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1.  The expression dynamics of transforming growth factor-β/Smad signaling in the liver fibrosis experimentally caused by Clonorchis sinensis 
Parasites & Vectors  2015;8:70.
Background
Liver fibrosis is a hallmark of clonorchiasis suffered by millions people in Eastern Asian countries. Recent studies showed that the activation of TGF-β/Smad signaling pathway can potently regulate the hepatic fibrogenesis including Schistosoma spp. and Echinococcus multilocularis-caused liver fibrosis. However, little is known to date about the expression of transforming growth factor-β (TGF-β) and other molecules in TGF-β/Smad signaling pathway which may play an important role in hepatic fibrosis caused by C. sinensis.
Methods
A total of 24 mice were individually infected orally with 45 metacercariae, both experimental mice and mocked-infected control mice were anesthetized at 4 week post-infection (wk p.i.), 8 wk p.i. and 16 wk p.i., respectively. For each time-point, the liver and serum from each animal were collected to analyze histological findings and various fibrotic parameters including TGF-β1, TGF-β receptors and down-stream Smads activation, as well as fibrosis markers expression.
Results
The results showed that collagen deposition indicated by hydroxyproline content and Masson’s trichrome staining was increased gradually with the development of infection. The expression of collagen type α1 (Col1a) mRNA transcripts was steadily increased during the whole infection. The mRNA levels of Smad2, Smad3 as well as the protein of Smad3 in the liver of C. sinensis-infected mice were increased after 4 wk p.i. (P < 0.05, compared with normal control) whereas the TGF-β1, TGF-β type I receptor (TGFβRI) and TGF-β type II receptor (TGFβRII) mRNA expression in C. sinensis-infected mice were higher than those of normal control mice after 8 wk p.i. (P < 0.05). However, the gene expression of Smad4 and Smad7 were peaked at 4 wk p.i. (P < 0.05), and thereafter dropped to the basal level at 8 wk p.i., and 16 wk p.i., respectively. The concentrations of TGF-β1 in serum in the C. sinensis-infected mice at 8 wk p.i. and 16 wk p.i (P < 0.05) were significantly higher than those in the control mice.
Conclusions
The results of the present study indicated for the first time that the activation of TGF-β/Smad signaling pathway might contribute to the synthesis of collagen type I which leads to liver fibrosis caused by C. sinensis.
doi:10.1186/s13071-015-0675-y
PMCID: PMC4329204  PMID: 25649869
Clonorchis sinensis; Liver fibrosis; Transforming growth factor-β; Smads
2.  Akt-independent GSK3 inactivation downstream of PI3K signaling regulates mammalian axon regeneration 
Inactivation of glycogen synthase kinase 3 (GSK3) has been shown to mediate axon growth during development and regeneration. Phosphorylation of GSK3 by the kinase Akt is well known to be the major mechanism by which GSK3 is inactivated. However, whether such regulatory mechanism of GSK3 inactivation is used in neurons to control axon growth has not been directly studied. Here by using GSK3 mutant mice, in which GSK3 is insensitive to Akt-mediated inactivation, we show that sensory axons regenerate normally in vitro and in vivo after peripheral axotomy. We also find that GSK3 in sensory neurons of the mutant mice is still inactivated in response to peripheral axotomy and such inactivation is required for sensory axon regeneration. Lastly, we provide evidence that GSK3 activity is negatively regulated by PI3K signaling in the mutant mice upon peripheral axotomy, and the PI3K-GSK3 pathway is functionally required for sensory axon regeneration. Together, these results indicate that in response to peripheral nerve injury GSK3 inactivation, regulated by an alternative mechanism independent of Akt-mediated phosphorylation, controls sensory axon regeneration.
doi:10.1016/j.bbrc.2013.12.037
PMCID: PMC3916952  PMID: 24333443
Axon regeneration; GSK3 signaling; PI3K signaling; In vivo electroporation
3.  Risk Factors and Prognostic Significance of Retropancreatic Lymph Nodes in Gastric Adenocarcinoma 
Background. The studies on risk factors and metastatic rate of retropancreatic (number 13) lymph nodes in gastric adenocarcinoma were few and the results were still controversial. The aim of this study was to elucidate risk factors and prognostic significance of number 13 lymph nodes in gastric adenocarcinoma. Method. From January 2000 to December 2011, 114 patients who underwent gastrectomy with number 13 lymph nodes dissection were enrolled and followed up to January 2014. Patients were grouped according to whether number 13 lymph nodes were positive or negative. Results. The metastatic rate of number 13 lymph nodes was 22.8%. In multivariate analysis, pT stage (P = 0.027), pN stage (P = 0.005), and number 11p (P = 0.015) lymph nodes were independent risk factors of positive number 13 lymph nodes. In all patients (P < 0.001) and subpopulation with TNM III stage (P = 0.007), positive number 13 lymph nodes had significantly worse prognosis than those of patients with negative number 13 LNs in Kaplan-Meier analysis. Conclusion. Number 13 lymph nodes had relatively high metastatic rate and led to poor prognosis. pT stage, pN stage, and number 11p lymph nodes were independent risk factors of positive number 13 lymph nodes.
doi:10.1155/2015/367679
PMCID: PMC4302373  PMID: 25642243
4.  Posttranscriptional Regulation of 2,4-Diacetylphloroglucinol Production by GidA and TrmE in Pseudomonas fluorescens 2P24 
Applied and Environmental Microbiology  2014;80(13):3972-3981.
