNA isolated from the plasma of participants. The results were validated in 64 MHD patients and 18 healthy controls.
Levels of plasma miR-133a decreased in MHD patients with LVH compared with those in healthy controls. Plasma miR-133a concentrations were negatively correlated with LVMI and IVS. After single hemodialytic treatment, plasma miR-133a levels remained unchanged. Cardiac Troponin I and T were not associated with LVMI and IVS.
Our observations supplied the possibility that circulating miR-133a could be a surrogate biomarker of cardiac hypertrophy in MHD patients.
PMCID: PMC4196728  PMID: 25313674
11.  Attitude Heading Reference System Using MEMS Inertial Sensors with Dual-Axis Rotation 
Sensors (Basel, Switzerland)  2014;14(10):18075-18095.
This paper proposes a low cost and small size attitude and heading reference system based on MEMS inertial sensors. A dual-axis rotation structure with a proper rotary scheme according to the design principles is applied in the system to compensate for the attitude and heading drift caused by the large gyroscope biases. An optimization algorithm is applied to compensate for the installation angle error between the body frame and the rotation table's frame. Simulations and experiments are carried out to evaluate the performance of the AHRS. The results show that the proper rotation could significantly reduce the attitude and heading drifts. Moreover, the new AHRS is not affected by magnetic interference. After the rotation, the attitude and heading are almost just oscillating in a range. The attitude error is about 3° and the heading error is less than 3° which are at least 5 times better than the non-rotation condition.
PMCID: PMC4239863  PMID: 25268911
AHRS; attitude sensor; MEMS inertial sensor; error compensation
12.  Agenesis of dorsal pancreas confirmed by three-dimensional reconstruction CT 
Agenesis of the dorsal pancreas (ADP) is a rare congenital pancreatic malformation in which all or part of the dorsal pancreatic body is absent. ADP is usually confirmed by magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP), but these methods are undesirable to patients because of strict limitations or invasiveness. We propose abdominal contrast-enhanced and three-dimensional reconstruction CT images as an improved method for ADP diagnosis, and present a case study of ADP confirmed with these methods.
PMCID: PMC4211839  PMID: 25356189
Dorsal pancreas; agenesis; CT
13.  Genome Wide Association Studies Using a New Nonparametric Model Reveal the Genetic Architecture of 17 Agronomic Traits in an Enlarged Maize Association Panel 
PLoS Genetics  2014;10(9):e1004573.
Association mapping is a powerful approach for dissecting the genetic architecture of complex quantitative traits using high-density SNP markers in maize. Here, we expanded our association panel size from 368 to 513 inbred lines with 0.5 million high quality SNPs using a two-step data-imputation method which combines identity by descent (IBD) based projection and k-nearest neighbor (KNN) algorithm. Genome-wide association studies (GWAS) were carried out for 17 agronomic traits with a panel of 513 inbred lines applying both mixed linear model (MLM) and a new method, the Anderson-Darling (A-D) test. Ten loci for five traits were identified using the MLM method at the Bonferroni-corrected threshold −log10 (P) >5.74 (α = 1). Many loci ranging from one to 34 loci (107 loci for plant height) were identified for 17 traits using the A-D test at the Bonferroni-corrected threshold −log10 (P) >7.05 (α = 0.05) using 556809 SNPs. Many known loci and new candidate loci were only observed by the A-D test, a few of which were also detected in independent linkage analysis. This study indicates that combining IBD based projection and KNN algorithm is an efficient imputation method for inferring large missing genotype segments. In addition, we showed that the A-D test is a useful complement for GWAS analysis of complex quantitative traits. Especially for traits with abnormal phenotype distribution, controlled by moderate effect loci or rare variations, the A-D test balances false positives and statistical power. The candidate SNPs and associated genes also provide a rich resource for maize genetics and breeding.
Author Summary
Genotype imputation has been used widely in the analysis of genome-wide association studies (GWAS) to boost power and fine-map associations. We developed a two-step data imputation method to meet the challenge of large proportion missing genotypes. GWAS have uncovered an extensive genetic architecture of complex quantitative traits using high-density SNP markers in maize in the past few years. Here, GWAS were carried out for 17 agronomic traits with a panel of 513 inbred lines applying both mixed linear model and a new method, the Anderson-Darling (A-D) test. We intend to show that the A-D test is a complement to current GWAS methods, especially for complex quantitative traits controlled by moderate effect loci or rare variations and with abnormal phenotype distribution. In addition, the traits associated QTL identified here provide a rich resource for maize genetics and breeding.
