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1.  Apolipoprotein E gene polymorphism and Alzheimer's disease in Chinese population: a meta-analysis 
Scientific Reports  2014;4:4383.
The relationship between Apolipoprotein E (ApoE) genotype and the risk of Alzheimer's disease (AD) is relatively well established in Caucasians, but less established in other ethnicities. To examine the association between ApoE polymorphism and the onset of AD in Chinese population, we searched the commonly used electronic databases between January 2000 and November 2013 for relevant studies. Total 20 studies, including 1576 cases and 1741 controls, were retrieved. The results showed statistically significant positive association between risk factor ε4 allele carriers and AD in Chinese population (OR = 3.93, 95% CI = 3.37–4.58, P < 0.00001). Genotype ApoE ε4/ε4 and ε4/ε3 have statistically significant association with AD as well (ε4/ε4: OR = 11.76, 95% CI = 6.38–21.47, P < 0.00001; ε4/ε3: OR = 3.08, 95% CI = 2.57–3.69, P < 0.00001). Furthermore, the frequency of the ApoE ε3 is lower in AD than that in the health controls, and the difference of ε3 allele is also statistically significant (OR = 0.42, 95% CI = 0.37–0.47, P < 0.00001). No significant heterogeneity was observed among all studies. This meta-analysis suggests that the subject with at least one ApoE ε4 allele has higher risk suffering from AD than controls in Chinese population. The results also provide a support for the protection effect of ApoE ε3 allele in developing AD.
doi:10.1038/srep04383
PMCID: PMC3955907  PMID: 24632849
2.  Impact of Serum Biomarkers and Clinical Factors on Intensive Care Unit Mortality and 6-Month Outcome in Relatively Healthy Patients with Severe Pneumonia and Acute Respiratory Distress Syndrome 
Disease Markers  2014;2014:804654.
Objectives. This study aimed to identify the independent biomarkers and clinical factors that could predict ICU mortality and 6-month outcomes in relatively healthy patients with severe pneumonia and acute respiratory distress syndrome (ARDS). Patients and Methods. We prospectively enrolled patients with severe pneumonia-related ARDS that required mechanical ventilation. Patients were excluded if they were unable to take care of themselves. Several biomarkers and clinical factors were evaluated prospectively on day 1 and day 3 after ICU admission. All biomarkers and clinical factors were collected for analysis. Results. 56 patients were enrolled in this study. We determined that the initial appropriate antibiotics use was an independent clinical factor and day 1 high-mobility group protein B1 (HMGB1) concentration was an independent biomarker for ICU mortality. Interestingly, we also found that a low day 1 albumin level was an independent biomarker for predicting patient life dependence 6 months after a pneumonia event. Conclusion. Patients with severe pneumonia and ARDS requiring mechanical ventilation experience high rates of ICU mortality or disability, even if they were quite healthy before. Initial appropriate antibiotics use and day 1 level of HMGB1 were independent factors for predicting ICU mortality. Day 1 albumin level was predictive of 6-month patient life dependence.
doi:10.1155/2014/804654
PMCID: PMC3958786  PMID: 24723739
3.  Regional Homogeneity Changes in Hemodialysis Patients with End Stage Renal Disease: In Vivo Resting-State Functional MRI Study 
PLoS ONE  2014;9(2):e87114.
Objective
To prospectively investigate and detect early cerebral regional homogeneity (ReHo) changes in neurologically asymptomatic patients with end stage renal disease (ESRD) using in vivo resting-state functional MR imaging (Rs-fMRI).
Methods
We enrolled 20 patients (15 men, 5 women; meanage, 37.1 years; range, 19–49 years) with ESRD and 20 healthy controls (15 men, 5 women; mean age, 38.3 years; range, 28–49 years). The mean duration of hemodialysis for the patient group was 10.7±6.4 monthes. There was no significant sex or age difference between the ESRD and control groups. Rs-fMRI was performed using a gradient-echo echo-planar imaging sequence. ReHo was calculated using software (DPARSF). Voxel-based analysis of the ReHo maps between ESRD and control groups was performed with a two-samples t test. Statistical maps were set at P value less than 0.05 and were corrected for multiple comparisons. The Mini-Mental State Examination (MMSE) was administered to all participants at imaging.
Results
ReHo values were increased in the bilateral superior temporal gyrus and left medial frontal gyrus in the ERSD group compared with controls, but a significantly decreased ReHo value was found in the right middle temporal gyrus. There was no significant correlation between ReHo values and the duration of hemodialysis in the ESRD group. Both the patients and control subjects had normal MMSE scores (≥28).