Pseudomonas fluorescens 2P24 is a soilborne bacterium that synthesizes and excretes multiple antimicrobial metabolites. The polyketide compound 2,4-diacetylphloroglucinol (2,4-DAPG), synthesized by the phlACBD locus, is its major biocontrol determinant. This study investigated two mutants defective in antagonistic activity against Rhizoctonia solani. Deletion of the gidA (PM701) or trmE (PM702) gene from strain 2P24 completely inhibited the production of 2,4-DAPG and its precursors, monoacetylphloroglucinol (MAPG) and phloroglucinol (PG). The transcription of the phlA gene was not affected, but the translation of the phlA and phlD genes was reduced significantly. Two components of the Gac/Rsm pathway, RsmA and RsmE, were found to be regulated by gidA and trmE, whereas the other components, RsmX, RsmY, and RsmZ, were not. The regulation of 2,4-DAPG production by gidA and trmE, however, was independent of the Gac/Rsm pathway. Both the gidA and trmE mutants were unable to produce PG but could convert PG to MAPG and MAPG to 2,4-DAPG. Overexpression of PhlD in the gidA and trmE mutants could restore the production of PG and 2,4-DAPG. Taken together, these findings suggest that GidA and TrmE are positive regulatory elements that influence the biosynthesis of 2,4-DAPG posttranscriptionally.
doi:10.1128/AEM.00455-14
PMCID: PMC4054201  PMID: 24747907
5.  Core Self-Evaluation and Burnout among Nurses: The Mediating Role of Coping Styles 
PLoS ONE  2014;9(12):e115799.
Objectives
This study aimed to determine the potential association between core self-evaluation and the burnout syndrome among Chinese nurses, and the mediating role of coping styles in this relationship.
Methods
A cross-sectional survey was conducted in Shenyang, China, from May to July, 2013. A questionnaire which consisted of the Maslach Burnout Inventory-General Survey (MBI-GS), the Core Self-Evaluation Scale (CSE), and the Simplified Coping Style Questionnaire (CSQ), was completed by a total of 1,559 nurses. Hierarchical linear regression analyses and the Sobel test were performed to determine the mediating role of coping styles on the relationship between CSE and burnout.
Results
Nurses who had higher self-evaluation characteristics, reported less emotional exhaustion and cynicism, and higher professional efficacy. Coping style had a partial mediating effect on the relationship between CSE and the burnout syndrome among nurses.
Conclusions
Core self-evaluation had effects on burnout and coping style was a mediating factor in this relationship among Chinese nurses. Therefore, the improvement of coping strategies may be helpful in the prevention of burnout among nurses, thus enhancing professional performance.
doi:10.1371/journal.pone.0115799
PMCID: PMC4277418  PMID: 25541990
6.  Ultrasound hepatic/renal ratio and hepatic attenuation rate for quantifying liver fat content 
World Journal of Gastroenterology : WJG  2014;20(47):17985-17992.
AIM: To establish and validate a simple quantitative assessment method for nonalcoholic fatty liver disease (NAFLD) based on a combination of the ultrasound hepatic/renal ratio and hepatic attenuation rate.
METHODS: A total of 170 subjects were enrolled in this study. All subjects were examined by ultrasound and 1H-magnetic resonance spectroscopy (1H-MRS) on the same day. The ultrasound hepatic/renal echo-intensity ratio and ultrasound hepatic echo-intensity attenuation rate were obtained from ordinary ultrasound images using the MATLAB program.
RESULTS: Correlation analysis revealed that the ultrasound hepatic/renal ratio and hepatic echo-intensity attenuation rate were significantly correlated with 1H-MRS liver fat content (ultrasound hepatic/renal ratio: r = 0.952, P = 0.000; hepatic echo-intensity attenuation r = 0.850, P = 0.000). The equation for predicting liver fat content by ultrasound (quantitative ultrasound model) is: liver fat content (%) = 61.519 × ultrasound hepatic/renal ratio + 167.701 × hepatic echo-intensity attenuation rate -26.736. Spearman correlation analysis revealed that the liver fat content ratio of the quantitative ultrasound model was positively correlated with serum alanine aminotransferase, aspartate aminotransferase, and triglyceride, but negatively correlated with high density lipoprotein cholesterol. Receiver operating characteristic curve analysis revealed that the optimal point for diagnosing fatty liver was 9.15% in the quantitative ultrasound model. Furthermore, in the quantitative ultrasound model, fatty liver diagnostic sensitivity and specificity were 94.7% and 100.0%, respectively, showing that the quantitative ultrasound model was better than conventional ultrasound methods or the combined ultrasound hepatic/renal ratio and hepatic echo-intensity attenuation rate. If the 1H-MRS liver fat content had a value < 15%, the sensitivity and specificity of the ultrasound quantitative model would be 81.4% and 100%, which still shows that using the model is better than the other methods.
