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1.  Increased Plasma Levels of FABP4 and PTEN are Associated with More Severe Insulin Resistance in Women with Gestational Diabetes Mellitus 
Background
The aim of this study was to investigate the relationship between plasma fatty acid binding protein 4 (FABP4), phosphatase and tensin homolog (PTEN), and insulin resistance in patients with gestational diabetes mellitus (GDM).
Material/Methods
Plasma FABP4 and PTEN were determined by ELISA in GDM patients (GDM group, n=30) and in euglycemic pregnant women (control group, n=30). The clinical features, body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR), and lipid profiles were compared between the 2 groups. The influence of risk factors on insulin resistance, including BMI, lipid profiles, FABP4, and PTEN, were further investigated by multiple-factor stepwise regression analysis.
Results
Higher levels of BMI, ΔBMI, triglyceride (TG), fasting plasma glucose (FPG), 2-hour plasma glucose (2hPG), fasting insulin, HOMA-IR, FABP4, PTEN, and lower level of high-density lipoprotein cholesterol (HDL-C) were found in the GDM patients than in the controls (all P<0.005). The plasma FABP4 was 1.47±0.25 vs. 0.20±0.07 ng/ml in the GDM and control group, respectively (P<0.0001). Plasma PTEN was 6.46±1.57 vs. 4.72±0.82 ng/ml in the GDM and control group, respectively (P<0.0001). There was a positive relation between plasma FABP4 and PTEN when all blood samples, including GDM and control groups, were analyzed (P<0.05). The multiple-factor regression analysis revealed that plasma FABP4, TG, and PTEN were independent risk factors for increased insulin resistance.
Conclusions
GDM patients have more severe insulin resistance compared to euglycemic pregnant women. Higher levels of plasma FABP4 and PTEN are associated with increased insulin resistance and may participate in the pathogenesis of insulin resistance during gestation.
doi:10.12659/MSM.892431
PMCID: PMC4329941  PMID: 25659997
Diabetes, Gestational; Fatty Acid-Binding Proteins; Insulin Resistance; PTEN Phosphohydrolase
2.  Common Variants Related to Serum Uric Acid Concentrations Are Associated with Glucose Metabolism and Insulin Secretion in a Chinese Population 
PLoS ONE  2015;10(1):e0116714.
Background
Elevated serum uric acid concentration is an independent risk factor and predictor of type 2 diabetes (T2D). Whether the uric acid-associated genes have an impact on T2D remains unclear. We aimed to investigate the effects of the uric acid-associated genes on the risk of T2D as well as glucose metabolism and insulin secretion.
Method
We recruited 2,199 normal glucose tolerance subjects from the Shanghai Diabetes Study I and II and 2,999 T2D patients from the inpatient database of Shanghai Diabetes Institute. Fifteen single nucleotide polymorphisms (SNPs) mapped in or near 11 loci (PDZK1, GCKR, LRP2, SLC2A9, ABCG2, LRRC16A, SLC17A1, SLC17A3, SLC22A11, SLC22A12 and SF1) were genotyped and serum biochemical parameters related to uric acid and T2D were determined.
Results
SF1 rs606458 showed strong association to T2D in both males and females (p = 0.034 and 0.0008). In the males, LRRC16A was associated with 2-h insulin and insulin secretion (p = 0.009 and 0.009). SLC22A11 was correlated with HOMA-B and insulin secretion (p = 0.048 and 0.029). SLC2A9 rs3775948 was associated with 2-h glucose (p = 0.043). In the females, LRP2 rs2544390 and rs1333049 showed correlations with fasting insulin, HOMA-IR and insulin secretion (p = 0.028, 0.033 and 0.052 and p = 0.034, 0.047 and 0.038, respectively). SLC2A9 rs11722228 was correlated with 2-h glucose, 2-h insulin and insulin secretion (p = 0.024, 0.049 and 0.049, respectively).
Conclusions
Our results indicated that the uric acid-associated genes have an impact on the risk of T2D, glucose metabolism and insulin secretion in a Chinese population.
doi:10.1371/journal.pone.0116714
PMCID: PMC4305305  PMID: 25617895
3.  Hes1, an important gene for activation of hepatic stellate cells, is regulated by Notch1 and TGF-β/BMP signaling 
AIM: To determine the role of Notch1 and Hes1 in regulating the activation of hepatic stellate cells (HSCs) and whether Hes1 is regulated by transforming growth factor (TGF)/bone morphogenetic protein (BMP) signaling.
METHODS: Immunofluorescence staining was used to detect the expression of desmin, glial fibrillary acidic protein and the myofibroblastic marker α-smooth muscle actin (α-SMA) after freshly isolated, normal rat HSCs had been activated in culture for different numbers of days (0, 1, 3, 7 and 10 d). The expression of α-SMA, collagen1α2 (COL1α2), Notch receptors (Notch1-4), and the Notch target genes Hes1 and Hey1 were analyzed by reverse transcriptase-polymerase chain reaction. Luciferase reporter assays and Western blot were used to study the regulation of α-SMA, COL1α1, COL1α2 and Hes1 by NICD1, Hes1, CA-ALK3, and CA-ALK5 in HSC-T6 cells. Moreover, the effects of inhibiting Hes1 function in HSC-T6 cells using a Hes1 decoy were also investigated.
