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1.  Diagnostic and prognostic value of plasma microRNA deregulation in nasopharyngeal carcinoma 
Cancer Biology & Therapy  2013;14(12):1133-1142.
Nasopharyngeal carcinoma (NPC) is uncommon worldwide but often highly invasive in late stages. Due to its special location and lack of specific symptoms, NPC is hardly detected in regular medical examination at the beginning. Development of sensitive and specific biomarkers should help to save lives against this type of disease. In the present report, we investigated the value of plasma miRNAs for diagnosis and prognosis of NPC. Using candidate approach, we selected 21 miRNAs from literature to compare their expression levels in the plasma of NPC patients and controls. As a result, 5 miRNAs showed diagnostic potentials (P < 0.01). Among them, miR-16, -21, -24, and -155 had increased levels in NPC patients, whereas the level of miR-378 was decreased. There was a negative correlation between plasma miRNA expression and cancer progression, where miR-21 was statistically significant in T and N staging and miR-16 and 24 were significant in N staging only. Combination of miR-16, -21, -24, -155, and -378 gives 87.7% of sensitivity and 82.0% of specificity for NPC diagnosis. Without miR-16, combination of the rest 4 miRNAs gives the same sensitivity but a slightly reduced specificity. After treatment, all 5 miRNAs were somewhat back to normal levels in patients without cancer recurrence but the prognostic value was not statistically significant. In conclusion, plasma miRNA expression is a useful biomarker for NPC diagnosis but not for its prognosis. More importantly, it is simple, effective, and non-invasive. Combination of several plasma miRNAs can increase both NPC diagnostic sensitivity and specificity.
doi:10.4161/cbt.26170
PMCID: PMC3912036  PMID: 24025417
nasopharyngeal carcinoma; NPC; miRNA; plasma; biomarker; diagnosis; prognosis
2.  Effects of Vietnamese Sophora Root on Growth, Adhesion, Invasion and Motility of Melanoma Cells 
Background
Vietnamese Sophora Root mainly contains active constituents such as alkaloids, and it has anti-tumour, antibacterial, and anti-inflammatory effects. The objective of the paper was to study the effects of Vietnamese Sophora Root on growth, adhesion, invasion and motility of mouse melanoma B16BL6 cells, and to preliminarily explore its mechanism of action.
Materials and Methods
MTT assay was used to detect the effect of Vietnamese Sophora Root aqueous extract on B16BL6 cell proliferation. Cell adhesion assay, reconstituted basement membrane invasion assay and chemotactic motility assay were used to observe the effects of Vietnamese Sophora Root aqueous extract on adhesion, invasion and motility of B16BL6 cells.
Results
Different concentrations of Vietnamese Sophora Root aqueous extracts had different degrees of inhibitory effects on B16BL6 proliferation. With the decrease of concentration, the proliferation inhibitory effect decreased and even turned to promoting effect. The extract significantly inhibited the adhesion of B16BL6 cells to the basement membrane component LN, and had a significant effect on both the invasive and migratory capacities of B16BL6 cells through the basement membrane.
Conclusion
We concluded that the aqueous extract of Vietnamese Sophora Root can inhibit the proliferation of melanoma cells, as well as their adhesion and movement.
PMCID: PMC3957242  PMID: 24653554
Vietnamese Sophora Root; B16BL6; adhesion; invasion
3.  Biochemical and biological properties of cortexillin III, a component of Dictyostelium DGAP1–cortexillin complexes 
Molecular Biology of the Cell  2014;25(13):2026-2038.
Cortexillin III, a member of the α-actinin/spectrin subfamily of Dictyostelium calponin homology proteins, forms heterodimers with cortexillins I and II that bind to the GAP protein DGAP1 in vivo. Cortexillin III complexes may be negative regulators of cell growth, pinocytosis, and phagocytosis, as all are enhanced in cortexillin III–null cells.