CONCLUSION: The quantitative ultrasound model is a simple, low-cost, and sensitive tool that can accurately assess hepatic fat content in clinical practice. It provides an easy and effective parameter for the early diagnosis of mild hepatic steatosis and evaluation of the efficacy of NAFLD treatment.
doi:10.3748/wjg.v20.i47.17985
PMCID: PMC4273150  PMID: 25548498
Non-alcoholic fatty liver disease; Ultrasound hepatic/renal ratio; Ultrasound hepatic echo-intensity attenuation rate
7.  Time trends and age-period-cohort analyses on incidence rates of thyroid cancer in Shanghai and Hong Kong 
BMC Cancer  2014;14(1):975.
Background
Increasing incidence rates of thyroid cancer have been noted worldwide, while the underlying reasons remain unclear.
Methods
Using data from population-based cancer registries, we examined the time trends of thyroid cancer incidence in two largest cities in China, Shanghai and Hong Kong, during the periods 1973–2009 and 1983–2011, respectively. We further performed age-period-cohort analyses to address the possible underlying reasons for the observed temporal trends.
Results
We observed continuous increases in the incidence rates of thyroid cancer in Shanghai and Hong Kong, since the 1980s, in addition to higher incidence rates in the 1970s in both sexes in Shanghai. The age-standardized incidence rate of thyroid cancer increased by 3.1% [95% confidence interval (CI): 1.0%, 5.1%] and 3.8% (95% CI: 1.9%, 5.7%) per year on average, respectively, in Shanghai men and women during the period 1973–2009, while it increased by 2.2% (95% CI: 1.5%, 2.8%) and 2.7% (1.6%, 3.8%) per year on average, respectively, in Hong Kong men and women during the period 1983–2011. We observed global changes in trends across all age groups in similar ways, in addition to varied trends across different generations (birth cohorts).
Conclusions
The increased incidence rates of thyroid cancer in these two Chinese populations during recent decades may be contributable to a combination of the introduction of more sensitive diagnostic techniques and the increasing prevalence of environmental exposures in the populations.
doi:10.1186/1471-2407-14-975
PMCID: PMC4301456  PMID: 25519305
Thyroid cancer; Incidence; Time trend; Age–period–cohort analysis; Etiology
8.  Purification, crystallization and preliminary X-ray crystallographic analysis of the CIDE-N domain of Fsp27 
The CIDE-N domain of Fsp27 expressed in E. coli was purified as a monomer and identified by LC/MS/MS. Crystals of the Fsp27 CIDE-N domain were grown in sitting-drop mode and diffracted to 1.92 Å resolution.
Fsp27, a member of the CIDE protein family which is selectively expressed in adipocytes, has emerged as a novel regulator for unilocular lipid droplet (LD) formation, lipid metabolism, differentiation of adipocytes and insulin sensitivity. An LD is a subcellular compartment that is used by adipocytes for the efficient storage of fats. The CIDE-N domain of Fsp27 functions as a recruitment platform that induces the correct configuration of the Fsp27 CIDE-C domain to facilitate LD fusion. This study reports the high-yield expression of the mouse Fsp27 CIDE-N domain in Escherichia coli; a two-step purification protocol with high efficiency was established and crystallographic analysis was performed. The purity of the recombinant Fsp27 was >95% as assessed by SDS–PAGE. Crystals were obtained at 291 K using 28% polyethylene glycol 4000 as a precipitant. Diffraction data were collected to 1.92 Å resolution and the crystal belonged to space group P65, with unit-cell parameters a = b = 63.3, c = 37.4 Å, α = β = 90, γ = 120°. The components of the crystal were identified by ion-trap LC/MS/MS spectrometric analysis. The structure has been solved by molecular replacement and refinement is in progress.
doi:10.1107/S1744309112043989
PMCID: PMC3509981  PMID: 23192040
CIDEC; Fsp27; obesity; prokaryotic expression; unilocular lipid droplets
9.  Evaluation of Long-term Vitamin E Insufficiency or Excess on Bone Mass, Density and Microarchitecture in Rodents 
Free radical biology & medicine  2013;65:10.1016/j.freeradbiomed.2013.09.004.
High dietary α-tocopherol levels reportedly result in osteopenia in growing rats, while α-tocopherol deficiency in α-tocopherol transfer protein knockout (α-TTP KO) mice results in increased cancellous bone mass. Since osteoporosis is a disease associated primarily with aging, we hypothesized that age-related bone loss would be attenuated in α-TTP KO mice. Cancellous and cortical bone mass and microarchitecture were assessed using dual energy x-ray absorptiometry and micro-computed tomography in 2-year-old α-TTP KO and wildtype (WT) male and female mice fed DL-α-tocopherol acetate. In contrast to our expectations, differences in cancellous bone were not detected between WT and α-TTP KO mice in either gender and α-TTP KO males had lower (p < 0.05) cortical bone mass than WT males. We therefore evaluated bone mass, density and microarchitecture in proximal femur of skeletally mature (8.5-months-old) male Sprague-Dawley rats fed diets containing low (15 IU/kg), adequate (75 IU/kg), or high (500 IU/kg diet) DL-α-tocopherol acetate for 13 weeks. Low dietary α-tocopherol did not increase bone mass. Furthermore, no reductions in cancellous or cortical bone mass were detected with high dietary α-tocopherol. Failure to detect increased bone mass in aged α-TTP KO mice or bone changes in skeletally mature rats fed either low or high levels of α-tocopherol does not support the hypothesis that α-tocopherol has a negative impact on bone mass, density or microarchitecture in rodents.
doi:10.1016/j.freeradbiomed.2013.09.004
PMCID: PMC3859709  PMID: 24051180
Vitamin E; osteoporosis; rodent; skeleton; oxidative stress
10.  Influence of Iron and Aeration on Staphylococcus aureus Growth, Metabolism, and Transcription 
Journal of Bacteriology  2014;196(12):2178-2189.
