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1.  Atorvastatin enhances neurite outgrowth in cortical neurons in vitro via up-regulating the Akt/mTOR and Akt/GSK-3β signaling pathways 
Acta Pharmacologica Sinica  2012;33(7):861-872.
To investigate whether atorvastatin can promote formation of neurites in cultured cortical neurons and the signaling mechanisms responsible for this effect.
Cultured rat cerebral cortical neurons were incubated with atorvastatin (0.05–10 μmol/L) for various lengths of time. For pharmacological experiments, inhibitors were added 30 min prior to addition of atorvastatin. Control cultures received a similar amount of DMSO. Following the treatment period, phase-contrast digital images were taken. Digital images of neurons were analyzed for total neurite branch length (TNBL), neurite number, terminal branch number, and soma area by SPOT Advanced Imaging software. After incubation with atorvastatin for 48 h, the levels of phosphorylated 3-phosphoinoside-dependent protein kinase-1 (PDK1), phospho-Akt, phosphorylated mammalian target of rapamycin (mTOR), phosphorylated 4E-binding protein 1 (4E-BP1), p70S6 kinase (p70S6K), and glycogen synthase kinase-3β (GSK-3β) in the cortical neurons were evaluated using Western blotting analyses.
Atorvastatin (0.05–10 μmol/L) resulted in dose-dependent increase in neurite number and length in these neurons. Pretreatment of the cortical neurons with phosphatidylinositol 3-kinase (PI3K) inhibitors LY294002 (30 μmol/L) and wortmannin (5 μmol/L), Akt inhibitor tricribine (1 μmol/L) or mTOR inhibitor rapamycin (100 nmol/L) blocked the atorvastatin-induced increase in neurite outgrowth, suggesting that atorvastatin promoted neurite outgrowth via activating the PI3K/Akt/mTOR signaling pathway. Atorvastatin (10 μmol/L) significantly increased the levels of phosphorylated PDK1, Akt and mTOR in the cortical neurons, which were prevented by LY294002 (30 μmol/L). Moreover, atorvastatin (10 μmol/L) stimulated the phosphorylation of 4E-BP1 and p70S6K, the substrates of mTOR, in the cortical neurons. In addition, atorvastatin (10 μmol/L) significantly increased the phosphorylated GSK-3β level in the cortical neurons, which was prevented by both LY294002 and tricribine.
These results suggest that activation of both the PI3K/Akt/mTOR and Akt/GSK-3β signaling pathways is responsible for the atorvastatin-induced neurite outgrowth in cultured cortical neurons.
PMCID: PMC4011150  PMID: 22705730
statin; atorvastatin; cortical neurons; neuritogenesis; PI3-kinase; GSK-3β
2.  Involvement of IRS-1 interaction with ADAM10 in the regulation of neurite extension 
Journal of cellular physiology  2014;229(8):1039-1046.
The insulin-like growth factor-1 (IGF-1) signaling pathway plays an important role in neuronal cell differentiation. Recent studies have shown that IGF-1 has the capacity to counteract the retraction of neuronal processes in response to inflammatory cytokines such as TNF-α, which is a known factor for neuronal injury in the CNS. This event is thought to be mediated via interference of TNF-α-induced interaction of β1-integrin with insulin receptor substrate-1 (IRS-1). Here we demonstrate the interaction of IRS-1 with disintegrin and metalloproteinase ADAM10 through the N-terminal domain of IRS-1 and that this is involved in the regulation of neurite extension and retraction by IGF-1 and TNF-α, respectively. PC12 cells expressing the N-terminal domain show enhanced neurite extension after IGF-1 treatment and reduced neurite depletion relative to control cells after TNF-α treatment. The level of ADAM10 was found to be increased in immunohistochemical studies of HIV encephalitis clinical samples and is present with TNF-α and TNFR1 in both astrocytes and neurons. Altogether, these observations suggest a role for ADAM10 in the mechanism for IGF1/IRS-1 signaling pathway in sustaining the stability of neuronal processes.
PMCID: PMC4204481  PMID: 24648009
IRS-1; ADAM10; IGF-1; TNF-α; neurite extension; signal transduction
3.  FGF21 protects against ox-LDL induced apoptosis through suppressing CHOP expression in THP1 macrophage derived foam cells 
FGF21,as a member of the fibroblast growth factor superfamily, is an important endogenous regulator to systemic glucose and lipid metabolism. Elevated serum FGF21 levels have been reported in subjects with coronary heart disease and carotid artery plaques. The formation and apoptosis of foam cell, induced by ox-LDL and oxysterols, are key steps in the development of atherosclerosis.
