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1.  High throughput immunosenor based on multi-label strategy and a novel array electrode 
Scientific Reports  2014;4:4747.
Accurate prediction of a particular cancer can be achieved by measuring multiplex biomarkers. Traditional methods for multi-biomarkers detection are either multi-spots assay with chip or multi-label assay with one detection spot. However, the detection throughput of these two approaches is limited by the substrate area and the numbers of available label respectively. To solve this problem, in the present study, an immunoassay was firstly prepared by combining multi-label strategy and multi-spot assay with a novel array electrode for simultaneous detection of six biomarkers for hepatocellular carcinoma (HCC). The detection throughput of the proposed method was doubled in comparison with traditional multi-spots assay (one target protein was detected on each analytic spot), which could greatly enhance the sensitivity and specificity of HCC diagnosis. This detection model may serve as the starting point for high throughput of multianalyte assay.
doi:10.1038/srep04747
PMCID: PMC3996466  PMID: 24756073
2.  Comparative profiling of miRNA expression of lung adenocarcinoma cells in two-dimensional and three-dimensional cultures 
Gene  2012;511(2):143-150.
Three-dimensional organotypic culture using reconstituted basement membrane matrix (rBM 3-D) is an invaluable tool to characterize morphogenesis of epithelial cells and to elucidate the tumor-modulating actions of extracellular matrix. microRNAs (miRNA) are a novel class of tumor modulating genes. A substantial amount of investigation of miRNAs in cancer is carried out using monolayer 2-D culture on plastic substratum, which lacks a consideration of the matrix-mediated regulation of miRNAs. In the current study we compared the expression of miRNAs in rBM 3-D and 2-D cultures of two lung adenocarcinoma cell lines. Our findings revealed a profound difference in miRNA profiles between 2-D and rBM 3-D cultures of lung adenocarcinoma cells. The rBM 3-D culture-specific miRNA profile was highlighted with higher expression of the tumor suppressive miRNAs (i.e., miR-200 family) and lower expression of the oncogenic miRNAs (i.e., miR-17~92 cluster and miR-21) than that of 2-D culture. Moreover, the expression pattern of miR-17, miR-21, and miR-200a in rBM 3-D culture correlated with the expression of their targets and acinar morphogenesis, a differentiation behavior of lung epithelial cells in rBM 3-D culture. Over-expression of miR-21 suppressed its target PTEN and disrupted acinar morphogenesis. In summary, we provide the first miRNA profile of lung adenocarcinoma cells in rBM 3-D culture with respect to acinar morphogenesis. These results indicate that rBM 3-D culture is essential to a comprehensive understanding of the miRNA biology in lung epithelial cells pertinent to lung adenocarcinoma.
doi:10.1016/j.gene.2012.09.093
PMCID: PMC3969815  PMID: 23036707
microRNA; three-dimensional organotypic culture; extracellular matrix; lung epithelial cells; morphogenesis
3.  Lymph Node Ratio for Postoperative Staging of Laryngeal Squamous Cell Carcinoma with Lymph Node Metastasis 
PLoS ONE  2014;9(1):e87037.
Background
Lymph node metastasis has a significant impact on laryngeal cancer prognosis. The role of lymph node ratio (LNR, ratio of metastatic to examined nodes) in the staging of laryngeal cancer was not reported.
Patients and Methods
Records of laryngeal cancer patients with lymph node involvement from Surveillance, Epidemiology, and End Results database (SEER, training set, N = 1963) and Fudan University Shanghai Cancer Center (FDSCC, validating set, N = 27) were analyzed for the prognostic value of LNR. Kaplan–Meier survival estimates, the Log-rank χ2 test and Cox proportional hazards model were used for univariate and multivariate analysis. Optimal LNR cutoff points were identified by X-tile.
