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1.  Disorganized vascular structures in sporadic venous malformations: a possible correlation with balancing effect between Tie2 and TGF-β 
Scientific Reports  2014;4:5457.
Venous malformations (VMs) are among the most common slow-flow vascular malformations characterized by irregular venous channels, luminal thrombi, and phleboliths. To systematically manifest the disorganized vascular structures in sporadic VMs, we initially evaluated histopathological characteristics, perivascular cell coverage, adhesion molecules expression and vascular ultrastructures. Then, the expression of Tie2 and TGF-β in VMs was detected. Meanwhile, the in vitro studies were performed for mechanism investigation. Our data showed that the perivascular α-SMA+ cell coverage and expression of adhesion molecules in VMs were significantly decreased compared with those in the normal skin tissues. We also found that the expression and phosphorylation levels of Tie2 were upregulated, whereas TGF-β was downregulated in VMs, and they were negatively correlated. Moreover, the in vitro results also revealed a possible balancing effect between Tie2 and TGF-β, as demonstrated by the findings that Ang-1 (agonist of Tie2) treatment significantly downregulated TGF-β expression, and treatment with recombinant TGF-β could also suppress Tie2 expression and phosphorylation. This study provided strong evidence supporting the disorganized vascular structures and dysregulation of related molecules in sporadic VMs, and demonstrated a possible balancing effect between Tie2 and TGF-β, which might help to develop novel therapeutics for vascular disorganization-related disorders.
PMCID: PMC4071312  PMID: 24966004
2.  Metastasis-Associated in Colon Cancer 1 Is a Novel Survival-Related Biomarker for Human Patients with Renal Pelvis Carcinoma 
PLoS ONE  2014;9(6):e100161.
Metastasis-associated in colon cancer 1 (MACC1) has recently been identified as a novel independent prognostic indicator for metastasis occurrence, overall survival and cancer-free survival for patients with colon cancer and other solid tumors. In this study, we investigated the role of MACC1 in the development and progression of renal pelvis carcinoma, a form of upper tract urothelial carcinomas. MACC1 protein has been found in the cytoplasm as well as in the nucleus of the transitional epithelial cells of the normal renal pelvis in immunohistochemical (IHC) assays. Quantitative IHC examinations revealed that MACC1 abnormal abundance in cancerous tissues might represent a biological indicator clinically suggestive of tumor malignancy in the renal pelvis. Furthermore, investigation of the association of MACC1 protein levels with clinicopathological parameters in this study has suggested a correlation of MACC1 expression with tumor-node-metastasis stage and histopathological grade of patients with renal pelvis carcinoma, with elevated MACC1 protein levels frequently associated with higher aggressiveness of the disease. Moreover, both disease-free survival and overall survival for the patients in the high MACC1 expression group were significantly lower than those in the low expression group. Multivariate analysis with a Cox proportional-hazards model suggested that MACC1 is indeed an independent prognostic indicator of overall survival and cancer-free survival for patients with renal pelvis carcinoma. Thus, MACC1 may represent a promising prognostic biomarker candidate, as well as a potential therapeutic target for this disease.
PMCID: PMC4064998  PMID: 24949951
3.  A Disturbance Rejection Framework for the Study of Traditional Chinese Medicine 
The traditional Chinese medicine (TCM) is explained in the language of engineering cybernetics (EC), an engineering science with the tradition of rigor and long history of practice. The inherent connection is articulated between EC, as a science of interrelations, and the Chinese conception of Wuxing. The combined cybernetic model of Wuxing seems to have significant explaining power for the TCM and could potentially facilitate better communications of the insights of the TCM to the West. In disturbance rejection, an engineering concept, a great metaphor, is found to show how the TCM is practiced, using the liver cancer pathogenesis and treatment as a case study. The results from a series of experimental studies seem to lend support to the cybernetic model of Wuxing and the principles of disturbance rejection.
PMCID: PMC4065676  PMID: 24995034
4.  High-throughput sequencing to identify miRNA biomarkers in colorectal cancer patients 
Oncology Letters  2014;8(2):711-713.
The altered expression of microRNAs (miRNAs) is associated with a number of cancer types. The study of the association between the miRNA profile and cancer may be useful to identify potential biomarkers of certain types of cancer. In the present study, 19 miRNAs were identified by high-throughput sequencing in the serum of colorectal cancer (CRC) patients. A network analysis was performed based on a computational approach to identify associations between CRC and miRNAs. The present study may be useful to identify cancer-specific signatures and potentially useful biomarkers for the diagnosis of CRC. The network analysis of miRNA-target genes may aid in identifying altered miRNA regulatory networks that are involved in tumor pathogenesis.