In this study, THP1 derived macrophages were induced into foam cells by ox-LDL or sterols. The formation and apoptosis of foam cells treated with or without FGF21 were analyzed.
We demonstrated that the accumulation of cholesterol was decreased after FGF21 treatment in THP1 macrophage derived foam cells. Consistently, the apoptosis of macrophage was alleviated dramatically with FGF21 treatment. ERK1/2 knockdown didn’t abrogate the effect of FGF21 on THP1 macrophage derived foam cells. However, FGF21 suppressed the induced expression of CHOP and DR5 in THP1 macrophage derived foam cells.
FGF21 protects against the formation and apoptosis of THP1 macrophages derived foam cells through suppressing the expression of CHOP.
PMCID: PMC4518604
Macrophage; ER stress; FGF21; Foam cell; CHOP
4.  Genetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study 
Nature Communications  2015;6:7633.
Graves' disease is the leading cause of hyperthyroidism affecting 1.0–1.6% of the population. Antithyroid drugs are the treatment cornerstone, but may cause life-threatening agranulocytosis. Here we conduct a two-stage association study on two separate subject sets (in total 42 agranulocytosis cases and 1,208 Graves' disease controls), using direct human leukocyte antigen genotyping and SNP-based genome-wide association study. We demonstrate HLA-B*38:02 (Armitage trend Pcombined=6.75 × 10−32) and HLA-DRB1*08:03 (Pcombined=1.83 × 10−9) as independent susceptibility loci. The genome-wide association study identifies the same signals. Estimated odds ratios for these two loci comparing effective allele carriers to non-carriers are 21.48 (95% confidence interval=11.13–41.48) and 6.13 (95% confidence interval=3.28–11.46), respectively. Carrying both HLA-B*38:02 and HLA-DRB1*08:03 increases odds ratio to 48.41 (Pcombined=3.32 × 10−21, 95% confidence interval=21.66–108.22). Our results could be useful for antithyroid-induced agranulocytosis and potentially for agranulocytosis caused by other chemicals.
Graves' disease is the leading cause of hyperthyroidism but treatment options can cause life-threatening complications. Chen et al. conduct two-stage direct HLA genotyping and genome-wide association studies to identify HLA-B*38:02 and HLA-DRB1*08:03 as major pharmacogenetic determinants.
PMCID: PMC4506516  PMID: 26151496
5.  A novel inflammation-based prognostic score in esophageal squamous cell carcinoma: the C-reactive protein/albumin ratio 
BMC Cancer  2015;15:350.
Plenty of studies have demonstrated the prognostic value of various inflammation-based indexes in cancer. This study was designed to investigate the prognostic value of the C-reactive protein/albumin (CRP/Alb) ratio in esophageal squamous cell carcinoma.
A retrospective study of 423 cases with newly diagnosed esophageal squamous cell carcinoma was conducted. We analyzed the association of the CRP/Alb ratio with clinicopathologic characteristics. The prognostic value was explored by univariate and multivariate survival analysis. In addition, we compared the discriminatory ability of the CRP/Alb ratio with other inflammation-based prognostic scores by evaluating the area under the receiver operating characteristics curves (AUC), including the modified Glasgow Prognostic Score (mGPS), neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR).
The optimal cut-off value was identified to be 0.095 for the CRP/Alb ratio. A higher level of the CRP/Alb ratio was associated with larger tumor size (P < 0.001), poorer differentiation (P = 0.019), deeper tumor invasion (P = 0.003), more lymph node metastasis (P = 0.015), more distant metastasis (P < 0.001) and later TNM stage (P < 0.001). The CRP/Alb ratio was identified to be the only inflammation-based prognostic score with independent association with overall survival by multivariate analysis (P = 0.031). The AUC value of the CRP/Alb ratio was higher compared with the NLR and PLR, but not mGPS at 6, 12 and 24 months of follow-up. In addition, the CRP/Alb ratio could identify a group of patients with mGPS score of 0 who had comparable overall survival with those with mGPS score of 1.