Cortexillins I–III are members of the α-actinin/spectrin subfamily of Dictyostelium calponin homology proteins. Unlike recombinant cortexillins I and II, which form homodimers as well as heterodimers in vitro, we find that recombinant cortexillin III is an unstable monomer but forms more stable heterodimers when coexpressed in Escherichia coli with cortexillin I or II. Expressed cortexillin III also forms heterodimers with both cortexillin I and II in vivo, and the heterodimers complex in vivo with DGAP1, a Dictyostelium GAP protein. Binding of cortexillin III to DGAP1 requires the presence of either cortexillin I or II; that is, cortexillin III binds to DGAP1 only as a heterodimer, and the heterodimers form in vivo in the absence of DGAP1. Expressed cortexillin III colocalizes with cortexillins I and II in the cortex of vegetative amoebae, the leading edge of motile cells, and the cleavage furrow of dividing cells. Colocalization of cortexillin III and F-actin may require the heterodimer/DGAP1 complex. Functionally, cortexillin III may be a negative regulator of cell growth, cytokinesis, pinocytosis, and phagocytosis, as all are enhanced in cortexillin III–null cells.
doi:10.1091/mbc.E13-08-0457
PMCID: PMC4072576  PMID: 24807902
4.  MiR-124 suppresses tumor growth and metastasis by targeting Foxq1 in nasopharyngeal carcinoma 
Molecular Cancer  2014;13(1):186.
Background
The molecular mechanisms underlying dysregulation of microRNAs have been documented in nasopharyngeal carcinoma (NPC). Our previous study demonstrated that plasma miR-124 was down-regulated in NPC using microarray analysis and quantitative PCR validation. Though growing studies showed that down-regulated miR-124 was closely related to tumourigenesis in various types of cancers, the role of miR-124 in NPC remains largely unknown.
Methods
The expression level of miR-124 was evaluated in NPC cell lines and patient specimens using quantitative reverse transcription-PCR (Real-time qPCR). The clinicopathological significance of the resultant data was later analyzed. Then, we explored the role of miR-124 in NPC tumorigenesis by in vitro and in vivo experiments. Homo sapiens forkhead box Q1 (Foxq1) was confirmed as a novel direct target gene of miR-124 by the dual-luciferase assay and western bolt.
Results
We found that miR-124 was commonly down-regulated in NPC specimens and NPC cell lines. The expression of miR-124 was inversely correlation with clinical stages and marked on T stages. Then, the ectopic expression of miR-124 dramatically inhibited cell proliferation, colony formation, migration and invasion in vitro, as well as tumor growth and metastasis in vivo. Furthermore, we identified Foxq1 as a novel direct target of miR-124. Functional studies showed that knockdown of Foxq1 inhibited cell growth, migration and invasion, whereas Foxq1 overexpression partially rescued the suppressive effect of miR-124 in NPC. In clinical specimens, Foxq1 was commonly up-regulated in NPC, and the level increased with clinical stages and T stages. Additionally, the level of Foxq1 was inversely correlated with miR-124.
Conclusions
Our results demonstrate that miR-124 functions as a tumor-suppressive microRNA in NPC, and that its suppressive effects are mediated chiefly by repressing Foxq1 expression. MiR-124 could serve as an independent biomarker to identify patients with different clinical characteristics. Therefore, our findings provide valuable clues toward the understanding the of mechanisms of NPC pathogenesis and provide an opportunity to develop new effective clinical therapies in the future.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-4598-13-186) contains supplementary material, which is available to authorized users.
doi:10.1186/1476-4598-13-186
PMCID: PMC4267157  PMID: 25098939
MicroRNA-124; Tumor growth; Metastasis; Nasopharyngeal carcinoma; Foxq1
5.  Biomechanical Comparison of Osteoporotic Distal Radius Fractures Fixed by Distal Locking Screws with Different Length 
PLoS ONE  2014;9(7):e103371.
Objectives
To evaluate the postoperative stability of osteoporotic distal radius fractures fixed with distal locking screws with different length.
Methods
A comminuted extra-articular dorsally unstable distal radius fracture, treated with volar locking plate system, was created. The 18 specimens were randomized into 3 groups based on distal locked screws with different length: Group A had unicortical screws with 50% length to the dorsal cortex. Group B had unicortical screws with 75% length to the dorsal cortex. Group C had bicortical screws. Axial compression and bending loads were imposed on the models before and after cycling testing as well as load to clinical and catastrophic failure.
Results
Minimum change in stiffness was observed before and after fatigue for all groups. The final stiffness to bending forces was statistically similar in all groups, but stiffness to axial compression was statistically significant different: Group A approached significance with respect to groups B and C (P = 0.017, 0.009), whereas stiffness in group B and C was statistically similar (P = 0.93). Load to clinical failure was significantly less for group A (456.54±78.59 N) compared with groups B (580.24±73.85 N) and C (591.07±38.40 N). Load to catastrophic failure was statistically similar between groups, but mean values for Group A were 18% less than means for Group C.