RESULTS: The expression of Notch1 and Hes1 mRNAs was significantly down-regulated during the culture of freshly isolated HSCs. In HSC-T6 cells, Notch1 inhibited the promoter activities of α-SMA, COL1α1 and COL1α2. On the other hand, Hes1 enhanced the promoter activities of α-SMA and COL1α2, and this effect could be blocked by inhibiting Hes1 function with a Hes1 decoy. Furthermore, co-transfection of pcDNA3-CA-ALK3 (BMP signaling activin receptor-like kinase 3) and pcDNA3.1-NICD1 further increased the expression of Hes1 compared with transfection of either vector alone in HSC-T6 cells, while pcDNA3-CA-ALK5 (TGF-β signaling activin receptor-like kinase 5) reduced the effect of NICD1 on Hes1 expression.
CONCLUSION: Selective interruption of Hes1 or maintenance of Hes1 at a reasonable level decreases the promoter activities of α-SMA and COL1α2, and these conditions may provide an anti-fibrotic strategy against hepatic fibrosis.
doi:10.3748/wjg.v21.i3.878
PMCID: PMC4299340  PMID: 25624721
Hes1; Notch1; TGF-β/BMP; Hepatic stellate cells; Hepatic fibrosis
4.  Digital PCR quantification of miRNAs in sputum for diagnosis of lung cancer 
Purpose
MicroRNAs (miRNAs) play important roles in the initiation and progression of lung cancer. Measuring miRNA expression levels in sputum could provide a potential approach for the diagnosis of lung cancer. The emerging digital PCR is a straightforward technique for precise, direct, and absolute quantification of nucleic acids. The objective of the study was to investigate whether digital PCR could be used to quantify miRNAs in sputum for lung cancer diagnosis.
Methods
We first determined and compared dynamic ranges of digital PCR and conventional quantitative reverse transcriptase PCR (qRT-PCR) for miRNA quantification using RNA isolated from sputum of five healthy individuals. We then used digital PCR to quantify copy number of two lung cancer-associated miRNAs (miR-31 and miR-210) in 35 lung cancer patients and 40 cancer-free controls.
Results
Copy number of the miRNAs measured by digital PCR displayed a linear response to input cDNA amount in a twofold dilution series over seven orders of magnitude. miRNA quantification determined by digital PCR assay was in good agreement with that obtained from qRT-PCR analysis in sputum. Furthermore, combined quantification of miR-31 and miR-210 copy number by using digital PCR in sputum of the cases and controls provided 65.71 % sensitivity and 85.00 % specificity for lung cancer diagnosis.
Conclusion
As digital PCR becomes more established, it would be a robust tool for quantitative assessment of miRNA copy number in sputum for lung cancer diagnosis.
doi:10.1007/s00432-013-1555-5
PMCID: PMC3898839  PMID: 24281335
Digital PCR; miRNAs; Sputum; Diagnosis; Lung cancer
5.  Overexpression of miR-145 in U87 cells reduces glioma cell malignant phenotype and promotes survival after in vivo implantation 
International Journal of Oncology  2014;46(3):1031-1038.
In the present study, we sought to elucidate the effect of miR-145 on glioma cell progression and its mechanisms of action. We examined the effects of miR-145 on proliferation and invasion of U87 glioma cells and on capillary tube formation. Our data show that restoration of miR-145 in U87 glioma cells significantly reduced their in vitro proliferation, invasion and angiogenesis. However, decreased miR-145 expression promoted U87 glioma cell proliferation, invasion and angiogenesis, and reduced-expression of miR-145 increased ADAM17 and EGFR expression in U87 cells. Overexpression of miR-145 reduced ADAM17 and EGFR expression. VEGF secretion and VEGF expression were decreased by increased miR-145 expression in U87 cells and were reversed by miR-145 down-regulation in vitro. Nude mice with intracerebral implantation of U87 overexpressing miR-145 cells exhibited significantly reduced tumor growth and promoted survival compared with control groups. Taken together, these results suggest a role for miR-145 as a tumor suppressor which inhibits glioma cell proliferation, invasion and angiogenesis in vitro and reduces glioma growth in vivo.
doi:10.3892/ijo.2014.2807
PMCID: PMC4324582  PMID: 25544346
miR-145; ADAM17; EGFR; glioma; migration; invasion; in vivo
6.  Magnetic Enrichment of Bronchial Epithelial Cells From Sputum for Lung Cancer Diagnosis 
Cancer  2008;114(4):275-283.
BACKGROUND
Sputum is an easily accessible diagnostic material for lung cancer early detection by cytologic and molecular genetic analysis of exfoliated airway epithelial cells. However, the use of sputum is limited by its cellular heterogeneity, which includes >95% macrophages and neutrophils and only about 1% bronchial epithelial cells. We propose to obtain concentrated and purified bronchial epithelial cells to improve early detection of lung cancer in sputum samples.
METHODS
Sputum was collected from patients with stage I nonsmall-cell lung cancer, cancer-free smokers, and healthy nonsmokers. Magnetic-assisted cell sorting (MACS) with anti-CD14 and anti-CD16 antibody beads were used to enrich bronchial epithelial cells by depleting macrophages and neutrophils from sputum. Fluorescence in situ hybridization (FISH) analysis for detection of FHIT deletion and cytology were evaluated in the enriched specimens.
RESULTS
The bronchial epithelial cells were concentrated to 40% purity from 1.1% of the starting population, yielding an average of 36-fold enrichment and at least 2.3 × 105 cells per sample. Detecting FHIT deletions for lung cancer diagnosis produced 58% sensitivity in the enriched sputum, whereas there was 42% sensitivity in the unenriched samples (P = .02). Cytologic examination of the enriched sputum resulted in 53% sensitivity, as compared with 39% sensitivity in unenriched sputum (P = .03). Furthermore, only 2 cytocentrifuge slides of the unenriched sputum were needed for the analyses, as compared with up to 10 cytocentrifuge slides required from the unprocessed specimens.
