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1.  Enriched Environment Inhibits Mouse Pancreatic Cancer Growth and Down-regulates the Expression of Mitochondria-related Genes in Cancer Cells 
Scientific Reports  2015;5:7856.
Psycho-social stress has been suggested to influence the development of cancer, but it remains poorly defined with regard to pancreatic cancer, a lethal malignancy with few effective treatment modalities. In this study, we sought to investigate the impacts of enriched environment (EE) housing, a rodent model of “eustress”, on the growth of mouse pancreatic cancer, and to explore the potential underlying mechanisms through gene expression profiling. The EE mice showed significantly reduced tumor weights in both subcutaneous (53%) and orthotopic (41%) models, while each single component of EE (inanimate stimulation, social stimulation or physical exercise) was not profound enough to achieve comparative anti-tumor effects as EE. The integrative transcriptomic and proteomic analysis revealed that in response to EE, a total of 129 genes in the tumors showed differential expression at both the mRNA and protein levels. The differentially expressed genes were mostly localized to the mitochondria and enriched in the citrate cycle and oxidative phosphorylation pathways. Interestingly, nearly all of the mitochondria-related genes were down-regulated by EE. Our data have provided experimental evidence in favor of the application of positive stress or of benign environmental stimulation in pancreatic cancer therapy.
doi:10.1038/srep07856
PMCID: PMC4297951  PMID: 25598223
2.  Inhibitory effects of transcription factor Ikaros on the expression of liver cancer stem cell marker CD133 in hepatocellular carcinoma 
Oncotarget  2014;5(21):10621-10635.
CD133 is a cellular surface glycoprotein that has been reported as a marker for the enrichment of cancer stem cells (CSCs). However, the regulatory mechanism of CD133 remains unknown. CSCs have been proposed to contribute to radioresistance and multi-drug resistance. The elucidation of key regulators of CD133 and CSCs is critical for the development of CSC-targeted therapy. In this study, we showed that Ikarosinhibited the expression of CD133 via direct binding to the CD133 P1 promoter and repressed the tumorigenic and self-renewal capacity of CD133+ cancer stem-like cells in hepatocellular carcinoma (HCC). We found that Ikaros interacted with CtBP as a transcription repressor complex, which inhibited CD133 expression in HCC. We also demonstrated that Ikaros expression was up-regulated by ETS1 which activity was regulated by MAPKs pathway. Furthermore, decreased expression of Ikaroswas significantly associated with poor survival in HCC patients. Overall, our study identifies that Ikaros plays a role as a transcription repressor in HCC and is a new reactivated therapeutic target for the treatment of HCC. Meanwhile, our findings provide evidence that Ikaros could be an attractive inhibitor of the target gene CD133, which reactivates anticancer mechanisms in targeted CSC therapy.
PMCID: PMC4279398  PMID: 25301737
Ikaros; CD133; hepatocellular carcinoma; cancer stem cells
3.  False esophageal hiatus hernia caused by a foreign body: A fatal event 
World Journal of Gastroenterology : WJG  2014;20(39):14510-14514.
Foreign body ingestion is a common complaint in gastrointestinal clinics. It is usually not difficult to diagnose because most of the patients report a definitive history of accidental foreign body ingestion. However, in rare cases, patients do not have a clear history. Thus, the actual condition of the patient is difficult to diagnosis or is misdiagnosed; consequently, treatment is delayed or the wrong treatment is administered, respectively. This report describes a fatal case of esophageal perforation caused by an unknowingly ingested fishbone, which resulted in lower esophageal necrosis, chest cavity infection, posterior mediastinum fester, and significant upper gastrointestinal accumulation of blood. However, his clinical symptoms and imaging data are very similar with esophageal hiatal hernia. Unfortunately, because the patient was too late in consulting a physician, he finally died of chest infection and hemorrhage caused by thoracic aortic rupture. First, this case report underlines the importance of immediate consultation with a physician as soon as symptoms are experienced so as not to delay diagnosis and treatment, and thus avoid a fatal outcome. Second, diagnostic imaging should be performed in the early stage, without interference by clinical judgment. Third, when computed tomography reveals esophageal hiatus hernia with stomach incarceration, posterior mediastinal hematoma, and pneumatosis caused by esophageal, a foreign body should be suspected. Finally, medical professionals are responsible for making people aware of the danger of foreign body ingestion, especially among children, those who abuse alcohol, and those who wear dentures, particularly among the elderly, whose discriminability of foreign bodies is decreased, to avoid dire consequences.
doi:10.3748/wjg.v20.i39.14510
PMCID: PMC4202382  PMID: 25339840
Esophageal hiatus hernia; Foreign body; Esophageal perforation; Gastrointestinal accumulation
4.  Induction of autophagy contributes to cisplatin resistance in human ovarian cancer cells 
Molecular Medicine Reports  2014;11(1):91-98.
