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1.  Disrupting the Interaction of BRD4 with Di-acetylated Twist Suppresses Tumorigenesis in Basal-like Breast Cancer 
Cancer cell  2014;25(2):210-225.
Summary
Twist is a key transcription activator of epithelial-mesenchymal transition (EMT). It remains unclear how Twist induces gene expression. Here we reported a mechanism by which Twist recruits BRD4 to direct WNT5A expression in basal-like breast cancer (BLBC). Twist contains a “histone H4 mimic” GK-X-GK motif that is di-acetylated by Tip60. The di-acetylated Twist binds the second bromodomain of BRD4, whose first bromodomain interacts with acetylated H4, thereby constructs an activated Twist/BRD4/P-TEFb/RNA-PolII complex at the WNT5A promoter and enhancer. Pharmacologic inhibition of the Twist-BRD4 association reduced WNT5A expression and suppressed invasion, cancer stem cell (CSC)-like properties, and tumorigenicity of BLBC cells. Our study indicates that the interaction with BRD4 is critical for the oncogenic function of Twist in BLBC.
doi:10.1016/j.ccr.2014.01.028
PMCID: PMC4004960  PMID: 24525235
2.  EIF4EBP1 Overexpression Is Associated with Poor Survival and Disease Progression in Patients with Hepatocellular Carcinoma 
PLoS ONE  2015;10(2):e0117493.
Objective
EIF4EBP1 acts as a crucial effector in mTOR signaling pathway. Studies have suggested that EIF4EBP1 plays a critical role in carcinogenesis. However, the clinical significance and biological role of EIF4EBP1 in hepatocellular carcinoma (HCC) have not been elucidated. Therefore, we aimed to investigate the clinical significance of EIF4EBP1 in HCC.
Methods
Total 128 cases of HCCs were included in this study. EIF4EBP1 expression in HCC tissues was detected by qRT-PCR, Western blot and immunohistochemistry, respectively. Then the relationships between EIF4EBP1 expression and clinical features as well as survival were analyzed.
Results
The expression level of EIF4EBP1 mRNA is significantly higher in 60% (24/40) of fresh HCC tissues than that in the matched adjacent nontumor liver (NCL) tissues (P = 0.044). Similarly, EIF4EBP1 protein is notably upregulated in 8 HCC tissues (randomly selected from the 40 HCCs) measured by Western blot and is significantly increased in another 88 paraffin-embedded HCCs (53%, 47/88) by immunohistochemistry compared with the matched NCLs (P < 0.001). EIF4EBP1 protein expression in HCC tissues is significantly correlated with serum AFP (P = 0.003) and marginally significantly associated with pathological grade (P = 0.085), tumor number (P = 0.084), tumor embolus (P = 0.084) and capsulation (P = 0.073). Patients with higher EIF4EBP1 protein expression have a much worse 5-year overall survival (40.3% vs 73.6%) and 5-year disease-free survival (33.0% vs 49.0%) than those with low expression. Furthermore, Cox regression analysis shows that EIF4EBP1 protein is an independent prognostic factor for overall survival (HR, 2.285; 95% CI, 1.154–4.527; P = 0.018) and disease-free survival (HR, 1.901; 95% CI, 1.067–3.386; P = 0.029) in HCC patients.
Conclusions
Our results demonstrate for the first time that EIF4EBP1 mRNA and protein are markedly up-regulated in HCC tissues, and the protein overexpression is significantly associated with poor survival and progression, which provide a potential new prognostic marker and therapeutic target for HCC patients.
doi:10.1371/journal.pone.0117493
PMCID: PMC4319970  PMID: 25658620
3.  Nanoscale simulation of shale transport properties using the lattice Boltzmann method: permeability and diffusivity 
Scientific Reports  2015;5:8089.
Porous structures of shales are reconstructed using the markov chain monte carlo (MCMC) method based on scanning electron microscopy (SEM) images of shale samples from Sichuan Basin, China. Characterization analysis of the reconstructed shales is performed, including porosity, pore size distribution, specific surface area and pore connectivity. The lattice Boltzmann method (LBM) is adopted to simulate fluid flow and Knudsen diffusion within the reconstructed shales. Simulation results reveal that the tortuosity of the shales is much higher than that commonly employed in the Bruggeman equation, and such high tortuosity leads to extremely low intrinsic permeability. Correction of the intrinsic permeability is performed based on the dusty gas model (DGM) by considering the contribution of Knudsen diffusion to the total flow flux, resulting in apparent permeability. The correction factor over a range of Knudsen number and pressure is estimated and compared with empirical correlations in the literature. For the wide pressure range investigated, the correction factor is always greater than 1, indicating Knudsen diffusion always plays a role on shale gas transport mechanisms in the reconstructed shales. Specifically, we found that most of the values of correction factor fall in the slip and transition regime, with no Darcy flow regime observed.
doi:10.1038/srep08089
PMCID: PMC4308705  PMID: 25627247
4.  Global analysis of the rat and human platelet proteome – the molecular blueprint for illustrating multi-functional platelets and cross-species function evolution 
Proteomics  2010;10(13):2444-2457.