Conclusions
Our finding revealed that abnormal brain activity was distributed mainly in the memory and cognition related cotices in patients with ESRD. The abnormal spontaneous neuronal activity in those areas provide information on the neural mechanisms underlying cognitive impairment in patients with ESRD, and demonstrate that Rs-fMRI with ReHo analysis is a useful non-invasive imaging tool for the detection of early cerebral ReHo changes in hemodialysis patients with ESRD.
doi:10.1371/journal.pone.0087114
PMCID: PMC3916321  PMID: 24516545
4.  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
5.  Correction: Comparison of Long-Term Survival of Patients with BCLC Stage B Hepatocellular Carcinoma after Liver Resection or Transarterial Chemoembolization 
PLoS ONE  2014;9(1):10.1371/annotation/32a8c7e3-5efc-478b-b374-c8cbfd1d3968.
doi:10.1371/annotation/32a8c7e3-5efc-478b-b374-c8cbfd1d3968
PMCID: PMC3897329
6.  Insights into the Role of Focal Adhesion Modulation in Myogenic Differentiation of Human Mesenchymal Stem Cells 
Stem Cells and Development  2012;22(1):136-147.
We report the establishment of a novel platform to induce myogenic differentiation of human mesenchymal stem cells (hMSCs) via focal adhesion (FA) modulation, giving insights into the role of FA on stem cell differentiation. Micropatterning of collagen type I on a polyacrylamide gel with a stiffness of 10.2 kPa efficiently modulated elongated FA. This elongated FA profile preferentially recruited the β3 integrin cluster and induced specific myogenic differentiation at both transcription and translation levels with expression of myosin heavy chain and α-sarcomeric actin. This was initiated with elongation of FA complexes that triggered the RhoA downstream signaling toward a myogenic lineage commitment. This study also illustrates how one could partially control myogenic differentiation outcomes of similar-shaped hMSCs by modulating FA morphology and distribution. This technology increases our toolkit choice for controlled differentiation in muscle engineering.
doi:10.1089/scd.2012.0160
PMCID: PMC3528092  PMID: 22765653
7.  Clinical Significance of Keap1 and Nrf2 in Oral Squamous Cell Carcinoma 
PLoS ONE  2013;8(12):e83479.
Oxidative stress has been reported to play an important role in progression and prognostication in various kinds of cancers. However, the role and clinical significance of oxidative stress markers Keap1 and Nrf2 in oral squamous cell carcinoma (OSCC) has not been elucidated. This study aimed to investigate the correlation of oxidative stress markers Keap1 and Nrf2 expression and pathological features in OSCC by using tissue microarray. Tissue microarrays containing 17 normal oral mucosa, 7 oral epithelial dysplasia and 43 OSCC specimens were studied by immunohistochemistry. The association among these proteins and pathological features were analyzed. Expression of oxidative stress markers Keap1, Nrf2, and antioxidants PPIA, Prdx6, as well as CD147 was found to increase consecutively from normal oral mucosa to OSCC, and the Keap1, Nrf2, PPIA, Prdx6, CD147 expression in OSCC were significantly higher when compared to normal oral mucosa. Expression of Keap1, Nrf2 in tumors was not found to be significantly associated with T category, lymph node metastases, and pathological grade. Furthermore, we checked the relationship among these oxidative stress markers and found that Keap1 was significantly correlated with Nrf2, Prdx6 and CD147. Significant relationship between Nrf2 and Prdx6 was also detected. Finally, we found patients with overexpression of Keap1 and Nrf2 had not significantly worse overall survival by Kaplan–Meier analysis. These findings suggest that ROS markers are associated with carcinogenesis and progression of OSCC, which may have prognostic value and could be regarded as potential therapeutic targets in OSCC.
doi:10.1371/journal.pone.0083479
PMCID: PMC3873935  PMID: 24386210
8.  Value of multidetector computed tomography in the diagnosis of mucosa-associated lymphoid tissue-lymphomas in the parotid gland: A case report and review of the literature 
Oncology Letters  2013;7(3):781-786.
The present study aimed to review the multidetector computed tomography (MDCT) imaging features of eight mucosa-associated lymphoid tissue (MALT)-lymphoma cases of the parotid gland and to explore the diagnostic value of MDCT. A total of eight patients with pathologically confirmed MALT-lymphomas of the parotid gland underwent pre-operative MDCT plain and dual-phase scans. The changes in the CT values and enhancement patterns of the tumors were assessed. Quantitative analysis was performed to determine the CT value changes of the tumors in the various enhanced phases compared with the plain scan. The MALT-lymphomas of the parotid gland exhibited even density isodense or hyperdense nodules, with occasional calcification and necrosis. The dual-phase scan of the MALT-lymphomas revealed a pattern of lower or moderate enhancement, circumambient enhancement or delayed enhancement. The MALT-lymphomas were closely associated with Sjögre’s syndrome and demonstrated malignant features and isodense or hyperdense nodules and lower or moderate enhancement on the CT scans.
doi:10.3892/ol.2013.1769
PMCID: PMC3919924  PMID: 24520295
parotid gland; mucosa-associated lymphoid tissue lymphomas; computer tomography; enhancement
9.  The Involvement of RhoA and Wnt-5a in the Tumorigenesis and Progression of Ovarian Epithelial Carcinoma 
Background
Ras homolog gene family member A (RhoA) is involved in Wnt-5a–induced migration of gastric and breast cancer cells. We investigated the roles of RhoA and Wnt-5a in ovarian carcinoma.