The CRP/Alb ratio is a novel but promising inflammation-based prognostic score in esophageal squamous cell carcinoma. It is a valuable coadjutant for the mGPS to further identify patients’ survival differences.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1379-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4423167  PMID: 25934640
Esophageal squamous cell carcinoma; C-reactive protein; Albumin; The modified Glasgow Prognostic Score; Inflammation-based prognostic score; Survival
6.  Fertility-sparing treatment of low-grade endometrial stromal sarcoma 
Low-grade endometrial stromal sarcoma (ESS) is a kind of uterine malignancy. Total hysterectomy and bilateral salpingo-oophorectomy was the main treatment. We evaluate the feasibility of fertility-sparing management in five patients with low-grade ESS who desired for childbearing. The patients aged 28-36 years old presented with symptoms of menometrorrhagia or without symptom. Ultrasound examinations demonstrated leiomyomas (with the diameter of 3.5-6 cm respectively). All the patients received conservative surgeries of local resection of the mass with uterine reconstruction. Then the adjuvant endocrine therapy was given to them with megestrol acetate (160-320 mg/day) or triptorelin (3.75 mg/28 days) for 5-6 months. The follow-up lasted 21-55 months. All the patients survived. Three of them underwent an uncomplicated pregnancy, and received cesarean delivery of a liveborn neonate. One of them is alive without disease recurrence. The other one found disease recurred during the megestrol acetate treatment, and received hysterectomy. We consider that fertility-sparing treatment is suitable in selected in young low-grade ESS patients especially for those whose lesion was with a clear borderline. Adjuvant endocrine therapy is recommended for about 6 months after operation.
PMCID: PMC4483844  PMID: 26131171
Endometrial stromal sarcoma; fertility-conservative; endocrine therapy
7.  Serum alkaline phosphatase predicts survival outcomes in patients with skeletal metastatic nasopharyngeal carcinoma 
Clinics  2015;70(4):264-272.
Bone metastasis is frequently associated with nasopharyngeal carcinoma. The diagnosis and follow-up of bone metastatic patients usually relies on skeletal X-ray and bone scintigraphy, which are time-consuming and costly. This study aimed to evaluate whether serum alkaline phosphatase offers clinical value in predicting the clinical response and survival outcome for skeletal metastatic nasopharyngeal carcinoma.
Serum alkaline phosphatase was measured at baseline and then before each cycle of treatment in 416 nasopharyngeal carcinoma patients with bone metastasis. The correlations between the pre-treatment and post-treatment alkaline phosphatase levels and the treatment efficacy were analyzed using the chi-square test. Survival was analyzed using the Kaplan–Meier method and then compared using the log-rank test.
Patients with elevated pre-treatment alkaline phosphatase (>110 IU/L) had significantly worse progression-free survival (P<0.001) and overall survival (P<0.001) than those with a normal level of this marker (≤110 IU/L). Patients with elevated post-treatment alkaline phosphatase had worse progression-free survival (P<0.001) and overall survival (P<0.001) compared with those with a normal level. Patients with normal pre-treatment and post-treatment alkaline phosphatase showed the most favorable prognosis. The Cox multivariate analysis revealed that only the pre-treatment and post-treatment alkaline phosphatase levels were independent prognostic factors for progression-free survival (HR ϝ 1.656, P<0.001; HR ϝ 2.226, P<0.001) and for overall survival (HR ϝ 1.794, P<0.001; HR ϝ 2.657, P<0.001).
Serum alkaline phosphatase appears to be a significant independent prognostic index in patients with skeletal metastatic nasopharyngeal carcinoma, which could reflect the short-term treatment response of palliative chemotherapy and the long-term survival outcomes.
PMCID: PMC4449461  PMID: 26017793
Nasopharyngeal carcinoma; Palliative chemotherapy; Serum alkaline phosphatase; Skeletal metastasis
8.  Analysis of gene expression profiles associated with glioma progression 
Molecular Medicine Reports  2015;12(2):1884-1890.
The present study aimed to investigate changes at the transcript level that are associated with spontaneous astrocytoma progression, and further, to discover novel targets for glioma diagnosis and therapy. GSE4290 microarray data downloaded from Gene Expression Omnibus were used to identify the differentially expressed genes (DGEs) by significant analysis of microarray (SAM). The Short Time Series Expression Miner (STEM) method was then applied to class these DEGs based on their degrees of differentiation in the process of tumor progression. Finally, EnrichNet was used to perform the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis based on a protein-protein interaction (PPI) network. A total of 4,506 DEGs were detected, and the number of DEGs was the highest in grade IV cells (2,580 DEGs). These DEGs were classified into nine clusters by the STEM method. In total, 11 KEGG pathways with XD-scores larger than the threshold (0.96) were obtained. The DEGs enriched in pathways 1 (extracellular matrix-receptor interaction), 3 (phagosome) and 6 (type I diabetes mellitus) mainly belonged to cluster 5. Pathway 2 (long-term potentiation), 4 (Vibrio cholerae infection) and 5 (epithelial cell signaling in Helicobacter pylori infection) was involved with DEGs that belonged to different clusters. Significant changes in gene expression occurred during glioma progression. Pathways 1, 3 and 6 may be important for the deterioration of glioma into glioblastoma, and pathways 2, 4 and 5 may have a role at each stage during glioma progression. The associated DEGs, including SV2, NMDAR and mGluRs, may be suitable as biomarkers or therapeutic targets for gliomas.