Cisplatin resistance is a major challenge in the clinical treatment of ovarian cancer, of which the underlying mechanisms remain unknown. The aim of the present study was to explore the role of autophagy in cisplatin resistance in ovarian cancer cells. A2780cp cisplatin-resistant ovarian carcinoma cells and the A2780 parental cell line, were used as a model throughout the present study. The cell viability was determined using a water soluble tetrazolium salt-8 assay, and western blot analysis was performed to determine the protein expression levels of microtubule-associated protein 1 light chain 3 (LC3 I and LC3 II), and Beclin 1. Beclin 1 small interfering (si)RNA and 3-methyladenine (3-MA) were used to determine whether inhibition of autophagy may re-sensitize cisplatin-resistant cells to cisplatin. The ultrastructural analysis of autophagosomes was performed using transmission electron microscopy, and apoptosis was measured by flow cytometry. In both A2780cp and A2780 cells, cisplatin induced the formation of autophagosomes and upregulated the expression levels of autophagy protein markers, LC3 II and Beclin 1. However, the levels of autophagy were significantly higher in A2780cp cells, as compared with the A2780 cells. The combined treatment of cisplatin with 3-MA, the autophagy pharmacological inhibitor, increased the cell death rate, but had no effects on apoptosis, as compared with cisplatin treatment alone in A2780cp cells. However, inhibition of autophagy by siRNA knockdown of Beclin 1 expression enhanced cisplatin-induced cell death and apoptosis. The findings of the present study suggest that autophagy has a protective role in human ovarian cancer cells, and that targeting autophagy may promote chemotherapeutic sensitivity.
doi:10.3892/mmr.2014.2671
PMCID: PMC4237096  PMID: 25322694
ovarian carcinoma; cisplatin; autophagy; resistance
5.  Maize and millet transcription factors annotated using comparative genomic and transcriptomic data 
BMC Genomics  2014;15(1):818.
Background
Transcription factors (TFs) contain DNA-binding domains (DBDs) and regulate gene expression by binding to specific DNA sequences. In addition, there are proteins, called transcription coregulators (TCs), which lack DBDs but can alter gene expression through interaction with TFs or RNA Polymerase II. Therefore, it is interesting to identify and classify the TFs and TCs in a genome. In this study, maize (Zea mays) and foxtail millet (Setaria italica), two important species for the study of C4 photosynthesis and kranz anatomy, were selected.
Result
We conducted a comprehensive genome-wide annotation of TFs and TCs in maize B73 and in two strains of foxtail millet, Zhang gu and Yugu1, and classified them into families. To gain additional support for our predictions, we searched for their homologous genes in Arabidopsis or rice and studied their gene expression level using RNA-seq and microarray data. We identified many new TF and TC families in these two species, and described some evolutionary and functional aspects of the 9 new maize TF families. Moreover, we detected many pseudogenes and transposable elements in current databases. In addition, we examined tissue expression preferences of TF and TC families and identified tissue/condition-specific TFs and TCs in maize and millet. Finally, we identified potential C4-related TF and TC genes in maize and millet.
Conclusions
Our results significantly expand current TF and TC annotations in maize and millet. We provided supporting evidence for our annotation from genomic and gene expression data and identified TF and TC genes with tissue preference in expression. Our study may facilitate the study of regulation of gene expression, tissue morphogenesis, and C4 photosynthesis in maize and millet. The data we generated in this study are available at http://sites.google.com/site/jjlmmtf.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-818) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2164-15-818
PMCID: PMC4189582  PMID: 25261191
Transcription factor annotation; Coregulators; Comparative genomics; Functional annotation
6.  Relationship between parameters from virtual touch tissue quantification (VTQ) imaging with clinicopathologic prognostic factors in women with invasive ductal breast cancer 
Objectives: To investigate the association of shear wave velocity (SWV) and its ratio (SWV ratio) using virtual touch tissue quantification (VTQ) imaging with clinicopathologic prognostic factors in women with invasive ductal breast cancer. Methods: 138 consecutive women with invasive ductal breast cancer, who were diagnosed by pathological examination, were recruited between September 2011 and October 2013. Clinicopathologic findings were investigated in each participant, including age, invasive size, lymph node status, histological grade, estrogen receptor (ER) expression, progesterone receptor (PR) expression and human epidermal growth factor receptor 2 (C-erbB-2) expression. SWV and its ratio (breast mass/adjacent breast tissue) were measured by the VTQ imaging, and univariate analysis and multivariate regression analyses were applied to investigate their relationship with all clinicopathologic abnormalities. Results: In univariate analyses, large mass size (P < 0.001), lymph node involvement (P < 0.001), High histological grade (P = 0.001) and C-erbB-2 expression (P = 0.029) were significantly associated with SWV, whereas large invasive size (P < 0.001), lymph node involvement (P = 0.001) and high histological grade (P = 0.007) were significantly related to SWV ratio. Multiple linear regression indicated that invasive size was the strongest pathologic determinant of SWV and its ratio (P < 0001). Conclusion: SWV and its ratio by the VTQ imagining were significantly associated with clinicopathologic abnormalities, and may therefore provide prognostic information in patients with invasive ductal breast cancer.