Methods
RhoA and Wnt-5a mRNA and protein expression in normal fallopian tube epithelium, benign tumors, primary ovarian carcinomas, and metastatic omentum were quantified. RhoA or Wnt-5a was knocked down in OVCAR3 ovarian carcinoma cells using siRNAs and cell phenotype and expression of relevant molecules were assayed.
Results
RhoA and Wnt-5a mRNA and protein expression were found to be significantly higher in metastatic omentum than in ovarian carcinomas, benign tumors, and normal fallopian tube epithelium (p < 0.05), and positively associated with differentiation and FIGO staging (stage I/II vs. stage III/IV) in ovarian carcinoma (p < 0.05). RhoA and Wnt-5a expression were positively correlated in ovarian carcinoma (p = 0.001, R2 = 0.1669). RhoA or Wnt-5a knockdown downregulated RhoA and Wnt-5a expression; reduced cell proliferation; promoted G1 arrest and apoptosis; suppressed lamellipodia formation, cell migration, and invasion; and reduced PI3K, Akt, p70S6k, Bcl-xL, survivin, and VEGF mRNA or protein expression.
Conclusions
This is the first demonstration that RhoA and Wnt-5a are associated with ovarian carcinogenesis and apoptosis inhibition; there might be positive correlation between RhoA and Wnt-5a expression. RhoA is a potential tumorigenesis, differentiation, and progression biomarker in ovarian carcinoma.
doi:10.3390/ijms141224187
PMCID: PMC3876104  PMID: 24351810
ovarian carcinoma; RhoA; Wnt-5a signaling; tumorigenesis and progression; phenotype
10.  The Anti-Tumor Effects and Molecular Mechanisms of Suberoylanilide Hydroxamic Acid (SAHA) on the Aggressive Phenotypes of Ovarian Carcinoma Cells 
PLoS ONE  2013;8(11):e79781.
Histone deacetylase inhibitors (HDACi), such as suberoylanilide hydroxamic acid (SAHA), have been shown to act selectively on gene expression, and are potent inducers of growth arrest, differentiation and apoptosis in various types of cancers in vitro and in vivo. This study aimed to elucidate the anti-tumor effects and molecular mechanisms of SAHA on the aggressive phenotypes of ovarian carcinoma. Two pairs of cell lines (SKOV3 and SKOV3/DDP; HO8910 and HO8910-PM) were exposed to SAHA treatment, and the effects on acetyl-Histone H3 and H4 expression levels were analyzed and compared against the aggressive behaviors of ovarian carcinoma. Our results showed that SAHA suppressed proliferation in both a concentration- and time-dependent manner in all four cell lines; induced S/G2 arrest in SKOV3 and SKOV3/DDP cells; and conversely, induced G1 arrest in HO8910 and HO8910-PM cells. SAHA treatment induced apoptosis and reduced migration, invasion and lamellipodia formation in the ovarian carcinoma cells; furthermore, SAHA decreased expression of Cyclin B1 and CDC2P34 mRNA, and downregulated CDC2P34, Erk1/2, CyclinB1 and MMP-9 proteins. In contrast, SAHA increased expression of Caspase-3, p21 and p53 mRNA, and upregulated acetyl-Histones H3 and H4, Caspase-8, and p53 proteins. Basal acetylation of histone H3 and H4 was higher in ovarian carcinoma compared to normal ovarian tissues and benign ovarian tumors, and in borderline tumor than in normal ovarian tissues, and was positively correlated with differentiation and expression of the proliferative marker, Ki-67 (P < 0.05). We suggest that SAHA may suppress growth, migration and invasion in ovarian carcinoma cells, including cisplatin-resistant or highly-invasive ovarian cells, by promoting histone acetylation and modulating their phenotype-related molecules. As such, aberrant acetylation of histone H3 and H4 may play an important role in the carcinogenesis and differentiation of ovarian carcinoma.
doi:10.1371/journal.pone.0079781
PMCID: PMC3827455  PMID: 24236158
11.  Curcumin cytotoxicity is enhanced by PTEN disruption in colorectal cancer cells 
AIM: To investigate the effects of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) deficiency on the cytotoxicity of chemotherapeutic agents toward colorectal cancer cells.
METHODS: PTEN-deficient colorectal cancer (CRC) cells were generated by human somatic cell gene targeting using the adeno-associated virus system. The cytotoxic effects of compounds including curcumin, 5-fluorouracil (5-FU), dihydroartemisinin (DHA), irinotecan (CPT-11) and oxaliplatin (OXA) on cancer cells were determined using the MTT assay. Enhanced cytotoxicity of curcumin in PTEN-deficient CRC cells was observed, and this was confirmed using clonogenic assays. Apoptosis and cell cycle progression were analyzed by flow cytometry. Levels of apoptosis and cell cycle-related proteins were examined by Western blotting.
