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1.  Overexpression of E2F mRNAs Associated with Gastric Cancer Progression Identified by the Transcription Factor and miRNA Co-Regulatory Network Analysis 
PLoS ONE  2015;10(2):e0116979.
Gene expression is regulated at the transcription and translation levels; thus, both transcription factors (TFs) and microRNAs (miRNA) play roles in regulation of gene expression. This study profiled differentially expressed mRNAs and miRNAs in gastric cancer tissues to construct a TF and miRNA co-regulatory network in order to identify altered genes in gastric cancer progression. A total of 70 cases gastric cancer and paired adjacent normal tissues were subjected to cDNA and miRNA microarray analyses. We obtained 887 up-regulated and 93 down-regulated genes and 41 down-regulated and 4 up-regulated miRNAs in gastric cancer tissues. Using the Transcriptional Regulatory Element Database, we obtained 105 genes that are regulated by the E2F family of genes and using Targetscan, miRanda, miRDB and miRWalk tools, we predicted potential targeting genes of these 45 miRNAs. We then built up the E2F-related TF and miRNA co-regulatory gene network and identified 9 hub-genes. Furthermore, we found that levels of E2F1, 2, 3, 4, 5, and 7 mRNAs associated with gastric cancer cell invasion capacity, and has associated with tumor differentiation. These data showed Overexpression of E2F mRNAs associated with gastric cancer progression.
doi:10.1371/journal.pone.0116979
PMCID: PMC4315469  PMID: 25646628
2.  Targeted Antiangiogenesis Gene Therapy Using Targeted Cationic Microbubbles Conjugated with CD105 Antibody Compared with Untargeted Cationic and Neutral Microbubbles 
Theranostics  2015;5(4):399-417.
Objective This study aimed to develop targeted cationic microbubbles conjugated with a CD105 antibody (CMB105) for use in targeted vascular endothelial cell gene therapy and ultrasound imaging. We compared the results with untargeted cationic microbubbles (CMB) and neutral microbubbles (NMB).
Methods CMB105 were prepared and compared with untargeted CMB and NMB. First, the microbubbles were characterized in terms of size, zeta-potential, antibody binding ability and plasmid DNA loading capacity. A tumor model of subcutaneous breast cancer in nude mice was used for our experiments. The ability of different types of microbubbles to target HUVECs in vitro and tumor neovascularization in vivo was measured. The endostatin gene was selected for its outstanding antiangiogenesis effect. For in vitro experiments, the transfection efficiency and cell cycle were analyzed using flow cytometry, and the transcription and expression of endostatin were measured by qPCR and Western blotting, respectively. Vascular tube cavity formation and tumor cell invasion were used to evaluate the antiangiogenesis gene therapy efficiency in vitro. Tumors were exposed to ultrasound irradiation with different types of microbubbles, and the gene therapy effects were investigated by detecting apoptosis induction and changes in tumor volume.
Results CMB105 and CMB differed significantly from NMB in terms of zeta-potential, and the DNA loading capacities were 16.76±1.75 μg, 18.21±1.22 μg, and 0.48±0.04 μg per 5×108 microbubbles, respectively. The charge coupling of plasmid DNA to CMB105 was not affected by the presence of the CD105 antibody. Both CMB105 and CMB could target to HUVECs in vitro, whereas only CMB105 could target to tumor neovascularization in vivo. In in vitro experiments, the transfection efficiency of CMB105 was 24.7-fold higher than the transfection efficiency of NMB and 1.47-fold higher than the transfection efficiency of CMB (P<0.05). With ultrasound-targeted microbubble destruction (UTMD)-mediated gene therapy, the transcription and expression of endostatin were the highest in the CMB105 group (P<0.001); the antiangiogenesis effect and inhibition of tumor cells invasion was better with CMB105 than CMB or NMB in vitro (P<0.01). After gene therapy, the tumor volumes of CMB105 group were significantly smaller than that of CMB and NMB, and many tumor cells had begun apoptosis in the CMB105 group, which had the highest apoptosis index (P<0.001).
Conclusions As a contrast agent and plasmid carrier, CMB105 can be used not only for targeted ultrasound imaging but also for targeted gene therapy both in vitro and in vivo. The plasmid DNA binding ability of the CMB was not affected by conjugation of the CMB with the CD105 antibody, and because of its targeting ability, the gene transfection efficiency and therapeutic effect were better compared with the untargeted CMB and NMB. The advantages of targeted gene therapy with CMB105 in vivo were more prominent than with CMB or NMB because neither can target the endothelia in vivo.