Staphylococcus aureus is a prominent nosocomial pathogen and a major cause of biomaterial-associated infections. The success of S. aureus as a pathogen is due in part to its ability to adapt to stressful environments. As an example, the transition from residing in the nares to residing in the blood or deeper tissues is accompanied by changes in the availability of nutrients and elements such as oxygen and iron. As such, nutrients, oxygen, and iron are important determinants of virulence factor synthesis in S. aureus. In addition to influencing virulence factor synthesis, oxygen and iron are critical cofactors in enzymatic and electron transfer reactions; thus, a change in iron or oxygen availability alters the bacterial metabolome. Changes in metabolism create intracellular signals that alter the activity of metabolite-responsive regulators such as CodY, RpiRc, and CcpA. To assess the extent of metabolomic changes associated with oxygen and iron limitation, S. aureus cells were cultivated in iron-limited medium and/or with decreasing aeration, and the metabolomes were examined by nuclear magnetic resonance (NMR) spectroscopy. As expected, oxygen and iron limitation dramatically decreased tricarboxylic acid (TCA) cycle activity, creating a metabolic block and significantly altering the metabolome. These changes were most prominent during post-exponential-phase growth, when TCA cycle activity was maximal. Importantly, many of the effects of iron limitation were obscured by aeration limitation. Aeration limitation not only obscured the metabolic effects of iron limitation but also overrode the transcription of iron-regulated genes. Finally, in contrast to previous speculation, we confirmed that acidification of the culture medium occurs independent of the availability of iron.
doi:10.1128/JB.01475-14
PMCID: PMC4054190  PMID: 24706736
11.  Ethanol extract of Portulaca Oleracea L. reduced the carbon tetrachloride induced liver injury in mice involving enhancement of NF-κB activity 
Acute hepatic injury causes high morbidity and mortality world-wide. Management of severe acute hepatic failure continues to be one of the most challenging problems in clinical medicine. In present study, carbon tetrachloride (CCl4) was used to induce acute liver damage in mice and the protective effects of ethanol extract of Portulaca Oleracea L. (PO) were examined. The aminotransferase activities were biochemical estimated and the liver damage was tested by morphological histological analysis and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. The role of PO on the activity of NF-κB was determined by luciferase reporter gene assay and immunohistochemistry. The level of p-p65 was tested by western blot. Our results showed that PO administration on mice would decrease the serum aminotransferase level and reduced the liver histological damage. We also found that nuclear translocation of p65 was enhanced in liver tissues of mice treated with PO compared with control animals. In addition, in cultured hepatic cells, PO increased the NF-κB luciferase reporter gene activity and upregulated the level of phosphorylation of p65, but had no effects on mice liver SOD activity and MDA level. Collectively, PO attenuated CCl4 induced mice liver damage by enhancement of NF-κB activity.
PMCID: PMC4297342  PMID: 25628785
Carbon tetrachloride (CCl4); ethanol extract of Portulaca Oleracea L (PO); liver injury; NF-κB
12.  LC–MS/MS determination and pharmacokinetic study of columbianadin in rat plasma after intravenous administration of pure columbianadin 
Background
Columbianadin, one of the active coumarins, is isolated from Radix Angelicae pubescentis which has been used as a traditional Chinese medicine for the treatment of rheumatic diseases for thousands of years. A fast and sensitive method is required for the determination of columbianadin for pharmacokinetic studies. Liquid chromatography–tandem mass spectrometry (LC-MS/MS) method is a preeminent analytical tool for rapid biomedical analysis.
Results
A sensitive LC-MS/MS method has been validated to determine the concentration of columbianadin in rat plasma after intravenous administration of columbianadin (1, 2.5 and 5 mg kg−1). Liquid-liquid extraction was used to extract columbianadin from the rat plasma. Bergapten was selected as an internal standard (IS). The separations were performed on an Eclipse plus C18 column (4.6 × 100 mm, 1.8 μm) with ammonium acetate aqueous solution (1 mmol L−1) and acetonitrile as the mobile phase. The flow rate was set at 0.300 mL min−1. Quantification was performed using multiple reaction monitoring (MRM) mode to monitor transitions of m/z 329.3 → 229.3 for columbianadin and m/z 217.2 → 202.2 for IS at positive ionization mode. The calibration curve was linear over the concentration range of 4–20000 ng mL−1 with a correlation coefficient (r) of 0.996 or better. The precision of intra- and inter-batch assays ranged from 4.02 to 7.33% and accuracies determined at three concentrations ranged between 91.9% and 106%. The lower limit of quantification was about 4 ng mL−1.