Emerging evidences indicate that blood platelets function in multiple biological processes including immune response, bone metastasis and liver regeneration in addition to their known roles in hemostasis and thrombosis. Global elucidation of platelet proteome will provide the molecular base of these platelet functions. Here, we set up a high throughput platform for maximum exploration of the rat/human platelet proteome using integrated proteomics technologies, and then applied to identify the largest number of the proteins expressed in both rat and human platelets. After stringent statistical filtration, a total of 837 unique proteins matched with at least two unique peptides were precisely identified, making it the first comprehensive protein database so far for rat platelets. Meanwhile, quantitative analyses of the thrombin-stimulated platelets offered great insights into the biological functions of platelet proteins and therefore confirmed our global profiling data. A comparative proteomic analysis between rat and human platelets was also conducted, which revealed not only a significant similarity, but also an across-species evolutionary link that the orthologous proteins representing ‘core proteome’, and the ‘evolutionary proteome’ is actually a relatively static proteome.
doi:10.1002/pmic.200900271
PMCID: PMC4302335  PMID: 20443191
Blood platelets; multidimensional separation; mass spectrometry; global profiling; cross-species comparison
5.  A high Notch pathway activation predicts response to γ secretase inhibitors in proneural subtype of glioma tumor initiating cells 
Stem cells (Dayton, Ohio)  2014;32(1):301-312.
Genomic, transcriptional, and proteomic analyses of brain tumors reveal subtypes that differ in pathway activity, progression, and response to therapy. However, a number of small molecule inhibitors under development vary in strength of subset and pathway-specificity, with molecularly targeted experimental agents tending toward stronger specificity. The Notch signaling pathway is an evolutionarily conserved pathway that plays an important role in multiple cellular and developmental processes. We investigated the effects of Notch pathway inhibition in glioma tumor initiating cell (GIC, hereafter GIC) populations using γ secretase inhibitors. Drug cytotoxicity testing of 16 GICs showed differential growth responses to the inhibitors, stratifying GICs into responders and non-responders. Responder GICs had an enriched proneural gene signature in comparison to non-responders. Also gene set enrichment analysis revealed 17 genes set representing active Notch signaling components NOTCH1, NOTCH3, HES1, MAML1, DLL-3, JAG2 etc., enriched in responder group. Analysis of TCGA expression data set identified a group (43.9%) of tumors with proneural signature showing high Notch pathway activation suggesting γ-secretase inhibitors might be of potential value to treat that particular group of proneural GBM. Inhibition of Notch pathway by γ-secretase inhibitor treatment attenuated proliferation and self-renewal of responder GICs and induces both neuronal and astrocytic differentiation. In vivo evaluation demonstrated prolongation of median survival in an intracranial mouse model. Our results suggest that proneural GBM characterized by high Notch pathway activation may exhibit greater sensitivity to γ-secretase inhibitor treatment, holding a promise to improve the efficiency of current glioma therapy.
doi:10.1002/stem.1528
PMCID: PMC3947402  PMID: 24038660
Notch activation; proneural genes; γ secretase inhibitors; Glioma
6.  Efficacy of docetaxel combined with oxaliplatin and fluorouracil against stage III/IV gastric cancer 
World Journal of Gastroenterology : WJG  2014;20(48):18413-18419.
AIM: To investigate the clinical efficacy and toxic effects of neoadjuvant chemotherapy using docetaxel combined with oxaliplatin and fluorouracil for treating stage III/IV gastric cancer.
METHODS: A total of 53 stage III/IV gastric cancer patients were enrolled into the study and treated with neoadjuvant chemotherapy. Two of the cases were excluded. The program was as follows: 75 mg/m2 docetaxel and 85 mg/m2 oxaliplatin on day 1 and 1500 mg/m2 fluorouracil on days 1 to 3 for three weeks.
RESULTS: The tumour changes, postoperative remission rate, changes in the symptoms and adverse reactions were observed. The overall clinical efficacy (complete remission + partial remission) of the neoadjuvant chemotherapy was 62.7%. R0 radical resection was performed on 60.8% of the patients, with a remission rate (pathological complete response + pathological subtotal response + pathological partial response) of 74.2%. The Karnofksy score improved in 42 cases. The toxicity reactions mostly included myelosuppression, followed by gastrointestinal mucosal lesions, nausea, vomiting and diarrhoea.