doi:10.7150/thno.10351
PMCID: PMC4329503
Ultrasound-mediated gene delivery (UMGD); Antiangiogenesis; Target; Cationic microbubbles
3.  Using a short screening scale for small-area estimation of mental illness prevalence for schools 
We use data collected in the National Comorbidity Survey - Adolescent (NCS-A) to develop a methodology to estimate the small-area prevalence of serious emotional distress (SED) in schools in the United States, exploiting the clustering of the main NCS-A sample by school. The NCS-A instrument includes both a short screening scale, the K6, and extensive diagnostic assessments of the individual disorders and associated impairment that determine the diagnosis of SED. We fitted a Bayesian bivariate multilevel regression model with correlated effects for the probability of SED and a modified K6 score at the individual and school levels. Our results provide evidence for the existence of variation in the prevalence of SED across schools and geographical regions. Although the concordance between the modified K6 scale and SED is only modest for individuals, the school-level random effects for the two measures are strongly correlated. Under this model we obtain a prediction equation for the rate of SED based on the mean K6 score and covariates. This finding supports the feasibility of using short screening scales like the K6 as an alternative to more comprehensive lay assessments in estimating school-level rates of SED. These methods may be applicable to other studies aiming at small-area estimation for geographical units.
doi:10.1198/jasa.2010.ap09185
PMCID: PMC4251785  PMID: 25477700
Bayesian; bivariate; hierarchical models; National Comorbidity Survey; prediction; serious emotional distress; small-area estimation; survey
4.  A Longitudinal Study of Sick Building Syndrome (SBS) among Pupils in Relation to SO2, NO2, O3 and PM10 in Schools in China 
PLoS ONE  2014;9(11):e112933.
There are fewer longitudinal studies from China on symptoms as described for the sick building syndrome (SBS). Here, we performed a two-year prospective study and investigated associations between environmental parameters such as room temperature, relative air humidity (RH), carbon dioxide (CO2), nitrogen dioxide (NO2), sulphur dioxide (SO2), ozone (O3), particulate matter (PM10), and health outcomes including prevalence, incidence and remission of SBS symptoms in junior high schools in Taiyuan, China. Totally 2134 pupils participated at baseline, and 1325 stayed in the same classrooms during the study period (2010–2012). The prevalence of mucosal symptoms, general symptoms and symptoms improved when away from school (school-related symptoms) was 22.7%, 20.4% and 39.2%, respectively, at baseline, and the prevalence increased during follow-up (P<0.001). At baseline, both indoor and outdoor SO2 were found positively associated with prevalence of school-related symptoms. Indoor O3 was shown to be positively associated with prevalence of skin symptoms. At follow-up, indoor PM10 was found to be positively associated with new onset of skin, mucosal and general symptoms. CO2 and RH were positively associated with new onset of mucosal, general and school-related symptoms. Outdoor SO2 was positively associated with new onset of skin symptoms, while outdoor NO2 was positively associated with new onset of skin, general and mucosal symptoms. Outdoor PM10 was found to be positively associated with new onset of skin, general and mucosal symptoms as well as school-related symptoms. In conclusion, symptoms as described for SBS were commonly found in school children in Taiyuan City, China, and increased during the two-year follow-up period. Environmental pollution, including PM10, SO2 and NO2, could increase the prevalence and incidence of SBS and decrease the remission rate. Moreover, parental asthma and allergy (heredity) and pollen or pet allergy (atopy) can be risk factors for SBS.
doi:10.1371/journal.pone.0112933
PMCID: PMC4232599  PMID: 25398002
5.  Complications in degenerative lumbar disease treated with a dynamic interspinous spacer (Coflex) 
International Orthopaedics  2013;37(11):2199-2204.
Purpose
The purpose of this study was to quantify the intra- and postoperative complications of an interspinous process device (Coflex) in managing degenerative lumbar diseases and to investigate corresponding therapeutic strategies.
Methods
Between January 2008 and December 2012, we retrospectively analysed a total of 131 patients who underwent decompressive surgery along with the Coflex system for the treatment of degenerative lumbar diseases. The related complications were reported, and appropriate measures were taken. Clinical outcomes and radiological data were collected and analysed, and clinical outcomes were evaluated with paired-samples T test.
Results
Related complications occurred in 11 patients. Among them, six cases were found with surgical technique-related complications, including device-related complications in three cases: spinal process fracture (n = 1), Coflex loosening (n = 1), fixed-wing breakage (n = 1), dura mater tear in two cases and superficial wound infection in one case. All of them received corresponding conservative treatment and obtained a good result. The other five cases had non-device-related complications and required additional spinal surgery. The conservative therapy group had apparent improvement of VAS score and ODI, and remained well to final follow-up (P < 0.05). The second operation group also improved postoperatively (each P < 0.05).
Conclusion
The Coflex dynamic interspinous process device shows a low complication and re-operation rate. Standard operation and strict follow-up observation can effectively avoid surgical technique-related complications. The key points to ensure surgical effect and to reduce non-device-related complications are mastering surgical indications and thorough intra-operative decompression.
doi:10.1007/s00264-013-2006-2
PMCID: PMC3824901  PMID: 23892467
Coflex; Spinal decompression; Spinous process fracture; Spinal stenosis; Recurrent disc herniation; Complications of coflex; Interspinous distraction; Interspinous device; Dynamic stabilisation
6.  Combined aberrant expression of N-Myc downstream-regulated gene 2 and CD24 is associated with disease-free survival and overall survival in patients with hepatocellular carcinoma 
Diagnostic Pathology  2014;9(1):209.