PMCID: PMC4161304  PMID: 25211220
14.  99mTc-Galacto-RGD2: A Novel 99mTc-Labeled Cyclic RGD Peptide Dimer Useful for Tumor Imaging 
Molecular pharmaceutics  2013;10(9):3304-3314.
This study sought to evaluate [99mTc(HYNIC-Galacto-RGD2)(tricine)(TPPTS)] (99mTc-Galacto-RGD2: HYNIC = 6-hydrazinonicotinyl; Galacto-RGD2 = Glu[cyclo[Arg-Gly-Asp-D-Phe-Lys(SAA-PEG2-(1,2,3-triazole)-1-yl-4-methylamide)]]2 (SAA = 7-amino-L-glycero-L-galacto-2,6-anhydro-7-deoxy-heptanamide, and PEG2 = 3,6-dioxaoctanoic acid); and TPPTS = trisodium triphenylphosphine-3,3',3"-trisulfonate) as a new radiotracer for tumor imaging. Galacto-RGD2 was prepared via the copper (I)-catalyzed 1,3-dipolar azide–alkyne Huisgen cycloaddition. HYNIC-Galacto-RGD2 was prepared by reacting Galacto-RGD2 with sodium succinimidyl 6-(2-(2-sulfonatobenzaldehyde)hydrazono)nicotinate (HYNIC-OSu) in the presence of diisopropylethylamine, and was evaluated for its integrin αvβ3 binding affinity against 125I-echistatin bound to U87MG glioma cells. The IC50 value for HYNIC-Galacto-RGD2 was determined to be 20 ± 2 nM. 99mTc-Galacto-RGD2 was prepared in high specific activity (~185 GBq/µmol) and high radiochemical purity (>95%), and was evaluated in athymic nude mice bearing U87MG glioma xenografts for its tumor-targeting capability and biodistribution. The tumor uptake of 99mTc-Galacto-RGD2 was 10.30 ± 1.67, 8.37 ± 2.13, 6.86 ± 1.33 and 5.61 ± 1.52 %ID/g at 5, 30, 60 and 120 min p.i., respectively, which was in agreement with high integrin αvβ3 expression on glioma cells and neovasculature. Its lower uptake in intestines, lungs and spleen suggests that 99mTc-Galacto-RGD2 has advantages over 99mTc-3P–RGD2 ([99mTc(HYNIC-3P–RGD2)(tricine)(TPPTS)]: 3P–RGD2 = PEG4-E[PEG4-c(RGDfK)]2; PEG4 = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) for imaging tumors in the chest and abdominal regions. U87MG tumors were readily detected by SPECT and the tumor uptake of 99mTc-Galacto-RGD2 was integrin αvβ3-specific. 99mTc-Galacto-RGD2 also had very high metabolic stability. On the basis of results from this study, it was concluded that 99mTc-Galacto-RGD2 is an excellent radiotracer for imaging integrin αvβ3-positive tumors and related metastases.
PMCID: PMC3946497  PMID: 23875883
integrin αvβ3; 99mTc-labeling; RGD-containing glycopeptide; tumor imaging; SPECT
15.  Role of RNase L in Viral PAMP/Influenza Virus and Cigarette Smoke-induced Inflammation and Remodeling 
Interactions between cigarette smoke (CS) exposure and viral infection play an important role(s) in the pathogenesis of chronic obstructive pulmonary disease (COPD) and a variety of other disorders. A variety of lines of evidence suggest that this interaction induces exaggerated inflammatory, cytokine and tissue remodeling responses. We hypothesized that the 2′-5′OAS/RNase L system, an innate immune antiviral pathway, plays an important role in the pathogenesis of these exaggerated responses. To test this hypothesis we characterize the activation of 2′-5′ oligoadenylate synthase (OAS) in lungs from mice exposed to CS and viral PAMPs/live virus, alone and in combination. We also evaluated the inflammatory and remodeling responses induced by CS and virus/viral PAMPs in lungs from RNase L null and wild type mice. These studies demonstrate that CS and viral PAMPs/live virus interact in a synergistic manner to stimulate the production of select OAS moieties. They also demonstrate that RNase L plays a critical role in the pathogenesis of the exaggerated inflammatory, fibrotic, emphysematous, apoptotic, TGF-β1 and type I IFN responses induced by CS plus virus/viral PAMP in combination. These studies demonstrate that CS is an important regulator of antiviral innate immunity, highlight novel roles of RNase L in CS plus virus induced inflammation, tissue remodeling, apoptosis and cytokine elaboration and highlight pathways that may be operative in COPD and mechanistically-related disorders.