RESULTS: We developed an isogenic set of CRC cell lines that differed only in their PTEN status. Using this set of cell lines, we found that disruption of the PTEN gene had no effect on the sensitivity of CRC cells to 5-FU, CPT-11, DHA, or OXA, whereas PTEN disruption increased the sensitivity of CRC cells to curcumin. Loss of PTEN did not alter the curcumin-induced apoptosis in CRC cells. However, PTEN deficiency led to an altered pattern of curcumin-mediated cell cycle arrest. In HCT116 PTEN+/+ cells, curcumin caused a G2/M phase arrest, whereas it caused a G0/G1 phase arrest in HCT116 PTEN-/- cells. Levels of cell cycle-related proteins were consistent with these respective patterns of cell cycle arrest.
CONCLUSION: Curcumin shows enhanced cytotoxicity toward PTEN-deficient cancer cells, suggesting that it might be a potential chemotherapeutic agent for cancers harboring PTEN mutations.
doi:10.3748/wjg.v19.i40.6814
PMCID: PMC3812480  PMID: 24187456
Phosphatase and tensin homolog deleted on chromosome 10; Curcumin; Chemotherapeutic agents; Cell cycle; AKT signaling
12.  BTG1 Expression Correlates with the Pathogenesis and Progression of Ovarian Carcinomas 
BTG (B-cell translocation gene) can inhibit cell proliferation, metastasis, and angiogenesis and regulate cell cycle progression and differentiation in a variety of cell types. We aimed to clarify the role of BTG1 in ovarian carcinogenesis and progression. A BTG1-expressing plasmid was transfected into ovarian carcinoma cells and their phenotypes and related proteins were examined. BTG1 mRNA expression was detected in ovarian normal tissue (n = 17), ovarian benign tumors (n = 12), and ovarian carcinoma (n = 64) using real-time RT-PCR. Ectopic BTG1 expression resulted in lower growth rate, high cisplatin sensitivity, G1 arrest, apoptosis, and decreased migration and invasion. Phosphoinositide 3-kinase, protein kinase B, Bcl-xL, survivin, vascular endothelial growth factor, and matrix metalloproteinase-2 mRNA and protein expression was reduced in transfectants as compared to control cells. There was higher expression of BTG1 mRNA in normal tissue than in carcinoma tissue (p = 0.001) and in benign tumors than in carcinoma tissue (p = 0.027). BTG1 mRNA expression in International Federation of Gynecology and Obstetrics (FIGO) stage I/II ovarian carcinomas was higher than that in FIGO stage III/IV ovarian carcinomas (p = 0.038). Altered BTG1 expression might play a role in the pathogenesis and progression of ovarian carcinoma by modulating proliferation, migration, invasion, the cell cycle, and apoptosis.
doi:10.3390/ijms141019670
PMCID: PMC3821579  PMID: 24084718
ovarian carcinoma; BTG1; phenotypes; tumorigenesis; progression
13.  The Noninvasive Retro-Mode Imaging Modality of Confocal Scanning Laser Ophthalmoscopy in Polypoidal Choroidal Vasculopathy: A Preliminary Application 
PLoS ONE  2013;8(9):e75711.
Purpose
To evaluate the validity of the novel and noninvasive retro-mode imaging modality of confocal scanning laser ophthalmoscopy (cSLO) for detecting the morphological features of polypoidal choroidal vasculopathy (PCV).
Design
Prospective, observational, consecutive case series.
Methods
Twenty-six patients (29 eyes) with PCV were enrolled in this study. All patients underwent comprehensive ophthalmologic examinations and imaging studies, including retro-mode imaging, fundus autofluorescence (FAF), fundus photography, fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA) and spectral-domain optical coherence tomography (SD-OCT). We investigated the retro-mode images and compared the results with those of SD-OCT, FFA and ICGA.
Results
In the 29 PCV eyes, the retro-mode images clearly revealed polypoidal lesions in 27 (93.1%) eyes as well as branching vascular networks in 16 (55.2%) eyes. Others findings, including pigment epithelial detachment (PED) in 20 (69.0%) eyes, neuroretinal detachment (NRD) in 3 (10.3%) eyes, cystoid macular edema (CME) in 3 (10.3%) eyes, drusen in 4 (13.8%) eyes and minute granular changes of the retinal pigment epithelium (RPE) in 12 (41.3%) eyes, were also clearly visualized. When we compared the results with those of SD-OCT, FFA and ICGA, there was no significant difference between ICGA and retro-mode imaging for finding polypoidal lesions and (or) branching choroidal vascular networks (P>0.05). However, the rate of PED detection was significantly better with retro-mode imaging than with the ICGA (P<0.05). The differences were not statistically significant between SD-OCT and retro-mode imaging for detecting PED, NRD, CME, drusen and minute granular RPE changes (P>0.05). The differences were not statistically significant between FFA and retro-mode imaging for detecting PED, NRD, CME (P>0.05).
Conclusions
The novel and noninvasive retro-mode imaging by cSLO is able to clearly visualize the morphological features of PCV.
doi:10.1371/journal.pone.0075711
PMCID: PMC3776759  PMID: 24058698
15.  An Enhancer Element Harboring Variants Associated with Systemic Lupus Erythematosus Engages the TNFAIP3 Promoter to Influence A20 Expression 
PLoS Genetics  2013;9(9):e1003750.