PMCID: PMC4081398  PMID: 25013489
colorectal cancer; high-throughput sequencing; miRNA; biomarker
5.  Germ-Line–Competent Embryonic Stem Cells of the Chinese Kunming Mouse Strain with Long-Term Self-Renewal Ability 
Cellular Reprogramming  2013;15(3):179-184.
Kunming (KM) mice are the most widely used strain in China. However, authentic embryonic stem cells (ESCs) from KM mice have never been available, and this hampers the genetic manipulation of this valuable mice strain. In this study, we show that KM ESCs can be efficiently derived and maintained in chemically defined N2B27 medium with the presence of two small molecules PD0325901 and CHIR99021 (2i medium). These KM ESCs exhibit all features of ESCs, including long-term self-renewal ability, expression of key molecular markers (Oct4, Nanog, and Sox2), the ability to form teratomas, and the capacity to incorporate into the developing embryo and then transmit through the germ line.
PMCID: PMC3666247  PMID: 23713430
6.  Distal Airway Stem Cells Render Alveoli in Vitro and During Lung Regeneration Following H1N1 Influenza Infection 
Cell  2011;147(3):525-538.
The extent of lung regeneration following catastrophic damage and the potential role of adult stem cells in such a process remains obscure. Sublethal infection of mice with an H1N1 influenza virus related to that of the 1918 pandemic triggers massive airway damage followed by apparent regeneration. We show here that p63-expressing stem cells in the bronchiolar epithelium undergo rapid proliferation after infection and radiate to interbronchiolar regions of alveolar ablation. Once there, these cells assemble into discrete, Krt5+ pods and initiate expression of markers typical of alveoli. Gene expression profiles of these pods suggest that they are intermediates in the reconstitution of the alveolar-capillary network eradicated by viral infection. The dynamics of this p63-expressing stem cell in lung regeneration mirrors our parallel finding that defined pedigrees of human distal airway stem cells assemble alveoli-like structures in vitro and suggests new therapeutic avenues to acute and chronic airway disease.
PMCID: PMC4040224  PMID: 22036562
7.  Renal metastasis after esophagectomy of esophageal squamous cell carcinoma: a case report and literature review 
Solitary metastatic renal tumors are rarely encountered. We report the case of a 63-year-old man who developed a solitary renal metastasis after undergoing an esophagectomy for esophageal squamous cell carcinoma and subsequent nephrectomy of the right kidney.
PMCID: PMC4037410  PMID: 24884912
Kidney; Metastasis; Esophageal carcinoma
8.  Correlation of survival and EGFR mutation with predominant histologic subtype according to the new lung adenocarcinoma classification in stage IB patients 
A new lung adenocarcinoma classification proposed by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) has recently been published. This study aimed to investigate the utility of the new histological classification for identifying the prognostic subtypes of adenocarcinomas in stage IB patients.Correlations between the classification and the presence of epidermal growth factor receptor (EGFR) mutation status was also studied.
One hundred and thirty-six patients with stage IB lung adenocarcinoma operated on in Zhejiang Cancer Hospital were identified between 2002 and 2011. Patients overall survival and disease-free survival were calculated using Kaplan-Meier and Cox regression analyses. EGFR mutations were detected using the amplification refractory mutation system.
A total of 136 cases were included in current study, of which 38 were papillary predominant, 39 were acinar predominant, 22 were micropapillary predominant, 21 were lepidic predominant subtypes, 14 were solid predominant, and 2 were variants of invasive adenocarcinoma. Patients with micropapillary- and solid-predominant tumors had the lowest five-year disease-free survival (28.4 and 36.7%, respectively). Univariate and multivariate analysis showed that the micropapillary-predominant subtype was an independent predictor of disease-free survival (P = 0.0041 and 0.048, respectively), but not overall survival (P = 0.175 and 0.214, respectively). EGFR mutations were significantly associated with the micropapillary-predominant subtype patients (P = 0.0026). The EGFR mutation frequency is lower in the solid-predominant subtype than other subtypes (P = 0.0508).
The predominant subtype in the primary tumor was associated with prognosis in resected stage IB lung adenocarcinoma. The EGFR mutation frequency of micropapillary-predominant subtype is higher than other subtypes.
PMCID: PMC4067105  PMID: 24885205
Lung adenocarcinoma; IASLC/ATS/ERS classification; Stage IB; Prognosis; EGFR mutation
9.  Vapor-deposited amorphous metamaterials as visible near-perfect absorbers with random non-prefabricated metal nanoparticles 
Scientific Reports  2014;4:4850.