CONCLUSION: Neoadjuvant chemotherapy consisting of docetaxel combined with oxaliplatin and fluorouracil is effective for stage III/IV gastric cancer. However, the treatment is associated with a high incidence of bone marrow suppression, which should be managed clinically.
doi:10.3748/wjg.v20.i48.18413
PMCID: PMC4277980  PMID: 25561810
Gastric cancer; Neoadjuvant chemotherapy; Docetaxel; Oxaliplatin
7.  Genome-Wide Identification of Hsp40 Genes in Channel Catfish and Their Regulated Expression after Bacterial Infection 
PLoS ONE  2014;9(12):e115752.
Heat shock proteins (HSPs) consist of a large group of chaperones whose expression is induced by high temperature, hypoxia, infection and a number of other stresses. Among all the HSPs, Hsp40 is the largest HSP family, which bind to Hsp70 ATPase domain in assisting protein folding. In this study, we identified 57 hsp40s in channel catfish (Ictalurus punctatus) through in silico analysis using RNA-Seq and genome databases. These genes can be classified into three different types, Type I, II and III, based on their structural similarities. Phylogenetic and syntenic analyses provided strong evidence in supporting the orthologies of these HSPs. Meta-analyses of RNA-Seq datasets were conducted to analyze expression profile of Hsp40s following bacterial infection. Twenty seven hsp40s were found to be significantly up- or down-regulated in the liver after infection with E. ictaluri; 19 hsp40s were found to be significantly regulated in the intestine after infection with E. ictaluri; and 19 hsp40s were found to be significantly regulated in the gill following infection with F. columnare. Altogether, a total of 42 Hsp40 genes were regulated under disease situations involving three tissues and two bacterial infections. The significant regulated expression of Hsp40 genes after bacterial infection suggested their involvement in disease defenses in catfish.
doi:10.1371/journal.pone.0115752
PMCID: PMC4277396  PMID: 25542027
8.  The association between abnormal microRNA-10b expression and cancer risk: a meta-analysis 
Scientific Reports  2014;4:7498.
Several studies have investigated the association between abnormal microRNA-10b expression and the risk of various developing cancers, but the results are inconsistent. We searched all publications addressing the level of microRNA-10b expression in cancer cases and noncancerous controls (Accessed: August 2014). Thirty-six studies on 14 types of cancer were included. Among them, 25 studies were subjected to the meta-analysis with a vote-counting strategy, 13 studies were estimated using odds ratio (OR) and diagnostic accuracy, and 2 studies were assessed by both methods. It was found that vestibular schwannomas ranked first among the reported cancer types with up-regulated microRNA-10b expression; melanoma ranked first among the reported cancer types with down-regulated microRNA-10b expression; while breast cancer and hepatocellular cancer presented inconsistent microRNA-10b regulation. Of 13 included studies calculated for OR and diagnostic accuracy, it was shown that high-expression of microRNA-10b could be significantly associated with cancer risk (OR = 32.80, 95% CI: 11.90–90.37, P<0.0001), and the area under the summary receiver operating characteristic (SROC) curve for microRNA-10b high-expression in the diagnosis of cancer is 0.81, which suggested that high-expression of microRNA-10b can predict worse outcomes in some types of cancer and the regular monitoring of miR-10b expression might be useful in the clinical practice.
doi:10.1038/srep07498
PMCID: PMC4267202  PMID: 25510966
9.  The BRCA1-interacting protein, Abraxas, is required for genomic stability and tumor suppression 
Cell reports  2014;8(3):807-817.
Summary
Germline mutations of BRCA1 confer hereditary susceptibility to breast and ovarian cancer. However, somatic mutation of BRCA1 is infrequent in sporadic breast cancers. The BRCA1 protein C-terminus BRCT domains interact with multiple proteins and are required for BRCA1's tumor suppressor function. In this study, we demonstrated that Abraxas, a BRCA1 BRCT domain-interacting protein, plays a role in tumor suppression. Abraxas exerts its function through binding to BRCA1 to regulate DNA repair and maintain genome stability. Both homozygous and heterozygous Abraxas knockout mice exhibited decreased survival and increased tumor incidence. The gene encoding Abraxas suffers from gene copy loss and somatic mutations in multiple human cancers including breast, ovarian, and endometrial cancers, suggesting that mutation and loss of function of Abraxas may contribute to tumor development in human patients.
doi:10.1016/j.celrep.2014.06.050
PMCID: PMC4149256  PMID: 25066119
10.  Targeted genomic capture and massively parallel sequencing to identify novel variants causing Chinese hereditary hearing loss 
Background
Hereditary hearing loss is genetically heterogeneous, and hundreds of mutations in than 60 genes are involved in this disease. Therefore, it is difficult to identify the causative gene mutations involved. In this study, we combined targeted genomic capture and massively parallel sequencing (MPS) to address this issue.