Functional characterization of causal variants present on risk haplotypes identified through genome-wide association studies (GWAS) is a primary objective of human genetics. In this report, we evaluate the function of a pair of tandem polymorphic dinucleotides, 42 kb downstream of the promoter of TNFAIP3, (rs148314165, rs200820567, collectively referred to as TT>A) recently nominated as causal variants responsible for genetic association of systemic lupus erythematosus (SLE) with tumor necrosis factor alpha inducible protein 3 (TNFAIP3). TNFAIP3 encodes the ubiquitin-editing enzyme, A20, a key negative regulator of NF-κB signaling. A20 expression is reduced in subjects carrying the TT>A risk alleles; however, the underlying functional mechanism by which this occurs is unclear. We used a combination of electrophoretic mobility shift assays (EMSA), mass spectrometry (MS), reporter assays, chromatin immunoprecipitation-PCR (ChIP-PCR) and chromosome conformation capture (3C) EBV transformed lymphoblastoid cell lines (LCL) from individuals carrying risk and non-risk TNFAIP3 haplotypes to characterize the effect of TT>A on A20 expression. Our results demonstrate that the TT>A variants reside in an enhancer element that binds NF-κB and SATB1 enabling physical interaction of the enhancer with the TNFAIP3 promoter through long-range DNA looping. Impaired binding of NF-κB to the TT>A risk alleles or knockdown of SATB1 expression by shRNA, inhibits the looping interaction resulting in reduced A20 expression. Together, these data reveal a novel mechanism of TNFAIP3 transcriptional regulation and establish the functional basis by which the TT>A risk variants attenuate A20 expression through inefficient delivery of NF-κB to the TNFAIP3 promoter. These results provide critical functional evidence supporting a direct causal role for TT>A in the genetic predisposition to SLE.
Author Summary
A key objective of human genetics is the identification and characterization of variants responsible for association with complex diseases. A pair of single nucleotide polymorphisms (rs148314165, rs200820567) 42 kb downstream from the promoter of TNFAIP3, have been proposed as the variants responsible for association with systemic lupus erythematosus based on comprehensive genetic and bioinformatic analyses. TNFAIP3 encodes for the ubiquitin-editing enzyme, A20, which plays a central role in maintaining immune system homeostasis through restriction of NF-κB signaling. Cells that carry this risk haplotype express low levels of TNFAIP3 compared to cells carrying the nonrisk haplotype. How the risk alleles of rs148314165 and rs200820567 might influence low TNFAIP3 expression is unknown. In this paper, we demonstrate that these variants reside in an enhancer element that binds NF-κB and SATB1 enabling the interaction of the enhancer with the TNFAIP3 promoter through long-range DNA looping. Impaired binding of NF-κB directly to the risk alleles or shRNA-mediated knockdown of SATB1 inhibits interaction of the enhancer with the TNFAIP3 promoter resulting in reduced A20 expression. These results clarify the functional mechanism by which rs148314165 and rs200820567 attenuate A20 expression and support a causal role for these variants in the predisposition to autoimmune disease.
doi:10.1371/journal.pgen.1003750
PMCID: PMC3764111  PMID: 24039598
16.  Constitutive phosphorylation of inhibitor-1 at Ser67 and Thr75 depresses calcium cycling in cardiomyocytes and leads to remodeling upon aging 
Basic research in cardiology  2012;107(5):279.
The activity of protein phosphatase-1 (PP1) inhibitor-1 (I-1) is antithetically modulated by the cAMP-protein kinase A (PKA) and Ca2+-protein kinase C (PKC) signaling axes. β-adrenergic (β-AR) stimulation results in PKA-phosphorylation of I-1 at threonine 35 (Thr35) and depressed PP1 activity, while PKC phosphorylation at serine 67 (Ser67) and/or Thr75 increases PP1 activity. In heart failure, pThr35 is decreased while pSer67 and pThr75 are elevated. However, the role of Ser67/Thr75 phosphorylation in vivo and its effects on Ca2+-cycling are not known. Thus, our aim was to investigate the functional significance of Ser67 and Thr75 phosphorylation in intact hearts. We generated transgenic mice (TG) with cardiac-specific overexpression of constitutively phosphorylated I-1 at Ser67 and Thr75 (S67D/T75D) and evaluated cardiac function. The S67D/T75D cardiomyocytes exhibited significantly depressed Ca2+-kinetics and contractile parameters, compared with wild-type (WT) cells. The decreased Ca2+-cycling was associated with a 27 % increase in PP1 activity, no alterations in PP2 activity and impaired phosphorylation of myosin-binding protein-C (MyBPC). Upon aging, there was cardiac remodeling associated with increases in systolic and diastolic left ventricular internal diameter dimensions (at 16 months), compared with WTs. The results indicate that phosphorylation of I-1 at Ser67 and Thr75 is associated with increased PP1 activity and depressed cardiomyocyte Ca2+-cycling, which manifests in geometrical alterations over the long term. Thus, hyper-phosphorylation of these sites in failing hearts may contribute to deteriorative remodeling.
doi:10.1007/s00395-012-0279-z
PMCID: PMC3587163  PMID: 22777184
Protein phosphatase 1; Inhibitor-1; Calcium cycling; Cardiac function
17.  Clinicopathological and prognostic significance of Ki-67, caspase-3 and p53 expression in gastric carcinomas 
Oncology Letters  2013;6(5):1277-1284.