Spatial order or periodicity is usually required and constructed with tens of nanometers in the feature size, which makes it difficult to process the near-perfect metamaterial absorbers (PMAs) working in the visible range in large-area and mass-production scale. Although many established technologies and theoretical modeling methods used for order-based metamaterials, aperiodic or disordered structures have been gradually recognized to achieve similar functionalities for which the ordered structures are overwhelmingly used. Here, we demonstrated the vapor-deposited ‘amorphous’ metamaterials as controlled-reflectance surfaces and tunable PMAs without the use of the lithographically ordered arrays, the prefabricated colloidal metal nanoparticles (MNPs) or the multilayer of nanoparticles. The flexible construction, the control of the monolayer of MNPs and the atomic-layer-deposited (ALD) dielectric spacer layer provide more insight for understanding the controlled-reflectance surfaces. Such processes have a few key advantages of CMOS-compatible simple processing, low cost and large-area plating, allowing the PMAs to be flexibly constructed in mass-production scale.
PMCID: PMC4014980  PMID: 24810434
10.  Corneal Inflammation Is Inhibited by the LFA-1 Antagonist, Lifitegrast (SAR 1118) 
Sterile corneal infiltrates can cause pain, blurred vision, and ocular discomfort in silicone hydrogel contact-lens users. The current study investigates the potential for the synthetic lymphocyte functional antigen-1 (LFA-1) antagonist lifitegrast (SAR 1118) to block corneal inflammation using a murine model.
The role of LFA-1 (CD11a/CD18) was examined either in CD18−/− mice, by intraperitoneal injection of anti-CD11a, or by topical application of lifitegrast. Corneal inflammation was induced by epithelial abrasion and exposure to either tobramycin-killed Pseudomonas aeruginosa or Staphylococcus aureus in the presence of a 2-mm-diameter punch from a silicone hydrogel contact lens. After 24 h, corneal thickness and haze were examined by in vivo confocal microscopy, and neutrophil recruitment to the corneal stroma was detected by immunohistochemistry.
Neutrophil recruitment to the corneal stroma and development of stromal haze were significantly impaired in CD18−/− mice or after injection of anti-CD11a. Topical lifitegrast also inhibited P. aeruginosa- and S. aureus–induced inflammation, with the optimal application being a 1% solution applied either 2 or 3 times prior.
As LFA-1-dependent neutrophil recruitment to the corneal stroma can be blocked by topical lifitegrast, this reagent could be used in combination with antibiotics to prevent leukocyte infiltration to the corneal stroma in association with contact-lens wear.
PMCID: PMC3643258  PMID: 23215542
11.  Physiological Consequences of Multiple-Target Regulation by the Small RNA SgrS in Escherichia coli 
Journal of Bacteriology  2013;195(21):4804-4815.
Cells use complex mechanisms to regulate glucose transport and metabolism to achieve optimal energy and biomass production while avoiding accumulation of toxic metabolites. Glucose transport and glycolytic metabolism carry the risk of the buildup of phosphosugars, which can inhibit growth at high concentrations. Many enteric bacteria cope with phosphosugar accumulation and associated stress (i.e., sugar-phosphate stress) by producing a small RNA (sRNA) regulator, SgrS, which decreases phosphosugar accumulation in part by repressing translation of sugar transporter mRNAs (ptsG and manXYZ) and enhancing translation of a sugar phosphatase mRNA (yigL). Despite a molecular understanding of individual target regulation by SgrS, previously little was known about how coordinated regulation of these multiple targets contributes to the rescue of cell growth during sugar-phosphate stress. This study examines how SgrS regulation of different targets impacts growth under different nutritional conditions when sugar-phosphate stress is induced. The severity of stress-associated growth inhibition depended on nutrient availability. Stress in nutrient-rich media necessitated SgrS regulation of only sugar transporter mRNAs (ptsG or manXYZ). However, repression of transporter mRNAs was insufficient for growth rescue during stress in nutrient-poor media; here SgrS regulation of the phosphatase (yigL) and as-yet-undefined targets also contributed to growth rescue. The results of this study imply that regulation of only a subset of an sRNA's targets may be important in a given environment. Further, the results suggest that SgrS and perhaps other sRNAs are flexible regulators that modulate expression of multigene regulons to allow cells to adapt to an array of stress conditions.
PMCID: PMC3807494  PMID: 23873911
12.  Novel Natural Mutations in the Hepatitis B Virus Reverse Transcriptase Domain Associated with Hepatocellular Carcinoma 
PLoS ONE  2014;9(5):e94864.
Hepatitis B Virus (HBV) mutations play a role in the development of hepatocellular carcinoma (HCC). However, the association between HBV polymerase gene mutations and HCC has not been reported. In this study, we conducted a multi-stage study to identify HCC-related mutations in the reverse transcriptase (RT) domain of the HBV polymerase gene.