Results
Optimal LNR cutoff points classified patients into three risk groups R1 (≤0.09), R2 (0.09–0.20) and R3 (>0.20), corresponding to 5-year cause-specific survival and overall survival in SEER patients of 55.1%, 40.2%, 28.8% and 43.1%, 31.5%, 21.8%, 2-year disease free survival and disease specific survival in FDSCC patients of 74.1%, 62.5%, 50.0%, and 67.7%, 43.2%, 25.0%, respectively. R3 stratified more high risk patients than N3 with the same survival rate, and R classification clearly separated N2 patients to 3 risk groups and N1 patients to 2 risk groups (R1–2 and R3).
Conclusions
R classification is a significant prognostic factor of laryngeal cancer and should be used as a complementary staging system of N classification.
doi:10.1371/journal.pone.0087037
PMCID: PMC3903600  PMID: 24475216
4.  3DScapeCS: application of three dimensional, parallel, dynamic network visualization in Cytoscape 
BMC Bioinformatics  2013;14:322.
Background
The exponential growth of gigantic biological data from various sources, such as protein-protein interaction (PPI), genome sequences scaffolding, Mass spectrometry (MS) molecular networking and metabolic flux, demands an efficient way for better visualization and interpretation beyond the conventional, two-dimensional visualization tools.
Results
We developed a 3D Cytoscape Client/Server (3DScapeCS) plugin, which adopted Cytoscape in interpreting different types of data, and UbiGraph for three-dimensional visualization. The extra dimension is useful in accommodating, visualizing, and distinguishing large-scale networks with multiple crossed connections in five case studies.
Conclusions
Evaluation on several experimental data using 3DScapeCS and its special features, including multilevel graph layout, time-course data animation, and parallel visualization has proven its usefulness in visualizing complex data and help to make insightful conclusions.
doi:10.1186/1471-2105-14-322
PMCID: PMC3835703  PMID: 24225050
5.  Induction of long intergenic non-coding RNA HOTAIR in lung cancer cells by type I collagen 
Background
The tumor microenvironment is a crucial determinant in tumor progression. Interstitial extracellular matrix (ECM), such as type I collagen (Col-1), is aberrantly enriched in the tumor microenvironment and promotes tumor progression. Long intergenic non-coding RNAs (lincRNA) are a new family of regulatory RNAs that modulate fundamental cellular processes via diverse mechanisms.
Findings
We investigated whether the expression of lincRNAs was regulated by the tumor promoting Col-1. In a three-dimensional organotypic culture model using the reconstituted basement membrane ECM Matrigel (rBM 3-D), supplementation of Col-1 disrupted acini, a differentiation feature of well-differentiated lung adenocarcinoma cells, and concurrently induced the expression of a tumor-promoting lincRNA, HOX transcript antisense RNA (HOTAIR). Induction of HOTAIR by Col-1 was diminished by a neutralizing antibody against the Col-1 receptor α2β1 integrin. Col-1 activates the expression of a reporter gene controlled by the human HOTAIR promoter. Moreover the expression of HOTAIR and Col-1 was concurrently up-regulated in human non-small cell lung cancer.
Conclusions
Our findings indicate that tumor-promoting Col-1 up-regulates the expression of HOTAIR in NSCLC cells. These initial results warrant further investigation of HOTAIR and other lincRNA genes in lung tumorigenesis.
doi:10.1186/1756-8722-6-35
PMCID: PMC3655931  PMID: 23668363
HOTAIR; lincRNA; Type I collagen; Three-dimensional ogranotypic culture
6.  ContigScape: a Cytoscape plugin facilitating microbial genome gap closing 
BMC Genomics  2013;14:289.
Background
With the emergence of next-generation sequencing, the availability of prokaryotic genome sequences is expanding rapidly. A total of 5,276 genomes have been released since 2008, yet only 1,692 genomes were complete. The final phase of microbial genome sequencing, particularly gap closing, is frequently the rate-limiting step either because of complex genomic structures that cause sequence bias even with high genomic coverage, or the presence of repeat sequences that may cause gaps in assembly.