Background
N-Myc downstream-regulated gene 2 (NDRG2), as a tumor suppressor, has been demonstrated to inhibit tumor invasion and migration of hepatocellular carcinoma (HCC) by reducing the expression of CD24, which has been identified as a prognostic factor for HCC patients. However, the clinical significance of combined NDRG2 and CD24 expression in HCC remains unclear. Thus, the aim of the current study was to investigate the relationship of NDRG2 and CD24 expression with clinicopathological parameters and patients’ survival.
Methods
Immunohistochemistry was performed to detect the expression and subcellular localizations of NDRG2 and CD24 proteins in 130 pairs of HCC and adjacent nonneoplastic liver tissues.
Results
NDRG2 protein was strongly expressed in the cytoplasm and plasma membrane of hepatocytes in adjacent nonneoplastic liver tissues, whereas its immunostaining was weak or negative in HCC tissues. In contrast, CD24 protein exhibited the cytoplasm immunostaining in tumor cells of HCC tissues but showed negative expression in adjacent nonneoplastic liver tissues. The statistical analysis also showed that the expression levels of NDRG2 and CD24 proteins in HCC tissues were respectively lower and higher than those in adjacent nonneoplastic liver tissues significantly (both P < 0.001). In addition, there was an inverse correlation between NDRG2 expression and CD24 expression in HCC tissues (P = 0.02). Moreover, combined NDRG2 downregulation and CD24 upregulation (NDRG2-low/CD24-high) more frequently occurred in HCC tissues with high serum AFP (P = 0.03), advanced tumor stage (P = 0.001) and high tumor grade (P = 0.02). Furthermore, HCC patients with NDRG2-low/CD24-high expression showed shortest 5-year disease-free survival and 5-year overall survival (both P < 0.001) of four groups (NDRG2-low/CD24-high, NDRG2-low/CD24-low, NDRG2-high/CD24-high, NDRG2-high/CD24-low). Of note, the multivariate survival analysis showed that the combined aberrant expression of NDRG2 and CD24 proteins was an independent prognostic factor for both 5-year disease-free survival and 5-year overall survival (both P = 0.01) in HCC.
Conclusions
These findings suggest that the downregulation of NDRG2 combined with the upregulation of CD24 may play a synergistic role in the occurrence and progression of HCC. A combined detection of NDRG2/CD24 expression may benefit us in determining the prognosis in patients with HCC.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_209
doi:10.1186/s13000-014-0209-5
PMCID: PMC4212122  PMID: 25338637
N-Myc downstream-regulated gene 2; CD24; Hepatocellular carcinoma; Disease-free survival; Overall survival
7.  Targeting SHP2 for EGFR Inhibitor Resistant Non-Small Cell Lung Carcinoma 
Biochemical and biophysical research communications  2013;439(4):10.1016/j.bbrc.2013.09.028.
Targeted therapy with inhibitors of epidermal growth factor receptor (EGFR) has produced a noticeable benefit to non-small cell lung cancer (NSCLC) patients whose tumors carry activating mutations (e.g. L858R) in EGFR. Unfortunately, these patients develop drug resistance after treatment, due to acquired secondary gatekeeper mutations in EGFR (e.g., T790M). Given the critical role of SHP2 in growth factor receptor signaling, we sought to determine whether targeting SHP2 could have therapeutic value for EGFR inhibitor resistant NSCLC. We show that SHP2 is required for EGF-stimulated ERK1/2 phosphorylation and proliferation in EGFR inhibitor resistant NSCLC cell line H1975, which harbors the EGFR T790M/L858R double-mutant. We demonstrate that treatment of H1975 cells with II-B08, a specific SHP2 inhibitor, phenocopies the observed growth inhibition and reduced ERK1/2 activation seen in cells treated with SHP2 siRNA. Importantly, we also find that II-B08 exhibits marked anti-tumor activity in H1975 xenograft mice. Finally, we observe that combined inhibition of SHP2 and PI3K impairs both the ERK1/2 and PI3K/AKT signaling axes and produces significantly greater effects on repressing H1975 cell growth than inhibition of either protein individually. Collectively, these results suggest that targeting SHP2 may represent an effective strategy for treatment of EGFR inhibitor resistant NSCLCs.
doi:10.1016/j.bbrc.2013.09.028
PMCID: PMC3822432  PMID: 24041688
SHP2; EGFR; lung cancer; drug resistance; phosphatase inhibitor
8.  Kinetic modeling in PET imaging of hypoxia 
Tumor hypoxia is associated with increased therapeutic resistance leading to poor treatment outcome. Therefore the ability to detect and quantify intratumoral oxygenation could play an important role in future individual personalized treatment strategies. Positron Emission Tomography (PET) can be used for non-invasive mapping of tissue oxygenation in vivo and several hypoxia specific PET tracers have been developed. Evaluation of PET data in the clinic is commonly based on visual assessment together with semiquantitative measurements e.g. standard uptake value (SUV). However, dynamic PET contains additional valuable information on the temporal changes in tracer distribution. Kinetic modeling can be used to extract relevant pharmacokinetic parameters of tracer behavior in vivo that reflects relevant physiological processes. In this paper, we review the potential contribution of kinetic analysis for PET imaging of hypoxia.