Conclusions
The volar locking plate system fixed with unicortical locking screws with at least 75% length not only produced early stability for osteoporotic distal radius fractures, but also avoided extensor tendon complications due to dorsal screw protrusion.
doi:10.1371/journal.pone.0103371
PMCID: PMC4117495  PMID: 25080094
6.  A deformation mechanism of hard metal surrounded by soft metal during roll forming 
Scientific Reports  2014;4:5017.
It is interesting to imagine what would happen when a mixture of soft-boiled eggs and stones is deformed together. A foil made of pure Ti is stronger than that made of Cu. When a composite Cu/Ti foil deforms, the harder Ti will penetrate into the softer Cu in the convex shapes according to previously reported results. In this paper, we describe the fabrication of multilayer Cu/Ti foils by the roll bonding technique and report our observations. The experimental results lead us to propose a new deformation mechanism for a hard metal surrounded by a soft metal during rolling of a laminated foil, particularly when the thickness of hard metal foil (Ti, 25 μm) is much less than that of the soft metal foil (Cu, 300 μm). Transmission Electron Microscope (TEM) imaging results show that the hard metal penetrates into the soft metal in the form of concave protrusions. Finite element simulations of the rolling process of a Cu/Ti/Cu composite foil are described. Finally, we focus on an analysis of the deformation mechanism of Ti foils and its effects on grain refinement, and propose a grain refinement mechanism from the inside to the outside of the laminates during rolling.
doi:10.1038/srep05017
PMCID: PMC4031491  PMID: 24853192
7.  NEIMiner: nanomaterial environmental impact data miner 
International Journal of Nanomedicine  2013;8(Suppl 1):15-29.
As more engineered nanomaterials (eNM) are developed for a wide range of applications, it is crucial to minimize any unintended environmental impacts resulting from the application of eNM. To realize this vision, industry and policymakers must base risk management decisions on sound scientific information about the environmental fate of eNM, their availability to receptor organisms (eg, uptake), and any resultant biological effects (eg, toxicity). To address this critical need, we developed a model-driven, data mining system called NEIMiner, to study nanomaterial environmental impact (NEI). NEIMiner consists of four components: NEI modeling framework, data integration, data management and access, and model building. The NEI modeling framework defines the scope of NEI modeling and the strategy of integrating NEI models to form a layered, comprehensive predictability. The data integration layer brings together heterogeneous data sources related to NEI via automatic web services and web scraping technologies. The data management and access layer reuses and extends a popular content management system (CMS), Drupal, and consists of modules that model the complex data structure for NEI-related bibliography and characterization data. The model building layer provides an advanced analysis capability for NEI data. Together, these components provide significant value to the process of aggregating and analyzing large-scale distributed NEI data. A prototype of the NEIMiner system is available at http://neiminer.i-a-i.com/.
doi:10.2147/IJN.S40974
PMCID: PMC3790276  PMID: 24098076
nanomaterial environmental impact; data integration; data management; content management system; data mining; modeling; model composition
8.  Predictive modeling of nanomaterial exposure effects in biological systems 
International Journal of Nanomedicine  2013;8(Suppl 1):31-43.
Background
Predictive modeling of the biological effects of nanomaterials is critical for industry and policymakers to assess the potential hazards resulting from the application of engineered nanomaterials.
Methods
We generated an experimental dataset on the toxic effects experienced by embryonic zebrafish due to exposure to nanomaterials. Several nanomaterials were studied, such as metal nanoparticles, dendrimer, metal oxide, and polymeric materials. The embryonic zebrafish metric (EZ Metric) was used as a screening-level measurement representative of adverse effects. Using the dataset, we developed a data mining approach to model the toxic endpoints and the overall biological impact of nanomaterials. Data mining techniques, such as numerical prediction, can assist analysts in developing risk assessment models for nanomaterials.
Results
We found several important attributes that contribute to the 24 hours post-fertilization (hpf) mortality, such as dosage concentration, shell composition, and surface charge. These findings concur with previous studies on nanomaterial toxicity using embryonic zebrafish. We conducted case studies on modeling the overall effect/impact of nanomaterials and the specific toxic endpoints such as mortality, delayed development, and morphological malformations. The results show that we can achieve high prediction accuracy for certain biological effects, such as 24 hpf mortality, 120 hpf mortality, and 120 hpf heart malformation. The results also show that the weighting scheme for individual biological effects has a significant influence on modeling the overall impact of nanomaterials. Sample prediction models can be found at http://neiminer.i-a-i.com/nei_models.