PMCID: PMC4230154  PMID: 25400743
Invasive ductal breast cancers; shear wave velocity; shear wave velocity ratio
7.  Predictive equations for central obesity via anthropometrics, stereovision imaging, and MRI in adults 
Obesity (Silver Spring, Md.)  2013;22(3):852-862.
Objective
Abdominal visceral adiposity is related to risks for insulin resistance and metabolic perturbations. Magnetic resonance imaging (MRI) and computed tomography are advanced instruments that quantify abdominal adiposity; yet field use is constrained by their bulkiness and costliness. The purpose of this study is to develop prediction equations for total abdominal, subcutaneous, and visceral adiposity via anthropometrics, stereovision body imaging (SBI), and MRI.
Design and Methods
Participants (67 men and 55 women) were measured for anthropometrics, and abdominal adiposity volumes evaluated by MRI umbilicus scans. Body circumferences and central obesity were obtained via SBI. Prediction models were developed via multiple linear regression analysis, utilizing body measurements and demographics as independent predictors, and abdominal adiposity as a dependent variable. Cross-validation was performed by the data-splitting method.
Results
The final total abdominal adiposity prediction equation was –470.28+7.10waist circumference–91.01gender+5.74sagittal diameter (R²=89.9%); subcutaneous adiposity was –172.37+8.57waist circumference–62.65gender–450.16stereovision waist-to-hip ratio (R²=90.4%); and visceral adiposity was –96.76+11.48central obesity depth–5.09 central obesity width+204.74stereovision waist-to-hip ratio–18.59gender (R²=71.7%). R² significantly improved for predicting visceral fat when SBI variables were included, but not for total abdominal or subcutaneous adiposity.
Conclusions
SBI is effective for predicting visceral adiposity and the prediction equations derived from SBI measurements can assess obesity.
doi:10.1002/oby.20489
PMCID: PMC3855593  PMID: 23613161
8.  C1GALT1 Promotes Invasive Phenotypes of Hepatocellular Carcinoma Cells by Modulating Integrin β1 Glycosylation and Activity 
PLoS ONE  2014;9(8):e94995.
Cancer cell invasion and metastasis are the primary causes of treatment failure and death in hepatocellular carcinoma (HCC). We previously reported that core 1 β1,3-galactosyltransferase (C1GALT1) is frequently overexpressed in HCC tumors and its expression is associated with advanced tumor stage, metastasis, and poor survival. However, the underlying mechanisms of C1GALT1 in HCC malignancy remain unclear. In this study, we found that overexpression of C1GALT1 enhanced HCC cell adhesion to extracellular matrix (ECM) proteins, migration, and invasion, whereas RNAi-mediated knockdown of C1GALT1 suppressed these phenotypes. The promoting effect of C1GALT1 on the metastasis of HCC cells was demonstrated in a mouse xenograft model. Mechanistic investigations showed that the C1GALT1-enhanced phenotypic changes in HCC cells were significantly suppressed by anti-integrin β1 blocking antibody. Moreover, C1GALT1 was able to modify O-glycans on integrin β1 and regulate integrin β1 activity as well as its downstream signaling. These results suggest that C1GALT1 could enhance HCC invasiveness through integrin β1 and provide novel insights into the roles of O-glycosylation in HCC metastasis.
doi:10.1371/journal.pone.0094995
PMCID: PMC4121071  PMID: 25089569
9.  Studies of Efficacy and Liver Toxicity Related to Adeno-Associated Virus–Mediated RNA Interference 
Human Gene Therapy  2013;24(8):739-750.
Abstract
Adeno-associated virus (AAV)–mediated RNA interference shows promise as a therapy for chronic hepatitis B virus (HBV) infection, but its low efficacy and hepatotoxicity pose major challenges. We have generated AAV vectors containing different promoters and a panel of HBV-specific short hairpin RNAs (shRNAs) to investigate factors that contribute to the efficacy and pathogenesis of AAV-mediated RNA interference. HBV transgenic mice injected with high doses of AAV vectors containing the U6 promoter produced abundant shRNAs, transiently inhibited HBV, but induced severe hepatotoxicity. Sustained HBV suppression without liver toxicity can be achieved by lowering the dose of AAV-U6 vectors. AAVs containing the weaker H1 promoter did not cause liver injury, but their therapeutic efficacy was highly dependent on the sequence of the shRNA. Mice treated with the toxic U6-promoter-driven shRNA showed little change in hepatic microRNA levels, but a dramatic increase in hepatic leukocytes and inflammatory cytokines and chemokines. Hepatotoxicity was completely absent in immunodeficient mice and significantly alleviated in wild-type mice depleted of macrophages and granulocytes, suggesting that host inflammatory responses are the major cause of liver injury induced by the overexpressed shRNAs from AAV-U6 vectors. Our results demonstrate that selection of a highly potent shRNA and control its expression level is critical to achieve sustained HBV suppression without inducing inflammatory side effects.