PMCID: PMC4171837  PMID: 25250200
Cu-ATSM; 18F-FMISO; 18F-FETNIM; 18F-FAZA; oxygenation
9.  Porphyra-334 Isolated from the Marine Algae Bangia atropurpurea: Conformational Performance for Energy Conversion 
Marine Drugs  2014;12(9):4732-4740.
Prophyra-334 (p-334) may play a role of energy transfer under an uncertain mechanism, and we speculate the possible model. Via 1D and 2D NMR experiments, it was simulated the correlation between dissociation and conformation of p-334. Intramolecular interactions were observed based on a series of changes in the 1H and 13C chemical shifts. Nuclear Overhauser effect spectroscopy experiments and molecular models in various pD conditions indicated the p-334 molecular dissociation process status. In addition, we also used Chem3D software to find the most possible molecular conformation. The relationship between the structural status and energy conversion is explained. Those are the primary results. More researches on it are highly expected in the future.
doi:10.3390/md12094732
PMCID: PMC4178487  PMID: 25192413
porphyra-334; pKa; titration; conformation
10.  Propensity Score Weighting with Multilevel Data 
Statistics in medicine  2013;32(19):3373-3387.
Propensity score methods are being increasingly used as a less parametric alternative to traditional regression to balance observed differences across groups in both descriptive and causal comparisons. Data collected in many disciplines often have analytically relevant multilevel or clustered structure. The propensity score, however, was developed and has been used primarily with unstructured data. We present and compare several propensity-score-weighted estimators for clustered data, including marginal, cluster-weighted and doubly-robust estimators. Using both analytical derivations and Monte Carlo simulations, we illustrate bias arising when the usual assumptions of propensity score analysis do not hold for multilevel data. We show that exploiting the multilevel structure, either parametrically or nonparametrically, in at least one stage of the propensity score analysis can greatly reduce these biases. These methods are applied to a study of racial disparities in breast cancer screening among beneficiaries in Medicare health plans.
doi:10.1002/sim.5786
PMCID: PMC3710526  PMID: 23526267
balance; multilevel; propensity score; racial disparity; treatment effect; unmeasured confounders; weighting
11.  The Frequency and Determinants of Liver Stiffness Measurement Failure: A Retrospective Study of “Real-Life” 38,464 Examinations 
PLoS ONE  2014;9(8):e105183.
Objective
To investigate the frequency and determinants of liver stiffness measurement (LSM) failure by means of FibroScan in “real-life” Chinese patients.
Methods
A total of 38,464 “real-life” Chinese patients in 302 military hospital of China through the whole year of 2013, including asymptomatic carrier, chronic hepatitis B, chronic hepatitis C, liver cirrhosis (LC), alcoholic liver disease, autoimmune liver disease, hepatocellular carcinoma (HCC) and other, were enrolled, their clinical and biological parameters were retrospectively investigated. Liver fibrosis was evaluated by FibroScan detection. S probe (for children with height less than 1.20 m) and M probe (for adults) were used. LSM failure defined as zero valid shots (unsuccessful LSM), or the ratio of the interquartile range to the median of 10 measurements (IQR/M) greater than 0.30 plus median LSM greater or equal to 7.1 kPa (unreliable LSM).
Results
LSM failure occurred in 3.34% of all examinations (1286 patients out of 38,464), among them, there were 958 cases (2.49%) with unsuccessful LSM, and 328 patients (0.85%) with unreliable LSM. Statistical analyses showed that LSM failure was independently associated with body mass index (BMI) greater than 30 kg/m2, female sex, age greater than 50 years, intercostal spaces (IS) less than 9 mm, decompensated liver cirrhosis and HCC patients. There were no significant differences among other diseases. By changing another skilled operator, success was achieved on 301 cases out of 1286, which reduced the failure rate to 2.56%, the decrease was significant (P<0.0001).
Conclusions
The principal reasons of LSM failure are ascites, obesity and narrow of IS. The failure rates of HCC, decompensated LC, elder or female patients are higher. These results emphasize the need for adequate operator training, technological improvements and optimal criteria for specific patient subpopulations.
doi:10.1371/journal.pone.0105183
PMCID: PMC4133303  PMID: 25122123
12.  Anti-apoptotic Mcl-1 is critical for the survival and niche-filling capacity of Foxp3+ regulatory T cells 
Nature immunology  2013;14(9):959-965.
Foxp3+ regulatory T (Treg) cells are a crucial immunosuppressive population of CD4+ T cells, yet the homeostatic processes and survival programs that maintain the Treg cell pool are poorly understood. Here we report that peripheral Treg cells markedly alter their proliferative and apoptotic rates to rapidly restore numerical deficit through an interleukin 2–dependent and costimulation-dependent process. By contrast, excess Treg cells are removed by attrition, dependent on the Bim-initiated Bak- and Bax-dependent intrinsic apoptotic pathway. The antiapoptotic proteins Bcl-xL and Bcl-2 were dispensable for survival of Treg cells, whereas Mcl-1 was critical for survival of Treg cells, and the loss of this antiapoptotic protein caused fatal autoimmunity. Together, these data define the active processes by which Treg cells maintain homeostasis via critical survival pathways.
doi:10.1038/ni.2649
PMCID: PMC4128388  PMID: 23852275
13.  The -1082A>G polymorphism in promoter region of interleukin-10 and risk of digestive cancer: a meta-analysis 
Scientific Reports  2014;4:5335.