Conclusion
The proposed LC-MS/MS method is simple, rapid and highly sensitive so that it could be used to evaluate pharmacokinetic properties of columbianadin in rat plasma after intravenous administration.
doi:10.1186/s13065-014-0064-1
PMCID: PMC4280029  PMID: 25550710
Radix angelicae pubescentis; Columbianadin; LC-MS/MS; Intravenous administration
13.  LC–MS/MS determination and pharmacokinetic study of columbianadin in rat plasma after intravenous administration of pure columbianadin 
Background
Columbianadin, one of the active coumarins, is isolated from Radix Angelicae pubescentis which has been used as a traditional Chinese medicine for the treatment of rheumatic diseases for thousands of years. A fast and sensitive method is required for the determination of columbianadin for pharmacokinetic studies. Liquid chromatography–tandem mass spectrometry (LC-MS/MS) method is a preeminent analytical tool for rapid biomedical analysis.
Results
A sensitive LC-MS/MS method has been validated to determine the concentration of columbianadin in rat plasma after intravenous administration of columbianadin (1, 2.5 and 5 mg kg−1). Liquid-liquid extraction was used to extract columbianadin from the rat plasma. Bergapten was selected as an internal standard (IS). The separations were performed on an Eclipse plus C18 column (4.6 × 100 mm, 1.8 μm) with ammonium acetate aqueous solution (1 mmol L−1) and acetonitrile as the mobile phase. The flow rate was set at 0.300 mL min−1. Quantification was performed using multiple reaction monitoring (MRM) mode to monitor transitions of m/z 329.3 → 229.3 for columbianadin and m/z 217.2 → 202.2 for IS at positive ionization mode. The calibration curve was linear over the concentration range of 4–20000 ng mL−1 with a correlation coefficient (r) of 0.996 or better. The precision of intra- and inter-batch assays ranged from 4.02 to 7.33% and accuracies determined at three concentrations ranged between 91.9% and 106%. The lower limit of quantification was about 4 ng mL−1.
Conclusion
The proposed LC-MS/MS method is simple, rapid and highly sensitive so that it could be used to evaluate pharmacokinetic properties of columbianadin in rat plasma after intravenous administration.
doi:10.1186/s13065-014-0064-1
PMCID: PMC4280029  PMID: 25550710
Radix angelicae pubescentis; Columbianadin; LC-MS/MS; Intravenous administration
14.  Live Birth Sex Ratio after In Vitro Fertilization and Embryo Transfer in China - An Analysis of 121,247 Babies from 18 Centers 
PLoS ONE  2014;9(11):e113522.
In order to study the impact of procedures of IVF/ICSI technology on sex ratio in China, we conducted this multi-center retrospective study including 121,247 babies born to 93,895 women in China. There were 62,700 male babies and 58,477 female babies, making the sex ratio being 51.8% (Male: Female  = 107∶100). In univariate logistic regression analysis, sex ratio was imbalance toward females of 50.3% when ICSI was preformed compared to 47.7% when IVF was used (P<0.01). The sex ratio in IVF/ICSI babies was significantly higher toward males in transfers of blastocyst (54.9%) and thawed embryo (52.4%) when compared with transfers of cleavage stage embryo (51.4%) and fresh embryo (51.5%), respectively. Multiple delivery was not associated with sex ratio. However, in multivariable logistic regression analysis after controlling for related factors, only ICSI (adjusted OR = 0.90, 95%CI: 0.88–0.93; P<0.01) and blastocyst transfer (adjusted OR = 1.14, 95% CI: 1.09–1.20; P<0.01) were associated with sex ratio in IVF/ICSI babies. In conclusion, the live birth sex ratio in IVF/ICSI babies was influenced by the use of ICSI, which may decrease the percentage of male offspring, or the use of blastocyst transfer, which may increase the percentage of male offspring.
doi:10.1371/journal.pone.0113522
PMCID: PMC4239103  PMID: 25412419
15.  The role of FKBP5 in mood disorders: Action of FKBP5 on steroid hormone receptors leads to questions about its evolutionary importance 
Research on the FKBP5 gene and FKBP51 protein has more than doubled since the discovery that polymorphisms in this gene could alter treatment outcomes and depressive behavior in humans. This coincided with other data suggesting that the stress hormone axis contributes to the development of numerous mental illnesses. As a result, FKBP51 now lies at the heart of the research of many stress related psychiatric disorders, which has led to advances in the understanding of this protein and its role in humans and in animal models. Specifically, FKBP5−/− mice and a naturally existing overexpression of FKBP5 in 3 genera of new world monkeys have helped understand the effects of FKBP5 in vivo. This review will highlight these finding as well as discuss the current evolutionary need for the FKBP5 gene.
PMCID: PMC4236834  PMID: 24040820
FK506-binding protein 51; FKBP5 gene; Heat shock protein 90; glucocorticoid receptor; depression; post-traumatic stress disorder; suicide; polymorphisms; genome-wide association studies; stress; behavior; resilience
16.  Transcatheter arterial chemoembolization combined with radiofrequency ablation delays tumor progression and prolongs overall survival in patients with intermediate (BCLC B) hepatocellular carcinoma 
BMC Cancer  2014;14(1):849.
Background
This study was designed to evaluate the effectiveness of radiofrequency ablation in patients with intermediate (BCLC B) stage hepatocellular carcinoma who underwent transcatheter arterial chemoembolization.