CONCLUSIONS
The enrichment of bronchial epithelial cells could improve the diagnostic value of sputum and the efficiency of genetic and cytologic analysis of lung cancer.
doi:10.1002/cncr.23596
PMCID: PMC4255556  PMID: 18484646
magnetic-assisted cell sorting; bronchial epithelial cells; sputum; lung cancer; diagnosis
7.  Aldehyde Dehydrogenase 1 Is a Tumor Stem Cell-Associated Marker in Lung Cancer 
Molecular cancer research : MCR  2009;7(3):330-338.
Tumor contains small population of cancer stem cells (CSC) that are responsible for its maintenance and relapse. Analysis of these CSCs may lead to effective prognostic and therapeutic strategies for the treatment of cancer patients. We report here the identification of CSCs from human lung cancer cells using Aldefluor assay followed by fluorescence-activated cell sorting analysis. Isolated cancer cells with relatively high aldehyde dehydrogenase 1 (ALDH1) activity display in vitro features of CSCs, including capacities for proliferation, self-renewal, and differentiation, resistance to chemotherapy, and expressing CSC surface marker CD133. In vivo experiments show that the ALDH1-positive cells could generate tumors that recapitulate the heterogeneity of the parental cancer cells. Immunohistochemical analysis of 303 clinical specimens from three independent cohorts of lung cancer patients and controls show that expression of ALDH1 is positively correlated with the stage and grade of lung tumors and related to a poor prognosis for the patients with early-stage lung cancer. ALDH1 is therefore a lung tumor stem cell-associated marker. These findings offer an important new tool for the study of lung CSCs and provide a potential prognostic factor and therapeutic target for treatment of the patients with lung cancer.
doi:10.1158/1541-7786.MCR-08-0393
PMCID: PMC4255559  PMID: 19276181
8.  An Interaction between a FNDC5 Variant and Obesity Modulates Glucose Metabolism in a Chinese Han Population 
PLoS ONE  2014;9(11):e109957.
Background
To investigate the impact of common variants of FNDC5 on type 2 diabetes and clinical traits related to glucose metabolism in a large Chinese population sample.
Methods
Three tagging single nucleotide polymorphisms within the region of the FNDC5 gene were selected and genotyped in 6822 participants. Detailed clinical investigations and biochemistry measurements were carried out in all of the participants. Subjects without diabetes were classified into normal weight and overweight/obese subgroups according to body mass index (BMI).
Results
None of the SNPs were associated with either the risk of type 2 diabetes in all of the participants or with any of the clinical quantitative traits in the controls with normal glucose regulation. Subgroup analysis showed that in controls with normal weight (BMI <25 kg/m2), the rs16835198 major allele G was significantly associated with fasting insulin levels, and that each additional copy of the allele resulted in a 0.0178 mU/L increment of the values (p = 0.046). Moreover, after adjusting for confounding variables, there were trends towards correlation of rs16835198 with HOMA-insulin resistance (HOMA-IR) (p = 0.057) and low-density lipoprotein cholesterol (LDL-C) levels (p = 0.083). In overweight/obese subjects (BMI ≥25 Kg/m2), we noted rs16835198 showed trends towards association with fasting insulin (p = 0.057) and HOMA-IR levels (p = 0.091), both of which declined with additional copies of the major allele G. Moreover, rs16835198 was significantly associated with high-density lipoprotein cholesterol (HDL-C) levels (p = 0.013), and HOMA-β cell function (p = 0.028) in the overweight/obese subjects. Finally, we observed a significant interaction between BMI-rs16835198 and fasting insulin levels in the control group (p = 0.003).
Conclusions
Our data indicate that the effect of the common FNDC5 SNP rs16835198 on fasting insulin was significantly modified by BMI in the Chinese Han population.
doi:10.1371/journal.pone.0109957
PMCID: PMC4219676  PMID: 25369206
9.  Pim-1 kinase is a target of miR-486-5p and eukaryotic translation initiation factor 4E, and plays a critical role in lung cancer 
Molecular Cancer  2014;13(1):240.
Background
Pim-1 kinase is a proto-oncogene and its dysregulation contributes to tumorigenesis and progression of a variety of malignancies. Pim-1 was suggested as a therapeutic target of cancers. The functional relevance of Pim-1 and the mechanism underlying its dysregulation in lung tumorigenesis remained unclear. This study aimed to investigate if Pim-1 has important functions in non-small-cell lung cancer (NSCLC) by: 1) evaluating the clinicopathologic significance of Pim-1 through analysing its expression in 101 human NSCLCs tissues using quantitative PCR, Western Blot and immunohistochemical studies, 2) determining its role in NSCLC and drug resistance using in vitro assays, and 3) investigating the regulatory mechanism of Pim-1 dysregulation in lung tumorigenesis.
