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1.  Pallidal Index as Biomarker of Manganese Brain Accumulation and Associated with Manganese Levels in Blood: A Meta-Analysis 
PLoS ONE  2014;9(4):e93900.
Objective
The current study was designed to evaluate the sensitivity, feasibility, and effectiveness of the pallidal index (PI) serving as a biomarker of brain manganese (Mn) accumulation, which would be used as an early diagnosis criteria for Mn neurotoxicity.
Methods
The weighted mean difference (WMD) of the PI between control and Mn-exposed groups was estimated by using a random-effects or fixed-effects meta-analysis with 95% confidence interval (CI) performed by STATA software version 12.1. Moreover, the R package “metacor” was used to estimate correlation coefficients between PI and blood Mn (MnB).
Results
A total of eight studies with 281 occupationally Mn-exposed workers met the inclusion criteria. Results were pooled and performed with the Meta-analysis. Our data indicated that the PI of the exposed group was significantly higher than that of the control (WMD: 7.76; 95% CI: 4.86, 10.65; I2 = 85.7%, p<0.0001). A random effects model was used to perform meta-analysis. These findings were remarkably robust in the sensitivity analysis, and publication bias was shown in the included studies. Seven out of the eight studies reported the Pearson correlation (r) values. Significantly positive correlation between PI and MnB was observed (r = 0.42; 95% CI, 0.31, 0.52).
Conclusions
PI can be considered as a sensitive, feasible, effective and semi-quantitative index in evaluating brain Mn accumulation. MnB can also augment the evaluation of brain Mn accumulation levels in the near future. However, the results should be interpreted with caution.
doi:10.1371/journal.pone.0093900
PMCID: PMC3981755  PMID: 24718592
2.  Expression of the Pupal Determinant broad during Metamorphic and Neotenic Development of the Strepsipteran Xenos vesparum Rossi 
PLoS ONE  2014;9(4):e93614.
Derived members of the endoparasitic order Strepsiptera have acquired an extreme form of sexual dimorphism whereby males undergo metamorphosis and exist as free-living adults while females remain larviform, reaching sexual maturity within their hosts. Expression of the transcription factor, broad (br) has been shown to be required for pupal development in insects in which both sexes progress through metamorphosis. A surge of br expression appears in the last larval instar, as the epidermis begins pupal development. Here we ask if br is also up-regulated in the last larval instar of male Xenos vesparum Rossi (Stylopidae), and whether such expression is lost in neotenic larviform females. We clone three isoforms of br from X. vesparum (Xv’br), and show that they share greatest similarity to the Z1, Z3 and Z4 isoforms of other insect species. By monitoring Xv’br expression throughout development, we detect elevated levels of total br expression and the Xv’Z1, Xv’Z3, and Xv’Z4 isoforms in the last larval instar of males, but not females. By focusing on Xv’br expression in individual samples, we show that the levels of Xv’BTB and Xv’Z3 in the last larval instar of males are bimodal, with some males expressing 3X greater levels of Xv’br than fourth instar femlaes. Taken together, these data suggest that neoteny (and endoparasitism) in females of Strepsiptera Stylopidia could be linked to the suppression of pupal determination. Our work identifies a difference in metamorphic gene expression that is associated with neoteny, and thus provides insights into the relationship between metamorphic and neotenic development.
doi:10.1371/journal.pone.0093614
PMCID: PMC3977908  PMID: 24709670
3.  Mutagenesis analysis of T380R mutation in the envelope protein of yellow fever virus 
Virology Journal  2014;11:60.
Background
The RGD motif in the mosquito-borne flaviviruses envelope protein domain III (EDIII) FG loop was shown to bind negatively charged cellular molecules and mediate virus entry in mammals. However, its importance in virus entry in the mosquito has not yet been defined. The sequences of RGD motifs are conserved in JEV-serocomplex members primarily transmitted by Culex mosquitoes but absent from members of the DENV serocomplex, which utilize Aedes mosquitoes as vectors. Interestingly, the RGD sequence is present in the attenuated 17D strain of yellow fever virus as a result of the T380R mutation in the EDIII of Asibi strain following extensive in vitro passage in mice and chicken embryos and was found to contribute to the more rapid clearance in mice challenged with 17D. However, viral infectivity and dissemination in mosquitoes had not been evaluated for this mutant.
Findings
The study utilized the reverse genetics system of YFV and Ae. aegypti RexD WE mosquitoes to assess the impact of a T380R mutation in YFV Asibi and 17D/Asibi M-E chimera. The T380R mutation led to higher infection rates but similar dissemination rates when introduced into the YFV Asibi strain and 17D/Asibi M-E chimera.
Conclusions
While the increase of the positive charge in EDIII may reduce the virulence of YFV in mice, this mutation favored the establishment of the viral infection in Ae. aegypti. However, such gain in viral infectivity did not increase dissemination in infected mosquitoes.
doi:10.1186/1743-422X-11-60
PMCID: PMC3974419  PMID: 24678844
Yellow fever virus; 17D vaccine; Aedes aegypti
4.  Asexuality Development among Middle Aged and Older Men 
PLoS ONE  2014;9(3):e92794.
Objectives
To assess erectile function in middle-aged and older men with asexuality status and further analyze their specific reasons for this condition.
Subjects and Methods
Men who had regular sexual intercourse attempts (sex frequency≥1 time per month) were classified into mild erectile dysfunction (ED), moderate to severe ED and non-ED according to International Index of Erectile Function-5, and men having no sexual intercourse attempts for at least 6 months were defined as having an asexuality status. The risk factors associated with ED were collected in a sample of 1,531 Chinese men aged 40 to 80 years, and the self-report reasons for asexuality were recorded in asexual cohort individually. Comparative analyses and multivariate regression models were conducted among these groups.