Methods
Included in this study were 211 patients with intermediate stage HCC who underwent initial transcatheter arterial chemoembolization and were potentially amendable for radiofrequency ablation (single tumor with diameter 5-8 cm, median 6.0 cm; 2–5 multiple nodules with diameter less than 5 cm) between January 2005 and December 2011. According to the inclusion and exclusion criteria, 55 patients were treated with following radiofrequency ablation, and the remaining 156 patients were treated with transcatheter arterial chemoembolization alone. The treatment effectiveness, local tumor control and survival outcome between the two groups were compared.
Results
The complete tumor necrosis rate after treatment was 76.9% in combination group vs. 46.5% in transcatheter arterial chemoembolization alone group (P = 0.02). The major complication rate was 1.8% in combination group vs. 2.6% in transcatheter arterial chemoembolization alone group. Follow-up observation showed that the total tumor control rate was 74.5% in combination group versus 54.5% in transcatheter arterial chemoembolization alone group (P < 0.001). The 1-, 3- and 5-year survival rates in combination group were significantly higher than those in TACE alone group (P = 0.01).
Conclusions
Radiofrequency ablation following initial transcatheter arterial chemoembolization delays tumor progression and prolongs overall survival of patients with intermediate stage HCC tumors.
doi:10.1186/1471-2407-14-849
PMCID: PMC4256894  PMID: 25409554
Hepatocellular carcinoma; Transcatheter arterial chemoembolization; Radiofrequency ablation; Combination therapy; Survival
17.  Cytoplasmic irradiation results in mitochondrial dysfunction and DRP1-dependent mitochondrial fission 
Cancer research  2013;73(22):6700-6710.
Direct DNA damage is often considered the primary cause of cancer in patients exposed to ionizing radiation or environmental carcinogens. While mitochondria are known to play an important role in radiation-induced cellular response, the mechanisms by which cytoplasmic stimuli modulate mitochondrial dynamics and functions are largely unknown. In the present study, we examined changes in mitochondrial dynamics and functions triggered by α particle damage to the mitochondria in human small airway epithelial cells, using a precision microbeam irradiator with a beam width of one micron. Targeted cytoplasmic irradiation using this device resulted in mitochondrial fragmentation and a reduction of cytochrome c oxidase and succinate dehydrogenase activity, when compared with nonirradiated controls, suggesting a reduction in respiratory chain function. Additionally, mitochondrial fragmentation or fission was associated with increased expression of the dynamin-like protein DRP1, which promotes mitochondrial fission. DRP1 inhibition by the drug mdivi-1 prevented radiation-induced mitochondrial fission, but respiratory chain function in mitochondria inhibited by radiation persisted for 12 hr. Irradiated cells also showed an increase in mitochondria-derived superoxide that could be quenched by dimethyl sulfoxide. Taken together, our results provide a mechanistic explanation for the extranuclear, non-targeted effects of ionizing radiation.
doi:10.1158/0008-5472.CAN-13-1411
PMCID: PMC3934017  PMID: 24080278
cytoplasmic irradiation; mitochondrial fission; fusion; dynamics; DRP1
18.  Polyethylene glycol–polylactic acid nanoparticles modified with cysteine–arginine–glutamic acid–lysine–alanine fibrin-homing peptide for glioblastoma therapy by enhanced retention effect 
For a nanoparticulate drug-delivery system, crucial challenges in brain-glioblastoma therapy are its poor penetration and retention in the glioblastoma parenchyma. As a prevailing component in the extracellular matrix of many solid tumors, fibrin plays a critical role in the maintenance of glioblastoma morphology and glioblastoma cell differentiation and proliferation. We developed a new drug-delivery system by conjugating polyethylene glycol–polylactic acid nanoparticles (NPs) with cysteine–arginine–glutamic acid–lysine–alanine (CREKA; TNPs), a peptide with special affinity for fibrin, to mediate glioblastoma-homing and prolong NP retention at the tumor site. In vitro binding tests indicated that CREKA significantly enhanced specific binding of NPs with fibrin. In vivo fluorescence imaging of glioblastoma-bearing nude mice, ex vivo brain imaging, and glioblastoma distribution demonstrated that TNPs had higher accumulation and longer retention in the glioblastoma site over unmodified NPs. Furthermore, pharmacodynamic results showed that paclitaxel-loaded TNPs significantly prolonged the median survival time of intracranial U87 glioblastoma-bearing nude mice compared with controls, Taxol, and NPs. These findings suggested that TNPs were able to target the glioblastoma and enhance retention, which is a valuable strategy for tumor therapy.
doi:10.2147/IJN.S72649
PMCID: PMC4235507  PMID: 25419130
CREKA peptide; nanoparticles; retention effect; paclitaxel; glioblastoma
19.  Hemangioendothelioma arising from the spleen: A case report and literature review 
Oncology Letters  2014;9(1):209-212.
Primary hemangioendotheliomas (HEs) of the spleen are rare, low-grade borderline-malignant vascular tumors. To date, only a few splenic HE cases have been reported in adults. In infants, one 9-year-old male patient has previously been reported, and the patient succumbed to the disease shortly following surgery. Currently, the clinical treatment and prognosis of the disease remains challenging to define, due to the extremely low number of cases reported. The current report presents the case of a 9-year-old pediatric patient with splenic HE, who survived with no recurrence or complications following a partial splenectomy. Additionally, a literature review was conducted to analyze the treatment and prognosis of the disease.
doi:10.3892/ol.2014.2693
PMCID: PMC4246698  PMID: 25435960
hemangioendotheliomas; spleen; partial splenectomy
20.  MicroRNA-21 and the clinical outcomes of various carcinomas: a systematic review and meta-analysis 
BMC Cancer  2014;14(1):819.