The -1082A>G polymorphism is located in promoter region of interleukin-10 (IL-10) and it could affect the production of IL-10. Numerous studies have investigated the association between IL-10 -1082A>G and risk of digestive cancer. However, the conclusion is still inconsistent. Here, we have performed a meta-analysis and systematic review to determine the association between the IL-10 -1082A>G and susceptibility to digestive cancer. In this meta-analysis, we identified 40 eligible studies, involving 7195 patients of digestive cancer and 11755 controls. By pooling all eligible studies, we found the variant -1082G allele significantly increased risk of digestive cancer (G vs. A: OR = 1.181, 95% CI: 1.057–1.319). Further stratified analysis was performed to evaluate the influence of cancer types, ethnicities, study design, sample size and Hardy–Weinberg equilibrium. Stratified analysis suggested that, the -1082A>G polymorphism was only associated with increased risk for gastric cancer (G vs. A: OR = 1.281, 95% CI: 1.102–1.488) and in Asian population (G vs. A: OR = 1.399, 95% CI: 1.188–1.646). No significant publication bias was detected. Based on 40 studies and 18950 participants, we found the variant IL-10 -1082G allele significantly increased susceptibility to digestive cancer, especially for gastric cancer and in Asian population.
doi:10.1038/srep05335
PMCID: PMC4121615  PMID: 25091209
14.  Oncogenic KIT-induced aggressive systemic mastocytosis requires SHP2/PTPN11 phosphatase for disease progression in mice 
Oncotarget  2014;5(15):6130-6141.
Acquired mutations in KIT are driver mutations in systemic mastocytosis (SM). Here, we tested the role of SHP2/PTPN11 phosphatase in oncogenic KIT signaling using an aggressive SM mouse model. Stable knock-down (KD) of SHP2 led to impaired growth, colony formation, and increased rates of apoptosis in P815 cells. This correlated with defects in signaling to ERK/Bim, Btk, Lyn, and Stat5 pathways in P815-KD cells compared to non-targeting (NT). Retro-orbital injections of P815 NT cells in syngeneic DBA/2 mice resulted in rapid development of aggressive SM within 13-16 days characterized by splenomegaly, extramedullary hematopoiesis, and multifocal liver tumors. In contrast, mice injected with P815 SHP2 KD cells showed less disease burden, including normal spleen weight and cellularity, and significant reductions in mastocytoma cells in spleen, bone marrow, peripheral blood and liver compared to NT controls. Treatment of human mast cell leukemia HMC-1 cells or P815 cells with SHP2 inhibitor II-B08, resulted in reduced colony formation and cell viability. Combining II-B08 with multi-kinase inhibitor Dasatinib showed enhanced efficacy than either inhibitor alone in blocking cell growth pathways and cell viability. Taken together, these results identify SHP2 as a key effector of oncogenic KIT and a therapeutic target in aggressive SM.
PMCID: PMC4171618  PMID: 25026279
aggressive systemic mastocytosis; KIT; SHP2/PTPN11; SHP2 inhibitor
15.  Review: Genomic era analyses of RNA secondary structure and RNA-binding proteins reveal their significance to post-transcriptional regulation in plants 
The eukaryotic transcriptome is regulated both transcriptionally and post-transcriptionally. Transcriptional control was the major focus of early research efforts, while more recently post-transcriptional mechanisms have gained recognition for their significant regulatory importance. At the heart of post-transcriptional regulatory pathways are cis- and trans-acting features and factors including RNA secondary structure as well as RNA-binding proteins and their recognition sites on target RNAs. Recent advances in genomic methodologies have significantly improved our understanding of both RNA secondary structure and RNA-binding proteins and their regulatory effects within the eukaryotic transcriptome. In this review, we focus specifically on the collection of these regulatory moieties in plant transcriptomes. We describe the approaches for studying RNA secondary structure and RNA-protein interaction sites, with an emphasis on recent methodological advances that produce transcriptome-wide datasets. We discuss how these methods that include genome-wide RNA secondary structure determination and RNA-protein interaction site mapping are significantly improving our understanding of the functions of these two elements in post-transcriptional regulation. Finally, we delineate the need for additional genome-wide studies of RNA secondary structure and RNA-protein interactions in plants.
doi:10.1016/j.plantsci.2013.01.009
PMCID: PMC4079699  PMID: 23498863
RNA secondary structure; RNA-binding proteins; post-transcriptional regulation; RNA genomics; RNA silencing; small RNAs
16.  Altered Expression of Hypoxia-Inducible Factor-1α (HIF-1α) and Its Regulatory Genes in Gastric Cancer Tissues 
PLoS ONE  2014;9(6):e99835.