Results
We have developed a Cytoscape plugin to facilitate gap closing for high-throughput sequencing data from microbial genomes. This plugin is capable of interactively displaying the relationships among genomic contigs derived from various sequencing formats. The sequence contigs of plasmids and special repeats (IS elements, ribosomal RNAs, terminal repeats, etc.) can be displayed as well.
Conclusions
Displaying relationships between contigs using graphs in Cytoscape rather than tables provides a more straightforward visual representation. This will facilitate a faster and more precise determination of the linkages among contigs and greatly improve the efficiency of gap closing.
doi:10.1186/1471-2164-14-289
PMCID: PMC3651407  PMID: 23627759
ContigScape; Repeat contig; Microbial; Visualization; Linkage; Gap closing
7.  Complete Genome Sequence of Amycolatopsis mediterranei S699 Based on De Novo Assembly via a Combinatorial Sequencing Strategy 
Journal of Bacteriology  2012;194(20):5699-5700.
The genome of Amycolatopsis mediterranei S699 was resequenced and assembled de novo. By comparing the sequences of S699 previously released and that of A. mediterranei U32, about 10 kb of major indels was found to differ between the two S699 genomes, and the differences are likely attributable to their different assembly strategies.
doi:10.1128/JB.01295-12
PMCID: PMC3458657  PMID: 23012281
8.  Revised Genome Sequence of Burkholderia thailandensis MSMB43 with Improved Annotation 
Journal of Bacteriology  2012;194(17):4749-4750.
There is growing interest in discovery of novel bioactive natural products from Burkholderia thailandensis. Here we report a significantly improved genome sequence and reannotation of Burkholderia thailandensis MSMB43, which will facilitate the discovery of new natural products through genome mining and studies of the metabolic versatility of this bacterium.
doi:10.1128/JB.00931-12
PMCID: PMC3415525  PMID: 22887659
9.  Association between the rs2910164 Polymorphism in Pre-Mir-146a Sequence and Thyroid Carcinogenesis 
PLoS ONE  2013;8(2):e56638.
Background
Rs2910164, a Single nucleotide polymorphism (SNP) located in the precursor microRNA sequence of miR-146a, is the only MicroRNA sequence SNP studied in papillary thyroid cancer (PTC). Association studies had been performed in US and UK-Northern European populations, but results were inconsistence. This study evaluated the association between rs2910164 and the risk of PTC as well as benign thyroid tumor (BN), and examined the clinicopathological characteristics of PTC and BN for different genotypes.
Methods
This case-control study genotyped rs2910164 in 753 PTCs, 484 BNs and 760 controls in a Chinese Han population. Clinicopathological and genetic data were collected and compared. Multivariate logistic regression was performed to calculate adjusted odds ratios (ORs).
Results
There were no differences in rs2910164 genotype distributions between the three groups. PTC cases with three genotypes (CC, CG, GG) had similar clinicopathological characteristics except the existence of “para-cancer” BN (PTC/BN, P = 0.006). PTC/BN patients were older (P = 0.009), and had smaller cancer lesions (P<0.001), lower serum thyrotropin levels (1.82±1.42 vs. 2.21±1.74, P = 0.04), and lower rates of level VI lymph node metastasis (20.8% vs. 52.7%, P<0.001) and lateral neck lymph node metastasis (11.5% vs. 23.0%, P = 0.011) compared with PTC only. Then we supposed a possible progression from BN to PTC which may involve rs2910164 in and performed a multivariate logistic regression analysis of PTC/BN and BN cases to determine risk factors of this progression. Results showed that the rs2910164 GG homozygote (OR = 2.25, 95% CI 1.22–4.14, P = 0.01) was the only risk factor in this study.