Methods
Using targeted genomic capture and MPS, 104 genes and three microRNA regions were selected and simultaneously sequenced in 23 unrelated probands of Chinese families with nonsyndromic hearing loss. The results were validated by Sanger sequencing for all available members of the probands’ families. To analyze the possible pathogenic functional effects of the variants, three types of prediction programs (Mutation Taster, PROVEAN and SIFT) were used. A total of 195 healthy Chinese Han individuals were compared as controls to verify the novel causative mutations.
Results
Of the 23 probands, six had mutations in DFNA genes [WFS1 (n = 2), COCH, ACTG1, TMC1, and POU4F3] known to cause autosomal dominant nonsyndromic hearing loss. These included one novel in-frame indel mutation, three novel missense mutations and two reported missense mutations. Furthermore, one proband from a family with recessive DFNB carried two monoallelic mutations in the GJB2 and USH2A genes. All of these mutations co-segregated with the hearing loss phenotype in 36 affected individuals from 7 families and were predicted to be pathogenic.
Conclusions
Mutations in uncommon deafness genes contribute to a portion of nonsyndromic deafness cases. In the future, critical gene mutations may be accurately and quickly identified in families with hereditary hearing loss by targeted genomic capture and MPS.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-014-0311-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12967-014-0311-1
PMCID: PMC4234825  PMID: 25388789
Targeted genomic capture; Exome sequencing; Hearing loss; Gene mutation
11.  Correlation between red blood cell transfusion volume and mortality in patients with massive blood transfusion: A large multicenter retrospective study 
This study aimed to explore the correlation between red blood cell (RBC) transfusion volume and patient mortality in massive blood transfusion. A multicenter retrospective study was carried out on 1,601 surgical inpatients who received massive blood transfusion in 20 large comprehensive hospitals in China. According to RBC transfusion volume and duration, the patients were divided into groups as follows: 0–4, 5–9, 10–14, 15–19, 20–24, 25–29, 30–39 and ≥40 units within 24 or 72 h. Mortality in patients with different RBC transfusion volumes was analyzed. It was found that patient mortality increased with the increase in the volume of RBC transfusion when the total RBC transfusion volume was ≥10 units within 24 or 72 h. Survival analysis revealed significant differences in mortality according to the RBC transfusion volume (χ2=72.857, P<0.001). Logistic regression analysis revealed that RBC transfusion volume is an independent risk factor [odds ratio (OR) = 0.52; confidence interval (CI): 0.43–0.64; P<0.01] for the mortality of patients undergoing a massive blood transfusion. When RBCs were transfused at a volume of 5–9 units within 24 and 72 h, the mortality rate was the lowest, at 3.7 and 2.3% respectively. It is concluded that during massive blood transfusion in surgical inpatients, there is a correlation between RBC transfusion volume within 24 or 72 h and the mortality of the patients. Patient mortality increases with the increase in the volume of RBC transfusion. RBC transfusion volume, the length of stay at hospital and intensive care unit stay constitute the independent risk factors for patient mortality.
doi:10.3892/etm.2014.2068
PMCID: PMC4247322  PMID: 25452789
massive blood transfusion; red blood cell; mortality; retrospective analysis; multicenter
12.  FXR agonist GW4064 alleviates endotoxin-induced hepatic inflammation by repressing macrophage activation 
World Journal of Gastroenterology : WJG  2014;20(39):14430-14441.
AIM: To examine the effect of farnesoid X receptor (FXR) activation by GW4064 on endotoxin-induced hepatic inflammation in nonalcoholic fatty liver disease (NAFLD) and the underlying mechanism.
METHODS: Six-week-old male C57BL/6 mice were fed a normal diet or a high-fat (HF) diet for 8 wk. HF diet-fed mice were intraperitoneally injected with GW4064 (30 mg/kg) or DMSO (vehicle) once daily for a week and then sacrificed after lipopolysaccharide (LPS, 50 μg/mouse) administration. Hepatic inflammation, levels of the macrophage marker F4/80, and apoptosis were measured at the end of the study. Additionally, the expression of proinflammatory genes involved in NAFLD (interleukin-6, interleukin-1β, interferon-γ, MCP-1) were analyzed by real-time PCR in the murine macrophage cell line RAW 264.7 cultured with or without GW4064 (2 μmol/L) before treatment with LPS.
RESULTS: In patients with NAFLD, the expression of FXR was detected by immunohistochemical staining and the relation between FXR expression and NAFLD activity score (NAS) was analyzed. Activation of FXR by GW4064 alleviated hepatic inflammation induced by endotoxin in a murine NAFLD model fed an HF diet as reflected by reduced serum levels of aspartate aminotransferase and alanine aminotransferase. Apoptosis and proinflammatory cytokine levels in liver tissues were also reduced by GW4064, and GW4064 could reduce induction of proinflammatory cytokines by LPS in vitro. FXR levels were reduced in patients with non-alcoholic steatohepatitis compared with healthy controls and were negatively correlated with NAS.