A total of 231 HCCs and 237 non-HCC controls from Qidong, China, were included in this study. The entire sequence of HBV RT was first compared between 29 HCC and 35 non-HCC cases, and candidate mutations were then evaluated in two independent validation sets.
There were 15 candidate mutations identified from the discovery set, with A799G and T1055A being consistently associated with HCC across all studies. A pooled analysis of samples revealed that A799G, A987G, and T1055A were independent risk factors for HCC, with adjusted odds ratios of 5.53 [95% confidence interval (CI), 1.69–18.10], 4.20 (95%CI, 1.15–15.35), and 3.78 (95%CI, 1.45–9.86), respectively. A longitudinal study showed that these mutations were detectable 4–5 years prior to HCC diagnosis.
Our study provides evidence the first that HBV RT contains naturally occurring mutations that can be used as predictive markers for HCC.
PMCID: PMC4006920  PMID: 24788140
13.  A case of horizontal gene transfer from Wolbachia to Aedes albopictus C6/36 cell line 
Mobile Genetic Elements  2014;4:e28914.
Horizontal gene transfer plays an essential role in evolution and ecological adaptation, yet this phenomenon has remained controversial, particularly where it occurs between prokaryotes and eukaryotes. There are a handful of reported examples of horizontal gene transfer occurring between prokaryotes and eukaryotes in the literature, with most of these documented cases pertaining to invertebrates and endosymbionts. However, the vast majority of these horizontally transferred genes were either eventually excluded or rapidly became nonfunctional in the recipient genome. In this study, we report the discovery of a horizontal gene transfer from the endosymbiont Wolbachia in the C6/36 cell line derived from the mosquito Aedes albopictus. Moreover, we report that this horizontally transferred gene displayed high transcription level. This finding and the results of further experimentation strongly suggest this gene is functional and has been expressed and translated into a protein in the mosquito host cells.
PMCID: PMC4013104  PMID: 24812591
horizontal gene transfer; endosymbiont; Wolbachia; mosquito; Aedes Albopictus; C6/36 cell line
14.  Changes in the Organics Metabolism in the Hepatopancreas Induced by Eyestalk Ablation of the Chinese Mitten Crab Eriocheir sinensis Determined via Transcriptome and DGE Analysis 
PLoS ONE  2014;9(4):e95827.
To understand the regulation mechanism of eyestalk ablation on the activities of hepatopancreas, Illumina RNA-Seq and digital gene expression (DGE) analyses were performed to investigate the transcriptome of the eyestalk, Y-organ, and hepatopancreas of E. sinensis and to identify the genes associated with the hepatopancreas metabolism that are differentially expressed under eyestalk ablation conditions.
A total of 58,582 unigenes were constructed from 157,168 contigs with SOAPdenovo. A BlastX search against the NCBI Nr database identified 21,678 unigenes with an E-value higher than 10−5. Using the BLAST2Go and BlastAll software programs, 6,883 unigenes (11.75% of the total) were annotated to the Gene Ontology (GO) database, 7,386 (12.6%) unigenes were classified into 25 Clusters of Orthologous Groups of Proteins (COGs), 16,200 (27.7%) unigenes were assigned to 242 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and1,846 unigenes were matched to “metabolism pathways”. The DGE analysis revealed that 1,416 unigenes were significantly differentially expressed in the hepatopancreas, of which 890 unigenes were up-regulated and 526 unigenes were down-regulated. Of the differentially expressed genes, 382 unigenes were annotated and 63 were classified into metabolism pathways. The results of the real-time polymerase chain reaction (PCR) analysis of four unigenes related to carbohydrate metabolism were consistent with those obtained from the DGE analysis, which demonstrates that the sequencing data were satisfactory for further gene expression analyses.
This paper reported the transcriptom of the eyestalk, Y-organ, and hepatopancreas from E. sinensis. DGE analysis provided the different expressed genes of the metabolism processes in hepatopancreas that are affected by eyestalk ablation. These findings will facilitate further investigations on the mechanisms of the metabolism of organic substances during development and reproduction in crustaceans.
PMCID: PMC3995808  PMID: 24755618
15.  Genome-Wide Linkage Analysis and Association Study Identifies Loci for Polydactyly in Chickens 
G3: Genes|Genomes|Genetics  2014;4(6):1167-1172.