PMCID: PMC4464167  PMID: 25845910
glioma progression; gene expression profile; differentially expressed genes; kyoto encyclopedia of genes and genomes enrichment pathway
9.  RNA Interference of Myocyte Enhancer Factor 2A Accelerates Atherosclerosis in Apolipoprotein E-Deficient Mice 
PLoS ONE  2015;10(3):e0121823.
Myocyte enhancer factor-2A (MEF 2A) has been shown to be involved in atherosclerotic lesion development, but its role in preexisting lesions is still unclear. In the present study we aim to assess the role of MEF 2A in the progression of pre-existing atherosclerosis.
Eighty apolipoprotein E-deficient mice (APOE KO) were randomly allocated to control, scramble and MEF 2A RNA interference (RNAi) groups, and constrictive collars were used to induce plaque formation. Six weeks after surgery, lentiviral shRNA construct was used to silence the expression of MEF 2A. Carotid plaques were harvested for analysis 4 weeks after viral vector transduction. Inflammatory gene expression in the plasma and carotid plaques was determined by using ELISAs and real-time RT-PCR.
The expression level of MEF 2A was significantly reduced in plasma and plaque in the RNAi group, compared to the control and NC groups, whereas the expression level of pro-inflammatory cytokines was markedly increased. Silencing MEF 2A using lentiviral shRNA significantly reduced the plaque collagen content and fibrous cap thickness, as well as increased plaque area. However, silencing MEF 2A had no obvious effect on plaque lipid content.
Lentivirus-mediated MEF 2A shRNA accelerates inflammation and atherosclerosis in APOE KO mice, but has no effect on lipoprotein levels in plasma.
PMCID: PMC4368513  PMID: 25793529
10.  Critical protein GAPDH and its regulatory mechanisms in cancer cells 
Cancer Biology & Medicine  2015;12(1):10-22.
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), initially identified as a glycolytic enzyme and considered as a housekeeping gene, is widely used as an internal control in experiments on proteins, mRNA, and DNA. However, emerging evidence indicates that GAPDH is implicated in diverse functions independent of its role in energy metabolism; the expression status of GAPDH is also deregulated in various cancer cells. One of the most common effects of GAPDH is its inconsistent role in the determination of cancer cell fate. Furthermore, studies have described GAPDH as a regulator of cell death; other studies have suggested that GAPDH participates in tumor progression and serves as a new therapeutic target. However, related regulatory mechanisms of its numerous cellular functions and deregulated expression levels remain unclear. GAPDH is tightly regulated at transcriptional and posttranscriptional levels, which are involved in the regulation of diverse GAPDH functions. Several cancer-related factors, such as insulin, hypoxia inducible factor-1 (HIF-1), p53, nitric oxide (NO), and acetylated histone, not only modulate GAPDH gene expression but also affect protein functions via common pathways. Moreover, posttranslational modifications (PTMs) occurring in GAPDH in cancer cells result in new activities unrelated to the original glycolytic function of GAPDH. In this review, recent findings related to GAPDH transcriptional regulation and PTMs are summarized. Mechanisms and pathways involved in GAPDH regulation and its different roles in cancer cells are also described.
PMCID: PMC4383849  PMID: 25859407
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH); mechanism; regulation; posttranslational modification (PTM); cancer
11.  Prognostic Significance of Lymphovascular Space Invasion in Epithelial Ovarian Cancer 
Journal of Cancer  2015;6(5):412-419.
Object: To assess the effects of lymphovascular space invasion (LVSI) on cancer recurrence and survival in patients with primary epithelial ovarian cancer.
Methods: A retrospective study was conducted of patients with stage I-IV primary epithelial ovarian cancer who underwent cytoreductive surgery. LVSI is defined as the presence of tumor cells within an endothelium-lined space, and the patients' pathologic slides were reevaluated by gynecological pathologists. Survival analysis was performed to compare risk factors.