Results
The prevalence rates of ED and asexuality status were 49.9% and 37.2%. The asexuality status group had higher risk factors than the moderate to severe ED group in terms of old age (age≥65, adjusted odds ratio (OR) 17.69 versus (Vs.) 7.19), diabetes (crude OR: 2.40 Vs. 2.36) and hypertension (crude OR: 1.78 Vs. 1.72). The specific reasons for the asexuality status were “erectile difficulty” (52.9%), “do not care about sexuality” (53.5%)”, “no longer necessary to have sexuality at this age” (47.7%), “severe stress” (44.4%), “severe fatigue” (26.3%) and “masturbation” (26.9%).
Conclusions
Men with an asexual status suffer from higher risk factors for ED than men with moderate to severe ED. The majority of this asexual status could be attributed to a full ED, although the reasons for this transient asexuality also involved sexual attitudes and interests, sexual partners and masturbation.
doi:10.1371/journal.pone.0092794
PMCID: PMC3965446  PMID: 24667838
5.  A Robust Method for Transcript Quantification with RNA-Seq Data 
Journal of Computational Biology  2013;20(3):167-187.
Abstract
The advent of high throughput RNA-seq technology allows deep sampling of the transcriptome, making it possible to characterize both the diversity and the abundance of transcript isoforms. Accurate abundance estimation or transcript quantification of isoforms is critical for downstream differential analysis (e.g., healthy vs. diseased cells) but remains a challenging problem for several reasons. First, while various types of algorithms have been developed for abundance estimation, short reads often do not uniquely identify the transcript isoforms from which they were sampled. As a result, the quantification problem may not be identifiable, i.e., lacks a unique transcript solution even if the read maps uniquely to the reference genome. In this article, we develop a general linear model for transcript quantification that leverages reads spanning multiple splice junctions to ameliorate identifiability. Second, RNA-seq reads sampled from the transcriptome exhibit unknown position-specific and sequence-specific biases. We extend our method to simultaneously learn bias parameters during transcript quantification to improve accuracy. Third, transcript quantification is often provided with a candidate set of isoforms, not all of which are likely to be significantly expressed in a given tissue type or condition. By resolving the linear system with LASSO, our approach can infer an accurate set of dominantly expressed transcripts while existing methods tend to assign positive expression to every candidate isoform. Using simulated RNA-seq datasets, our method demonstrated better quantification accuracy and the inference of dominant set of transcripts than existing methods. The application of our method on real data experimentally demonstrated that transcript quantification is effective for differential analysis of transcriptomes.
doi:10.1089/cmb.2012.0230
PMCID: PMC3590898  PMID: 23461570
transcriptome; transcript quantification; RNA-seq
6.  Perineural Dexmedetomidine Attenuates Inflammation in Rat Sciatic Nerve via the NF-κB Pathway 
Recent studies have shown that dexmedetomidine exerts an anti-inflammatory effect by reducing serum levels of inflammatory factors, however, the up-stream mechanism is still unknown. The transcription factor NF-κB enters the nucleus and promotes the transcription of its target genes, including those encoding the pro-inflammatory cytokines IL-6 and TNF-α. In this study, we established a rat model that simulates a clinical surgical procedure to investigate the anti-inflammatory effect of perineural administration of dexmedetomidine and the underlying mechanism. Dexmedetomidine reduced the sciatic nerve levels of IL-6 and TNF-α at both the mRNA and protein level. Dexmedetomidine also inhibited the translocation of activated NF-κB to the nucleus and the binding activity of NF-κB. The anti-inflammatory effect is confirmed to be dose-dependent. Finally, pyrrolidine dithiocarbamate also reduced the levels of IL-6 and TNF-α and the activation of NF-κB. In conclusion, dexmedetomidine inhibited the nuclear translocation and binding activity of activated NF-κB, thus reducing inflammatory cytokines.
doi:10.3390/ijms15034049
PMCID: PMC3975383  PMID: 24663080
dexmedetomidine; NF-κB; IL-6; TNF-α; nerve block
7.  Structure and Antitumor and Immunomodulatory Activities of a Water-Soluble Polysaccharide from Dimocarpus longan Pulp 
A new water-soluble polysaccharide (longan polysaccharide 1 (LP1)) was extracted and successfully purified from Dimocarpus longan pulp via diethylaminoethyl (DEAE)-cellulose anion-exchange and Sephacryl S-300 HR gel chromatography. The chemical structure was determined using Infrared (IR), gas chromatography (GC) and nuclear magnetic resonance (NMR) analysis. The results indicated that the molecular weight of the sample was 1.1 × 105 Da. Monosaccharide composition analysis revealed that LP1 was composed of Glc, GalA, Ara and Gal in a molar ratio of 5.39:1.04:0.74:0.21. Structural analysis indicated that LP1 consisted of a backbone of →4)-α-d-Glcp-(1→4)-α-d-GalpA-(1→4)-α-d-Glcp-(1→4)-β-d-Glcp-(1→ units with poly saccharide side chains composed of →2)-β-d-Fruf-(1→2)-l-sorbose-(1→ attached to the O-6 position of the α-d-Glcp residues. In vitro experiments indicated that LP1 had significantly high antitumor activity against SKOV3 and HO8910 tumor cells, with inhibition percentages of 40% and 50%, respectively. In addition, LP1 significantly stimulated the production of the cytokine interferon-γ (IFN-γ), increased the activity of murine macrophages and enhanced B- and T-lymphocyte proliferation. The results of this study demonstrate that LP1 has potential applications as a natural antitumor agent with immunomodulatory activity.
doi:10.3390/ijms15035140
PMCID: PMC3975445  PMID: 24663085
structure; antitumor activity; immunomodulatory activity; polysaccharide; Dimocarpus longan pulp
8.  Telomere regulation in pluripotent stem cells 
Protein & Cell  2014;5(3):194-202.