Polydactyly occurs in some chicken breeds, but the molecular mechanism remains incompletely understood. Combined genome-wide linkage analysis and association study (GWAS) for chicken polydactyly helps identify loci or candidate genes for the trait and potentially provides further mechanistic understanding of this phenotype in chickens and perhaps other species. The linkage analysis and GWAS for polydactyly was conducted using an F2 population derived from Beijing-You chickens and commercial broilers. The results identified two QTLs through linkage analysis and seven single-nucleotide polymorphisms (SNPs) through GWAS, associated with the polydactyly trait. One QTL located at 35 cM on the GGA2 was significant at the 1% genome-wise level and another QTL at the 1% chromosome-wide significance level was detected at 39 cM on GGA19. A total of seven SNPs, four of 5% genome-wide significance (P < 2.98 × 10−6) and three of suggestive significance (5.96 × 10−5) were identified, including two SNPs (GGaluGA132178 and Gga_rs14135036) in the QTL on GGA2. Of the identified SNPs, the eight nearest genes were sonic hedgehog (SHH), limb region 1 homolog (mouse) (LMBR1), dipeptidyl-peptidase 6, transcript variant 3 (DPP6), thyroid-stimulating hormone, beta (TSHB), sal-like 4 (Drosophila) (SALL4), par-6 partitioning defective 6 homolog beta (Caenorhabditis elegans) (PARD6B), coenzyme Q5 (COQ5), and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, etapolypeptide (YWHAH). The GWAS supports earlier reports of the importance of SHH and LMBR1 as regulating genes for polydactyly in chickens and other species, and identified others, most of which have not previously been associated with limb development. The genes and associated SNPs revealed here provide detailed information for further exploring the molecular and developmental mechanisms underlying polydactyly.
PMCID: PMC4065260  PMID: 24752238
chicken; polydactyly; linkage analysis; GWAS; candidate genes
16.  Disruption of the Homogentisate Solanesyltransferase Gene Results in Albino and Dwarf Phenotypes and Root, Trichome and Stomata Defects in Arabidopsis thaliana 
PLoS ONE  2014;9(4):e94031.
Homogentisate solanesyltransferase (HST) plays an important role in plastoquinone (PQ) biosynthesis and acts as the electron acceptor in the carotenoids and abscisic acid (ABA) biosynthesis pathways. We isolated and identified a T-DNA insertion mutant of the HST gene that displayed the albino and dwarf phenotypes. PCR analyses and functional complementation also confirmed that the mutant phenotypes were caused by disruption of the HST gene. The mutants also had some developmental defects, including trichome development and stomata closure defects. Chloroplast development was also arrested and chlorophyll (Chl) was almost absent. Developmental defects in the chloroplasts were consistent with the SDS-PAGE result and the RNAi transgenic phenotype. Exogenous gibberellin (GA) could partially rescue the dwarf phenotype and the root development defects and exogenous ABA could rescue the stomata closure defects. Further analysis showed that ABA and GA levels were both very low in the pds2-1 mutants, which suggested that biosynthesis inhibition by GAs and ABA contributed to the pds2-1 mutants' phenotypes. An early flowering phenotype was found in pds2-1 mutants, which showed that disruption of the HST gene promoted flowering by partially regulating plant hormones. RNA-sequencing showed that disruption of the HST gene resulted in expression changes to many of the genes involved in flowering time regulation and in the biosynthesis of PQ, Chl, GAs, ABA and carotenoids. These results suggest that HST is essential for chloroplast development, hormone biosynthesis, pigment accumulation and plant development.
PMCID: PMC3990575  PMID: 24743244
17.  Ribosomal Protein S29 Regulates Metabolic Insecticide Resistance through Binding and Degradation of CYP6N3 
PLoS ONE  2014;9(4):e94611.
Many diseases are transmitted by mosquitoes, including malaria, dengue fever, yellow fever, filariasis, and West Nile fever. Chemical control plays a major role in managing mosquito-borne diseases. However, excessive and continuous application of insecticides has caused the development of insecticide resistance in many species including mosquito, and this has become the major obstacle to controlling mosquito-borne diseases. Insecticide resistance is the result of complex polygenic inheritance, and the mechanisms are not well understood. Ribosomal protein RPS29 was found to be associated with DM resistance in our previous study. In this study, we aim to further investigate the involvement of RPS29 in deltamethrin resistance.
Methodology and Principal Findings
In this study, tandem affinity purification was used to identify proteins that can interact with RPS29. Among the candidate proteins, CYP6N3, a member of the CYP450 superfamily, was identified, and binding to RPS29 was confirmed in vitro and in vivo by GST pull-down and immunofluorescence. CCK-8 assay was used to investigate the RPS29-CTP6N3 interaction in relation to DM resistance. CYP6N3 overexpression significantly enhanced DM resistance and insect cell viability, but this was reversed by RPS29 overexpression. Western blot was used to study the mechanism of interaction between RPS29 and CYP6N3. RPS29 increases CYP6N3 protein degradation through the proteasome.
Conclusions and Significance
These observations indicate that CYP6N3, a novel RPS29-interacting partner, could stimulate deltamethrin resistance in mosquito cells and RPS29 overexpression targeted CYP6N3 for proteosomal degradation, abrogating the CYP6N3-associated resistence to deltamethrin. Our findings provide a novel mechanism associated with CYP450s mediated DM resistance.