Conclusion
Rs2910164 was not associated with increased risk of PTC and BN in Chinese patients, but may play a latent role in the transformation from BN to PTC.
doi:10.1371/journal.pone.0056638
PMCID: PMC3579867  PMID: 23451063
10.  Src-mediated morphology transition of lung cancer cells in three-dimensional organotypic culture 
A fribotic tumor microenvironment promotes progression of cancer. In this study, we utilize a reconstituted basement membrane mimics Matrigel based three-dimensional organotypic culture (rBM 3-D) to investigate the mechanisms that mediate the tumor promoting effects of the fibrogenic mediators TGF-β1 and type I collagen (Col-1) on lung adenocarcinoma cells. Similar to normal alveolar epithelial cells, the well-differentiated lung adenocarcinoma cells in rBM 3-D culture undergo acinar morphogeneis that features polarized epithelial cell spheres with a single central lumen. Either TGF-β1 or Col-1 modestly distorts acinar morphogenesis. On the other hand, TGF-β1 and Col-1 synergistically induce a transition from acinar morphology into stellate morphology that is characteristic of invasive and metastatic cancer cells. Inhibition of the Src kinase activity abrogates induction of stellate morphology, activation of Akt and mTOR, and the expression of tumor promoting genes by TGF-β1 and Col-1. To a similar extent, pharmacological inhibition of mTOR abrogates the cellular responses to TGF-β1 and Col-1. In summary, we demonstrate that TGF-β1 and Col-1 promote stellate morphogenesis of lung cancer cells. Our findings further suggest that the Src-Akt-mTOR axis mediates stellate morphogenesis. These findings also indicate that rBM 3-D culture can serve as an ideal platform for swift and cost-effective screening of therapeutic candidates at the interface of the tumor and its microenvironment.
doi:10.1186/1475-2867-13-16
PMCID: PMC3626791  PMID: 23409704
TGF-β1; Src; Type I collagen; Three-dimensional culture; Extracellular matrix
11.  The clinical features of papillary thyroid cancer in Hashimoto’s thyroiditis patients from an area with a high prevalence of Hashimoto’s disease 
BMC Cancer  2012;12:610.
Background
The goal of this study was to identify the clinicopathological factors of co-existing papillary thyroid cancer (PTC) in patients with Hashimoto’s thyroiditis (HT) and provide information to aid in the diagnosis of such patients.
Methods
This study included 6109 patients treated in a university-based tertiary care cancer hospital over a 3-year period. All of the patients were categorised based on their final diagnosis. Several clinicopathological factors, such as age, gender, nodular size, invasive status, central compartment lymph node metastasis (CLNM) and serum thyroid-stimulating hormone (TSH) level, were compared between the various groups of patients.
Results
There were 653 patients with a final diagnosis of HT. More PTC was found in those with HT (58.3%; 381 of 653) than those without HT (2416 of 5456; 44.3%; p < 0.05). The HT patients with co-occurring PTC were more likely to be younger, be female, have smaller nodules and have higher TSH levels than those without PTC. A multivariate analysis indicated that the presence of HT and higher TSH levels were risk factors for a diagnosis of PTC. In the PTC patients, the presence of HT or another benign nodule was a protective factor for CLNM, whereas no significant association was found for TSH levels.
Conclusion
PTC and HT have a close relationship in this region of highly prevalent HT disease. Based on the results of our study, we hypothesise that long-term HT leads to elevated serum TSH, which is the real risk factor for thyroid cancer.
doi:10.1186/1471-2407-12-610
PMCID: PMC3547693  PMID: 23256514
Papillary thyroid carcinoma; Thyroid-stimulating hormone; Hashimoto’s thyroiditis
12.  Cloning and characterization of a novel 2-ketoisovalerate reductase from the beauvericin producer Fusarium proliferatum LF061 
BMC Biotechnology  2012;12:55.