Results
Pim-1 was upregulated in 66.2% of the lung tumor tissues and its expression was significantly related to advanced stage (P = 0.019) and lymph node metastasis (P = 0.026). Reduced Pim-1 expression suppressed NSCLC cell growth, cell cycle progression and migration in vitro. Pim-1 was a novel target of miR-486-5p determined by luciferase report assay, and ectopic miR-486-5p expression in cancer cells reduced Pim-1 expression. Furthermore, eukaryotic translation initiation factor 4E (eIF4E) controlled the synthesis of Pim-1 in NSCLC cells, and its expression was positively associated with that of Pim-1 in NSCLC tissue specimens (r = 0.504, p < 0.001). The downregulated miR-486-5p and upregulated eIF4E in NSCLC cells led to the overexpression of Pim-1 by relieving the inhibitory effect of the 3′-UTR or 5′-UTR of Pim-1 mRNA, respectively. Moreover, Pim-1 knockdown sensitized NSCLC cells to cisplatin and EGFR tyrosine kinase inhibitor, gefitinib.
Conclusions
Pim-1 kinase could be a critical survival signaling factor in NSCLC, and regulated by miR-486-5p and eIF4E. Pim-1 kinase may provide a potential target for diagnosis and treatment for lung cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-4598-13-240) contains supplementary material, which is available to authorized users.
doi:10.1186/1476-4598-13-240
PMCID: PMC4213487  PMID: 25342548
10.  Juvenile Hormone-Receptor Complex Acts on Mcm4 and Mcm7 to Promote Polyploidy and Vitellogenesis in the Migratory Locust 
PLoS Genetics  2014;10(10):e1004702.
Juvenile hormone (JH), a sesquiterpenoid produced by the corpora allata, coordinates insect growth, metamorphosis, and reproduction. While JH action for the repression of larval metamorphosis has been well studied, the molecular basis of JH in promoting adult reproduction has not been fully elucidated. Methoprene-tolerant (Met), the JH receptor, has been recently shown to mediate JH action during metamorphosis as well as in vitellogenesis, but again, the precise mechanism underlying the latter has been lacking. We have now demonstrated using Met RNAi to phenocopy a JH-deprived condition in migratory locusts, that JH stimulates DNA replication and increases ploidy in preparation for vitellogenesis. Mcm4 and Mcm7, two genes in the DNA replication pathway were expressed in the presence of JH and Met. Depletion of Mcm4 or Mcm7 inhibited de novo DNA synthesis and polyploidization, and resulted in the substantial reduction of vitellogenin mRNA levels as well as severely impaired oocyte maturation and ovarian growth. By using luciferase reporter and electrophoretic mobility shift assays, we have shown that Met directly regulates the transcription of Mcm4 and Mcm7 by binding to upstream consensus sequences with E-box or E-box-like motifs. Our work suggests that the JH-receptor complex acts on Mcm4 and Mcm7 to regulate DNA replication and polyploidy for vitellogenesis and oocyte maturation.
Author Summary
Vitellogenesis, a hormonally-regulated process for the synthesis of yolk proteins by the fat body or liver and their sequestration in developing oocytes, takes place in all oviparous animals except mammals. Polyploidy has also been implicated in hormone-regulated development and reproduction. Although juvenile hormone (JH) is known to regulate polyploidy in insect models and also plays a pivotal role in stimulating insect vitellogenesis, the molecular mechanisms remain poorly understood. In the migratory locust, Locusta migratoria, vitellogenesis is dependent on JH, and JH stimulates DNA replication and increases ploidy in the fat body. Here, we show that a JH-receptor complex comprised of Methoprene-tolerant (Met) and a steroid receptor co-activator activates the transcription of two mini-chromosome maintenance (Mcm) genes, Mcm4 and Mcm7. Knockdown of Mcm4 or Mcm7 via RNAi can phenocopy JH-deprivation and Met-depletion, resulting in reduced ploidy, blocked vitellogenin (Vg) expression, as well as arrested oocyte maturation and ovarian growth. This study provides evidence that JH acts through its receptor on the Mcm machinery to replicate the genome of fat body cells in preparation for the massive synthesis of Vg and possibly other proteins required for oocyte maturation and egg production.
doi:10.1371/journal.pgen.1004702
PMCID: PMC4207617  PMID: 25340846
11.  Vitreous and Plasma VEGF Levels as Predictive Factors in the Progression of Proliferative Diabetic Retinopathy after Vitrectomy 
PLoS ONE  2014;9(10):e110531.
Purpose
To investigate the vitreous and plasma levels of vascular endothelial growth factor (VEGF) in patients with proliferative diabetic retinopathy (PDR) and to determine whether they predict a disease prognosis after primary vitrectomy.
Methods
Fifty patients (50 eyes) with PDR who underwent pars plana vitrectomy (PPV) and 56 healthy controls (56 eyes) were enrolled in this retrospective study. Clinical data were collected and analyzed. Vitreous and plasma VEGF concentrations were measured using enzyme-linked immunosorbent assays. VEGF levels and clinical data were compared and analyzed to see if they provide a prognosis of PDR progression after primary vitrectomy at more than 6 months follow-up. Correlation of VEGF concentrations between vitreous fluid and plasma was analyzed.
Results
The average BCVA was significantly improved after surgery (P<0.001). Vitreous and plasma VEGF levels were significantly elevated in PDR patients than those in healthy controls (Pvitreous<0.001; Pplasma<0.001). Both vitreous and plasma VEGF levels were significantly higher in PDR progression group than in stable group (Pvitreous<0.001; Pplasma = 0.004). Multivariate logistic regression analyses showed that the increased vitreous VEGF level was associated with the progression of PDR after primary PPV (OR = 1.539; P = 0.036). Vitreous VEGF level was positively associated with plasma VEGF level in PDR patients (P<0.001).