PMCID: PMC3984272  PMID: 24728095
18.  Associations of oxidative balance-related exposures with incident, sporadic colorectal adenoma according to antioxidant enzyme genotypes 
Annals of epidemiology  2013;23(4):223-226.
Previous research found inverse associations between oxidative balance and risk of colorectal adenoma. However, these measures were limited to extrinsic (dietary and lifestyle) exposures and did not account for intrinsic factors, specifically antioxidant enzymes responsible for cellular defense against oxidative stress. We investigated whether the association between an oxidative balance score (OBS) and colorectal adenoma may vary according to polymorphisms in genes that encode three antioxidant enzymes: manganese superoxide dismutase (SOD2), catalase (CAT), and glutathione-S-transferase P1 (GSTP1).
Using data pooled from three colonoscopy-based case-control studies of incident, sporadic colorectal adenoma, we constructed an OBS reflecting pro- and anti-oxidant exposures. We used multivariable logistic regression to assess whether the association between the OBS and colorectal adenoma differed according to polymorphisms in the genes encoding the antioxidant enzymes.
The OBS was inversely associated with colorectal adenoma, adenoma risk was not associated with the genetic polymorphisms, and there was no consistent pattern of effect modification by individual genotypes or combined gene scores.
Variations in the antioxidant enzyme genes SOD2, CAT, and GSTP1 do not appear to substantially modify associations of environmental exposures related to oxidative balance with risk for sporadic colorectal adenoma.
PMCID: PMC3605204  PMID: 23290999
19.  A Genome-Wide Association Study of Depressive Symptoms 
Hek, Karin | Demirkan, Ayse | Lahti, Jari | Terracciano, Antonio | Teumer, Alexander | Cornelis, Marilyn C. | Amin, Najaf | Bakshis, Erin | Baumert, Jens | Ding, Jingzhong | Liu, Yongmei | Marciante, Kristin | Meirelles, Osorio | Nalls, Michael A. | Sun, Yan V. | Vogelzangs, Nicole | Yu, Lei | Bandinelli, Stefania | Benjamin, Emelia J. | Bennett, David A. | Boomsma, Dorret | Cannas, Alessandra | Coker, Laura H. | de Geus, Eco | De Jager, Philip L. | Diez-Roux, Ana V. | Purcell, Shaun | Hu, Frank B. | Rimma, Eric B. | Hunter, David J. | Jensen, Majken K. | Curhan, Gary | Rice, Kenneth | Penman, Alan D. | Rotter, Jerome I. | Sotoodehnia, Nona | Emeny, Rebecca | Eriksson, Johan G. | Evans, Denis A. | Ferrucci, Luigi | Fornage, Myriam | Gudnason, Vilmundur | Hofman, Albert | Illig, Thomas | Kardia, Sharon | Kelly-Hayes, Margaret | Koenen, Karestan | Kraft, Peter | Kuningas, Maris | Massaro, Joseph M. | Melzer, David | Mulas, Antonella | Mulder, Cornelis L. | Murray, Anna | Oostra, Ben A. | Palotie, Aarno | Penninx, Brenda | Petersmann, Astrid | Pilling, Luke C. | Psaty, Bruce | Rawal, Rajesh | Reiman, Eric M. | Schulz, Andrea | Shulman, Joshua M. | Singleton, Andrew B. | Smith, Albert V. | Sutin, Angelina R. | Uitterlinden, André G. | Völzke, Henry | Widen, Elisabeth | Yaffe, Kristine | Zonderman, Alan B. | Cucca, Francesco | Harris, Tamara | Ladwig, Karl-Heinz | Llewellyn, David J. | Räikkönen, Katri | Tanaka, Toshiko | van Duijn, Cornelia M. | Grabe, Hans J. | Launer, Lenore J. | Lunetta, Kathryn L. | Mosley, Thomas H. | Newman, Anne B. | Tiemeier, Henning | Murabito, Joanne
Biological psychiatry  2013;73(7):10.1016/j.biopsych.2012.09.033.
Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms.
In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p < 1 × 10−5) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies.
The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05 × 10−7). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19 × 10−3). This 5q21 region reached genome-wide significance (p = 4.78 × 10−8) in the overall meta-analysis combining discovery and replication studies (n = 51,258).
The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.
PMCID: PMC3845085  PMID: 23290196
Center for Epidemiologic Studies Depression Scale; CHARGE consortium; depression; depressive symptoms; genetics; genome-wide association study; meta-analysis
20.  GPER-mediated proliferation and estradiol production in breast cancer-associated fibroblasts 
Endocrine-Related Cancer  2014;21(2):355-369.