Conclusion
The EZ Metric-based data mining approach has been shown to have predictive power. The results provide valuable insights into the modeling and understanding of nanomaterial exposure effects.
doi:10.2147/IJN.S40742
PMCID: PMC3790277  PMID: 24098077
nanomaterial exposure effects; biological response; toxicity; embryonic zebrafish; data mining; numerical prediction
9.  Nanoinformatics for biomedicine: emerging approaches and applications 
This special issue on nanoinformatics for biomedicine is a collection of recent papers from the 2012 IEEE Workshop on Nanoinformatics for Biomedicine (NanoInfo 2012) and other work in the area. These papers illustrate different aspects of nanoinformatics to support biomedical research and to advance knowledge on nanomaterial–biological interactions. The topics covered include data curation, data standards, data mining and predictive modeling, machine learning, and translational research. The objectives of this special issue are multifold: (1) to bring together and showcase some of the latest research results in the field; (2) to introduce some useful repositories, systems, and analysis tools; and (3) to stimulate more research activities in the field.
doi:10.2147/IJN.S41253
PMCID: PMC3790274  PMID: 24101873
nanobiotechnology; nanoinformatics; data curation; data mining; machine learning; translational research
10.  miR-26a inhibits invasion and metastasis of nasopharyngeal cancer by targeting EZH2 
Oncology Letters  2013;5(4):1223-1228.
Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic type of cancer that is widely prevalent in Southern China. Studies have shown that several microRNAs (miRNAs) are implicated in NPC metastasis. Our previous studies have demonstrated that miRNA miR-26a inhibits cell growth and tumorigenesis of NPC through the repression of enhancer of zeste homolog 2 (EZH2). However, the role of miR-26a in NPC metastasis remains unknown. In this study, we showed that ectopic expression of miR-26a inhibited the migratory and invasive capacities of NPC cells in vitro. Additionally, we used a murine model to investigate the role of miR-26a in NPC metastasis and results showed that miR-26a overexpression suppresses the metastatic behavior of NPC cells in vivo. Furthermore, the data demonstrated that miR-26a decreased the expression levels of EZH2 in vitro and in vivo, suggesting that the antimetastatic effect of miR-26a in NPC was mediated by regulating EZH2. Therefore, these findings indicate that miR-26a functions as an antimetastatic miRNA in NPC and that its antimetastatic effects are mediated mainly by repressing EZH2 expression.
doi:10.3892/ol.2013.1173
PMCID: PMC3629195  PMID: 23599767
nasopharyngeal carcinoma; miR-26a; enhancer of zeste homolog 2; metastasis
11.  The Long-Term Differentiation of Embryonic Stem Cells into Cardiomyocytes: An Indirect Co-Culture Model 
PLoS ONE  2013;8(1):e55233.
Background
Embryonic Stem Cells (ESCs) can differentiate into cardiomyocytes (CMs) in vitro but the differentiation level from ESCs is low. Here we describe a simple co-culture model by commercially available Millicell™ hanging cell culture inserts to control the long-term differentiation of ESCs into CMs.
Methodology/Principal Findings
Mouse ESCs were cultured in hanging drops to form embryoid bodies (EBs) and treated with 0.1 mmol/L ascorbic acid to induce the differentiation of ESCs into CMs. In the indirect co-culture system, EBs were co-cultured with epidermal keratinocytes (EKs) or neonatal CMs (NCMs) by the hanging cell culture inserts (PET membranes with 1 µm pores). The molecular expressions and functional properties of ESC-derived CMs in prolonged culture course were evaluated. During time course of ESC differentiation, the percentages of EBs with contracting areas in NCMs co-culture were significantly higher than that without co-culture or in EKs co-culture. The functional maintenance of ESC-derived CMs were more prominent in NCMs co-culture model.
Conclusions/Significance
These results indicate that NCMs co-culture promote ESC differentiation and has a further effect on cell growth and differentiation. We assume that the improvement of the differentiating efficiency of ESCs into CMs in the co-culture system do not result from the effect of co-culture directly on cell differentiation, but rather by signaling effects that influence the cells in proliferation and long-term function maintenance.
doi:10.1371/journal.pone.0055233
PMCID: PMC3557249  PMID: 23383121
12.  Collagen/β1 integrin interaction is required for embryoid body formation during cardiogenesis from murine induced pluripotent stem cells 
BMC Cell Biology  2013;14:5.