Sun and colleagues generate a panel of AAV vectors containing various promoters and hepatitis B virus (HBV)-specific short hairpin RNAs (shRNAs) to investigate factors that contribute to the efficacy and pathogenesis of AAV-mediated RNA interference. They show that injecting HBV transgenic mice with high doses of AAV vectors containing the U6 promoter produce abundant shRNAs, transiently inhibit HBV, but induce severe hepatotoxicity. By contrast, AAVs containing the weaker H1 promoter do not cause liver injury, but their therapeutic efficacy is highly dependent on the sequence of the shRNA.
doi:10.1089/hum.2012.239
PMCID: PMC3747597  PMID: 23829557
10.  Purification, crystallization and preliminary X-ray analysis of the DNA-binding domain of AdpA, the central transcription factor in the A-factor regulatory cascade in the filamentous bacterium Streptomyces griseus, in complex with a duplex DNA 
The DNA-binding domain of AdpA, the central transcription factor in the A-factor regulatory cascade in the filamentous bacterium S. griseus, was heterologously expressed, purified and crystallized in complex with a duplex DNA by the sitting-drop vapour-diffusion method. The best crystal diffracted X-rays to 2.8 Å resolution and belonged to space group C2221.
Streptomyces griseus AdpA is the central transcription factor in the A-factor regulatory cascade and activates a number of genes that are required for both secondary metabolism and morphological differentiation, leading to the onset of streptomycin biosynthesis as well as aerial mycelium formation and sporulation. The DNA-binding domain of AdpA consists of two helix–turn–helix DNA-binding motifs and shows low nucleotide-sequence specificity. To reveal the molecular basis of the low nucleotide-sequence specificity, an attempt was made to obtain cocrystals of the DNA-binding domain of AdpA and several kinds of duplex DNA. The best diffracting crystal was obtained using a 14-mer duplex DNA with two-nucleotide overhangs at the 5′-ends. The crystal diffracted X-rays to 2.8 Å resolution and belonged to space group C2221, with unit-cell parameters a = 76.86, b = 100.96, c = 101.25 Å. The Matthews coefficient (V M = 3.71 Å3 Da−1) indicated that the crystal was most likely to contain one DNA-binding domain of AdpA and one duplex DNA in the asymmetric unit, with a solvent content of 66.8%.
doi:10.1107/S1744309112026899
PMCID: PMC3412780  PMID: 22869129
AdpA; Streptomyces griseus; A-factor regulatory cascade; DNA-binding domain
11.  Expanding the selection criteria of laparoscopic hepatectomy for hepatocellular carcinoma 
doi:10.3978/j.issn.1000-9604.2014.07.01
PMCID: PMC4153940  PMID: 25232204
12.  miRNA-200c inhibits invasion and metastasis of human non-small cell lung cancer by directly targeting ubiquitin specific peptidase 25 
Molecular Cancer  2014;13:166.
Background
Growing evidence indicates that miR-200c is involved in carcinogenesis and tumor progression in non-small-cell lung cancer (NSCLC). However, its precise biological role remains largely elusive.
Methods
The functions of miR-200c and USP25 in migration/invasion and lung metastasis formation were determined by transwell and tail vein injection assays, respectively. The potential regulatory targets of miR-200c were determined by prediction tools, correlation with target protein expression, and luciferase reporter assay. The mRNA expression levels of miR-200c and USP25 were examined in NSCLC cell lines and patient specimens using quantitative reverse transcription-PCR. The protein expression levels of USP25 were examined in NSCLC cell lines and patient specimens using western blot and immunohistochemical staining.
Results
We demonstrated that over-expression of miR-200c inhibited NSCLC cells migration, invasion, epithelial-mesenchymal transition (EMT) in vitro and lung metastasis formation in vivo. Further studies revealed that USP25 was a downstream target of miR-200c in NSCLC cells as miR-200c bound directly to the 3’-untranslated region of USP25, thus reducing both the messenger RNA and protein levels of USP25. Silencing of the USP25 gene recapitulated the effects of miR-200c over-expression. Clinical analysis indicated that miR-200c was negatively correlated with clinical stage, lymph node metastasis in NSCLC patients. Moreover, USP25 protein and mRNA level expressions were higher in NSCLC patients, compared to healthy control, and correlated with clinical stage and lymphatic node metastasis.
Conclusions
These findings indicate that miR-200c exerts tumor-suppressive effects for NSCLC through the suppression of USP25 expression and suggests a new therapeutic application of miR-200c in the treatment of NSCLC.
doi:10.1186/1476-4598-13-166
PMCID: PMC4105889  PMID: 24997798
miR-200c; Metastasis; NSCLC; Ubiquitin specific peptidase 25
13.  14-3-3σ induces heat shock protein 70 expression in hepatocellular carcinoma 
BMC Cancer  2014;14:425.
Background
14-3-3σ is implicated in promoting tumor development of various malignancies. However, the clinical relevance of 14-3-3σ in hepatocellular carcinoma (HCC) tumor progression and modulation and pathway elucidation remain unclear.