Tissue hypoxia induces reprogramming of cell metabolism and may result in normal cell transformation and cancer progression. Hypoxia-inducible factor 1-alpha (HIF-1α), the key transcription factor, plays an important role in gastric cancer development and progression. This study aimed to investigate the underlying regulatory signaling pathway in gastric cancer using gastric cancer tissue specimens. The integration of gene expression profile and transcriptional regulatory element database (TRED) was pursued to identify HIF-1α ↔ NFκB1 → BRCA1 → STAT3 ← STAT1 gene pathways and their regulated genes. The data showed that there were 82 differentially expressed genes that could be regulated by these five transcription factors in gastric cancer tissues and these genes formed 95 regulation modes, among which seven genes (MMP1, TIMP1, TLR2, FCGR3A, IRF1, FAS, and TFF3) were hub molecules that are regulated at least by two of these five transcription factors simultaneously and were associated with hypoxia, inflammation, and immune disorder. Real-Time PCR and western blot showed increasing of HIF-1α in mRNA and protein levels as well as TIMP1, TFF3 in mRNA levels in gastric cancer tissues. The data are the first study to demonstrate HIF-1α-regulated transcription factors and their corresponding network genes in gastric cancer. Further study with a larger sample size and more functional experiments is needed to confirm these data and then translate into clinical biomarker discovery and treatment strategy for gastric cancer.
doi:10.1371/journal.pone.0099835
PMCID: PMC4057318  PMID: 24927122
17.  Progress and challenge of microRNA research in immunity 
Frontiers in Genetics  2014;5:178.
MicroRNAs (miRNAs) are 19–24 nucleotide long non-coding RNA species that regulate the expression of multiple target genes at the post-transcriptional level. They are required for normal immune system development and function, and their expression is dynamically regulated in different immune cell subsets during lineage differentiation and immune response. Aberrant expression of miRNAs results in dysregulated innate and adaptive immunity. This in turn can lead to failure to fight against invading pathogens and the development of autoimmune diseases and hematopoietic malignancies. In this article, we review current progress in miRNA research in immunity in both physiological and pathological settings. We also discuss research limitations and challenges that researchers are just beginning to solve.
doi:10.3389/fgene.2014.00178
PMCID: PMC4053854  PMID: 24971086
microRNA (miRNA); post-transcriptional regulation; hematopoiesis; immune regulation; immune dysfunction
18.  Thiophenic Sulfur Compounds Released During Coal Pyrolysis 
Environmental Engineering Science  2013;30(6):273-279.
Abstract
Thiophenic sulfur compounds are released during coal gasification, carbonization, and combustion. Previous studies indicate that thiophenic sulfur compounds degrade very slowly in the environment, and are more carcinogenic than polycyclic aromatic hydrocarbons and nitrogenous compounds. Therefore, it is very important to study the principle of thiophenic sulfur compounds during coal conversion, in order to control their emission and promote clean coal utilization. To realize this goal and understand the formation mechanism of thiophenic sulfur compounds, this study focused on the release behavior of thiophenic sulfur compounds during coal pyrolysis, which is an important phase for all coal thermal conversion processes. The pyrolyzer (CDS-5250) and gas chromatography–mass spectrometry (Focus GC-DSQII) were used to analyze thiophenic sulfur compounds in situ. Several coals with different coal ranks and sulfur contents were chosen as experimental samples, and thiophenic sulfur compounds of the gas produced during pyrolysis under different temperatures and heating rates were investigated. Levels of benzothiophene and dibenzothiophene were obtained during pyrolysis at temperatures ranging from 200°C to 1300°C, and heating rates ranging from 6°C/ms to 14°C/ms and 6°C/s to 14°C/s. Moreover, the relationship between the total amount of benzothiophene and dibenzothiophene released during coal pyrolysis and the organic sulfur content in coal was also discussed. This study is beneficial for understanding the formation and control of thiophenic sulfur compounds, since it provides a series of significant results that show the impact that operation conditions and organic sulfur content in coal have on the amount and species of thiophenic sulfur compounds produced during coal pyrolysis.
doi:10.1089/ees.2011.0540
PMCID: PMC3680983  PMID: 23781126
coal pyrolysis; benzothiophene; dibenzothiophene; PY-GC-MS
19.  A facile hydroxyindole carboxylic acid-based focused library approach for potent and selective inhibitors of Mycobacterium protein tyrosine phosphatase B** 
ChemMedChem  2013;8(6):904-908.
A facile hydroxyindole carboxylic acid-based focused amide library approach was designed to target both the PTP active site and a unique nearby pocket for enhanced affinity and selectivity. High throughput screening of the focused library let to the identification of a highly potent (Ki=50 nM) and selective (>100-fold against a large panel of PTPs) inhibitor 11a for mPTPB, an essential virulence factor for Mycobacterium tuberculosis. Importantly, 11a displayed highly efficacious cellular activity and was capable of reversing the altered immune responses induced by mPTPB in macrophages.
doi:10.1002/cmdc.201300115
PMCID: PMC3755370  PMID: 23568546
Focused amide library; HydroxyIndole carboxylic acid; PTP; mPTPB inhibitor; Tuberculosis
20.  HIV Incidence and Risk Factors in Chinese Young Men Who Have Sex with Men—A Prospective Cohort Study 
PLoS ONE  2014;9(5):e97527.