Background
MicroRNA-21 (miR-21) has been suggested to play a significant role in the prognosis of carcinoma. The recognition of novel biomarkers for the prediction of cancer outcomes is urgently required. However, the potential prognostic value of miR-21 in various types of human malignancy remains controversial. The present meta-analysis summarises and analyses the associations between miR-21 status and overall survival (OS) in a variety of tumours.
Methods
Eligible published studies were identified by searching the PubMed and Chinese Biomedicine databases. The patients’ clinical characteristics and survival results were pooled, and a pooled hazard ratio (HR) with 95% confidence intervals (95% CI) was used to calculate the strength of this association. A random-effects model was adopted, and then, meta-regression and subgroup analyses were performed. In addition, an analysis of publication bias was also conducted.
Results
Twenty-seven eligible articles (including 31 studies) were identified that included survival data for 3273 patients. The pooled HR suggested that high miR-21 was clearly related to worse overall survival (HR = 2.27, 95% CI: 1.81-2.86), with a heterogeneity measure index of I2 = 76.0%, p = 0.001, showing that miR-21 might be a considerable prognostic factor for poor survival in cancer patients.
Conclusions
MiR-21 might be a potentially useful biomarker for predicting cancer prognosis in future clinical applications.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-819) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2407-14-819
PMCID: PMC4232634  PMID: 25376700
miR-21; Cancer; Prognosis; Meta-analysis
21.  Comparison of genetic variation of breast cancer susceptibility genes in Chinese and German populations 
European Journal of Human Genetics  2013;21(11):1286-1292.
Genome-wide association studies (GWAS) identified several genetic risk factors for breast cancer, however, most of them were validated among women of European ancestry. This study examined single-nucleotide polymorphisms (SNPs) contributing to breast cancer in Chinese (984 cases and 2206 controls) and German (311 cases and 960 controls) populations. Eighteen SNPs significantly associated with breast cancer, previously identified in GWAS were genotyped. Twelve SNPs passed quality control and were subjected to statistical analysis. Seven SNPs were confirmed to be significantly associated with breast cancer in the Chinese population, reflecting three independent loci (ESR1, FGFR2, TOX3) and five of these were also confirmed in the German population. The strongest association was identified for rs2046210 in the Chinese (odds ratio (OR)=1.42, 95% confidence interval (CI)=1.28–1.59, P=1.9 × 10−10) and rs3803662 in the German population (OR=1.43, 95% CI=1.17–1.74, P=4.01 × 10−4), located upstream of the ESR1 and TOX3 gene, respectively. For the first time, rs3757318 at 6q25.1, located next to the gene encoding estrogen receptor α (ESR1) was found to be strongly associated with breast cancer (OR=1.33, 95% CI=1.18–1.49, P=1.94 × 10−6) in the Chinese population. The frequency of this variant was markedly lower in the German population and the association was not significant. Despite the genetic differences, essentially the same risk loci were identified in the Chinese and the German populations. Our study suggested the existence of common genetic factors as well as disease susceptibility differences for breast cancer in both populations and highlighted the importance of performing comparison analyses for disease susceptibility within ethnic populations.
doi:10.1038/ejhg.2013.38
PMCID: PMC3798843  PMID: 23486537
breast cancer; single-nucleotide polymorphism (SNP); association studies; Chinese population; German population
22.  The Stent-Assisted Coil-Jailing Technique Facilitates Efficient Embolization of Tiny Cerebral Aneurysms 
Korean Journal of Radiology  2014;15(6):850-857.
Objective
Tiny cerebral aneurysms are difficult to embolize because the aneurysm's sac is too small for a single small coil, and coils within the aneurysm may escape from the confinement of a stent. This study was performed to introduce the stent-assisted coil-jailing technique and to investigate its effect on the coil embolization of tiny intracranial aneurysms.
Materials and Methods
Sixteen patients with tiny intracranial aneurysms treated with the stent-assisted coil-jailing technique between January 2011 and December 2013 were retrospectively reviewed and followed-up.
Results
All aneurysms were successfully treated with the coil-jailing technique, and at the end of embolization, complete occlusion of the aneurysm was achieved in 9 cases (56.3%), incomplete occlusion in 6 (37.5%), and partial occlusion in 1 (6.3%). Intraprocedural complications included acute thrombosis in one case (6.3%) and re-rupture in another (6.3%). Both complications were managed appropriately with no sequela. Follow-up was performed in all patients for 3-24 months (mean, 7.7 months) after embolization. Complete occlusion was sustained in the 9 aneurysms with initial complete occlusion, progressive thrombosis to complete occlusion occurred in the 6 aneurysms with initial near-complete occlusion, and one aneurysm resulted in progressive thrombosis to complete occlusion after initial partial occlusion. No migration of stents or coils occurred at follow-up as compared with their positions immediately after embolization. At follow-up, all patients had recovered with no sequela.