PMCID: PMC3750064  PMID: 23913960
16.  Chitinase 3-like 1 Regulates Cellular and Tissue Responses via IL-13 Receptor α2 
Cell reports  2013;4(4):830-841.
Members of the 18 glycosyl hydrolase (GH 18) gene family have been conserved over species and time and are dysregulated in inflammatory, infectious, remodeling, and neoplastic disorders. This is particularly striking for the prototypic chitinase-like protein chitinase 3-like 1 (Chi3l1), which plays a critical role in antipathogen responses where it augments bacterial killing while stimulating disease tolerance by controlling cell death, inflammation, and remodeling. However, receptors that mediate the effects of GH 18 moieties have not been defined. Here, we demonstrate that Chi3l1 binds to interleukin-13 receptor α2 (IL-13Rα2) and that Chi3l1, IL-13Rα2, and IL-13 are in a multimeric complex. We also demonstrate that Chi3l1 activates macrophage mitogen-activated protein kinase, protein kinase B/AKT, and Wnt/β-catenin signaling and regulates oxidant injury, apoptosis, pyroptosis, inflammasome activation, antibacterial responses, melanoma metastasis, and TGF-β1 production via IL-13Rα2-dependent mechanisms. Thus, IL-13Rα2 is a GH 18 receptor that plays a critical role in Chi3l1 effector responses.
PMCID: PMC3988532  PMID: 23972995
17.  Blockade of IL-6 Trans Signaling Attenuates Pulmonary Fibrosis 
Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease with progressive fibrosis and death within 2–3 y of diagnosis. IPF incidence and prevalence rates are increasing annually with few effective treatments available. Inhibition of IL-6 results in the attenuation of pulmonary fibrosis in mice. It is unclear whether this is due to blockade of classical signaling, mediated by membrane-bound IL-6Rα, or trans signaling, mediated by soluble IL-6Rα (sIL-6Rα). Our study assessed the role of sIL-6Rα in IPF. We demonstrated elevations of sIL-6Rα in IPF patients and in mice during the onset and progression of fibrosis. We demonstrated that protease-mediated cleavage from lung macrophages was important in production of sIL-6Rα. In vivo neutralization of sIL-6Rα attenuated pulmonary fibrosis in mice as seen by reductions in myofibroblasts, fibronectin, and collagen in the lung. In vitro activation of IL-6 trans signaling enhanced fibroblast proliferation and extracellular matrix protein production, effects relevant in the progression of pulmonary fibrosis. Taken together, these findings demonstrate that the production of sIL-6Rα from macrophages in the diseased lung contributes to IL-6 trans signaling that in turn influences events crucial in pulmonary fibrosis.
PMCID: PMC4169999  PMID: 25172494
18.  Gastrointestinal symptoms: A comparison between patients undergoing peritoneal dialysis and hemodialysis 
World Journal of Gastroenterology : WJG  2014;20(32):11370-11375.
AIM: To compare the prevalence and diversity of gastrointestinal (GI) symptoms in patients undergoing peritoneal dialysis (PD) and hemodialysis (HD).
METHODS: Two hundred and ninety-four end-stage renal disease patients participated in the study, including 182 HD and 112 PD patients. Dimension scores were calculated from a modified gastrointestinal symptom rating scale (GSRS) 18-item questionnaire, including items concerning eating dysfunction, and were used for measuring GI symptoms. Information on patient age, condition contributing to end-stage renal disease and the most recent dialysis adequacy assessment (serum Kt/V urea value) was obtained from the follow-up database and by interviewing patients and/or reviewing the medical records. Differences between the HD and PD groups were evaluated using Student’s t, Pearson’s χ2 or Fisher’s exact tests.