Conclusion
The increased VEGF level in vitreous fluid may be identified as a significant predictive factor for the outcome of vitrectomy in patients with PDR.
doi:10.1371/journal.pone.0110531
PMCID: PMC4199758  PMID: 25329921
12.  Safety and efficacy of laparoscopy-assisted gastrectomy for advanced gastric cancer in the elderly 
To evaluate safety and efficacy of laparoscopy-assisted radical gastrectomy (LARG) for advanced gastric cancer patients aged 70 years or older. Clinical data were retrospectively collected from patients with IIA-IIIC gastric cancer who underwent LARG (n = 30) and open radical gastrectomy (ORG, n = 34) in Department of Gastrointestinal Surgery in the Ningbo First Hospital from January 2012 to December 2013. The mean operative time was longer in the LARG group than in the ORG group but there was no statistical difference between the two groups. The intraoperative blood loss (120 ± 52.7 ml vs 227.3 ± 146.9 ml), incidence of postoperative complication (23.0% vs 47%) were lower in the LARG group than those in the ORG group. In addition, the time to first flatus (2.9 ± 0.8 d vs 4.6 ± 1.2 d), time to first ambulation (1.2 ± 0.4 vs 4.1 ± 1.0 d), time of nasogastric intubation (2.5 ± 1.0 d vs 3.5 ± 1.4 d), and postoperative hospital stay (13.0 ± 4.2 d vs 16.9 ± 4.1 d) were significantly shorter in the LARG group than in the ORG group, respectively. No statistical difference in the number of harvested lymph nodes was noted between the two groups (30.2 ± 12.0 vs 28.1 ± 11.8, P > 0.05). LARG is safer, more effective and less invasive for the elderly patients with advanced gastric cancer.
PMCID: PMC4238507  PMID: 25419398
Laparoscopy-assisted gastrectomy; open gastrectomy; gastric cancer; clinical efficacy
13.  L-BLP25 as a peptide vaccine therapy in non-small cell lung cancer: a review 
Journal of Thoracic Disease  2014;6(10):1513-1520.
Lung cancer is one of the most prevalent malignancies worldwide and the leading cause of cancer-related death. Most cases are non-small cell lung cancer (NSCLC). The median overall survival of patients with advanced stage undergoing current standard chemotherapy is approximately 10 months. The addition of new compounds, including targeted agents, to standard first-line cytotoxic doublets, which are administered concurrently and/or as maintenance therapy in patients who have not experienced disease progression after first-line treatment, has shown potential in improving the efficacy in patients with advanced disease. L-BLP25 is a mucin 1 (MUC1) antigen-specific immunotherapy induces a T-cell response to MUC1 in both a preclinical MUC1-transgenic lung cancer mouse model and patients. This review is aimed at introducing the mechanism by which L-BLP25 targets MUC1, summarizing the achievements gained in the completed clinical trials with L-BLP25 administered as maintenance therapy in the treatment of unresectable stage III/IV NSCLC, and discussing the research trends.
doi:10.3978/j.issn.2072-1439.2014.08.17
PMCID: PMC4215136  PMID: 25364531
L-BLP25; mucin 1 (MUC1); non-small cell lung cancer (NSCLC); clinical trial; cancer vaccines
14.  Mild hypothermia combined with neural stem cell transplantation for hypoxic-ischemic encephalopathy: neuroprotective effects of combined therapy 
Neural Regeneration Research  2014;9(19):1745-1752.
Neural stem cell transplantation is a useful treatment for ischemic stroke, but apoptosis often occurs in the hypoxic-ischemic environment of the brain after cell transplantation. In this study, we determined if mild hypothermia (27–28°C) can increase the survival rate of neural stem cells (1.0 × 105/μL) transplanted into neonatal mice with hypoxic-ischemic encephalopathy. Long-term effects on neurological functioning of the mice were also examined. After mild hypothermia combined with neural stem cell transplantation, we observed decreased expression levels of inflammatory factor nuclear factor-kappa B and apoptotic factor caspase-3, reduced cerebral infarct volumes, increased survival rate of transplanted cells, and marked improvements in neurological function. Thus, the neuroprotective effects of mild hypothermia combined with neural stem cell transplantation are superior to those of monotherapy. Moreover, our findings suggest that the neuroprotective effects of mild hypothermia combined with neural stem cell transplantation on hypoxic-ischemic encephalopathy are achieved by anti-inflammatory and anti-apoptotic mechanisms.
doi:10.4103/1673-5374.143417
PMCID: PMC4238162  PMID: 25422635
nerve regeneration; brain injury; hypoxic-ischemic encephalopathy; neural precursor cells; hypothermia; neural stem cells; cell transplantation; hippocampus; neuron; cell apoptosis; astrocytes; oligodendrocytes; neuroprotection; NSFC grants; neural regeneration
15.  Allogeneic corneoscleral limbus tissue transplantation for treatment of the necrosis in porphyria eye disease 
Porphyria cutanea tarda (PCT) with ocular complications are rarely reported. To the best of our knowledge, no reports exist on allogeneic corneoscleral limbus tissue transplantation for treatment of these. Amniotic membrane grafting had been performed in their patient suffering from porphyria eye disease, but necrosis developed in the grafts. Nevertheless, in our patient, allogeneic corneoscleral limbus transplantation prevented necrosis from development at corneoscleral limbus. So we considered that the allogeneic corneoscleral limbus transplantation might be an option to repair the necrosis in porphyria eye disease with avoiding sunlight and using artificial tear drops.
doi:10.3980/j.issn.2222-3959.2014.04.27
PMCID: PMC4137216  PMID: 25161952
porphyria; scleral necrosis; allogeneic; transplantation
16.  Association study of two inflammation-related polymorphisms with susceptibility to hepatocellular carcinoma: a meta-analysis 
BMC Medical Genetics  2014;15:92.