Pluripotent stem cells (PSCs) have the potential to produce any types of cells from all three basic germ layers and the capacity to self-renew and proliferate indefinitely in vitro. The two main types of PSCs, embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), share common features such as colony morphology, high expression of Oct4 and Nanog, and strong alkaline phosphatase activity. In recent years, increasing evidences suggest that telomere length represents another important internal factor in maintaining stem cell pluripotency. Telomere length homeostasis and its structural integrity help to protect chromosome ends from recombination, end fusion, and DNA damage responses, ensuring the divisional ability of mammalian cells. PSCs generally exhibit high telomerase activity to maintain their extremely long and stable telomeres, and emerging data indicate the alternative lengthening of telomeres (ALT) pathway may play an important role in telomere functions too. Such characteristics are likely key to their abilities to differentiate into diverse cell types in vivo. In this review, we will focus on the function and regulation of telomeres in ESCs and iPSCs, thereby shedding light on the importance of telomere length to pluripotency and the mechanisms that regulate telomeres in PSCs.
doi:10.1007/s13238-014-0028-1
PMCID: PMC3967062  PMID: 24563217
telomere; pluripotent stem cells; alternative lengthening of telomeres (ALT); regulators
9.  Telomere regulation in pluripotent stem cells 
Protein & Cell  2014;5(3):194-202.
Pluripotent stem cells (PSCs) have the potential to produce any types of cells from all three basic germ layers and the capacity to self-renew and proliferate indefinitely in vitro. The two main types of PSCs, embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), share common features such as colony morphology, high expression of Oct4 and Nanog, and strong alkaline phosphatase activity. In recent years, increasing evidences suggest that telomere length represents another important internal factor in maintaining stem cell pluripotency. Telomere length homeostasis and its structural integrity help to protect chromosome ends from recombination, end fusion, and DNA damage responses, ensuring the divisional ability of mammalian cells. PSCs generally exhibit high telomerase activity to maintain their extremely long and stable telomeres, and emerging data indicate the alternative lengthening of telomeres (ALT) pathway may play an important role in telomere functions too. Such characteristics are likely key to their abilities to differentiate into diverse cell types in vivo. In this review, we will focus on the function and regulation of telomeres in ESCs and iPSCs, thereby shedding light on the importance of telomere length to pluripotency and the mechanisms that regulate telomeres in PSCs.
doi:10.1007/s13238-014-0028-1
PMCID: PMC3967062  PMID: 24563217
telomere; pluripotent stem cells; alternative lengthening of telomeres (ALT); regulators
10.  Mir-184 Post-Transcriptionally Regulates SOX7 Expression and Promotes Cell Proliferation in Human Hepatocellular Carcinoma 
PLoS ONE  2014;9(2):e88796.
Hepatocellular carcinoma (HCC) is one of the most common human malignancies and the third leading cause of cancer mortality worldwide. The development and progression of HCC is a complicated process, involving the deregulation of multiple genes that are essential to cell biological processes. Recently, microRNAs (miRNAs) have been suggested to be closely associated with tumorigenesis. Our study showed that miR-184 is upregulated in HCC cell lines and tissues. Overexpression of miR-184 in HCC cells increased cell proliferation, tumorigenicity, and cell cycle progression, whereas inhibition of miR-184 reduced cell proliferation, tumorigenicity, and cell cycle progression. Additionally, we identified SOX7 as a direct target of miR-184. Ectopic expression of miR-184 led to downregulation of the SOX7 protein, resulting in upregulation of c-Myc, Cyclin D1, and phosphorylation of Rb. Our findings suggested that miR-184 represents a potential onco-miR and plays an important role in HCC progression by suppressing SOX7 expression.
doi:10.1371/journal.pone.0088796
PMCID: PMC3928300  PMID: 24558429
11.  MiR-200a inhibits epithelial-mesenchymal transition of pancreatic cancer stem cell 
BMC Cancer  2014;14:85.
Background
Pancreatic cancer is one of the most aggressive cancers, and the aggressiveness of pancreatic cancer is in part due to its intrinsic and extrinsic drug resistance characteristics, which are also associated with the acquisition of epithelial-to-mesenchymal transition (EMT). Increasing evidence suggests that EMT-type cells share many biological characteristics with cancer stem-like cells. And miR-200 has been identified as a powerful regulator of EMT.
Methods
Cancer Stem Cells (CSCs) of human pancreatic cancer cell line PANC-1 were processed for CD24, CD44 and ESA multi-colorstaining, and sorted out on a BD FACS Aria II machine. RT-qPCR was performed using the miScript PCR Kit to assay the expression of miR-200 family. In order to find the role of miR-200a in the process of EMT, miR-200a mimic was transfected to CSCs.
Results
Pancreatic cancer cells with EMT phenotype displayed stem-like cell features characterized by the expression of cell surface markers CD24, CD44 and epithelial-specific antigen (ESA), which was associated with decreased expression of miR-200a. Moreover, overexpression of miR-200a was resulted in down-regulation of N-cadherin, ZEB1 and vimentin, but up-regulation of E-cadherin. In addition, miR-200a overexpression inhibited cell migration and invasion in CSCs.