RESULTS: The overall prevalence of GI symptoms, defined by a GSRS > 1, in end-stage renal disease patients was 70.7% (208/294), which differed between HD and PD patients (76.4% vs 61.6%, P < 0.01). HD patients had a higher prevalence of constipation, abdominal pain and diarrhea compared to PD patients (36.3% vs 17.9%, 32.4% vs 5.4%, 17.6% vs 4.5%, respectively, P < 0.05). PD patients had a higher prevalence of reflux compared to HD patients (32.1% vs 24.2%, P < 0.05). Additionally, reflux and eating dysfunction were more severe in PD patients (GSRS: 1.71 ± 1.15 vs 1.30 ± 0.67, 1.57 ± 0.84 vs 1.39 ± 0.61, respectively, P < 0.05), whereas HD patients had greater abdominal pain, diarrhea and constipation (GSRS: 1.22 ± 0.39 vs 1.04 ± 0.19, 1.19 ± 0.53 vs 1.07 ± 0.35, 1.51 ± 0.83 vs 1.23 ± 0.58, respectively, P < 0.05). Finally, 14.8% (27/182) of HD patients presented with more than three GI symptoms, compared to 7.2% (8/112) of PD patients (P < 0.01).
CONCLUSION: HD and PD patients differ in prevalence, severity and diversity of GI symptoms.
PMCID: PMC4145778  PMID: 25170224
Gastrointestinal symptom; Hemodialysis; Peritoneal dialysis; End-stage renal disease; Constipation; Reflux; Eating dysfunction; Abdominal pain; Diarrhea; Indigestion
19.  Preparation, pharmacokinetics and biodistribution of baicalin-loaded liposomes 
Baicalin (BA) is a major constituent of Scutellaria baicalensis Georgi, a medicinal herb. Previous pharmacokinetic studies of BA showed its low oral bioavailability. The aim of the present study was to develop a novel BA-loaded liposome (BA-LP) to enhance oral bioavailability. BA-LP, composed of BA, Tween® 80, Phospholipon® 90H, and citric acid at weight ratio of 96/50/96/50, respectively, was prepared by the effervescent dispersion technique and characterized in terms of morphology, size, zeta potential, encapsulation efficiency, and the in vitro release. Pharmacokinetics and biodistribution studies were carried out in rats after oral administration of BA-LP and a carboxymethyl cellulose suspension containing BA (BA-CMC) as a control. BA-LP exhibited a spherical shape by transmission electron microscopy observation. BA-LP had a mean particle size of 373±15.5 nm, zeta potential of −20.1±0.22 mV, and encapsulation efficiency of 82.7%±0.59%. The BA-LP showed a sustained-release behavior, and the in vitro drug-release kinetic model fit well with the Weibull distribution equation: lnln (1/(1−Q)) =0.609 lnt −1.230 (r=0.995). The oral bioavailability and the peak concentration of the BA-LP was threefold and 2.82-fold that of BA-CMC, respectively. The in vivo distribution results indicated that drug concentrations were significantly increased in the liver, kidney, and lung in the case of BA-LP, which were 5.59-fold, 2.33-fold, and 1.25-fold higher than those of BA-CMC, respectively. In conclusion, the study suggested that BA-LP might be a potential oral drug delivery system to improve bioavailability of BA.
PMCID: PMC4128791  PMID: 25120360
nanoliposomes; bioavailability; nanoliposomes; in vitro release; bioavailability; in vivo evaluation
20.  Let-7g reverses malignant phenotype of osteosarcoma cells by targeting Aurora-B 
Accumulating studies revealed that the expression levels of several miRNAs are up or down-regulated in osteosarcoma (OS). The aim of this study was to investigate the functional significance and molecular of the let-7g in OS cells. The expression levels of let-7g was significantly down-regulated in OS cell lines U2-OS and HOS cell compared to osteoblast cell lines HOB cell. Moreover, bioinformatic prediction suggested that Aurora-B, which is overexpressed and functions as an oncogene in OS cells, is a putative target gene of let-7g. Using mRNA and protein expression analysis and luciferase assays, we further identified let-7g directly regulated Aurora-B expression in OS cells. Functional investigation revealed both restoration of let-7g and silencing Aurora-B induce cell apoptosis and suppressed cell viability, migratory and invasive ability in OS cells. Finally, we found that silencing Aurora-B in OS cells could partly dampen anti-let-7g mediated tumor promotion. Thus, our findings suggested that let-7g inhibits OS cell malignant phenotype at least partly through targeting Aurora-B. Targeting of let-7g and Aurora-B may be a novel therapeutic strategy for treating OS.