Methods
We investigated 14-3-3σ expression in 109 HCC tissues by immunohistochemistry. Overexpression and knockdown experiments were performed by transfection with cDNA or siRNA. Protein expression and cell migration were determined by Western blot and Boyden chamber assay.
Results
In this study, we found that 14-3-3σ is abundantly expressed in HCC tumors. Stable or transient overexpression of 14-3-3σ induces the expression of heat shock factor-1α (HSF-1α) and heat shock protein 70 (HSP70) in HCC cells. Moreover, expression of 14-3-3σ significantly correlates with HSF-1α/HSP70 in HCC tumors and both 14-3-3σ and HSP70 overexpression are associated with micro-vascular thrombi in HCC patients, suggesting that 14-3-3σ/HSP70 expression is potentially involved in cell migration/invasion. Results of an in vitro migration assay indicate that 14-3-3σ promotes cell migration and that 14-3-3σ-induced cell migration is impaired by siRNA knockdown of HSP70. Finally, 14-3-3σ-induced HSF-1α/HSP70 expression is abolished by the knockdown of β-catenin or activation of GSK-3β.
Conclusions
Our findings indicate that 14-3-3σ participates in promoting HCC cell migration and tumor development via β-catenin/HSF-1α/HSP70 pathway regulation. Thus, 14-3-3σ alone or combined with HSP70 are potential prognostic biomarkers for HCC.
doi:10.1186/1471-2407-14-425
PMCID: PMC4061114  PMID: 24923353
14-3-3σ; β-catenin; Hepatocellular carcinoma; HSF-1; HSP70
14.  Expression of cereblon protein assessed by immunohistochemicalstaining in myeloma cells is associated with superior response of thalidomide- and lenalidomide-based treatment, but not bortezomib-based treatment, in patients with multiple myeloma 
Annals of Hematology  2014;93(8):1371-1380.
Cereblon (CRBN) is essential for the anti-myeloma (MM) activity of immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide. However, the clinical implications of CRBN in MM patients are unclear. Using immunohistochemical (IHC) staining on paraffin-embedded bone marrow sections, the expression of CRBN protein in myeloma cells (MCs) was assessed in 40 relapsed/refractory MM (RRMM) patients who received lenalidomide/dexamethasone (LD) and 45 and 22 newly diagnosed MM (NDMM) patients who received thalidomide/dexamethasone (TD) and melphalan/bortezomib/prednisolone (MVP), respectively. IHC staining were scored on a scale representing the diffuseness and intensity of positive-staining MCs (range, 0–8) and a score ≥4.5 was used for CRBN positivity (CRBN+) on a cut-point analysis of all possible scores and response of TD and LD. Compared to CRBN+ NDMM patients, CRBN− NDMM patients had more international staging system (ISS) III (26 vs. 61 %, respectively; P = 0.006). In the LD and TD cohorts, the response rate (RR) was higher in CRBN+ patients than CRBN− patients (LD 79 vs. 33 %, respectively; P = 0.005) (TD 75 vs. 29 %, respectively; P = 0.005); however, this trend was not observed in the MVP cohort. In the LD and TD cohorts, the positive and negative prediction value of CRBN+ for treatment response was 79 and 67 % and 75 and 71 %, respectively. Multivariate analysis showed that CRBN+ was a significant factor associated with superior RR for LD and TD. The data suggest that expression of CRBN protein in MCs assessed using the IHC is a feasible approach to predict the response of IMiDs in MM patients.
doi:10.1007/s00277-014-2063-7
PMCID: PMC4082140  PMID: 24687382
Cereblon; Immunohistochemistry; Immunomodulatory drugs; Multiple myeloma; Prognosis
15.  Construction of a SSR-Based Genetic Map and Identification of QTLs for Catechins Content in Tea Plant (Camellia sinensis) 
PLoS ONE  2014;9(3):e93131.
Catechins are the most important bioactive compounds in tea, and have been demonstrated to possess a wide variety of pharmacological activities. To characterize quantitative trait loci (QTLs) for catechins content in the tender shoots of tea plant, we constructed a moderately saturated genetic map using 406 simple sequence repeat (SSR) markers, based on a pseudo-testcross population of 183 individuals derived from an intraspecific cross of two Camellia sinensis varieties with diverse catechins composition. The map consisted of fifteen linkage groups (LGs), corresponding to the haploid chromosome number of tea plant (2n = 2x = 30). The total map length was 1,143.5 cM, with an average locus spacing of 2.9 cM. A total of 25 QTLs associated with catechins content were identified over two measurement years. Of these, nine stable QTLs were validated across years, and clustered into four main chromosome regions on LG03, LG11, LG12 and LG15. The population variability explained by each QTL was predominantly at moderate-to-high levels and ranged from 2.4% to 71.0%, with an average of 17.7%. The total number of QTL for each trait varied from four to eight, while the total population variability explained by all QTLs for a trait ranged between 38.4% and 79.7%. This is the first report on the identification of QTL for catechins content in tea plant. The results of this study provide a foundation for further cloning and functional characterization of catechin QTLs for utilization in improvement of tea plant.