Conclusion
In our study, we found that miR-200a played an important role in linking the characteristics of cancer stem-like cells with EMT-like cell signatures in pancreatic cancer. Selective elimination of cancer stem-like cells by reversing the EMT phenotype to mesenchymal-to-epithelial transition (MET) phenotype using novel agents would be useful for prevention and/or treatment of pancreatic cancer.
doi:10.1186/1471-2407-14-85
PMCID: PMC3923443  PMID: 24521357
CSC; EMT; Pancreatic cancer; miR-200a
12.  Network Meta-Analysis of Erlotinib, Gefitinib, Afatinib and Icotinib in Patients with Advanced Non-Small-Cell Lung Cancer Harboring EGFR Mutations 
PLoS ONE  2014;9(2):e85245.
Background
Several EGFR-tyrosine kinase inhibitors (EGFR-TKIs) including erlotinib, gefitinib, afatinib and icotinib are currently available as treatment for patients with advanced non-small-cell lung cancer (NSCLC) who harbor EGFR mutations. However, no head to head trials between these TKIs in mutated populations have been reported, which provides room for indirect and integrated comparisons.
Methods
We searched electronic databases for eligible literatures. Pooled data on objective response rate (ORR), progression free survival (PFS), overall survival (OS) were calculated. Appropriate networks for different outcomes were established to incorporate all evidences. Multiple-treatments comparisons (MTCs) based on Bayesian network integrated the efficacy and specific toxicities of all included treatments.
Results
Twelve phase III RCTs that investigated EGFR-TKIs involving 1821 participants with EGFR mutation were included. For mutant patients, the weighted pooled ORR and 1-year PFS of EGFR-TKIs were significant superior to that of standard chemotherapy (ORR: 66.6% vs. 30.9%, OR 5.46, 95%CI 3.59 to 8.30, P<0.00001; 1-year PFS: 42.9% vs. 9.7%, OR 7.83, 95%CI 4.50 to 13.61; P<0.00001) through direct meta-analysis. In the network meta-analyses, no statistically significant differences in efficacy were found between these four TKIs with respect to all outcome measures. Trend analyses of rank probabilities revealed that the cumulative probabilities of being the most efficacious treatments were (ORR, 1-year PFS, 1-year OS, 2-year OS): erlotinib (51%, 38%, 14%, 19%), gefitinib (1%, 6%, 5%, 16%), afatinib (29%, 27%, 30%, 27%) and icotinib (19%, 29%, NA, NA), respectively. However, afatinib and erlotinib showed significant severer rash and diarrhea compared with gefitinib and icotinib.
Conclusions
The current study indicated that erlotinib, gefitinib, afatinib and icotinib shared equivalent efficacy but presented different efficacy-toxicity pattern for EGFR-mutated patients. Erlotinib and afatinib revealed potentially better efficacy but significant higher toxicities compared with gefitinib and icotinib.
doi:10.1371/journal.pone.0085245
PMCID: PMC3922700  PMID: 24533047
13.  The role of HMGB1-RAGE axis in migration and invasion of hepatocellular carcinoma cell lines 
High mobility group protein box1 (HMGB1) and its receptor—receptor for advanced glycation end products (RAGE) are pivotal factors in the development and progression of many types of tumor, but the role of HMGB1-RAGE axis in hepatocellular carcinoma (HCC) especially its effects on metastasis and recurrence remains obscure. Here, we report the role of HMGB1-RAGE axis in the biological behaviors of HCC cell lines and the underlying molecular mechanism. We show that the expressions of HMGB1, RAGE, and extracellular HMGB1 increase consistently according to cell metastasis potentials, while the concentration of soluble form of RAGE (sRAGE) is inversely related to metastasis potential of HCC cells. Furthermore, our data show that rhHMGB1 promotes cellular proliferation, migration, and invasion, and increases the level of nuclear factor kappa B (NF-κB), while administrations of HMGB1-siRNA, RAGE-siRNA, anti-HMGB1 neutralizing antibody, anti-RAGE neutralizing antibody, and sRAGE inhibit cellular proliferation, migration, and invasion. Moreover, we also demonstrate that the expression of NF-кB is inhibited by knockdown of HMGB1 or RAGE. Collectively, these data demonstrate that HMGB1 activates RAGE signaling pathways and induces NF-кB activation to promote cellular proliferation, invasion, and metastasis, in HCC cell lines. Taken together, HMGB1-RAGE axis may become a potential target in HCC therapy.
doi:10.1007/s11010-014-1978-6
PMCID: PMC3972434  PMID: 24510323
HMGB1; RAGE; Hepatocellular carcinoma; Invasion; Migration
14.  A Novel Role of Globular Adiponectin in Treatment with HFD/STZ Induced T2DM Combined with NAFLD Rats 
The Scientific World Journal  2014;2014:230835.
Aims. To evaluate the effects of globular adiponectin (gAd) on treatment of type 2 diabetic rats combined with NAFLD. Materials and Methods. Twenty-one male wistar rats were fed with normal diet (7 rats) or high fat diet (HFD) (14 rats) for 4 weeks, and then HFD-fed rats were injected with streptozotocin (STZ) to induce type 2 diabetes mellitus (T2DM). Half of T2DM rats were randomly injected with gAd intraperitoneally for 7 days. The expressions of adiponectin receptors (adipoR1/R2) in liver and skeletal muscle tissues were detected through western blotting or RT-qPCR, respectively. Results. Globular adiponectin alleviated the hepatic steatosis and increased insulin secretion. In liver, both the protein and mRNA expressions of adipoR2 in T2DM group decreased (P < 0.05, resp.) in contrast to NC group and increased (P < 0.05 and P < 0.001, resp.) after gAd treatment. But the protein and mRNA expressions of adipoR1 increased (P < 0.05, resp.) in T2DM group and no change was found in the gAd-treated group. In skeletal muscle, the protein and mRNA expressions of adipoR1 and adipoR2 were upregulated in T2DM group and were downregulated after gAd treatment. Conclusions. Globular adiponectin could ameliorate the hepatic steatosis and vary the expressions of adiponectin receptors in liver and skeletal muscle by stimulating insulin secretion.
doi:10.1155/2014/230835
PMCID: PMC3933409
15.  Early Lung Cancer Detection Using the Self-Evaluation Scoring Questionnaire and Chest Digital Radiography: A 3-Year Follow-up Study in China 
Journal of Digital Imaging  2012;26(1):72-81.