Background
The ketoisovalerate reductase (EC 1.2.7.7 ) is required for the formation of beauvericin via the nonribosomal peptide synthetase biosynthetic pathway. It catalyzes the NADPH-specific reduction of ketoisovaleric acid to hydroxyisovalerate. However, little is known about the bioinformatics’ data about the 2-Kiv reductase in Fusarium. To date, heterologous production of the gene KivRFp from Fusarium has not been achieved.
Results
The KivRFp gene was subcloned and expressed in Escherichia coli BL21 using the pET expression system. The gene KivRFp contained a 1,359 bp open reading frame (ORF) encoding a polypeptide of 452 amino acids with a molecular mass of 52 kDa. Sequence analysis indicated that it showed 61% and 52% amino acid identities to ketoisovalerate reductase from Beauveria bassiana ATCC 7159 (ACI30654) and Metarhizium acridum CQMa 102 (EFY89891), respectively; and several conserved regions were identified, including the putative nucleotide-binding signature site, GXGXXG, a catalytic triad (Glu405, Asn184, and Lys285). The KivRFp exhibited the highest activity at 35°C and pH 7.5 respectively, by reduction of ketoisovalerate. It also exhibited the high level of stability over wide temperature and pH spectra and in the presence of metal ions or detergents.
Conclusions
A new ketoisovalerate reductase KivRFp was identified and characterized from the depsipeptide-producing fungus F. proliferatum. KivRFp has been shown to have useful properties, such as moderate thermal stability and broad pH optima, and may serve as the starting points for future protein engineering and directed evolution, towards the goal of developing efficient enzyme for downstream biotechnological applications.
doi:10.1186/1472-6750-12-55
PMCID: PMC3478992  PMID: 22916830
2-Kiv Reductase; Beauvericin; Fusarium proliferatum LF061
13.  Magnetic Field Is the Dominant Factor to Induce the Response of Streptomyces avermitilis in Altered Gravity Simulated by Diamagnetic Levitation 
PLoS ONE  2011;6(10):e24697.
Background
Diamagnetic levitation is a technique that uses a strong, spatially varying magnetic field to simulate an altered gravity environment, as in space. In this study, using Streptomyces avermitilis as the test organism, we investigate whether changes in magnetic field and altered gravity induce changes in morphology and secondary metabolism. We find that a strong magnetic field (12T) inhibit the morphological development of S. avermitilis in solid culture, and increase the production of secondary metabolites.
Methodology/Principal Findings
S. avermitilis on solid medium was levitated at 0 g*, 1 g* and 2 g* in an altered gravity environment simulated by diamagnetic levitation and under a strong magnetic field, denoted by the asterix. The morphology was obtained by electromicroscopy. The production of the secondary metabolite, avermectin, was determined by OD245 nm. The results showed that diamagnetic levitation could induce a physiological response in S. avermitilis. The difference between 1 g* and the control group grown without the strong magnetic field (1 g), showed that the magnetic field was a more dominant factor influencing changes in morphology and secondary metabolite production, than altered gravity.
Conclusion/Significance
We have discovered that magnetic field, rather than altered gravity, is the dominant factor in altered gravity simulated by diamagnetic levitation, therefore care should to be taken in the interpretation of results when using diamagnetic levitation as a technique to simulate altered gravity. Hence, these results are significant, and timely to researchers considering the use of diamagnetic levitation to explore effects of weightlessness on living organisms and on physical phenomena.
doi:10.1371/journal.pone.0024697
PMCID: PMC3198441  PMID: 22039402
14.  Assessing the Potential of an Induced-Mutation Strategy for Avermectin Overproducers▿ § 
Applied and Environmental Microbiology  2010;76(13):4583-4586.
Mutant libraries of avermectin-producing Streptomyces avermitilis strains were constructed by different mutagenesis strategies. A metric was applied to assess the mutation spectrum by calculating the distribution of average phenotypic distance of each population. The results showed for the first time that a microgravity environment could introduce larger phenotype distribution and diversity than UV and N-methyl-N-nitro-N-nitrosoguanidine (NTG) could.
doi:10.1128/AEM.01682-09
PMCID: PMC2897423  PMID: 20453119
15.  Thy-1 Attenuates TNF-α-Activated Gene Expression in Mouse Embryonic Fibroblasts via Src Family Kinase 
PLoS ONE  2010;5(7):e11662.