doi:10.1371/journal.pone.0093131
PMCID: PMC3968092  PMID: 24676054
16.  Nrf2 induces cisplatin resistance through activation of autophagy in ovarian carcinoma 
Cisplatin resistance is a major problem affecting ovarian carcinoma treatment. NF-E2-related factor 2 (Nrf2), a nuclear transcription factor, plays an important role in chemotherapy resistance. However, the underlying mechanism by which Nrf2 mediates cisplatin chemoresistance is unclear. Methods: The human ovarian carcinoma cell line, A2780, and its cisplatin-resistant variant, A2780cp were cultivated. Cell viability was determined with WST-8 assay. Western blot was applied to detect the expression of Nrf2, Nrf2 target genes, and autophagy-related proteins. RNA interference was used to knock down target genes. Annexin V and propidium iodide (PI) staining was utilized to quantify apoptosis. The ultrastructural analysis of autophagosomes was performed by transmission electron microscopy (TEM). Results: Nrf2 and its targeting genes, NQO1 and HO-1, are overexpressed in A2780cp cells compared with A2780 cells. Knocking down Nrf2 sensitized A2780cp cells to cisplatin treatment and decreased autophagy-related genes, Atg3, Atg6, Atg12 and p62 in both mRNA and protein levels. Furthermore, we demonstrated that in both cell lines cisplatin could induce the formation of autophagosomes and upregulate the expression of autophagy-related genes Atg3, Atg6 and Atg12. Treatment with an autophagy inhibitor, 3-Methyladenine (3-MA), or beclin 1 siRNA enhanced cisplatin-induced cell death in A2780cp cells, suggesting that inhibition of autophagy renders resistant cells to be more sensitive to cisplatin. Taken together, Nrf2 signaling may regulate cisplatin resistance by activating autophagy. Conclusions: Nrf2-activated autophagy may function as a novel mechanism causing cisplatin-resistance.
PMCID: PMC4014230  PMID: 24817946
Ovarian carcinoma; Nrf2; autophagy; cisplatin; chemoresistance
17.  MiR-525-3p Enhances the Migration and Invasion of Liver Cancer Cells by Downregulating ZNF395 
PLoS ONE  2014;9(3):e90867.
Liver cancer is one of leading causes of cancer-related deaths. A deeper mechanistic understanding of liver cancer could lead to the development of more effective therapeutic strategies. In our previous work, we screened 646 miRNAs and identified 11 that regulate liver cancer cell migration. The current study shows that miR-525-3p is frequently up-regulated in liver cancer tissues, and enhanced expression of miR-525-3p can promote liver cancer cell migration and invasion. Zinc finger protein 395 (ZNF395) is the direct functional target gene for miR-525-3p, and it is frequently down-regulated in liver cancer tissues. High expression of ZNF395 can significantly inhibit while knockdown of ZNF395 expression can markedly enhance the migration and invasion of liver cancer cells, suggesting that ZNF395 suppresses metastasis in liver cancer. Down-regulation of ZNF395 can mediate miR-525-3p induced liver cancer cell migration and invasion. In conclusion, miR-525-3p promotes liver cancer cell migration and invasion by directly targeting ZNF395, and the fact that miR-525-3p and ZNF395 both play important roles in liver cancer progression makes them potential therapeutic targets.
doi:10.1371/journal.pone.0090867
PMCID: PMC3944804  PMID: 24599008
18.  Transperineal Ultrasound-Guided 12-Core Prostate Biopsy: An Extended Approach to Diagnose Transition Zone Prostate Tumors 
PLoS ONE  2014;9(2):e89171.
Objective
Transperineal ultrasound-guided (TPUS) 12-core prostate biopsy was evaluated as an initial strategy for the diagnosis of prostate cancer, The distribution of prostate cancer lesions was assessed with zone-specific biopsy.
Methods
From January 2010 to December 2012, 287 patients underwent TPUS-guided 12-core prostate biopsy. Multiple cores were obtained from both the peripheral zone (PZ) and the transition zone (TZ) of the prostate. Participants' clinical data and the diagnostic yield of the cores were recorded and prospectively analyzed as a cross-sectional study.
Results
The diagnostic yield of the 12-core prostate biopsy was significantly higher compared to the 6-core scheme (42.16 vs. 21.6%). The diagnostic yield of the 10-core prostate biopsy was significantly higher compared to the 6-core scheme (37.6 vs. 21.6%). The 12-core scheme improved the diagnostic yield in prostates >50 ml (12-core scheme: 28.1% vs. 10-core scheme: 20.4%; p = 0.034).
Conclusions
The 12-core biopsy scheme is a safe and effective approach for the diagnosis of prostate cancer. TZ biopsies in patients with larger prostates should be included in the initial biopsy strategy.
doi:10.1371/journal.pone.0089171
PMCID: PMC3934905  PMID: 24586569
19.  Up-Regulation of MicroRNA-190b Plays a Role for Decreased IGF-1 That Induces Insulin Resistance in Human Hepatocellular Carcinoma 
PLoS ONE  2014;9(2):e89446.