Background
Inflammation is a response of body tissues to injury or irritation. Small RNAs, such as miR-146a and miR-499, participate in various processes of tumorigenesis. A recent study indicates that inflammation and abnormal immune responses may promote malignant progression in cancer development, indicating that inflammation-related polymorphisms such as miR-146a rs2910164 and miR-499 rs3746444 are crucial. However, studies on the association of these two polymorphisms with hepatocellular carcinoma (HCC) are inconclusive and inconsistent. We aimed at accessing the combined result of reported studies and make a more precise estimate of the relationship.
Methods
Meta-analysis was performed on the associations between the miR-146a rs2910164 C > G and miR-499 rs3746444 T > C polymorphisms and hepatocellular carcinoma, using: allele contrast, dominant, and recessive models. A total of 12 studies(8 on miR-146a rs2910164 and 4 on miR-499 rs3746444) with three populations (Chinese, Korean, Turkish) were included in this study.
Results
Results show that both allele frequency and genotype distributions of miR-146a rs2910164 polymorphism are significantly associated with susceptibility to HCC (G versus C: OR = 1.153, 95% CI 1.083–1.228, P < 0.001; GC versus CC: OR = 1.165, 95% CI 1.054–1.286, P = 0.003; GG versus CC: OR = 1.361, 95% CI 1.192–1.553, P < 0.001; GG/GC versus CC: OR = 1.213, 95% CI 1.104–1.333, P < 0.001; GG versus GC/CC: OR = 1.210, 95% CI 1.080–1.356, P < 0.001). Our data suggest that people with G allele have a higher susceptibility to HCC as compared to those with C allele. However, meta-analysis failed to detect associations between miR-499 rs3746444 and HCC risk under each genetic model tested. Subgroup analysis showed that Chinese population with CC genotype are more vulnerable to HCC (OR = 2.171, 95% CI = 1.149–4.104, P = 0.017) than those with TT genotype.
Conclusions
We conclude that rs2910164 in miR-146a may confer susceptibility to HCC, especially in the Chinese population. No significant association was found between miR-499 rs3746444 and HCC, but subgroup study showed that subjects with CC genotype are more vulnerable to HCC than TT genotype in the Chinese population.
doi:10.1186/s12881-014-0092-7
PMCID: PMC4236519  PMID: 25108400
17.  Serum Vitamin D is Llow and Inversely Associated with LDL Cholesterol in the Kazak Ethnic Population: A Cross-Sectional Study 
Background
Accumulating evidence suggests that low concentrations of serum 25(OH)D is coupled with increased risks of hypertension, obesity, and cardiovascular disease. However, this relationship has not been established in populations with very low levels of 25(OH)D. Therefore, the aim of our study was to clarify the associations between 25(OH)D and blood pressure, obesity, sex, and lipid profiles in the Kazak ethnic population, who have an extremely low level of 25(OH)D.
Material/Methods
A multistage-cluster sampling survey was carried out for residents with Kazak ethnicity in Xinjiang, China. Anthropometric measurements of each participant were taken and the concentrations of 25(OH)D, calcium, alkaline phosphatase, and lipid profiles were measured. Individuals were classified into different groups in terms of vitamin D status, degree of adiposity, presence of hypertension, and other comorbidities.
Results
The madian concentration of 25(OH)D was 16.2 (11.8–20.5) ng/mL and the prevalence of vitamin D deficiency was 72.4% in this Kazak population (n=928, 59.0% women). Females had a lower 25(OH)D concentration than males – 14.6 (10.5–19.4) ng/mL vs. 17.7 (14.8–22.5) ng/mL, P<0.001. The subjects were classified into 3 groups according to their vitamin D status. There were significant differences in BMI (P=0.046), waist circumference (P=0.037), hip circumference (P=0.003), systolic BP (P=0.035), and LDL cholesterol (P=0.008) among the groups after adjustment for sex and age. On the other hand, there was no significant difference in vitamin D levels between groups with or without hypertension (P=0.586), and groups with or without obesity (P=0.639). A multifactor-regression analysis revealed that every increment of 1mg/dL in LDL cholesterol was associated with a 1.0 ng/mL decline in serum 25(OH)D.
Conclusions
The insufficiency of vitamin D is highly prevalent in Kazaks. Sex, LDL cholesterol, and hip circumference are 3 variables strongly associated with serum 25(OH)D concentration. In a population with low levels of 25(OH)D, the negative relationship between obesity and serum 25(OH)D, a common finding from most previous studies, could not be established.
doi:10.12659/MSM.890930
PMCID: PMC4114700  PMID: 25064492
Blood Pressure; Calcifediol; Gender Identity; Obesity
18.  Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth 
Cancer letters  2013;335(1):201-204.
Exosomes are 30–150 nm vesicles secreted by a wide range of mammalian cells that can contain microRNA (miRNA). To test if marrow stromal cell (MSC) exosomes could be used as a vehicle for delivery of anti-tumor miRNAs, we transfected MSCs with a miR-146b expression plasmid, and harvested exosomes released by the MSCs. Intra-tumor injection of exosomes derived from miR-146-expressing MSCs significantly reduced glioma xenograft growth in a rat model of primary brain tumor.
doi:10.1016/j.canlet.2013.02.019
PMCID: PMC3665755  PMID: 23419525
19.  Fecal lactoferrin in discriminating inflammatory bowel disease from Irritable bowel syndrome: a diagnostic meta-analysis 
BMC Gastroenterology  2014;14:121.