Background
The interactions between stem cells and extracellular matrix (ECM) mediated by integrins play important roles in the processes that determine stem cell fate. However, the role of ECM/integrin interaction in the formation of embryoid bodies (EBs) during cardiogenesis from murine induced pluripotent stem cells (miPSCs) remains unclear.
Results
In the present study, collagen type I and β1 integrin were expressed and upregulated synergistically during the formation of miPSC-derived EBs, with a peak expression at day 3 of differentiation. The blockage of collagen/β1 integrin interaction by β1 integrin blocking antibody resulted in the production of defective EBs that were characterized by decreased size and the absence of a shell-like layer composed of primitive endoderm cells. The quantification of spontaneous beating activity, cardiac-specific gene expression and cardiac troponin T (cTnT) immunostaining showed that the cardiac differentiation of these defective miPSC-derived EBs was lower than that of control EBs.
Conclusions
These findings indicate that collagen/β1 integrin interaction is required for the growth and cardiac differentiation of miPSC-derived EBs and will be helpful in future engineering of the matrix microenvironment within EBs to efficiently direct the cardiac fate of pluripotent stem cells to promote cardiovascular regeneration.
doi:10.1186/1471-2121-14-5
PMCID: PMC3562267  PMID: 23350814
Collagen/β1 integrin interaction; Embryoid body; Cardiac differentiation; Induced pluripotent stem cell
13.  Suppressing tumor growth of nasopharyngeal carcinoma by hTERTC27 polypeptide delivered through adeno-associated virus plus adenovirus vector cocktail 
Chinese Journal of Cancer  2012;31(12):588-597.
Nasopharyngeal carcinoma (NPC) is a metastatic carcinoma that is highly prevalent in Southeast Asia. Our laboratory has previously demonstrated that the C-terminal 27-kDa polypeptide of human telomerase reverse transcriptase (hTERTC27) inhibits the growth and tumorigenicity of human glioblastoma and melanoma cells. In this study, we investigated the antitumor effect of hTERTC27 in human C666-1 NPC cells xenografted in a nude mouse model. A cocktail of vectors comprising recombinant adeno-associated virus (rAAV) and recombinant adenovirus (rAdv) that each carry hTERTC27 (rAAV-hTERTC27 and rAdv-hTERTC27; the cocktail was abbreviated to rAAV/rAdv-hTERTC27) was more effective than either rAAV-hTERTC27 or rAdv-hTERTC27 alone in inhibiting the growth of C666-1 NPC xenografts. Furthermore, we established three tumors on each mouse and injected rAAV/rAdv-hTERTC27 into one tumor per mouse. Although hTERTC27 expression could only be detected in the injected tumors, reduced tumor growth was observed in the injected tumor as well as the uninjected tumors, demonstrating that the vector cocktail could provoke an antitumor effect on distant, metastasized tumors. Further studies showed the observed antitumor effects included inducing necrosis and apoptosis and reducing microvessel density. Together, our data suggest that the rAAV/rAdv-hTERTC27 cocktail can potently inhibit NPC tumor growth in both local and metastasized tumors and should be further developed as a novel gene therapy strategy for NPC.
doi:10.5732/cjc.011.10378
PMCID: PMC3777457  PMID: 23149313
rAAV; Adv; nasopharyngeal carcinoma; hTERTC27
14.  High-Mobility Group Box 1 Induces Calcineurin-Mediated Cell Hypertrophy in Neonatal Rat Ventricular Myocytes 
Mediators of Inflammation  2012;2012:805149.
Cardiac hypertrophy is an independent predictor of cardiovascular morbidity and mortality. In recent years, evidences suggest that high-mobility group box 1 (HMGB1) protein, an inflammatory cytokine, participates in cardiac remodeling; however, the involvement of HMGB1 in the pathogenesis of cardiac hypertrophy remains unknown. The aim of this study was to investigate whether HMGB1 is sufficient to induce cardiomyocyte hypertrophy and to identify the possible mechanisms underlying the hypertrophic response. Cardiomyocytes isolated from 1-day-old Sprague-Dawley rats were treated with recombinant HMGB1, at concentrations ranging from 50 ng/mL to 200 ng/mL. After 24 hours, cardiomyocytes were processed for the evaluation of atrial natriuretic peptide (ANP) and calcineurin A expression. Western blot and real-time RT-PCR was used to detect protein and mRNA expression levels, respectively. The activity of calcineurin was also evaluated using a biochemical enzyme assay. HMGB1 induced cardiomyocyte hypertrophy, characterized by enhanced expression of ANP, and increased protein synthesis. Meanwhile, increased calcineurin activity and calcineurin A protein expression were observed in cardiomyocytes preconditioned with HMGB1. Furthermore, cyclosporin A pretreatment partially inhibited the HMGB1-induced cardiomyocyte hypertrophy. Our findings suggest that HMGB1 leads to cardiac hypertrophy, at least in part through activating calcineurin.