CONCLUSION: FXR activation attenuates LPS-induced hepatic inflammation in murine NAFLD by reducing expression of proinflammatory cytokines in macrophages.
doi:10.3748/wjg.v20.i39.14430
PMCID: PMC4202371  PMID: 25339829
Farnesoid X receptor; Nonalcoholic fatty liver disease; GW4064; Nonalcoholic fatty liver disease activity score; Lipopolysaccharide-induced hepatic inflammation; Macrophage activation
13.  Acetylation of Metabolic Enzymes Coordinates Carbon Source Utilization and Metabolic Flux 
Science (New York, N.Y.)  2010;327(5968):1004-1007.
Lysine acetylation regulates many eukaryotic cellular processes, but its function in prokaryotes is largely unknown. We demonstrated that central metabolism enzymes in Salmonella were acetylated extensively and differentially in response to different carbon sources, concomitantly with changes in cell growth and metabolic flux. The relative activities of key enzymes controlling the direction of glycolysis versus gluconeogenesis and the branching between citrate cycle and glyoxylate bypass were all regulated by acetylation. This modulation is mainly controlled by a pair of lysine acetyltransferase and deacetylase, whose expressions are coordinated with growth status. Reversible acetylation of metabolic enzymes ensure that cells respond environmental changes via promptly sensing cellular energy status and flexibly altering reaction rates or directions. It represents a metabolic regulatory mechanism conserved from bacteria to mammals.
doi:10.1126/science.1179687
PMCID: PMC4183141  PMID: 20167787
14.  Galectin-3 is associated with a poor prognosis in primary hepatocellular carcinoma 
Background
Galectin-3, a member of the beta-galactoside-binding lectin family, is a multifunctional protein with various biological functions, including the proliferation and differentiation of tumor cells, angiogenesis, cancer progression, and metastasis. We aimed to clarify if expression of galectin-3 is related to the clinicopathological characteristics and prognosis of hepatocellular carcinoma (HCC) patients, and to explore the possible mechanisms of galectin-3 in hepatocellular carcinoma.
Methods
First, we investigated galectin-3 mRNA and protein expression by using RT-PCR and Western blotting. Second, tissues from 165 HCC patients were used to evaluate clinicopathological characteristics and prognosis through immunohistochemical analyses. Furthermore, the functions of galectin-3 were analyzed with respect to the proliferation, cell cycle,apoptosis, migration, and invasion of HCC cell lines. Finally, we analyzed galectin-3 expression and micro-vessel density (MVD) by immunohistochemistry (IHC) to find its correlation with angiogenesis in Hepatocellular Carcinoma. Flow cytometer was used to explore apoptosis and Western-blot was used to detect the pathway proteins of apoptosis.
Results
Galectin-3 showed high expression at the mRNA and protein levels in HCC cancer tissues and cell lines. Clinicopathological analyses revealed that increased expression of galectin-3 in tumors was closely associated with a poor prognosis. Galectin-3 knockdown by siRNA significantly inhibited cell growth, migration, and invasion, and induced apoptosis in HCC cells in vitro, whereas galectin-3 overexpression promoted cell growth, migration, and invasion. Correlation analysis of galectin-3 expression and micro-vessel density (MVD) showed that galectin-3 expression in tumor cells stimulates angiogenesis. The observed regulation of cell apoptosis was accompanied by the galectin-3-mediated modulation of caspase3 signaling pathways in HCC cells.
Conclusions
These data suggest that galectin-3 plays an important part in HCC progression and may serve as a prognostic factor for HCC.
doi:10.1186/s12967-014-0273-3
PMCID: PMC4179848  PMID: 25260879
Galectin-3; Hepatocellular carcinoma; Angiogenesis; Apoptosis; Prognostic factor
15.  Comparison of one-year clinical outcomes between intravascular ultrasound-guided versus angiography-guided implantation of drug-eluting stents for left main lesions: a single-center analysis of a 1,016-patient cohort 
Background
The importance of intravascular ultrasound (IVUS)-guided stenting of the unprotected left main coronary artery (ULMCA) remains controversial and has not been fully studied in the subset of patients with ULMCA. This study evaluated the clinical outcome of IVUS-guided stenting using a drug-eluting stent for ULMCA.
Methods
A total of 1,016 consecutive patients with ULMCA stenosis who underwent drug-eluting stent implantation from January 2006 to December 2011 were prospectively registered. The primary endpoint of this nonrandomized registry was the rate of one-year major adverse cardiac events (MACE, including cardiac death, myocardial infarction, and target vessel revascularization). Stent thrombosis served as the safety endpoint. Propensity score matching was used to calculate the adjusted event rate.