PMCID: PMC4152022  PMID: 25197332
Osteosarcoma; let-7; Aurora-B; metastasis
21.  Mapping Biological Behaviors by Application of Longer-Lived Positron Emitting Radionuclides 
Advanced drug delivery reviews  2012;65(8):1098-1111.
With the technological development of positron emission tomography (PET) and the advent of novel antibody-directed drug delivery systems, longer-lived positron-emitting radionuclides are moving to the forefront to take important roles in tracking the distribution of biotherapeutics such as antibodies, and for monitoring biological processes and responses. Longer half-life radionuclides possess advantages of convenient on-site preparation procedures for both clinical and non-clinical applications. The suitability of the long half-life radionuclides for imaging intact monoclonal antibodies (mAbs) and their respective fragments, which have inherently long biological half-lives, has attracted increased interest in recent years. In this review, we provide a survey of the recent literature as it applies to the development of nine-selected longer-lived positron emitters with half-lives of 9–140 hours (e.g., 124I, 64Cu, 86Y and 89Zr), and describe the biological behaviors of radionuclide-labeled mAbs with respect to distribution and targeting characteristics, potential toxicities, biological applications, and clinical translation potentials.
PMCID: PMC3593806  PMID: 23123291
immuno-PET; radioimmunoimaging; monoclonal antibodies; oncology; 86Y; 89Zr; 124I; 64Cu
22.  Characterization of Transcriptional Complexity during Adipose Tissue Development in Bovines of Different Ages and Sexes 
PLoS ONE  2014;9(7):e101261.
Adipose tissue has long been recognized to play an extremely important role in development. In bovines, it not only serves a fundamental function but also plays a key role in the quality of beef and, consequently, has drawn much public attention. Age and sex are two key factors that affect the development of adipose tissue, and there has not yet been a global study detailing the effects of these two factors on expressional differences of adipose tissues.
In this study, total RNA from the back fat of fetal bovines, adult bulls, adult heifers and adult steers were used to construct libraries for Illumina next-generation sequencing. We detected the expression levels of 12,233 genes, with over 3,000 differently expressed genes when comparing fetal and adult patterns and an average of 1000 differently expressed genes when comparing adult patterns. Multiple Gene Ontology terms and pathways were found to be significantly enriched for these differentially expressed genes. Of the 12,233 detected genes, a total of 4,753 genes (38.85%) underwent alternative splicing events, and over 50% were specifically expressed in each library. Over 4,000 novel transcript units were discovered for one library, whereas only approximately 30% were considered to have coding ability, which supplied a large amount of information for the lncRNA study. Additionally, we detected 56,564 (fetal bovine), 65,154 (adult bull), 78,061 (adult heifer) and 86,965 (adult steer) putative single nucleotide polymorphisms located in coding regions of the four pooled libraries.
Here, we present, for the first time, a complete dataset involving the spatial and temporal transcriptome of bovine adipose tissue using RNA-seq. These data will facilitate the understanding of the effects of age and sex on the development of adipose tissue and supply essential information towards further studies on the genomes of beef cattle and other related mammals.
PMCID: PMC4077742  PMID: 24983926
23.  Detection of copy number variations and their effects in Chinese bulls 
BMC Genomics  2014;15(1):480.
Copy number variations (CNVs) are a main source of genomic structural variations underlying animal evolution and production traits. Here, with one pure-blooded Angus bull as reference, we describe a genome-wide analysis of CNVs based on comparative genomic hybridization arrays in 29 Chinese domesticated bulls and examined their effects on gene expression and cattle growth traits.