Objectives
To assess HIV incidence and its associated risk factors among young men who have sex with men (YMSM) in urban areas, China.
Design
The study used a prospective cohort study design and standard diagnostic tests.
Methods
A twelve-month prospective cohort study was conducted among YMSM (18–25 years old) in 8 large cities in China. The participants were recruited via snowball sampling. A total of 1102 HIV-negative YMSM completed baseline assessment, 878 YMSM participants completed 6-month follow-up, and 902 completed 12-month follow-up. HIV was screened by an enzyme-linked immunosorbent assay and confirmed with Western Blot. Syphilis was screened via rapid plasma reagent and confirmed by treponema pallidum particle agglutination assay.
Results
78 HIV seroconversions were identified within 1168.4 person-year observations yielding an incidence rate of 6.7 per 100 person-years. HIV seroconversion was associated with non-student status (RR = 2.61, 90% CI = 1.3–5.26), low HIV transmission knowledge (RR = 8.87, 90% CI = 2.16–36.43), and syphilis infection (RR = 5.04, 90% CI = 2.57–9.90).
Conclusions
Incidence of HIV among YMSM is high in urban areas of China. Interventions measures are required to contain the HIV epidemic within this population.
doi:10.1371/journal.pone.0097527
PMCID: PMC4039446  PMID: 24878586
21.  Mechanics and Composition of Middle Cerebral Arteries from Simulated Microgravity Rats with and without 1-h/d –Gx Gravitation 
PLoS ONE  2014;9(5):e97737.
Background
To elucidate further from the biomechanical aspect whether microgravity-induced cerebral vascular mal-adaptation might be a contributing factor to postflight orthostatic intolerance and the underlying mechanism accounting for the potential effectiveness of intermittent artificial gravity (IAG) in preventing this adverse effect.
Methodology/Principal Findings
Middle cerebral arteries (MCAs) were isolated from 28-day SUS (tail-suspended, head-down tilt rats to simulate microgravity effect), S+D (SUS plus 1-h/d −Gx gravitation by normal standing to simulate IAG), and CON (control) rats. Vascular myogenic reactivity and circumferential stress-strain and axial force-pressure relationships and overall stiffness were examined using pressure arteriography and calculated. Acellular matrix components were quantified by electron microscopy. The results demonstrate that myogenic reactivity is susceptible to previous pressure-induced, serial constrictions. During the first-run of pressure increments, active MCAs from SUS rats can strongly stiffen their wall and maintain the vessels at very low strains, which can be prevented by the simulated IAG countermeasure. The strains are 0.03 and 0.14 respectively for SUS and S+D, while circumferential stress being kept at 0.5 (106 dyn/cm2). During the second-run pressure steps, both the myogenic reactivity and active stiffness of the three groups declined. The distensibility of passive MCAs from S+D is significantly higher than CON and SUS, which may help to attenuate the vasodilatation impairment at low levels of pressure. Collagen and elastin percentages were increased and decreased, respectively, in MCAs from SUS and S+D as compared with CON; however, elastin was higher in S+D than SUS rats.
Conclusions
Susceptibility to previous myogenic constrictions seems to be a self-limiting protective mechanism in cerebral small resistance arteries to prevent undue cerebral vasoconstriction during orthostasis at 1-G environment. Alleviating of active stiffening and increasing of distensibility of cerebral resistance arteries may underlie the countermeasure effectiveness of IAG.
doi:10.1371/journal.pone.0097737
PMCID: PMC4026390  PMID: 24840155
22.  The Investigation of Reducing PAHs Emission from Coal Pyrolysis by Gaseous Catalytic Cracking 
The Scientific World Journal  2014;2014:528413.
The catalytic cracking method of PAHs for the pyrolysis gaseous products is proposed to control their pollution to the environment. In this study, the Py-GC-MS is used to investigate in situ the catalytic effect of CaO and Fe2O3 on the 16 PAHs from Pingshuo coal pyrolysis under different catalytic temperatures and catalyst particle sizes. The results demonstrate that Fe2O3 is effective than that of CaO for catalytic cracking of 16 PAHs and that their catalytic temperature corresponding to the maximum PAHs cracking rates is different. The PAHs cracking rate is up to 60.59% for Fe2O3 at 600°C and is 52.88% at 700°C for CaO. The catalytic temperature and particle size of the catalysts have a significant effect on PAHs cracking rate and CaO will lose the capability of decreasing 16 PAHs when the temperature is higher than 900°C. The possible cracking process of 16 PAHs is deduced by elaborately analyzing the cracking effect of the two catalysts on 16 different species of PAHs.
doi:10.1155/2014/528413
PMCID: PMC4052105  PMID: 24963507
23.  Paternal Poly (ADP-ribose) Metabolism Modulates Retention of Inheritable Sperm Histones and Early Embryonic Gene Expression 
PLoS Genetics  2014;10(5):e1004317.