Results
The unadjusted one-year MACE rate was 14.8% in the IVUS-guided group (n=337, 33.2%), significantly different from the 27.7% (P<0.001) in the angiography-guided group (n=679, 66.8%). After propensity score matching, 291 paired patients were matched between the two groups, and the difference in one-year MACE between IVUS-guided (16.2%) versus angiography-guided (24.4%) groups was still significant (P=0.014), mainly driven by decreased rates of cardiac death (1.7%) and target vessel revascularization (3.4%) in the IVUS-guided group when compared with 5.2% (P=0.023) and 10.0% (P=0.002) in the angiography-guided group, respectively. Although it did not reach significance (P=0.075), the adjusted one-year rate of stent thrombosis in the angiography-guided group was higher than in the IVUS-guided group.
Conclusion
Compared with angiography guidance, IVUS-guided treatment of ULMCA using a drug-eluting stent was associated with a significant reduction of one-year cardiac death and target vessel revascularization, resulting in less frequent one-year MACE after propensity score matching.
doi:10.2147/PPA.S65768
PMCID: PMC4179827  PMID: 25278749
unprotected left main; intravascular ultrasound; major adverse cardiac events
16.  Caveolin-1 upregulation mediates suppression of primary breast tumor growth and brain metastases by Stat3 inhibition 
Cancer research  2011;71(14):4932-4943.
Stat3 activation has been implicated as an important driver of brain metastasis in breast cancer, but the critical targets of Stat3 in this process are yet to be fully defined. In this study, we identified the lipid raft organizing protein Caveolin-1 (Cav-1) as a critical genetic target of Stat3 in this process. In human breast cancers, we found that activated Stat3 correlated with attenuation of Cav-1 in brain metastases relative to primary tumors. Cav-1 promoter activity and gene expression was increased by overexpressing an activated form of Stat3, but decreased by attenuation of Stat3 activity or expression. We identified putative Stat3-binding elements in the Cav-1 promoter and demonstrated a direct repression of Cav-1 transcription by Stat3. Reciprocally, we demonstrated that strategies to increase or decrease Cav-1 expression were sufficient to attenuate or promote breast cancer cell invasion. Further, increased expression of Cav-1 phenocopied the effects of Stat3 activation in blocking primary tumor growth and abrogating formation of brain metastases. Collectively, our findings provide clinical and mechanistic evidence that Cav-1 is a critical target for suppression by Stat3 in driving invasion and metastasis of breast cancer cells.
doi:10.1158/0008-5472.CAN-10-4249
PMCID: PMC4170798  PMID: 21622714
Stat3; caveolin-1; SOCS-1; brain metastases; breast cancer; invasion
17.  Identification of I411K, a novel missense EYA4 mutation causing autosomal dominant non-syndromic hearing loss 
Hearing loss is the most common sensory deficit in humans and gaining a better understanding of the underlying causes is necessary to improve counseling and rehabilitation. In the present study, a genetic analysis of a Chinese family with autosomal dominant non-syndromic progressive hearing impairment was conducted and assessed. Whole-exome sequencing in combination with a co-segregation analysis identified a novel missense mutation in EYA4 exon 15 (c.T1301A; p.I411K). The mutation segregated with the hearing loss of the family. This mutation was not identified in the databases of 1000 Genome Project, dbSNP 130, HapMap and YH project or in matched controls. Bioinformatic analysis confirmed the pathogenic effects of this mutation. To the best of our knowledge, this is the first report to provide a description of a missense mutation in the EYA4 gene resulting in non-syndromic hearing loss. Our results provide additional molecular and clinical information in order to gain improved understanding of the pathogenesis of EYA4 mutations and the genotype-phenotype correlations of DFNA10 hearing loss.
doi:10.3892/ijmm.2014.1939
PMCID: PMC4214331  PMID: 25242383
non-syndromic hearing loss; autosomal dominant 10; EYA4 gene; whole-exome sequencing
18.  Apo E Gene Polymorphism Affects Development of Type 2 Diabetic Nephropathy in Asian Populations, Especially in East Asians: An Updated Meta-Analysis 
Background
Many studies have determined the correlation between the Apolipoprotein E (APO E) gene polymorphisms and diabetic nephropathy, but their results are inconclusive.
Material/Methods
With the aim to confirm this correlation, we performed a meta-analysis of 16 studies. The dichotomous data are presented as the odds ratio (OR) with a 95% confidence interval (CI).