doi:10.1155/2012/805149
PMCID: PMC3388313  PMID: 22778498
15.  Actin cross-linking proteins cortexillin I and II are required for cAMP signaling during Dictyostelium chemotaxis and development 
Molecular Biology of the Cell  2012;23(2):390-400.
Double deletion of actin-binding proteins cortexillin I and II alters the actin cytoskeleton (bundled actin filaments accumulate in the cell cortex) of Dictyostelium, substantially inhibits all molecular responses to extracellular cAMP, and completely blocks cell streaming and development of cells into mature fruiting bodies.
Starvation induces Dictyostelium amoebae to secrete cAMP, toward which other amoebae stream, forming multicellular mounds that differentiate and develop into fruiting bodies containing spores. We find that the double deletion of cortexillin (ctx) I and II alters the actin cytoskeleton and substantially inhibits all molecular responses to extracellular cAMP. Synthesis of cAMP receptor and adenylyl cyclase A (ACA) is inhibited, and activation of ACA, RasC, and RasG, phosphorylation of extracellular signal regulated kinase 2, activation of TORC2, and stimulation of actin polymerization and myosin assembly are greatly reduced. As a consequence, cell streaming and development are completely blocked. Expression of ACA–yellow fluorescent protein in the ctxI/ctxII–null cells significantly rescues the wild-type phenotype, indicating that the primary chemotaxis and development defect is the inhibition of ACA synthesis and cAMP production. These results demonstrate the critical importance of a properly organized actin cytoskeleton for cAMP-signaling pathways, chemotaxis, and development in Dictyostelium.
doi:10.1091/mbc.E11-09-0764
PMCID: PMC3258182  PMID: 22114350
16.  Co-evolution of cancer microenvironment reveals distinctive patterns of gastric cancer invasion: laboratory evidence and clinical significance 
Background
Cancer invasion results from constant interactions between cancer cells and their microenvironment. Major components of the cancer microenvironment are stromal cells, infiltrating inflammatory cells, collagens, matrix metalloproteinases (MMP) and newly formed blood vessels. This study was to determine the roles of MMP-9, MMP-2, type IV collagen, infiltrating macrophages and tumor microvessels in gastric cancer (GC) invasion and their clinico-pathological significance.
Methods
Paraffin-embedded tissue sections from 37 GC patients were studied by Streptavidin-Peroxidase (SP) immunohistochemical technique to determine the levels of MMP-2, MMP-9, type IV collagen, macrophages infiltration and microvessel density (MVD). Different invasion patterns were delineated and their correlation with major clinico-pathological information was explored.
Results
MMP2 expression was higher in malignant gland compared to normal gland, especially nearby the basement membrane (BM). High densities of macrophages at the interface of cancer nests and stroma were found where BM integrity was destroyed. MMP2 expression was significantly increased in cases with recurrence and distant metastasis (P = 0.047 and 0.048, respectively). Infiltrating macrophages were correlated with serosa invasion (P = 0.011) and TNM stage (P = 0.001). MVD was higher in type IV collagen negative group compared to type IV collagen positive group (P = 0.026). MVD was related to infiltrating macrophages density (P = 0.040). Patients with negative MMP9 expression had better overall survival (OS) compared to those with positive MMP9 expression (Median OS 44.0 vs 13.5 mo, P = 0.036). Median OS was significantly longer in type IV collagen positive group than negative group (Median OS 25.5 vs 10.0 mo, P = 0.044). The cumulative OS rate was higher in low macrophages density group than in high macrophages density group (median OS 40.5 vs 13.0 mo, P = 0.056). Median OS was significantly longer in low MVD group than high MVD group (median OS 39.0 vs 8.5 mo, P = 0.001). The difference of disease-free survival (DFS) between low MVD group and high MVD group was not statistically significant (P = 0.260). Four typical patterns of cancer invasion were identified based on histological study of the cancer tissue, including Washing pattern, Ameba-like pattern, Spindle pattern and Linear pattern.