To achieve the extreme nuclear condensation necessary for sperm function, most histones are replaced with protamines during spermiogenesis in mammals. Mature sperm retain only a small fraction of nucleosomes, which are, in part, enriched on gene regulatory sequences, and recent findings suggest that these retained histones provide epigenetic information that regulates expression of a subset of genes involved in embryo development after fertilization. We addressed this tantalizing hypothesis by analyzing two mouse models exhibiting abnormal histone positioning in mature sperm due to impaired poly(ADP-ribose) (PAR) metabolism during spermiogenesis and identified altered sperm histone retention in specific gene loci genome-wide using MNase digestion-based enrichment of mononucleosomal DNA. We then set out to determine the extent to which expression of these genes was altered in embryos generated with these sperm. For control sperm, most genes showed some degree of histone association, unexpectedly suggesting that histone retention in sperm genes is not an all-or-none phenomenon and that a small number of histones may remain associated with genes throughout the genome. The amount of retained histones, however, was altered in many loci when PAR metabolism was impaired. To ascertain whether sperm histone association and embryonic gene expression are linked, the transcriptome of individual 2-cell embryos derived from such sperm was determined using microarrays and RNA sequencing. Strikingly, a moderate but statistically significant portion of the genes that were differentially expressed in these embryos also showed different histone retention in the corresponding gene loci in sperm of their fathers. These findings provide new evidence for the existence of a linkage between sperm histone retention and gene expression in the embryo.
Author Summary
That not all histones are replaced by protamines in the sperm nucleus during spermiogenesis has been known for almost three decades, along with the notion that protamines do not bear any specific epigenetic information whereas histones typically carry posttranslational modifications with epigenetic regulatory functions. The enrichment of histones with distinct epigenetic modifications around transcriptional start sites, as well as unmethylated GC-rich promoter regions and exons in murine and human sperm, has recently been demonstrated by others at high resolution. The evolutionary conservation of the common principles underlying sperm histone retention provides a plausible rationale for epigenetic inheritance by nucleosomes. The present study takes a different approach towards testing the overarching hypothesis that sperm histones are linked to early embryonic gene expression by analyzing expression of genes in 2-cell embryos originating from sperm in which gene histone association of these genes was experimentally altered. The results are consistent with the aforementioned hypothesis and support the view of sperm histones as potential mediators of epigenetic inheritance through the male germ line, which could also contribute to phenotypic variation in mammals in response to environmental or dietary factors that affect sensitive chromatin-modulating pathways such as PAR metabolism.
doi:10.1371/journal.pgen.1004317
PMCID: PMC4014456  PMID: 24810616
24.  Characterization of the pathologic and endoscopic measurements of colorectal polyp sizes with a focus on sessile serrated adenoma and high-grade dysplasia 
Background: The characteristics of pathologically measured (PMS) and endoscopically measured sizes (EMS) of the colorectal polyps (CRPs) is poorly understood, particularly in polypoid unremarkable mucosa (PUM), sessile serrated adenoma (SSA), and high-grade dysplasia (HGD). Methods: To characterize the discordance and correlation between the PMS and EMS of CRPs including PUM, SSA, HGD, hyperplastic polyp (HP) and adenomas, we conducted this prospective observational study on the polyps collected between August 2012 and December 2013. Results: PMS was significantly smaller than EMS in the 497 qualified CRPs regardless of the sites (left, transverse and right colorectum) or EMS (≥1 cm and <1 cm) subgroups. The PMS and EMS discordance was associated with a diagnosis of HP and adenoma (versus PUM, SSA or HGD), single fragment (versus multiple), 3 of the 8 endoscopists and PMS<1 cm (versus ≥1 cm). Despite a good correlation between EMS and PMS in the adenomas (ĸ=0.626, 95% confidence intervals [CI], 0.505-0.746) and a moderate correlation in the serrated polyps (SPs) including HP and SSA, (ĸ=0.424, 95% CI, 0.244-0.604), 40.4% (23/57) of the adenomas and 63.6% (21/33) of the SPs with EMS≥1 cm might warrant longer follow-up intervals since their PMS were <1 cm. The PMS and EMS had linear correlations except in CRPs with HGD or EMS≥1 cm. Conclusions: The discordance between PMS and EMS is associated with the pathologic diagnosis, fragment number, endoscopists and PMS, and may lead to different follow-ups in a considerable portion of adenomas and SPs.
PMCID: PMC4014244  PMID: 24817960
Polyp; surveillance; measurement; colonoscopy; pathology; cancer
25.  Organocatalytic Multicomponent Reaction for the Acquisition of a Selective Inhibitor of mPTPB, a Virulence Factor of Tuberculosis 
Mycobacterium protein tyrosine phosphatase B (mPTPB) is essential for the survival and persistence of Mycobacterium in the host. Thus small molecule inhibitors of mPTPB are potential anti-TB agents. We developed an efficient organocatalytic multicomponent reaction (MCR) between pyrrole, formaldehyde and aniline, affording a potent and selective mPTPB inhibitor with IC50 at 1.5 µM and >50-fold specificity. Our studies provide a successful example of using organocatalysis as a discovery tool for the acquisition of PTP inhibitors.
doi:10.1039/c3cc38961h
PMCID: PMC3586706  PMID: 23380872

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