Results
The results of our study indicate that APO ɛ2 allele among the pooled Asian populations were more likely to show high risk of DN development (2 allele vs. ɛ3 allele: pooled OR =1.629, 95% CI=1.010–2.628, P=0.045). For further analysis, the APO ɛ2 allele was associated with progress of DN in the group with duration >10 years, but not in the group with duration <10 years (ɛ2 allele vs. ɛ3 allele: pooled OR=1.920, 95% CI=1.338–2.754, P<0.001). The APO ɛ2 polymorphism increased the susceptibility to DN in Asian population compared with healthy people (ɛ2 allele vs. ɛ3 allele: pooled OR=1.629, 95% CI=1.010–2.628, P=0.045).
Conclusions
Development of DN is associated with APO E polymorphisms in Asian populations, especially in East Asians.
doi:10.12659/MSM.892111
PMCID: PMC4166221  PMID: 25196797
Diabetic Nephropathies; Disease Susceptibility; Meta-Analysis
19.  Partial greater trochanter osteotomy for hip reduction in total hip arthroplasty for high dislocated hip: a preliminary report 
Background
Hip reduction in total hip arthroplasty for high dislocated hips is difficult. Various femur osteotomy procedures have been used for hip reduction, but these methods increase operative time and risk of nonunion. We investigated the efficacy of a novel partial greater trochanter osteotomy technique for hip reduction in total hip arthroplasty for patients with high hip dislocation.
Methods
Twenty-one patients (23 hips) with high dislocated hip were treated with total hip arthroplasty that included partial greater trochanter osteotomy, i.e., the upper 2/3 greater trochanter was resected, and the gluteus medius muscle attachment was spared. The clinical outcome was evaluated by comparing the Harris hip scores and radiographic exam results, obtained before surgery and at follow-ups.
Results
Follow-ups of 21 patients ranged from 13 to 56 months. The mean Harris hip score increased from preoperative 55.0 (36–69) to postoperative 86.1 (71–93; P = 0.00). The average preoperative leg length discrepancy in patients with unilateral high hip dislocation was 46 mm (28–65 mm); postoperatively leg length discrepancy was less than 1 cm in 11 patients, between 1 and 2 cm in 8 patients, and more than 2 cm in 2 patients. The average leg lengthening at the time of surgery was 36 mm (24–54 mm). Trendelenburg’s gait changed from positive to negative in 20 hips by the last follow-up. No nerve injury occurred postoperative.
Conclusion
Partial greater trochanter osteotomy is an effective method to render hip reduction in total hip arthroplasty for patients with high dislocation of the hip.
doi:10.1186/1471-2474-15-293
PMCID: PMC4174664  PMID: 25186094
Partial greater trochanter osteotomy; Hip reduction; High dislocated hip; Total hip arthroplasty
20.  Combination treatment of PD98059 and DAPT in gastric cancer through induction of apoptosis and downregulation of WNT/β-catenin 
Cancer Biology & Therapy  2013;14(9):833-839.
γ-secretase inhibitors (GSIs), the indirect inhibitors of Notch, are emerging as a new class of anticancer agents for the treatment of solid and hematological malignancies, but little is known about their effects on gastric cancer. In this study, we demonstrate that DAPT, a potent GSI, was effective to inhibit γ-secretase activity in gastric cancer (GC) cell lines that contained a fragment with approximately the size of the Notch1 intracellular domain (NICD), but was limited in their ability to induce apoptosis. However, activation of extracellular signal-regulated kinase (ERK)1/2 upon DAPT treatment was detected. Selective inhibition of ERK1/2 activation dramatically sensitized GC cells to apoptosis via downregulating β-catenin signaling in these GC cells. Notably, in a xenograft mouse tumor model, combination therapy using ERK inhibitor PD98059 plus DAPT yielded additive antitumor effects as compared with either agent alone. Taken together, these data demonstrated that γ-secretase inhibition combined with ERK1/2 inhibitor enhances cell death in GC cells partly through downregulation of WNT/β-catenin pathways.
doi:10.4161/cbt.25332
PMCID: PMC3909552  PMID: 23792588
DAPT; ERK; Notch1; PD98059; apoptosis; gastric cancer; β-catenin
21.  Tissue-specific isoform switch and DNA hypomethylation of the pyruvate kinase PKM gene in human cancers 
Oncotarget  2013;5(18):8202-8210.
The M2 isoform of pyruvate kinase (PKM2) plays an important role in aerobic glycolysis and is a mediator of the Warburg effect in tumors. It was previously thought that tumor cells switch expression of PKM from normal tissue-expressed PKM1 to tumor-specific PKM2 via an alternative splicing mechanism. This view was challenged by a recent report demonstrating that PKM2 is already the major PKM isoform expressed in many differentiated normal tissues. Here, through analyses on sixteen tumor types using the cancer genome atlas RNA-Seq and exon array datasets, we confirmed that isoform switch from PKM1 to PKM2 occurred in glioblastomas but not in other tumor types examined. Despite lacking of isoform switches, PKM2 expression was found to be increased in all cancer types examined, and correlated strongly to poor prognosis in head and neck cancers. We further demonstrated that elevated PKM2 expression correlated well with the hypomethylation status of intron 1 of the PKM gene in multiple cancer types, suggesting epigenetic regulation by DNA methylation as a major mechanism in controlling PKM transcription in tumors. Our study suggests that isoform switch of PKM1 to PKM2 in cancers is tissue-specific and targeting PKM2 activity in tumors remains a promising approach for clinical intervention of multiple cancer types.