The standard definition of high-risk individuals for lung cancer was not uniform and the value of chest digital radiography (DR) in lung cancer screening was still unproven. The aim of this study was to assess whether the original questionnaire named as “Self-evaluation Scoring Questionnaire for High-risk Individuals of Lung Cancer” combined with DR examinations could detect early stage of lung cancer effectively. The Self-evaluation Scoring Questionnaire for High-risk Individuals of Lung Cancer had been designed in previous studies. Subjects with scores over 116 points were regarded as high-risk individuals and underwent the current DR scans at least once a year from 2007 to 2009. Noncalcified nodules with a diameter over 30 mm, along with enlarged pulmonary hilus and atelectasis, were considered to be positive and subjected to further special examinations. Efficacy of the scoring questionnaire combined with DR scans was estimated by 3-year results. Among 1,537 subjects, 13, 11, and 7 were diagnosed with lung cancer in the first, second, and third year, respectively, indicating the detection rate of 2.02 % (31/1,537). In addition, 77.42 % (24/31) of the patients were in stage I and 51.61 % (16/31) were adenocarcinomas. For the 31 cases, 28 were defined as detected cancers, while the other three were interval ones, only accounting for 0.20 % (3/1,504) of individuals with negative judgments. The protocol of Self-evaluation Scoring Questionnaire for High-risk Individuals of Lung Cancer combined with DR scans is a cost-effective and safe approach to detect early stage of lung cancer.
doi:10.1007/s10278-012-9468-4
PMCID: PMC3553372  PMID: 22411060
Lung neoplasm; Pulmonary nodule; Smoking; Screening
16.  Suppression of Wnt1-induced mammary tumor growth and lower serum insulin in offspring exposed to maternal blueberry diet suggest early dietary influence on developmental programming 
Carcinogenesis  2012;34(2):464-474.
Despite the well-accepted notion that early maternal influences persist beyond fetal life and may underlie many adult diseases, the risks imposed by the maternal environment on breast cancer development and underlying biological mechanisms remain poorly understood. In this study, we investigated whether early exposure to blueberry (BB) via maternal diet alters oncogene Wnt1-induced mammary tumorigenesis in offspring. Wnt1-transgenic female mice were exposed to maternal Casein (CAS, control) or blueberry-supplemented (CAS + 3%BB) diets throughout pregnancy and lactation. Offspring were weaned to CAS and mammary tumor development was followed until age 8 months. Tumor incidence and latency were similar for both groups; however, tumor weight at killing and tumor volume within 2 weeks of initial detection were lower (by 50 and 60%, respectively) in offspring of BB- versus control-fed dams. Dietary BB exposure beginning at weaning did not alter mammary tumor parameters. Tumors from maternal BB-exposed offspring showed higher tumor suppressor (Pten and Cdh1) and lower proproliferative (Ccnd1), anti-apoptotic (Bcl2) and proangiogenic (Figf, Flt1 and Ephb4) transcript levels, and displayed attenuated microvessel density. Expression of Pten and Cdh1 genes was also higher in mammary tissues of maternal BB-exposed offspring. Mammary tissues and tumors of maternal BB-exposed offspring showed increased chromatin-modifying enzyme Dnmt1 and Ezh2 transcript levels. Body weight, serum insulin and serum leptin/adiponectin ratio were lower for maternal BB-exposed than control tumor-bearing offspring. Tumor weights and serum insulin were positively correlated. Results suggest that dietary influences on the maternal environment contribute to key developmental programs in the mammary gland to modify breast cancer outcome in adult progeny.
doi:10.1093/carcin/bgs353
PMCID: PMC3564444  PMID: 23144318
17.  Infection of Aedes albopictus with Chikungunya Virus Rectally Administered by Enema 
Abstract
Chikungunya virus (CHIKV) is an alphavirus transmitted by Aedes albopictus and Aedes aegypti mosquitoes in tropical areas of Africa, Asia, and the islands of the Indian Ocean. In 2007 and 2009, CHIKV was transmitted outside these tropical areas and caused geographically localized infections in people in Italy and France. To temporally and spatially characterize CHIKV infection of Ae. albopictus midguts, a comparison of viral distribution in mosquitoes infected per os or by enema was conducted. Ae. albopictus infected with CHIKV LR 5′ green fluorescent protein (GFP) at a titer 106.95 tissue culture infective dose50 (TCID50)/mL, were collected and analyzed for virus dissemination by visualizing GFP expression and titration up to 14 days post inoculation (dpi). Additionally, midguts were dissected from the mosquitoes and imaged by fluorescence microscopy for comparison of midgut infection patterns between orally- and enema-infected mosquitoes. When virus was delivered via enema, the anterior midgut appeared more readily infected by 3 dpi, with increased GFP presentation observed in this same location of the midgut at 7 and 14 dpi when compared to orally-infected mosquitoes. This work demonstrates that enema delivery of virus is a viable technique for use of mosquito infection. Enema injection of mosquitoes may be an alternative to intrathoracic inoculation because the enema delivery more closely models natural infection and neither compromises midgut integrity nor involves a wound that can induce immune responses. Furthermore, unlike intrathoracic delivery, the enema does not bypass midgut barriers to infect tissues artificially in the hemocoel of the mosquito.
doi:10.1089/vbz.2012.1013
PMCID: PMC3564464  PMID: 23249139
Chikungunya virus; Aedes albopictus; Aedes aegypti; Enema injection
18.  The impact of both platinum-based chemotherapy and EGFR-TKIs on overall survival of patients with advanced non-small cell lung cancer 
Chinese Journal of Cancer  2014;33(2):105-114.