Background
To perform a meta-analysis evaluating the diagnostic ability of fecal lactoferrin (FL) to distinguish inflammatory bowel disease (IBD) from irritable bowel syndrome (IBS).
Methods
The Medline, EMBASE, Web of Science, Cochrane library and CNKI databases were systematically searched for studies that used FL concentrations to distinguish between IBD and IBS. The sensitivity, specificity, and other diagnostic indexes of FL were pooled using a random-effects model.
Results
Seven studies, involving 1012 patients, were eligible for inclusion. In distinguishing IBD from IBS, FL had a pooled sensitivity of 0.78 (95% confidence interval [CI]: 0.75, 0.82), a specificity of 0.94 (95% CI: 0.91, 0.96), a positive likelihood ratio of 12.31 (95% CI: 5.93, 29.15), and a negative likelihood ratio of 0.23 (95% CI: 0.18, 0.29). The area under the summary receiver-operating characteristic curve was 0.94 (95% CI: 0.90, 0.98) and the diagnostic odds ratio was 52.65 (95% CI: 25.69, 107.91).
Conclusions
FL, as a noninvasive and simple marker, is useful in differentiating between IBD and IBS.
doi:10.1186/1471-230X-14-121
PMCID: PMC4105129  PMID: 25002150
Fecal lactoferrin; Inflammatory bowel disease; Irritable bowel syndrome; Meta-analysis
20.  High expression of peroxiredoxin 4 affects the survival time of colorectal cancer patients, but is not an independent unfavorable prognostic factor 
Molecular and Clinical Oncology  2014;2(5):767-772.
Peroxiredoxin 4 (Prx4) has a number of important biological functions, such as efficient antioxidant capacity and promotion of cell proliferation and differentiation. The purpose of this study was to investigate the expression and significance of Prx4 in human colorectal cancer (CRC). Quantitative polymerase chain reaction (qPCR) was performed to detect Prx4 in 8 freshly frozen specimens of CRC and their adjacent normal tissues. In addition, immunohistochemical analysis was performed to detect Prx4 in 59 specimens of CRC and 26 of adjacent normal tissues. The immunohistochemical and qPCR results demonstrated that the expressions of the Prx4 gene and protein were higher in CRC compared to those in the adjacent normal tissues. The expression intensity of the Prx4 protein was correlated with depth of invasion (P=0.001), lymph node metastasis (P=0.006) and Dukes’ classification (P=0.004) in CRC. The Kaplan-Meier survival curves revealed that high Prx4 expression was correlated with short survival time. However, the Cox proportional hazards regression analysis did not identify Prx4 as an independent prognostic marker for CRC (P>0.05). These results suggested that Prx4 may be associated with carcinogenesis and the development of CRC and it may be a prognostic marker for postoperative CRC patients.
doi:10.3892/mco.2014.317
PMCID: PMC4106752  PMID: 25054044
peroxiredoxin; colorectal cancer; expression; prognostic marker
21.  Comparative Transcriptional Analysis of Asexual and Sexual Morphs Reveals Possible Mechanisms in Reproductive Polyphenism of the Cotton Aphid 
PLoS ONE  2014;9(6):e99506.
Aphids, the destructive insect pests in the agriculture, horticulture and forestry, are capable of reproducing asexually and sexually upon environmental change. However, the molecular basis of aphid reproductive mode switch remains an enigma. Here we report a comparative analysis of differential gene expression profiling among parthenogenetic females, gynoparae and sexual females of the cotton aphid Aphis gossypii, using the RNA-seq approach with next-generation sequencing platforms, followed by RT-qPCR. At the cutoff criteria of fold change ≥2 and P<0.01, we identified 741 up- and 879 down-regulated genes in gynoparae versus parthenogenetic females, 2,101 up- and 2,210 down-regulated genes in sexual females compared to gynoparae, and 1,614 up- and 2,238 down-regulated genes in sexual females relative to parthenogenetic females. Gene ontology category and KEGG pathway analysis suggest the involvement of differentially expressed genes in multiple cellular signaling pathways into the reproductive mode transition, including phototransduction, cuticle composition, progesterone-mediated oocyte maturation and endocrine regulation. This study forms a basis for deciphering the molecular mechanisms underlying the shift from asexual to sexual reproduction in the cotton aphid. It also provides valuable resources for future studies on this host-alternating aphid species, and the insight into the understanding of reproductive mode plasticity in different aphid species.
doi:10.1371/journal.pone.0099506
PMCID: PMC4051768  PMID: 24915491
22.  Liver resection for young patients with large hepatocellular carcinoma: a single center experience from China 
Background
To investigate retrospectively the clinicopathological characteristics and outcomes of young patients with large hepatocellular carcinoma after hepatectomy.
Methods
From January 2003 to December 2012, a total of 153 patients with large hepatocellular carcinoma (HCC) who received liver resection were included in the study. The clinicopathological features were analyzed retrospectively. The perioperative data were compared between those aged <40 years (the young group) and those aged >40 years (the older group). Prognostic factors and long-term survival were evaluated.