Background & Aims
Insulin-like growth factor, (IGF)-1, is produced mainly by the liver and plays important roles in promoting growth and regulating metabolism. Previous study reported that development of hepatocellular carcinoma (HCC) was accompanied by a significant reduction in serum IGF-1 levels. Here, we hypothesized that dysregulation of microRNAs (miRNA) in HCC can modulate IGF-1 expression post-transcriptionally.
Methods
The miRNAs expression profiles in a dataset of 29 HCC patients were examined using illumina BeadArray. Specific miRNA (miR)-190b, which was significantly up-regulated in HCC tumor tissues when compared with paired non-tumor tissues, was among those predicted to interact with 3′-untranslated region (UTR) of IGF-1. In order to explore the regulatory effects of miR-190b on IGF-1 expression, luciferase reporter assay, quantitative real-time PCR, western blotting and immunofluorecence analysis were performed in HCC cells.
Results
Overexpression of miR-190b in Huh7 cells attenuated the expression of IGF-1, whereas inhibition of miR-190b resulted in up-regulation of IGF-1. Restoration of IGF-1 expression reversed miR-190b-mediated impaired insulin signaling in Huh7 cells, supporting that IGF-1 was a direct and functional target of miR-190b. Additionally, low serum IGF-1 level was associated with insulin resistance and poor overall survival in HCC patients.
Conclusions
Increased expression of miR-190 may cause decreased IGF-1 in HCC development. Insulin resistance appears to be a part of the physiopathologic significance of decreased IGF-1 levels in HCC progression. This study provides a novel miRNA-mediated regulatory mechanism for controlling IGF-1 expression in HCC and elucidates the biological relevance of this interaction in HCC.
doi:10.1371/journal.pone.0089446
PMCID: PMC3930738  PMID: 24586785
20.  Expanded explorations into the optimization of an energy function for protein design 
Nature possesses a secret formula for the energy as a function of the structure of a protein. In protein design, approximations are made to both the structural representation of the molecule and to the form of the energy equation, such that the existence of a general energy function for proteins is by no means guaranteed. Here we present new insights towards the application of machine learning to the problem of finding a general energy function for protein design. Machine learning requires the definition of an objective function, which carries with it the implied definition of success in protein design. We explored four functions, consisting of two functional forms, each with two criteria for success. Optimization was carried out by a Monte Carlo search through the space of all variable parameters. Cross-validation of the optimized energy function against a test set gave significantly different results depending on the choice of objective function, pointing to relative correctness of the built-in assumptions. Novel energy cross-terms correct for the observed non-additivity of energy terms and an imbalance in the distribution of predicted amino acids. This paper expands on the work presented at ACM-BCB, Orlando FL , October 2012.
doi:10.1109/TCBB.2013.113
PMCID: PMC3919130  PMID: 24384706
Biology and Genetics; Physics; Chemistry; Protein design; energy function; machine learning; correlation; rotamers; dead-end elimination
21.  Genome-Wide Screening Identified That miR-134 Acts as a Metastasis Suppressor by Targeting Integrin β1 in Hepatocellular Carcinoma 
PLoS ONE  2014;9(2):e87665.
MicroRNAs (miRNAs) are small, single-stranded, non-coding RNAs that play pivotal roles in human cancer development and progression, such as tumor metastasis. Here, we identified the miRNAs that regulate hepatocellular carcinoma (HCC) cell migration by a high-throughput screening method using the classical wound-healing assay with time-lapse video microscopy and validation with a transwell migration assay. Eleven miRNAs (miR-134, -146b-3p, -188-3p, -525-3p, -661, -767-5p, -891a, -891b, -1244, -1247 and miR-1471) were found to promote or inhibit HCC cell migration. Further investigation revealed that miR-134 suppressed the invasion and metastasis of HCC cells in vitro and in vivo, and integrin beta 1 (ITGB1) was a direct and functional target gene of miR-134. Moreover, miR-134 inhibited the phosphorylation of focal adhesion kinase (FAK) and the activation of RhoA downstream of the ITGB1 pathway, thereby decreasing stress fiber formation and cell adhesion in HCC cells. In conclusion, we demonstrated that miR-134 is a novel metastasis suppressor in HCC and could be a potential therapeutic target for the treatment of HCC.
doi:10.1371/journal.pone.0087665
PMCID: PMC3912066  PMID: 24498348
22.  High-resolution MRI findings in patients with capsular warning syndrome 
BMC Neurology  2014;14:16.
Background
Capsular warning syndrome (CWS) is rare (1.5% of TIA presentations) but has a poor prognosis (7-day stroke risk of 60%). Up to date, the exact pathogenic mechanism of CWS has not been fully understood. We report the clinical presentations and high-resolution MRI (HR MRI) findings of two cases with capsular warning symptoms.