Both platinum-based doublet chemotherapy (PBC) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) prolong the survival of patients with advanced non-small cell lung cancer (NSCLC). In early studies, most patients underwent PBC as first-line treatment, but not all patients could afford EGFR-TKIs as second-line treatment. To understand the impact of PBC and EGFR-TKIs on NSCLC prognosis, we evaluated the association between the receipt of both regimens and overall survival (OS). Using MEDLINE and EMBASE, we identified prospective, randomized, controlled phase III clinical trials in advanced NSCLC that met the inclusion criteria: in general population with advanced NSCLC, the percentage of patients treated with both PBC and EGFR-TKIs was available in the trial and OS was reported. After collecting data from the selected trials, we correlated the percentage of patients treated with both PBC and EGFR-TKIs with the reported OS, using a weighted analysis. Fifteen phase III clinical trials—involving 11,456 adult patients in 32 arms—were included in the analysis, including 6 trials in Asian populations and 9 in non-Asian (predominantly Caucasian) populations. The OS was positively correlated with the percentage of patients treated with both PBC and EGFR-TKIs (r = 0.797, P < 0.001). The correlation was obvious in the trials in Asian populations (r = 0.936, P < 0.001) but was not statistically significant in the trials in predominantly Caucasian populations (r = 0.116, P = 0.588). These results suggest that treatment with PBC and EGFR-TKIs may provide a survival benefit to patients with advanced NSCLC, highlighting the importance of having both modalities available for therapy.
doi:10.5732/cjc.012.10274
PMCID: PMC3935012  PMID: 23816558
NSCLC; platinum-based doublet chemotherapy; correlation; EGFR-TKIs; overall survival
19.  Review of risk factors for human echinococcosis prevalence on the Qinghai-Tibet Plateau, China: a prospective for control options 
Objective
Echinococcosis is a major parasitic zoonosis of public health importance in western China. In 2004, the Chinese Ministry of Health estimated that 380,000 people had the disease in the region. The Qinghai-Tibet Plateau is highly co-endemic with both alveolar echinococcosis (AE) and cystic echinococcosis (CE). In the past years, the Chinese government has been increasing the financial support to control the diseases in this region. Therefore, it is very important to identify the significant risk factors of the diseases by reviewing studies done in the region in the past decade to help policymakers design appropriate control strategies.
Review
Selection criteria for which literature to review were firstly defined. Medline, CNKI (China National Knowledge Infrastructure), and Google Scholar were systematically searched for literature published between January 2000 and July 2011. Significant risk factors found by single factor and/or multiple factors analysis were listed, counted, and summarized. Literature was examined to check the comparability of the data; age and sex specific prevalence with same data structures were merged and used for further analysis.
A variety of assumed social, economical, behavioral, and ecological risk factors were studied on the Plateau. Those most at risk were Tibetan herdsmen, the old and female in particular. By analyzing merged comparable data, it was found that females had a significant higher prevalence, and a positive linearity relationship existed between echinococcosis prevalence and increasing age. In terms of behavioral risk factors, playing with dogs was mostly correlated with CE and/or AE prevalence. In terms of hygiene, employing ground water as the drinking water source was significantly correlated with CE and AE prevalence. For definitive hosts, dog related factors were most frequently identified with prevalence of CE or/and AE; fox was a potential risk factor for AE prevalence only. Overgrazing and deforestation were significant for AE prevalence only.
Conclusion
Tibetan herdsmen communities were at the highest risk of echinococcosis prevalence and should be the focus of echinococcosis control. Deworming both owned and stray dogs should be a major measure for controlling echinococcosis; treatment of wild definitive hosts should also be considered for AE endemic areas. Health education activities should be in concert with the local people’s education backgrounds and languages in order to be able to improve behaviors. Further researches are needed to clarify the importance of wild hosts for AE/CE prevalence, the extent and range of the impacts of ecologic changes (overgrazing and deforestation) on the AE prevalence, and risk factors in Tibet.
doi:10.1186/2049-9957-3-3
PMCID: PMC3910240  PMID: 24475907
Echinococcosis; Risk factors; Qinghai-Tibet Plateau; Control options
20.  ERK/CANP rapid signaling mediates 17β-estradiol-induced proliferation of human breast cancer cell line MCF-7 cells 
Objective: 17β-estradiol (E2) exerts its functions through both genomic and non-genomic signaling pathways. Because E2 is important in breast cancer development, we investigated whether its actions in promoting breast cancer cell proliferation occur through the non-genomic signaling pathway via extracellular signal-regulated kinase 1/2 (ERK1/2)/calcium-activated neutral protease (CANP). Methods: MCF-7 breast cancer cells were treated with ERKl/2 inhibitor (PD98059) or CANP inhibitor (calpeptin) before exposure to 1×10-8 M E2. MTT colorimetry and flow cytometry were used to analyze effects on cell proliferation and cell cycle progression, respectively. Expression of phosphorylated-ERK (p-ERK), total ERK, and Capn4 proteins were assessed by Western blotting. Results: Cell proliferation increased in cells treated with E2 for 24 h (P<0.05), and the proportion of cells in G0/G1 was decreased, accompanied by accelerated G1/S. Calpeptin pre-treatment significantly inhibited the E2-induced proliferation of MCF-7 cells (P<0.05), while also ameliorating the effects of E2 on cell cycle progression. Further, expression of p-ERK was rapidly up-regulated (after 10 min) by E2 (P<0.05), an effect that persisted 16 h after E2 exposure but which was significantly inhibited by PD98059 (P<0.05). Conclusions: Finally, expression of Capn4 protein was rapidly up-regulated in E2-exposed cells (P<0.05), but this change was significantly inhibited by PD98059 or calpeptin (P<0.05) pre-treatment. Thus, the rapid, non-genomic ERK/CANP signaling pathway mediates E2-induced proliferation of human breast cancer cells.