The understanding of proliferative and apoptotic changes has aided the improvement of the diagnosis, treatment and prevention of gastric cancer. The present study aimed to investigate the clinicopathological and prognostic significance of Ki-67, caspase-3 and p53 in gastric cancer. The expression levels of Ki-67, caspase-3 and p53 were evaluated on tissue microarrays of gastric carcinomas specimens by immunohistochemistry and compared with the clinicopathological parameters and survival time of the patients. It was observed that the elder or male patients with gastric cancer showed p53 overexpression compared with the younger or female patients, respectively (P<0.05). The expression of Ki-67 and p53 was positively associated with tumor-node-metastasis (TNM) staging (P<0.05). There was higher caspase-3 and p53 expression in the intestinal-type compared with the diffuse-type of carcinomas (P<0.05). There was a positive correlation among Ki-67, caspase-3 and p53 expression in gastric cancer (P<0.05). A Kaplan-Meier analysis indicated that there was positive correlation between caspase-3 expression and the adverse prognosis of the patients (P>0.05). Cox’s proportional hazards model indicated that the patient age, gender, depth of invasion, lymphatic invasion, lymph node metastasis, TNM staging, Lauren’s classification and caspase-3 expression were independent prognostic factors for gastric carcinomas (P<0.05). The data indicated that the expression of Ki-67, caspase-3 and p53 may be involved in the progression or differentiation of gastric carcinoma. This expression may be employed as an indicator of the pathobiological behavior and prognosis of gastric carcinomas.
doi:10.3892/ol.2013.1532
PMCID: PMC3813574  PMID: 24179508
gastric carcinoma; Ki-67; caspase-3; p53; clinicopathological significance; prognosis
18.  TRPP2 and TRPV4 Form an EGF-Activated Calcium Permeable Channel at the Apical Membrane of Renal Collecting Duct Cells 
PLoS ONE  2013;8(8):e73424.
Objective
Regulation of apical calcium entry is important for the function of principal cells of the collecting duct. However, the molecular identity and the regulators of the transporter/channel, which is responsible for apical calcium entry and what factors regulate the calcium conduction remain unclear.
Methods and Results
We report that endogenous TRPP2 and TRPV4 assemble to form a 23-pS divalent cation-permeable non-selective ion channel at the apical membrane of renal principal cells of the collecting duct. TRPP2\TRPV4 channel complex was identified by patch-clamp, immunofluorescence and co-immunprecipitation studies in both principal cells that either possess normal cilia (cilia (+)) or in which cilia are absent (cilia (-)). This channel has distinct biophysical and pharmacological and regulatory profiles compared to either TRPP2 or TRPV4 channels. The rate of occurrence detected by patch clamp was higher in cilia (-) compared to cilia (+) cells. In addition, shRNA knockdown of TRPP2 increased the prevalence of TRPV4 channel activity while knockdown of TRPV4 resulted in TRPP2 activity and knockdown of both proteins vastly decreased the 23-pS channel activity. Epidermal growth factor (EGF) stimulated TRPP2\TRPV4 channel through the EGF receptor (EGFR) tyrosine kinase-dependent signaling. With loss of cilia, apical EGF treatment resulted in 64-fold increase in channel activity in cilia (-) but not cilia (+) cells. In addition EGF increased cell proliferation in cilia (-) cell that was dependent upon TRPP2\TRPV4 channel mediated increase in intracellular calcium.
Conclusion
We conclude that in the absence of cilia, an EGF activated TRPP2\TRPV4 channel may play an important role in increased cell proliferation and cystogenesis.
doi:10.1371/journal.pone.0073424
PMCID: PMC3745395  PMID: 23977387
19.  The role of EMMPRIN expression in ovarian epithelial carcinomas 
Cell Cycle  2013;12(17):2899-2913.
Purpose: Extracellular matrix metalloproteinase inducer (EMMPRIN) was reported to involve in the invasion and metastasis of malignancies by regulating the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) in stromal and cancer cells. The study aimed to clarify the role of EMMPRIN expression in tumorigenesis and progression of ovarian epithelial carcinomas.
Methods: EMMPRIN siRNA were transfected into ovarian carcinoma cells with the phenotypes and their related molecules examined. EMMPRIN expression was determined in ovarian normal tissue, benign and borderline tumors, and epithelial carcinomas by real-time PCR, western blot, and immunohistochemisty.