Case presentation
Case 1 was a 63-year-old man with a history of hypertension with recurrent episodes of left hemiparesis and dysarthria lasting 10 ~ 30 minutes. Case 2 was a 54-year-old woman with repetitive episodes of transient left hemiparesis and dysarthria lasting about 10 minutes. Capsular infarctions on DWI were demonstrated in the territory of a lenticulostriate artery in both 2 patients. HR MRI disclosed atherosclerotic plaques on the ventral wall of the MCA where enticulostriate arteries were arisen from, although traditional digital subtraction angiography showed normal. Aggressive medical therapy with dual antithrombotic agents and statin was effective in these two cases.
Conclusion
Our HR MRI data offer an insight into the pathophysiology of CWS which might be caused by atherosclerotic plaque in non-stenotic MCA wall. HR MRI might be a useful modality for characterizing atherosclerotic plaques in the MCA and detecting the pathophysiology of the CWS.
doi:10.1186/1471-2377-14-16
PMCID: PMC3898091  PMID: 24438445
Capsular warning syndrome; High-resolution MRI; Middle cerebral artery; Atherosclerotic plaque
23.  Early hemopoietic lineage restrictions directed by Ikaros 
Nature immunology  2006;7(4):10.1038/ni1314.
Ikaros is expressed in early hematopoietic progenitors and is required for lymphoid differentiation. Analysis of Ikaros null populations revealed a lack of defining markers for early fate-restricted progenitors, but it was difficult to discern whether Ikaros was required for formation of these populations, or for expression of these markers. Here we use a GFP reporter based on Ikaros regulatory elements to identify the HSC and separate early progenitors in both wild-type and Ikaros-null mice. The presence of lympho-myeloid progenitors is revealed in Ikaros-null mice, which lack the defining factor Flt3 and are capable of myeloid, but not lymphoid differentiation. In contrast, lack of Ikaros in the common myeloid progenitor results in increased formation of erythro-megakaryocyte at the expense of myeloid progenitors and influences their subsequent differentiation. By this approach, pivotal roles for Ikaros in distinct fate decisions in the early hematopoietic hierarchy are revealed.
doi:10.1038/ni1314
PMCID: PMC3872276  PMID: 16518393
Ikaros-reporter; hematopoiesis; progenitors; cell fate
24.  Awakening lineage potential by Ikaros-mediated transcriptional priming 
Current opinion in immunology  2010;22(2):10.1016/j.coi.2010.02.011.
Bioinformatic studies on a revised hierarchy of hematopoietic progenitors have provided a genome-wide view of lineage-affiliated transcriptional programs directing early hematopoiesis. Unexpectedly, lymphoid, myeloid and erythroid gene expression programs were primed with similar frequency at the multi-potent progenitor stage indicating a stochastic nature to this process. Multi-lineage transcriptional priming is quickly resolved upon erythroid lineage restriction with both lymphoid and myeloid transcriptional programs rapidly extinguished. However, expression of lymphoid and myeloid factors remains active past nominal lymphoid and myeloid lineage restrictions, revealing a common genetic network utilized by both pathways. Priming and resolution of multi-lineage potential is dependent on the activity of the DNA binding factor Ikaros. Ikaros primes the lymphoid transcriptional program in the HSC and represses the stem cell and other disparate transcriptional programs downstream of the HSC. Loss of Ikaros removes the lymphoid leg of the immune system and may confer aberrant self-renewing properties to myeloid progenitors.
doi:10.1016/j.coi.2010.02.011
PMCID: PMC3869949  PMID: 20299195
25.  Contrast-enhanced ultrasonography follow-up after radiofrequency ablation in normal rabbit kidney 
Introduction
The aim of this study was to evaluate the diagnostic performance of SonoVue-enhanced ultrasonography in the follow-up of rabbit kidney lesions induced by percutaneous radiofrequency ablation.
Material and methods
New Zealand rabbits (28) underwent percutaneous radiofrequency ablation (RFA) to generate renal lesions. Lesions were evaluated by conventional 2D ultrasound and contrast-enhanced ultrasonography (CEUS) at 1 day, 1 week, 1 month and 3 months after RFA, and the results were compared to gross pathology.
Results
One day and 1 week after RFA, renal lesions were wedge-shaped in the gross dissection cross-sectional profiles. Conventional ultrasound could not indicate the extent of the lesions; however, CEUS could exactly delineate the lesion shape and size. At 1 and 3 months, lesions were observed as hyperechogenic areas on conventional ultrasound, and as small perfusion defects on CEUS. The differences in the lesion measurements obtained by CEUS and in pathological specimens were not statistically significant (p > 0.05).
Conclusions
The conclusion could be deduced from the study that SonoVue-enhanced ultrasonography was effective for the follow-up of normal rabbit kidney percutaneous radiofrequency ablation.
doi:10.5114/aoms.2013.37271
PMCID: PMC3776188  PMID: 24049518
contrast-enhanced ultrasonography; radiofrequency ablation; kidney; intervention

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