Conclusion
The stent-assisted coil-jailing technique can be an efficient approach for tiny intracranial aneurysms, even though no definite conclusion regarding its safety can be drawn from the current data.
doi:10.3348/kjr.2014.15.6.850
PMCID: PMC4248643  PMID: 25469099
Tiny intracranial aneurysm; Stent-assisted coiling; Redundant coil tails; Coil migration
23.  Preoperative imatinib for patients with primary unresectable or metastatic/recurrent gastrointestinal stromal tumor 
Clinics  2014;69(11):758-762.
OBJECTIVES:
Despite its rising popularity, reports on the use of preoperative imatinib mesylate (IM) in patients with advanced gastrointestinal stromal tumor (GIST) are limited. This study aims to explore the clinical efficacy of preoperative IM in patients with primarily unresectable or metastatic/recurrent GIST.
METHODS:
Between September 2009 and February 2014, patients with primarily unresectable or metastatic/recurrent GIST treated by a single medical team were recruited and considered for preoperative IM therapy. Re-examination was conducted regularly and abdominal enhanced CT data, blood biochemistry and responses to IM were recorded.
RESULTS:
A total of 18 patients were enrolled, including 13 with a primary tumor (7 stomach, 3 small bowel, 2 rectal and 1 pelvic tumor) and 5 with recurrent or metastatic GIST (2 with liver metastasis, 2 with anastomotic recurrence and 1 with pelvic GIST). The median follow-up time was 9.5 months (range of 3-63). The median tumor sizes before and after initiation of IM treatment were 9.1 cm and 6.0 cm (p = 0.003) based on the CT findings, respectively. All patients showed a decrease in tumor burden and the median tumor size reduction was 35%. Sixteen of the 18 patients showed a partial response to IM and two possessed stable disease. Nine of the 18 patients (50%) underwent surgical resection of primary or metastatic/recurrent tumors, with a median of 7 months of IM therapy. One case each of multivisceral resection and tumor recurrence were noted.
CONCLUSIONS:
IM as a preoperative therapy is feasible and safe for unresectable or metastatic/recurrent GIST that can effectively decrease tumor size, facilitating resection.
doi:10.6061/clinics/2014(11)09
PMCID: PMC4255202  PMID: 25518034
Gastrointestinal Stromal Tumor; Imatinib Mesylate; Preoperative Therapy
24.  Tumor suppression by miR-31 in esophageal carcinoma is p21-dependent 
Genes & Cancer  2014;5(11-12):436-444.
microRNA regulation network is important for the cancer genetic heterogeneity. Relative to the increasing numbers of microRNA's targets identified, upstream regulatory mechanisms that control functional microRNAs are less well-documented. Here, we investigated the function of miR-31, a pleiotropically-acting microRNA, in esophageal squamous cell cancer (ESCC). We demonstrated that miR-31 only exerted tumor-suppressive effects in TE-7 ESCC cells, but not in TE-1 ESCC cells, although both of these cell lines harbor inactive p53. Interestingly, TE-1 cells highly expressed p21, while p21 levels were virtually undetectable in TE-7 cells, suggesting a p21-dependent mechanism of miR-31-mediated tumor suppression. Accordingly, knockdown of p21 in TE-1 cells reversed the tumor suppressive actions of miR-31. In patient ESCC specimens, real-time RT-PCR analysis revealed that expression of E2F2 and STK40, two known miR-31 target oncogenes, was negatively correlated with the expression of miR-31 in a p21-dependent manner, supporting the conclusion that miR-31 only downregulates its target oncogenes when p21 levels are low. Collectively, these data suggest a novel mechanism through which the tumor-suppressive effect of miR-31 is p21-dependent. In addition, we speculate that delivery of miR-31 could provide therapeutic benefit in the personalized management of a subgroup of ESCC patients with p21-deficient tumors.
PMCID: PMC4279440  PMID: 25568668
microRNA; miR-31; p21; esophageal squamous cell cancer; personalized medicine
25.  Procalcitonin as a predictor of moderate to severe acute respiratory distress syndrome after cardiac surgery with cardiopulmonary bypass: a study protocol for a prospective cohort study 
BMJ Open  2014;4(10):e006344.
Introduction
Procalcitonin (PCT) is activated during cardiopulmonary bypass (CPB) and may be a predictor of acute respiratory distress syndrome (ARDS). The objective of this study is to determine whether patients with different serum PCT concentrations exhibit different rates of developing moderate to severe ARDS.
Methods and analysis
This is a prospective, single centre, observational cohort study. All patients admitted to the cardiosurgery department for cardiac surgery with CPB were screened for study eligibility. All eligible patients received a CPB procedure. Blood samples were obtained to determine white cell counts as well as N-terminal pro-B-type natriuretic peptide, C reactive protein and PCT levels. Patients were assigned to the PCT elevated cohort or the control cohort based on serum PCT concentrations on the first postoperative day with a cut-off value of 7.0 ng/mL. Data, including baseline, perioperative and outcome data, were collected daily for 7 days. The primary end point was the incidence of moderate to severe ARDS, which was diagnosed according to the Berlin definition.
Ethics and dissemination
The study was approved by the Institutional Review Board of Fujian Provincial Hospital. Study findings are disseminated through peer-reviewed publications and conference presentations.
Study registration
Chinese Clinical Trial Registry (ChiCTR-OCH-14005076).
doi:10.1136/bmjopen-2014-006344
PMCID: PMC4216854  PMID: 25354826

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