Results
The young group had more hepatitis B virus-related HCC than the older group (87.2% vs 66.3%, P = 0.031). In the young group, 15 patients (21.5%) were overweight (body mass index 25 to 29.9 kg/m2) or obese (body mass index ≥30 kg/m2), and 38 patients (45.8%) were overweight or obese in the older group (P = 0.032). Other clinicopathological characteristics were similar between the two groups. The perioperative data showed that the older group had more pulmonary infection after hepatectomy. Vascular invasion and high Edmondson-Steiner grade were the independent prognostic factors for long-term survival. There was no statistical difference between the young group and the older group in overall survival and disease-free survival (P = 0.109 and P = 0.087, respectively).
Conclusions
Liver resection for young patients with large HCC was safe and efficacious and should be recommended.
doi:10.1186/1477-7819-12-175
PMCID: PMC4049471  PMID: 24894964
Liver resection; Young patients; Large hepatocellular carcinoma
23.  Prohibitin Interacts with Envelope Proteins of White Spot Syndrome Virus and Prevents Infection in the Red Swamp Crayfish, Procambarus clarkii 
Journal of Virology  2013;87(23):12756-12765.
Prohibitins (PHBs) are ubiquitously expressed conserved proteins in eukaryotes that are associated with apoptosis, cancer formation, aging, stress responses, cell proliferation, and immune regulation. However, the function of PHBs in crustacean immunity remains largely unknown. In the present study, we identified a PHB in Procambarus clarkii red swamp crayfish, which was designated PcPHB1. PcPHB1 was widely distributed in several tissues, and its expression was significantly upregulated by white spot syndrome virus (WSSV) challenge at the mRNA level and the protein level. These observations prompted us to investigate the role of PcPHB1 in the crayfish antiviral response. Recombinant PcPHB1 (rPcPHB1) significantly reduced the amount of WSSV in crayfish and the mortality of WSSV-infected crayfish. The quantity of WSSV in PcPHB1 knockdown crayfish was increased compared with that in the controls. The effects of RNA silencing were rescued by rPcPHB1 reinjection. We further confirmed the interaction of PcPHB1 with the WSSV envelope proteins VP28, VP26, and VP24 using pulldown and far-Western overlay assays. Finally, we observed that the colloidal gold-labeled PcPHB1 was located on the outer surface of the WSSV, which suggests that PcPHB1 specifically binds to the envelope proteins of WSSV. VP28, VP26, and VP24 are structural envelope proteins and are essential for attachment and entry into crayfish cells. Therefore, PcPHB1 exerts its anti-WSSV effect by binding to VP28, VP26, and VP24, preventing viral infection. This study is the first report on the antiviral function of PHB in the innate immune system of crustaceans.
doi:10.1128/JVI.02198-13
PMCID: PMC3838164  PMID: 24049173
24.  Ginsenoside Rd Attenuates Mitochondrial Permeability Transition and Cytochrome c Release in Isolated Spinal Cord Mitochondria: Involvement of Kinase-Mediated Pathways 
Ginsenoside Rd (Rd), one of the main active ingredients in Panax ginseng, has multifunctional activity via different mechanisms and neuroprotective effects that are exerted probably via its antioxidant or free radical scavenger action. However, the effects of Rd on spinal cord mitochondrial dysfunction and underlying mechanisms are still obscure. In this study, we sought to investigate the in vitro effects of Rd on mitochondrial integrity and redox balance in isolated spinal cord mitochondria. We verified that Ca2+ dissipated the membrane potential, provoked mitochondrial swelling and decreased NAD(P)H matrix content, which were all attenuated by Rd pretreatment in a dose-dependent manner. In contrast, Rd was not able to inhibit Ca2+ induced mitochondrial hydrogen peroxide generation. The results of Western blot showed that Rd significantly increased the expression of p-Akt and p-ERK, but had no effects on phosphorylation of PKC and p38. In addition, Rd treatment significantly attenuated Ca2+ induced cytochrome c release, which was partly reversed by antagonists of Akt and ERK, but not p-38 inhibitor. The effects of bisindolylmaleimide, a PKC inhibitor, on Rd-induced inhibition of cytochrome c release seem to be at the level of its own detrimental activity on mitochondrial function. Furthermore, we also found that pretreatment with Rd in vivo (10 and 50 mg/kg) protected spinal cord mitochondria against Ca2+ induced mitochondrial membrane potential dissipation and cytochrome c release. It is concluded that Rd regulate mitochondrial permeability transition pore formation and cytochrome c release through protein kinases dependent mechanism involving activation of intramitochondrial Akt and ERK pathways.
doi:10.3390/ijms15069859
PMCID: PMC4100126  PMID: 24897022
spinal cord injury; mitochondria; Ca2+; cytochrome c; protein kinases
25.  High fever as an initial symptom of primary gastric inflammatory myofibroblastic tumor in an adult woman 
Inflammatory myofibroblastic tumor, also known as inflammatory pseudotumor, plasma cell granuloma or inflammatory myofibroblastoma, is characterized histopathologically by myofibroblastic spindle cells with inflammatory cell infiltrates composed of plasma cells, lymphocytes and eosinophils. Inflammatory myofibroblastic tumor is typically seen in children or young adults and is most commonly localized to the lungs, but it can occur anywhere in the body. To date, however, only a few cases involving the stomach have been reported. Herein, we present a case of gastric inflammatory myofibroblastic tumor in an adult woman with an initial symptom of high fever.
PMCID: PMC4073775  PMID: 24995114
Inflammatory myofibroblastic tumor; stomach; inflammatory pseudotumor; high fever; surgery

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