PMCID: PMC4226677  PMID: 24077665
PKM2; alternative splicing; DNA methylation
22.  High performance current and spin diode of atomic carbon chain between transversely symmetric ribbon electrodes 
Scientific Reports  2014;4:6157.
We demonstrate that giant current and high spin rectification ratios can be achieved in atomic carbon chain devices connected between two symmetric ferromagnetic zigzag-graphene-nanoribbon electrodes. The spin dependent transport simulation is carried out by density functional theory combined with the non-equilibrium Green's function method. It is found that the transverse symmetries of the electronic wave functions in the nanoribbons and the carbon chain are critical to the spin transport modes. In the parallel magnetization configuration of two electrodes, pure spin current is observed in both linear and nonlinear regions. However, in the antiparallel configuration, the spin-up (down) current is prohibited under the positive (negative) voltage bias, which results in a spin rectification ratio of order 104. When edge carbon atoms are substituted with boron atoms to suppress the edge magnetization in one of the electrodes, we obtain a diode with current rectification ratio over 106.
doi:10.1038/srep06157
PMCID: PMC4139955  PMID: 25142376
23.  Transarterial chemoembolization vs. conservative treatment for unresectable infiltrating hepatocellular carcinoma: A retrospective comparative study 
Molecular and Clinical Oncology  2014;2(6):1047-1054.
This study was conducted to compare long-term survival between patients with unresectable infiltrating hepatocellular carcinoma (HCC) who were treated with transarterial chemoembolization (TACE) and those who received conservative treatment (best supportive care). Between January, 2007 and January, 2012, a total of 131 consecutive patients with unresectable infiltrating HCC underwent TACE in a cancer center (TACE group), while 156 similar consecutive HCC patients received conservative treatment in another cancer center (conservative treatment group). The diagnosis of unresectable infiltrating HCC was established by agreement between two radiologists coming from the two centers, who performed an independent review of all the cross-sectional imagings of the patients. The two groups were comparable regarding patient characteristics, preoperative liver function, tumor burden and general condition. In the TACE group, 52 patients received one session and 79 patients received more than one session of TACE (mean, 1.5 and range, 1–4 sessions). There was no reported TACE-related mortality. The 1-month mortality rate was 0.8 and 3.8% in the TACE and the conservative groups, respectively (P=0.134). The median survival for the TACE and conservative treatment groups was 7.0 and 3.0 months, respectively. The 6-, 12- and 24-month overall survival rates for the TACE and conservative treatment groups were 61.7, 18.5 and 2.3% vs. 22.7, 12.1 and 0%, respectively (P<0.001). On multivariate analysis, treatment allocation [odds ratio (OR)=1.777; 95% confidence interval (CI): 1.499–2.107; P<0.001] and portal vein tumor thrombosis (OR=1.721; 95% CI: 1.504–1.907; P<0.001) were independent predictors of overall survival. In conclusion, TACE was found to be a safe and feasible treatment option for patients with unresectable infiltrating HCC and it conferred survival benefit over conservative treatment.
doi:10.3892/mco.2014.391
PMCID: PMC4179804  PMID: 25279196
unresectable infiltrating hepatocellular carcinoma; transarterial chemoembolization; conservative treatment; survival; independent predictor
24.  Application status of blood constituents during massive blood transfusion in some regions of China 
Objective: This study aims to learn about the current situation of surgical massive blood transfusion in China’s Class III general hospitals, which could provide the basis for the formulation of guidelines on massive blood transfusion. Methods: A multicenter retrospective research on the application status of blood constituents during massive blood transfusion was conducted and a comparative analysis on the distribution of the population infused with other blood constituents and the transfusion volume at different periods of time when red blood cells are infused in different units within 24 hours as well as on the blood applied for both the death group and survival group was made in this study. Results: In China, during massive blood transfusion the ratio of the dosage of fresh frozen plasma to the dosage of red blood cell suspension reached 1:1-2, while the dosage of platelet and cryocepitate appeared to be very small. Conclusion: During massive blood transfusion, clinicians in 20 Chinese hospitals paid more attention to the infusion of fresh frozen plasma while making the infusion of red blood cells. However, they paid little attention to the supplement of platelet and cryocepitate.
PMCID: PMC4132143  PMID: 25126179
Massive blood transfusion; blood constituents; retrospective analysis

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