PMCID: PMC3902254  PMID: 24482702
Breast cancer cell; estradiol; cell proliferation; extracellular signal-regulated kinase
21.  The tetratricopeptide repeat-containing protein slow green1 is required for chloroplast development in Arabidopsis  
Journal of Experimental Botany  2014;65(4):1111-1123.
Summary
A chloroplast-localized tetratricopeptide repeat-containing protein, SG1, was identified through a slow-greening mutant in Arabidopsis. SG1 is required for proplastid to chloroplast transition and its mutation disrupted the transcriptions of chloroplast-related genes. It also genetically interacts with GUN1 or GUN4.
A new gene, SG1, was identified in a slow-greening mutant (sg1) isolated from an ethylmethanesulphonate-mutagenized population of Arabidopsis thaliana. The newly formed leaves of sg1 were initially albino, but gradually became pale green. After 3 weeks, the leaves of the mutant were as green as those of the wild-type plants. Transmission electron microscopic observations revealed that the mutant displayed delayed proplastid to chloroplast transition. The results of map-based cloning showed that SG1 encodes a chloroplast-localized tetratricopeptide repeat-containing protein. Quantitative real-time reverse transcription–PCR data demonstrated the presence of SG1 gene expression in all tissues, particularly young green tissues. The sg1 mutation disrupted the expression levels of several genes associated with chloroplast development, photosynthesis, and chlorophyll biosynthesis. The results of genetic analysis indicated that gun1 and gun4 partially restored the expression patterns of the previously detected chloroplast-associated genes, thereby ameliorating the slow-greening phenotype of sg1. Taken together, the results suggest that the newly identified protein, SG1, is required for chloroplast development in Arabidopsis.
doi:10.1093/jxb/ert463
PMCID: PMC3935568  PMID: 24420572
Albino; Arabidopsis thaliana; chloroplast development; proplastid to chloroplast transition; slow greening; tetratricopeptide repeat-containing protein.
22.  Comparison of concurrent chemoradiotherapy followed by radical surgery and high-dose-rate intracavitary brachytherapy: a retrospective study of 240 patients with FIGO stage IIB cervical carcinoma 
OncoTargets and therapy  2014;7:91-100.
Background
The aim of this study was to compare the long-term survival outcome and late toxicity in patients with FIGO (International Federation of Gynecology and Obstetrics) stage IIB cervical carcinoma after two treatment modalities, ie, concurrent chemoradiotherapy followed by radical surgery and concurrent chemoradiotherapy followed by high-dose-rate intracavitary brachytherapy.
Methods
Between November 2004 and November 2011, 240 patients with FIGO stage IIB cervical carcinoma were analyzed, comprising 119 patients treated with concurrent chemoradiotherapy followed by radical surgery (group 1) and 121 patients treated with concurrent chemoradiotherapy followed by high-dose-rate intracavitary brachytherapy (group 2). Local control, overall survival, progression-free survival, and treatment-related complications were compared between the two groups.
Results
The median follow-up duration was 36 months. Concurrent chemoradiotherapy followed by radical surgery showed a survival benefit when comparing group 1 and group 2 (3-year overall survival, 94.9% versus 84.6%, P=0.011; 3-year progression-free survival, 91.0% versus 81.8%, P=0.049, respectively). Three-year local pelvic control was 94.6% in group 1 and 93.3% in group 2 (P=0.325). Prognostic factors in group 1 were: age (≤35 years versus >35 years), 3-year progression-free survival (74.1% versus 90.9%, P=0.037); tumor diameter (≥6 cm versus <6 cm); and 3-year progression-free survival, (60.6% versus 92.9%, P=0.004). Prognostic factors in group 2 were: tumor diameter (≥4 cm versus <4 cm); 3-year overall survival (78.0% versus 94.8%, P=0.043); tumor diameter (≥6 cm versus <6 cm); 3-year progression-free survival (42.9% versus 84.2%, P=0.032); and 3-year overall survival (42.9% versus 87.1%, P=0.013). Further, 50 patients (42.02%) in group 1 and 46 patients (38.02%) in group 2 suffered from late complications. Analysis of the difference in composition of late complications showed that the rate of leg edema was higher in group 1 (35.29% versus 4.96%, P=0.000) while the rate of radiation enteritis was higher in group 2 (30.58% versus 5.04%, P=0.000).
Conclusion
In patients with FIGO stage IIB cervical carcinoma, concurrent chemoradiotherapy followed by radical surgery achieved higher overall survival and progression-free survival rates in comparison with radical radiotherapy associated with concurrent chemotherapy. Tumor diameter could be a common prognostic factor in these two groups of patients.
doi:10.2147/OTT.S52710
PMCID: PMC3888351  PMID: 24421644
cervical carcinoma; preoperative concurrent chemoradiotherapy; radical radiotherapy; prognostic factors; late toxicity
23.  Mediator MED23 regulates basal transcription in vivo via an interaction with P-TEFb 
Transcription  2013;4(1):39-51.