Cancer-associated fibroblasts (CAFs) are crucial co-mediators of breast cancer progression. Estrogen is the predominant driving force in the cyclic regulation of the mammary extracellular matrix, thus potentially affecting the tumor-associated stroma. Recently, a third estrogen receptor, estrogen (G-protein-coupled) receptor (GPER), has been reported to be expressed in breast CAFs. In this study, GPER was detected by immunohistochemical analysis in stromal fibroblasts of 41.8% (59/141) of the primary breast cancer samples. GPER expression in CAFs isolated from primary breast cancer tissues was confirmed by immunostaining and RT-PCR analyses. Tamoxifen (TAM) in addition to 17β-estradiol (E2) and the GPER agonist G1 activated GPER, resulting in transient increases in cell index, intracellular calcium, and ERK1/2 phosphorylation. Furthermore, TAM, E2, and G1 promoted CAF proliferation and cell-cycle progression, both of which were blocked by GPER interference, the selective GPER antagonist G15, the epidermal growth factor receptor (EGFR) inhibitor AG1478, and the ERK1/2 inhibitor U0126. Importantly, TAM as well as G1 increased E2 production in breast CAFs via GPER/EGFR/ERK signaling when the substrate of E2, testosterone, was added to the medium. GPER-induced aromatase upregulation was probably responsible for this phenomenon, as TAM- and G1-induced CYP19A1 gene expression was reduced by GPER knockdown and G15, AG1478, and U0126 administration. Accordingly, GPER-mediated CAF-dependent estrogenic effects on the tumor-associated stroma are conceivable, and CAF is likely to contribute to breast cancer progression, especially TAM resistance, via a positive feedback loop involving GPER/EGFR/ERK signaling and E2 production.
PMCID: PMC3959763  PMID: 24481325
CAF; GPER; tamoxifen resistance; breast cancer
21.  Sexually Dimorphic Expression of vasa Isoforms in the Tongue Sole (Cynoglossus semilaevis) 
PLoS ONE  2014;9(3):e93380.
The vasa gene encodes an ATP-dependent RNA helicase of the DEAD box protein family that functions in a broad range of molecular events involving duplex RNA. In most species, the germline specific expression of vasa becomes a molecular marker widely used in the visualization and labeling of primordial germ cells (PGCs) and a tool in surrogate broodstock production through PGC transplantation. The vasa gene from tongue sole (Cynoglossus semilaevis) was characterized to promote the development of genetic breeding techniques in this species. Three C. semilaevis vasa transcripts were isolated, namely vas-l, vas-m, and vas-s. Quantitative real-time PCR results showed that C. semilaevis vasa transcripts were prevalently expressed in gonads, with very weak expression of vas-s in other tissues. Embryonic development expression profiles revealed the onset of zygotic transcription of vasa mRNAs and the maternal deposit of the three transcripts. The genetic ZW female juvenile fish was discriminated from genetic ZZ males by a pair of female specific primers. Only the expression of vas-s can be observed in both sexes during early gonadal differentiation. Before PGCs started mitosis, there was sexually dimorphic expression of vas-s with the ovary showing higher levels and downward trend. The results demonstrated the benefits of vasa as a germline specific marker for PGCs during embryonic development and gonadal differentiation. This study lays the groundwork for further application of C. semilaevis PGCs in fish breeding.
PMCID: PMC3966880  PMID: 24671276
22.  Application of three-dimensionally area-selective atomic layer deposition for selectively coating the vertical surfaces of standing nanopillars 
Scientific Reports  2014;4:4458.
We describe a strategy for selectively coating the vertical surfaces of standing nanopillars using area-selective atomic layer deposition (ALD). Hydrophobic self-assembled monolayers (SAMs) are utilised to selectively inhibit the coating of oxides on the modified horizontal regions to ensure that only the vertical surfaces of vertical standing nanorods are coated using ALD processes. This method makes it possible to fabricate vertical nanodevices using a simple process of depositing oxide layer on a vertical surface, and can also be applied to the area-selective surface passivation of other standing structures.