Conclusions
Proteolytic enzymes MMP9, MMP2 and macrophages in stroma contribute to GC progression by facilitating the angiogenesis. Cancer invasion patterns may help predict GC metastasis.
doi:10.1186/1479-5876-8-101
PMCID: PMC2965128  PMID: 20950454
17.  TiGER: A database for tissue-specific gene expression and regulation 
BMC Bioinformatics  2008;9:271.
Background
Understanding how genes are expressed and regulated in different tissues is a fundamental and challenging question. However, most of currently available biological databases do not focus on tissue-specific gene regulation.
Results
The recent development of computational methods for tissue-specific combinational gene regulation, based on transcription factor binding sites, enables us to perform a large-scale analysis of tissue-specific gene regulation in human tissues. The results are stored in a web database called TiGER (Tissue-specific Gene Expression and Regulation). The database contains three types of data including tissue-specific gene expression profiles, combinatorial gene regulations, and cis-regulatory module (CRM) detections. At present the database contains expression profiles for 19,526 UniGene genes, combinatorial regulations for 7,341 transcription factor pairs and 6,232 putative CRMs for 2,130 RefSeq genes.
Conclusion
We have developed and made publicly available a database, TiGER, which summarizes and provides large scale data sets for tissue-specific gene expression and regulation in a variety of human tissues. This resource is available at [1].
doi:10.1186/1471-2105-9-271
PMCID: PMC2438328  PMID: 18541026
18.  Subfamily specific conservation profiles for proteins based on n-gram patterns 
BMC Bioinformatics  2008;9:72.
Background
A new algorithm has been developed for generating conservation profiles that reflect the evolutionary history of the subfamily associated with a query sequence. It is based on n-gram patterns (NP{n,m}) which are sets of n residues and m wildcards in windows of size n+m. The generation of conservation profiles is treated as a signal-to-noise problem where the signal is the count of n-gram patterns in target sequences that are similar to the query sequence and the noise is the count over all target sequences. The signal is differentiated from the noise by applying singular value decomposition to sets of target sequences rank ordered by similarity with respect to the query.
Results
The new algorithm was used to construct 4,248 profiles from 120 randomly selected Pfam-A families. These were compared to profiles generated from multiple alignments using the consensus approach. The two profiles were similar whenever the subfamily associated with the query sequence was well represented in the multiple alignment. It was possible to construct subfamily specific conservation profiles using the new algorithm for subfamilies with as few as five members. The speed of the new algorithm was comparable to the multiple alignment approach.
Conclusion
Subfamily specific conservation profiles can be generated by the new algorithm without aprioi knowledge of family relationships or domain architecture. This is useful when the subfamily contains multiple domains with different levels of representation in protein databases. It may also be applicable when the subfamily sample size is too small for the multiple alignment approach.
doi:10.1186/1471-2105-9-72
PMCID: PMC2267698  PMID: 18234090
19.  Biological, Biochemical and Kinetic Effects of Mutations of the Cardiomyopathy-loop of Dictyostelium Myosin II: Importance of Ala400 
The Journal of biological chemistry  2005;280(29):26974-26983.
The cardiomyopathy (CM)-loop of the heavy chain of class-II myosins begins with a highly conserved Arg residue (whose mutation in human β-cardiac myosin II results in familial hypertrophic cardiomyopathy). The CM-loop of Dictyostelium myosin II (R397-Q407) is essential for its biological functions and biochemical activities. We found that the CM-loop of smooth muscle myosin II substituted partially and the CM-loop of β-cardiac myosin II much less well for growth, capping of surface receptors and development, and the actin-activated MgATPase and in vitro motility activities of purified myosins. There was little correlation between the biochemical and biological activities of the two chimeras and 19 point mutants but only the five mutants with kcat/Kactin values equivalent to wild-type myosin supported essentially full biological function. The three point mutations of R397 equivalent to those that result in hypertrophic cardiomyopathy in humans had minimal biological effects and different biochemical effects. The A400V mutation rendered full-length wild-type myosin almost completely inactive, both in vitro and in vivo, and the reverse V400A mutation in the cardiac CM-loop chimera restored almost full activity, even though the sequence still differed from wild-type in 7 of 11 positions. Transient kinetic studies of acto-subfragment-1 (S1) showed that the chimeras and the Ala/Val, Val/Ala mutations do not affect the equilibrium or the association and dissociation rate constants for either ATP or ADP binding to acto-S1 or the rate of ATP-induced dissociation of acto-S[0–9] We conclude that the Ala/Val, Val/Ala mutations affect the release of Pi from acto-S1·ADP·Pi. In addition, Val at position 400 substantially reduces the affinity of actin for S1 in the absence of nucleotide.
doi:10.1074/jbc.M504453200
PMCID: PMC1201472  PMID: 15897189
20.  iGNM: a database of protein functional motions based on Gaussian Network Model 
Bioinformatics (Oxford, England)  2005;21(13):2978-2987.