The Mediator is a multi-subunit complex that transduces regulatory information from transcription regulators to the RNA polymerase II apparatus. Growing evidence suggests that Mediator plays roles in multiple stages of eukaryotic transcription, including elongation. However, the detailed mechanism by which Mediator regulates elongation remains elusive. In this study, we demonstrate that Mediator MED23 subunit controls a basal level of transcription by recruiting elongation factor P-TEFb, via an interaction with its CDK9 subunit. The mRNA level of Egr1, a MED23-controlled model gene, is reduced 4–5 fold in Med23−/− ES cells under an unstimulated condition, but Med23-deficiency does not alter the occupancies of RNAP II, GTFs, Mediator complex, or activator ELK1 at the Egr1 promoter. Instead, Med23 depletion results in a significant decrease in P-TEFb and RNAP II (Ser2P) binding at the coding region, but no changes for several other elongation regulators, such as DSIF and NELF. ChIP-seq revealed that Med23-deficiency partially reduced the P-TEFb occupancy at a set of MED23-regulated gene promoters. Further, we demonstrate that MED23 interacts with CDK9 in vivo and in vitro. Collectively, these results provide the mechanistic insight into how Mediator promotes RNAP II into transcription elongation.
doi:10.4161/trns.22874
PMCID: PMC3644042  PMID: 23340209
basal transcription; Egr1; elongation; Mediator MED23; P-TEFb
24.  Molecular characterization and immune modulation properties of Clonorchis sinensis-derived RNASET2 
Parasites & Vectors  2013;6:360.
Background
Clonorchis sinensis (C. sinensis, Cs) is a trematode parasite that often causes chronic cumulative infections in the hepatobiliary ducts of the host and can lead to pathological changes by continuously released excretory/secretory proteins (ESPs). A T2 ribonuclease in trematode ESPs, has been identified as a potent regulator of dendritic cell (DCs) modulation. We wondered whether there was a counterpart present in CsESPs with similar activity. To gain a better understanding of CsESPs associated immune responses, we identified and characterized RNASET2 of C. sinensis (CsRNASET2) in this paper.
Methods
We expressed CsRNASET2 in Pichia pastoris and identified its molecular characteristics using bioinformatic analysis and experimental approaches. The immune modulation activities of CsRNASET2 were confirmed by evaluating cytokine production and surface markers of recombinant CsRNASET2 (rCsRNASET2) co-cultured DCs, and monitoring levels of IgG isotypes from rCsRNASET2 administered BALB/c mice.
Results
CsRNASET2 appeared to be a glycoprotein of T2 ribonuclease family harboring conserved CAS motifs and rich in B-cell epitopes. Furthermore, CsRNASET2 was present in CsESPs and was able to modulate cytokine production of DCs. In addition, rCsRNASET2 could significantly suppress the expression of lipopolysaccharide-induced DCs maturation markers. In addition, when subcutaneously administered with rCsRNASET2 there was a marked effect on IgG isotypes in mouse sera.
Conclusion
Collectively, we revealed that CsRNASET2, a T2 ribonuclease present in CsESPs, could modulate DCs maturation and might play an important role in C. sinensis associated immune regulation in the host.
doi:10.1186/1756-3305-6-360
PMCID: PMC3878043  PMID: 24365605
Clonorchis sinensis; RNASET2; T2 ribonuclease; Excretory/secretory product; Dendritic cell; Immune modulation
25.  A cross-sectional study of the clinical characteristics of hospitalized children with community-acquired pneumonia in eight eastern cities in China 
Background
Community-acquired pneumonia in children is common in China. To understand current clinical characteristics and practice, we conducted a cross-sectional study to analyze quality of care on childhood pneumonia in eight eastern cities in China.
Methods
Consecutive hospital records between January 1, 2010 and December 31, 2010 were collected from 13 traditional Chinese medicine (TCM) and western medicine (WM) hospitals in February, May, August, and November (25 cases per season, 100 cases over the year), respectively. A predesigned case report form was used to extract data from the hospital medical records.
Results
A total of 1298 cases were collected and analyzed. Symptoms and signs upon admission at TCM and WM hospitals were cough (99.3% vs. 98.6%), rales (84.8% vs. 75.0%), phlegm (83.3% vs. 49.1%), and fever (74.9% vs. 84.0%) in frequency. Patients admitted to WM hospitals had symptoms and signs for a longer period prior to admission than patients admitted to TCM hospitals. Testing to identify etiologic agents was performed in 1140 cases (88.4%). Intravenous antibiotics were administered in 99.3% (595/598) of cases in TCM hospitals and in 98.6% (699/700) of cases in WM hospitals. Besides, Chinese herbal extract injection was used more frequently in TCM hospitals (491 cases, 82.1%) than in WM hospitals (212 cases, 30.3%) (p < 0.01). At discharge, 818 cases (63.0%) were clinically cured, with a significant difference between the cure rates in TCM (87.6%) and WM hospitals (42.0%) (OR = 9.8, 95% confidence interval (CI): 7.3 ~ 12.9, p < 0.01). Pathogen and previous medical history were more likely associated with the disappearance of rales (OR = 7.2, 95% CI: 4.8 ~ 10.9). Adverse effects were not reported from the medical records.
Conclusions
Intravenous use of antibiotics is highly prevalent in children with community-acquired pneumonia regardless of aetiology. There was difference between TCM and WM hospitals with regard to symptom profile and the use of antibiotics. Intravenous use of herbal injection was higher in TCM hospitals than in WM hospitals. Most of the cases were diagnosed based on clinical signs and symptoms without sufficient confirmation of aetiology. Audit of current practice is urgently needed to improve care.
doi:10.1186/1472-6882-13-367
PMCID: PMC3880031  PMID: 24364897
Childhood pneumonia; Community-acquired; Clinical characteristics; Treatment; Cross-sectional study; Chinese population

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