Results: EMMPRIN siRNA treatment resulted in a lower growth, G1 arrest, apoptotic induction, decreased migration, and invasion. The transfectants showed reduced expression of Wnt5a, Akt, p70s6k, Bcl-xL, survivin, VEGF, and MMP-9 than mock and control cells at both mRNA and protein levels. According to real-time PCR and western blot, EMMPRIN mRNA or protein level was higher in ovarian borderline tumor and carcinoma than normal ovary and benign tumors (P < 0.05), and positively correlated with dedifferentiation and FIGO staging (P < 0.05). Immuhistochemically, EMMPRIN expression was positively correlated with FIGO staging, dedifferentiation, Ki-67 expression, the lower cumulative and relapse-free survival rate (P < 0.05).
Conclusions: Upregulated expression of EMMPRIN protein and mRNA might be involved in the pathogenesis, differentiation, and progression of ovarian carcinomas, possibly by modulating cellular events, such as proliferation, cell cycle, apoptosis, migration, and invasion.
doi:10.4161/cc.25950
PMCID: PMC3899202  PMID: 23966157
ovarian cancer; EMMPRIN; cellular phenotypes; carcinogenesis; progression; prognosis
20.  High-Resolution Transcriptomic Analyses of Sinorhizobium sp. NGR234 Bacteroids in Determinate Nodules of Vigna unguiculata and Indeterminate Nodules of Leucaena leucocephala 
PLoS ONE  2013;8(8):e70531.
The rhizobium-legume symbiosis is a model system for studying mutualistic interactions between bacteria and eukaryotes. Sinorhizobium sp. NGR234 is distinguished by its ability to form either indeterminate nodules or determinate nodules with diverse legumes. Here, we presented a high-resolution RNA-seq transcriptomic analysis of NGR234 bacteroids in indeterminate nodules of Leucaena leucocephala and determinate nodules of Vigna unguiculata. In contrast to exponentially growing free-living bacteria, non-growing bacteroids from both legumes recruited several common cellular functions such as cbb3 oxidase, thiamine biosynthesis, nitrate reduction pathway (NO-producing), succinate metabolism, PHB (poly-3-hydroxybutyrate) biosynthesis and phosphate/phosphonate transporters. However, different transcription profiles between bacteroids from two legumes were also uncovered for genes involved in the biosynthesis of exopolysaccharides, lipopolysaccharides, T3SS (type three secretion system) and effector proteins, cytochrome bd ubiquinol oxidase, PQQ (pyrroloquinoline quinone), cytochrome c550, pseudoazurin, biotin, phasins and glycolate oxidase, and in the metabolism of glutamate and phenylalanine. Noteworthy were the distinct expression patterns of genes encoding phasins, which are thought to be involved in regulating the surface/volume ratio of PHB granules. These patterns are in good agreement with the observed granule size difference between bacteroids from L. leucocephala and V. unguiculata.
doi:10.1371/journal.pone.0070531
PMCID: PMC3732241  PMID: 23936444
21.  Comparison of Long-Term Survival of Patients with BCLC Stage B Hepatocellular Carcinoma after Liver Resection or Transarterial Chemoembolization 
PLoS ONE  2013;8(7):e68193.
Background and Aims
Treatment of patients with Barcelona Clinic Liver Cancer Stage B hepatocellular carcinoma (BCLC-B HCC) is controversial. This study compared the long-term survival of patients with BCLC-B HCC who received liver resection (LR) or transarterial chemoembolization (TACE).
Methods
A total of 257 and 135 BCLC-B HCC patients undergoing LR and TACE, respectively, were retrospectively evaluated. Kaplan–Meier method was used for long-term survival analysis. Independent prognostic predictors were determined by the Cox proportional hazards model.
Results
The hospital mortality rate was similar between groups (3.1% vs. 3.7%; P = 0.76). However, the LR group showed a significantly higher postoperative complication rate than the TACE group (28 vs. 18.5%; P = 0.04). At the same time, the LR group showed significantly higher overall survival rates (1 year, 84 vs. 69%; 3 years, 59 vs. 29%; 5 years, 37 vs. 14%; P<0.001). Moreover, similar results were observed in the propensity score model. Three independent prognostic factors were associated with worse overall survival: serum AFP level (≥400 ng/ml), serum ALT level, and TACE.
Conclusions
LR appears to be as safe as TACE for patients with BCLC-B HCC, and it provides better long-term overall survival. However, prospective studies are needed to disclose if LR may be regarded as the preferred treatment for these patients as long as liver function is preserved.
doi:10.1371/journal.pone.0068193
PMCID: PMC3706592  PMID: 23874536
22.  An M2e-based synthetic peptide vaccine for influenza A virus confers heterosubtypic protection from lethal virus challenge 
Virology Journal  2013;10:227.