Motivation
The knowledge of protein structure is not sufficient for understanding and controlling its function. Function is a dynamic property. Although protein structural information has been rapidly accumulating in databases, little effort has been invested to date toward systematically characterizing protein dynamics. The recent success of analytical methods based on elastic network models, and in particular the Gaussian Network Model (GNM), permits us to perform a high-throughput analysis of the collective dynamics of proteins.
Results
We computed the GNM dynamics for 20 058 structures from the Protein Data Bank, and generated information on the equilibrium dynamics at the level of individual residues. The results are stored on a web-based system called i GNM and configured so as to permit the users to visualize or download the results through a standard web browser using a simple search engine. Static and animated images for describing the conformational mobility of proteins over a broad range of normal modes are accessible, along with an online calculation engine available for newly deposited structures. A case study of the dynamics of 20 non-homologous hydrolases is presented to illustrate the utility of the iGNM database for identifying key residues that control the cooperative motions and revealing the connection between collective dynamics and catalytic activity.
Availability
http://ignm.ccbb.pitt.edu/
doi:10.1093/bioinformatics/bti469
PMCID: PMC1752228  PMID: 15860562
21.  oGNM: online computation of structural dynamics using the Gaussian Network Model 
Nucleic Acids Research  2006;34(Web Server issue):W24-W31.
An assessment of the equilibrium dynamics of biomolecular systems, and in particular their most cooperative fluctuations accessible under native state conditions, is a first step towards understanding molecular mechanisms relevant to biological function. We present a web-based system, oGNM that enables users to calculate online the shape and dispersion of normal modes of motion for proteins, oligonucleotides and their complexes, or associated biological units, using the Gaussian Network Model (GNM). Computations with the new engine are 5–6 orders of magnitude faster than those using conventional normal mode analyses. Two cases studies illustrate the utility of oGNM. The first shows that the thermal fluctuations predicted for 1250 non-homologous proteins correlate well with X-ray crystallographic data over a broad range [7.3–15 Å] of inter-residue interaction cutoff distances and the correlations improve with increasing observation temperatures. The second study, focused on 64 oligonucleotides and oligonucleotide–protein complexes, shows that good agreement with experiments is achieved by representing each nucleotide by three GNM nodes (as opposed to one-node-per-residue in proteins) along with uniform interaction ranges for all components of the complexes. These results open the way to a rapid assessment of the dynamics of DNA/RNA-containing complexes. The server can be accessed at .
doi:10.1093/nar/gkl084
PMCID: PMC1538811  PMID: 16845002
22.  Correlated spin currents generated by resonant-crossed Andreev reflections in topological superconductors 
Nature Communications  2014;5:3232.
Topological superconductors, which support Majorana fermion excitations, have been the subject of intense studies due to their novel transport properties and their potential applications in fault-tolerant quantum computations. Here we propose a new type of topological superconductors that can be used as a novel source of correlated spin currents. We show that inducing superconductivity on a AIII class topological insulator wire, which respects a chiral symmetry and supports protected fermionic end states, will result in a topological superconductor. This topological superconductor supports two topological phases with one or two Majorana fermion end states, respectively. In the phase with two Majorana fermions, the superconductor can split Cooper pairs efficiently into electrons in two spatially separated leads due to Majorana-induced resonant-crossed Andreev reflections. The resulting currents in the leads are correlated and spin-polarized. Importantly, the proposed topological superconductors can be realized using quantum anomalous Hall insulators in proximity to superconductors.
Materials that exhibit topologically protected electronic structures are expected to enable the development of more efficient spintronic devices. He et al. suggest that combining a quantum anomalous Hall insulator with a superconductor could be used to generate correlated spin currents.
doi:10.1038/ncomms4232
PMCID: PMC3926009  PMID: 24492649

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