PMCID: PMC3964512  PMID: 24662775
23.  Monosodium Urate and Tumor Necrosis Factor-α Increase Apoptosis in Human Chondrocyte Cultures 
Monosodium urate and tumor necrosis factor-α, are two potent mediators of separate inflammatory response pathways in arthritic joints where inflammation may be accompanied by the loss of chondrocyte vitality via apoptosis. To address this possibility in vitro, chondrocyte cultures were employed to determine the extent to which monosodium urate and recombinant TNF-α altered the frequency of apoptotic chondrocytes. Apoptosis as a function of the activation of p38 kinase, C-Jun-terminal kinase, signal transducer and activator of transcription-3 and/or the activity of xanthine oxidase was also studied. Using normal human chondrocytes, monosodium urate or recombinant tumor necrosis factor-α increased the frequency of apoptosis and activity of xanthine oxidase. However, the xanthine oxidase-specific inhibitor, febuxostat, failed to blunt this response. Monosodium urate, tumor necrosis factor-α or the Janus kinase inhibitor, AG-490, increased the frequency of apoptotic nuclei in macroaggregate pellet cultures initiated from juvenile human chondrocytes, but not in pellet cultures derived from mesenchymal stem cells. In OA chondrocytes, activation of p38, C-Jun-NH2-kinase and signal transducer and activator of transcription-3 preceded apoptosis. Activation of signal transducer and activator of transcription-3 also was seen in pellet cultures initiated from juvenile chondrocytes and MSCs incubated with MSU, recombinant tumor necrosis factor-α or febuxostat, but apoptosis was increased only in the pellet cultures derived from juvenile chondrocytes. Although AG-490 or the combination of AG-490 and febuxostat inhibited signal transducer and activator of transcription-3 activation, apoptosis was unaffected. These results showed that recombinant tumor necrosis factor-α, monosodium urate and AG-490 increased apoptosis in normal human chondrocytes, OA chondrocytes and human juvenile chondrocyte pellet cultures, but not in chondrocyte pellet cultures initiated from MSCs. The increased frequency of apoptotic chondrocytes in response to recombinant tumor necrosis factor-α or monosodium urate was not dependent on either activation of STAT3 or the activity of XO.
PMCID: PMC3959644  PMID: 24660115
Apoptosis; Arthritis; Chondrocytes; Human; Monosodium urate; Tumor Necrosis Factor-α (TNF-α)
24.  C-Jun NH2 terminal kinase (JNK) is an essential mediator of Toll-like receptor 2-induced corneal inflammation 
Journal of leukocyte biology  2008;83(4):991-997.
TLRs play an important role in the host inflammatory response to bacteria and bacterial products by activating a cascade of intracellular events leading to production of proinflammatory and chemotactic cytokines. To determine the role of MAPKs in TLR- induced corneal inflammation, we stimulated human corneal epithelial (HCE) cells with TLR2 ligands, tripalmitoyl-S-glycero-Cys-(Lys)4 (Pam3Cys) or inactivated Staphylococcus aureus, and examined the time course of expression of MAPKs and the effect of MAPK inhibition on IkBα degradation and CXC chemokine production. We found that S. aureus and Pam3Cys stimulate phosphorylation of JNK, p38 MAPK, and ERK within 4 h and that blockade of JNK, but not p38 or ERK phosphorylation, had an inhibitory effect on IkBα degradation and CXC chemokine production. To determine if JNK is also important in TLR2-induced corneal inflammation in vivo, we examined JNK1−/− mice and pharmacological inhibitors in a murine model of TLR2-induced corneal inflammation which is characterized by neutrophil recruitment to the corneal stroma and development of corneal haze. We found that corneal inflammation was significantly impaired in JNK1−/− mice compared with control mice, and in mice treated with the JNK inhibitor compared with vehicle control. Taken together with results from HCE cells, these findings demonstrate that JNK has an essential role in TLR2-induced corneal inflammation.
PMCID: PMC3959745  PMID: 18218857
TLR2; S. aureus; corneal epithelial cells; inflammation; MAP kinase; neutrophil; chemokines; innate immunity
25.  Plasma microRNA-320, microRNA-let-7e and microRNA-21 as novel potential biomarkers for the detection of retinoblastoma 
Biomedical Reports  2014;2(3):424-428.
Retinoblastoma (RB) is a childhood malignancy caused by inactivation of the RB gene, with neuron-specific enolase (NSE) levels considered as its diagnostic marker. MicroRNAs (miRNAs) have been proven to play a significant role in multiple physiological and pathological processes and several miRNAs were identified as tumor biomarkers in recent studies. In the present study, 65 plasma samples were collected from RB patients and 65 samples from healthy individuals to serve as controls. The miRNA levels were measured via quantitative reverse transcription-polymerase chain reaction and their association with RB was assessed by statistical data analysis and receiver operating characteristic curves. Plasma miRNA (miR)-320, miR-let-7e and miR-21 levels were downregulated in the patient samples, the areas under the curves (AUCs) were 0.548–0.660, whereas the AUCs of combined classifiers were ≥0.990. The plasma miRNA levels, particularly of miR-320, were found to be of value in RB diagnosis and may be considered as novel diagnostic biomarkers.
PMCID: PMC3990201  PMID: 24748987
retinoblastoma; microRNA; plasma; biomarker

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