Background
Vaccination is considered as the most effective preventive method to control influenza. The hallmark of influenza virus is the remarkable variability of its major surface glycoproteins, HA and NA, which allows the virus to evade existing anti-influenza immunity in the target population. So it is necessary to develop a novel vaccine to control animal influenza virus. Also we know that the ectodomain of influenza matrix protein 2 (M2e) is highly conserved in animal influenza A viruses, so a vaccine based on the M2e could avoid several drawbacks of the traditional vaccines. In this study we designed a novel tetra-branched multiple antigenic peptide (MAP) based vaccine, which was constructed by fusing four copies of M2e to one copy of foreign T helper (Th) cell epitope, and then investigated its immune responses.
Results
Our results show that the M2e-MAP induced strong M2e-specific IgG antibody,which responses following 2 doses immunization in the presence of Freunds’ adjuvant. M2e-MAP vaccination limited viral replication substantially. Also it could attenuate histopathological damage in the lungs of challenged mice and counteracted weight loss. M2e-MAP-based vaccine protected immunized mice against the lethal challenge with PR8 virus.
Conclusions
Based on these findings, M2e-MAP-based vaccine seemed to provide useful information for the research of M2e-based influenza vaccine. Also it show huge potential to study vaccines for other similarly viruses.
doi:10.1186/1743-422X-10-227
PMCID: PMC3716895  PMID: 23834899
Influenza A virus; Influenza; M2e; Synthetic peptide vaccine
23.  [6-(Furan-2-yl)-7-nitro-2,3,4,6,7,8-hexa­hydro-1H-pyrido[1,2-a]pyrimidin-9-yl](phen­yl)methanone 
The asymmetric unit of the title compound, C19H19N3O4, contains two mol­ecules with very few conformational differences; a C atom in the pyrimidine ring in one of the mol­ecules is disordered in a 0.688 (15):0.312 (15) ratio. In both mol­ecules, the fused pyridine and pyrimidine rings adopt half-chair conformations. The dihedral angles between the furan and benzene rings are 81.00 (13) and 84.99 (10)° in the two mol­ecules. The mol­ecular structure is consolidated by intra­molecular N—H⋯O hydrogen bonding. In the crystal, C—H⋯O hydrogen bonds connect the molecules into a three-dimensional network.
doi:10.1107/S160053681301386X
PMCID: PMC3685119  PMID: 23795138
24.  Formation of the world's largest REE deposit through protracted fluxing of carbonatite by subduction-derived fluids 
Scientific Reports  2013;3:1776.
Rare Earth Elements (REE) are essential to modern society but the origins of many large REE deposits remain unclear. The U-Th-Pb ages, chemical compositions and C, O and Mg isotopic compositions of Bayan Obo, the world's largest REE deposit, indicate a protracted mineralisation history with unusual chemical and isotopic features. Coexisting calcite and dolomite are in O isotope disequilibrium; some calcitic carbonatite samples show highly varied δ26Mg which increases with increasing Si and Mg; and ankerite crystals show decreases in Fe and REE from rim to centre, with highly varied REE patterns. These and many other observations are consistent with an unusual mineralisation process not previously considered; protracted fluxing of calcitic carbonatite by subduction-released high-Si fluids during the closure of the Palaeo-Asian Ocean. The fluids leached Fe and Mg from the mantle wedge and scavenged REE, Nb and Th from carbonatite, forming the deposit through metasomatism of overlying sedimentary carbonate.
doi:10.1038/srep01776
PMCID: PMC3646268
25.  Ablation of junctin or triadin is associated with increased cardiac injury following ischaemia/reperfusion 
Cardiovascular Research  2012;94(2):333-341.
Aims
Junctin and triadin are calsequestrin-binding proteins that regulate sarcoplasmic reticulum (SR) Ca2+ release by interacting with the ryanodine receptor. The levels of these proteins are significantly down-regulated in failing human hearts. However, the significance of such decreases is currently unknown. Here, we addressed the functional role of these accessory proteins in the heart's responses to ischaemia/reperfusion (I/R) injury.
Methods and results
Isolated mouse hearts were subjected to global I/R, and contractile parameters were assessed in wild-type (WT), junctin-knockout (JKO), and triadin-knockout (TKO) hearts. Both JKO and TKO were associated with significantly depressed post-I/R contractile recovery. However, ablation of triadin resulted in the most severe post-I/R phenotype. The additional contractile impairment of TKO hearts was not related to a mitochondrial death pathway, but attributed to endoplasmic reticulum (ER) stress-mediated apoptosis. Activation of the X-box-binding protein-1 and transcriptional up-regulation of C/EBP-homologous protein (CHOP) provided a molecular mechanism of caspase-12-dependent apoptosis in myocytes. In addition, elevation of cytosolic Ca2+ during reperfusion was associated with the activation of calpain proteases and troponin I breakdown. Accordingly, treatment with the calpain inhibitor MDL-28170 significantly ameliorated post-I/R impairment of contractile recovery in intact hearts.
Conclusion
These findings indicate that deficiency of either junctin or triadin impairs the contractile recovery in post-ischaemic hearts, which appears to be primarily attributed to increased ER stress and activation of calpain.
doi:10.1093/cvr/cvs119
PMCID: PMC3331615  PMID: 22411973
Junctin; Triadin; Ischaemia/reperfusion; ER stress; Calpain

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