We identified 486 copy number variable regions (CNVRs), covering 2.45% of the bovine genome, in 24 taurine (Bos taurus), together with 161 ones in 2 yaks (Bos grunniens) and 163 ones in 3 buffaloes (Bubalus bubalis). Totally, we discovered 605 integrated CNVRs, with more “loss” events than both “gain” and “both” ones, and clearly clustered them into three cattle groups. Interestingly, we confirmed their uneven distributions across chromosomes, and the differences of mitochondrion DNA copy number (gain: taurine, loss: yak & buffalo). Furthermore, we confirmed approximately 41.8% (253/605) and 70.6% (427/605) CNVRs span cattle genes and quantitative trait loci (QTLs), respectively. Finally, we confirmed 6 CNVRs in 9 chosen ones by using quantitative PCR, and further demonstrated that CNVR22 had significantly negative effects on expression of PLA2G2D gene, and both CNVR22 and CNVR310 were associated with body measurements in Chinese cattle, suggesting their key effects on gene expression and cattle traits.
The results advanced our understanding of CNV as an important genomic structural variation in taurine, yak and buffalo. This study provides a highly valuable resource for Chinese cattle’s evolution and breeding researches.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-480) contains supplementary material, which is available to authorized users.
PMCID: PMC4073501  PMID: 24935859
Copy number variations; Bos taurus; Bos grunniens; Bubalus bubalis; Gene expression
24.  Numerical Simulation on Slabs Dislocation of Zipingpu Concrete Faced Rockfill Dam during the Wenchuan Earthquake Based on a Generalized Plasticity Model 
The Scientific World Journal  2014;2014:572407.
After the Wenchuan earthquake in 2008, the Zipingpu concrete faced rockfill dam (CFRD) was found slabs dislocation between different stages slabs and the maximum value reached 17 cm. This is a new damage pattern and did not occur in previous seismic damage investigation. Slabs dislocation will affect the seepage control system of the CFRD gravely and even the safety of the dam. Therefore, investigations of the slabs dislocation's mechanism and development might be meaningful to the engineering design of the CFRD. In this study, based on the previous studies by the authors, the slabs dislocation phenomenon of the Zipingpu CFRD was investigated. The procedure and constitutive model of materials used for finite element analysis are consistent. The water elevation, the angel, and the strength of the construction joints were among major variables of investigation. The results indicated that the finite element procedure based on a modified generalized plasticity model and a perfect elastoplastic interface model can be used to evaluate the dislocation damage of face slabs of concrete faced rockfill dam during earthquake. The effects of the water elevation, the angel, and the strength of the construction joints are issues of major design concern under seismic loading.
PMCID: PMC4071857  PMID: 25013857
25.  Nucleotide excision repair gene polymorphisms and prognosis of non-small cell lung cancer patients receiving platinum-based chemotherapy: A meta-analysis based on 44 studies 
Biomedical Reports  2014;2(4):452-462.
Genetic variations are linked to DNA repair ability and varied drug metabolism that largely affects the prognosis of antineoplastic agents, including platinum. The purpose of the present meta-analysis was to determine the roles of the genetic variants of the nucleotide excision repair genes on the prognosis of platinum-based chemotherapy in patients with non-small cell lung cancer (NSCLC). A meta-analysis was performed, including 44 original studies with a total number of 5,944 patients with NSCLC according to the search strategy. The tumor responses [complete response, partial response, stable disease (SD) and progressive disease (PD)] were estimated and the Stata package was used for the comprehensive quantitative analyses. The results showed that the XPG C46T polymorphism was significantly associated with tumor chemotherapy when SD or PD was considered as a non-response [TT vs. CC: risk ratio (RR), 1.31; 95% confidence interval (CI), 1.14–1.5; and P=0.00; TT/CT vs. CC: RR, 1.23; 95% CI, 1.11–1.36; and P=0.00; and TT vs. CC/CT: RR, 1.22; 95% CI, 1.11–1.36; and P=0.00]. No significant association between the ERCC1 C118T/C8092A XPDLys751Gln and XPA A23G polymorphisms and tumor response was found. There was also no evidence found to support the use of the ERCC1 C118T/C8092A XPDLys751Gln and XPA A23G polymorphisms as prognostic predictors of platinum-based chemotherapies in NSCLC in the meta-analysis. For the XPG C46T polymorphisms, a significant association with an objective response was detected. Multiple and large-scale studies are required to further investigate the association between biomarkers and tumor prognosis.
PMCID: PMC4051473  PMID: 24944789
platinum-based chemotherapy; non-small cell lung cancer; nucleotide excision repair; polymorphism; meta-analysis

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