Heterogeneous surface expression of Thy-1 in fibroblasts modulates inflammation and may thereby modulate injury and repair. As a paradigm, patients with idiopathic pulmonary fibrosis, a disease with pathologic features of chronic inflammation, demonstrate an absence of Thy-1 immunoreactivity within areas of fibrotic activity (fibroblast foci) in contrast to the predominant Thy-1 expressing fibroblasts in the normal lung. Likewise, Thy-1 deficient mice display more severe lung fibrosis in response to an inflammatory injury than wildtype littermates. We investigated the role of Thy-1 in the response of fibroblasts to the pro-inflammatory cytokine TNF-α. Our study demonstrates distinct profiles of TNF-α-activated gene expression in Thy-1 positive (Thy-1+) and negative (Thy-1−) subsets of mouse embryonic fibroblasts (MEF). TNF-α induced a robust activation of MMP-9, ICAM-1, and the IL-8 promoter driven reporter in Thy-1− MEFs, in contrast to only a modest increase in Thy-1+ counterparts. Consistently, ectopic expression of Thy-1 in Thy-1− MEFs significantly attenuated TNF-α-activated gene expression. Mechanistically, TNF-α activated Src family kinase (SFK) only in Thy-1− MEFs. Blockade of SFK activation abrogated TNF-α-activated gene expression in Thy-1− MEFs, whereas restoration of SFK activation rescued the TNF-α response in Thy-1+ MEFs. Our findings suggest that Thy-1 down-regulates TNF-α-activated gene expression via interfering with SFK- and NF-κB-mediated transactivation. The current study provides a novel mechanistic insight to the distinct roles of fibroblast Thy-1 subsets in inflammation.
doi:10.1371/journal.pone.0011662
PMCID: PMC2906514  PMID: 20657842
16.  Clinicopathologic study of 1176 salivary gland tumors in a Chinese population: Experience of one cancer center 1997–2007 
Acta Oto-Laryngologica  2012;132(8):879-886.
Conclusion: Chinese patients have a higher rate of lymphoepithelial carcinoma (LEC) and salivary duct carcinoma (SDC). Comprehensive use of diagnostic modalities, neck dissection, and postoperative radiation will improve the treatment results for salivary gland tumors (SGTs). Objectives: To study the clinicopathological characteristics of SGTs in a Chinese population. Methods: The records of SGT patients operated in a tertiary cancer hospital of China were retrieved. Results: From December 1997 to December 2007, 289 malignant and 887 benign SGTs were operated at Cancer Hospital, Shanghai, China. Pleomorphic adenoma and Warthin's tumor were the most common types of SGT. Mucoepidermoid carcinoma (24.6% of malignant cases) and adenoid cystic carcinoma (18.0%) were the most frequent malignant cases, followed by acinic cell carcinoma (12.1%), LEC (9.7%), and SDC (9.3%). The sensitivity and specificity of ultrasound scan, fine needle aspiration biopsy, and frozen section were 58.3 and 88.6%, 87.2 and 96.7%, 86.9 and 99.6%, respectively. Neck dissections and postoperative radiation were carried out for 48.6 and 48.0% of carcinomas, respectively. The percentage of tumors by pathologic TNM stage were 23.7% for stage I, 32.9% for stage II, 17.3% for stage III, and 26.1% for stage IV. The 5-year overall survival rate was 88.0%.
doi:10.3109/00016489.2012.662715
PMCID: PMC3433083  PMID: 22497626
Lymphoepithelial carcinoma; salivary duct carcinoma; incidence; fine needle aspiration; frozen section

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