Results: A total of 492 patients were included in the analysis. The incidence of LVSI was 58.5% in our cohort (288 cases), and it was significantly associated with advanced stage, high-grade serous histology, high grade, and lymph node metastasis (P<0.001). Kaplan-Meier analysis demonstrated that LVSI was only correlated with decreased PFS (5-year rate, 39% vs. 66%, P<0.001) and OS (5-year rate, 44% vs. 78%, P<0.001) in patients at early stage but not at advanced stage (5-year rate, PFS: 14% vs. 11%, P<0.001; OS: 29% vs. 29%, P=0.141). Multivariate analysis showed that LVSI remained a significant variable with PFS and OS in early-stage ovarian cancer (PFS: HR 2.29, 95% CI 1.45-3.57; OS: HR 2.20, 95% CI 1.59-3.44, both P<0.001).
Conclusion: LVSI is an independent predictor of progression and survival in patients with primary epithelial ovarian cancer at early stage but not at advanced stage.
PMCID: PMC4392049  PMID: 25874004
Lymphovascular space invasion; Ovarian carcinoma; Prognosis; Survival rate.
12.  Annexin A3 Is a Potential Predictor of Platinum Resistance in Epithelial Ovarian Cancer Patients in a Prospective Cohort 
Journal of Cancer  2015;6(7):678-685.
Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological malignancies and is rarely cured in the recurrent setting, mainly because of progressive chemoresistance, especially platinum resistance. In our previous studies, the platinum-resistance-related protein, annexin A3, was selected by comparative proteomics. In this study, we detected serum annexin A3 levels using a self-developed chemiluminescence immunoassay kit in a prospective EOC patient cohort. We also evaluated the capacity of serum annexin A3 levels to predict platinum resistance. Serum annexin A3 levels in healthy women exhibited a similar normal distribution (Z=0.723, P=0.673), allowing determination of a normal cutoff level of 0.11-1.45 ng/mL. Of the 89 EOC patients, 21 were platinum resistant and 68 were platinum sensitive. Residual disease after primary surgery (p=0.004) and serum annexin A3 levels (p=0.036) were both independent factors associated with platinum resistance. The AUC was 0.733 (95% confidence interval (CI), 0.627-0.823). The optimal cutoff value for serum annexin A3 levels was 2.05 ng/mL. Multivariate logistic analysis showed that expression of annexin A3 as assessed by immunohistochemistry (P=0.005) and residual tumor size (P=0.000) had a significant influence on platinum resistance. The AUC of ROC curve of annexin A3 expression by immunohistochemistry was 0.664 (95% CI, 0.554-0.763) and the cut off value was “>=moderate scores”. In conclusion, we demonstrate that annexin A3 is a secreted protein that may be measured in the peripheral blood using a self-developed, chemiluminescence immunoassay kit. Serum annexin A3 levels may be a potential predictor of platinum resistance in epithelial ovarian cancer patients.
PMCID: PMC4466418  PMID: 26078799
ovarian cancer; annexin A3; platinum resistance; chemiluminescence immunoassay
13.  Coccomyxa Gloeobotrydiformis Improves Learning and Memory in Intrinsic Aging Rats 
Declining in learning and memory is one of the most common and prominent problems during the aging process. Neurotransmitter changes, oxidative stress, mitochondrial dysfunction and abnormal signal transduction were considered to participate in this process. In the present study, we examined the effects of Coccomyxa gloeobotrydiformis (CGD) on learning and memory ability of intrinsic aging rats. As a result, CGD treated (50 mg/kg·d or 100 mg/kg ·d for a duration of 8 weeks) 22-month-old male rats, which have shown significant improvement on learning and spatial memory ability compared with control, which was evidently revealed in both the hidden platform tasks and probe trials. The following immunohistochemistry and Western blot experiments suggested that CGD could increase the content of Ach and thereby improve the function of the cholinergic neurons in the hippocampus, and therefore also improving learning and memory ability of the aged rats by acting as an anti-inflammatory agent. The effects of CGD on learning and memory might also have an association with the ERK/CREB signalling. The results above suggest that the naturally made drug CGD may have several great benefit as a multi-target drug in the process of prevention and/or treatment of age-dependent cognitive decline and aging process.
PMCID: PMC4466463  PMID: 26078724
Coccomyxa gloeobotrydifomemory; aging; hippocampus; cholinergic neurons; inflammation; ERK/CREB signalling
14.  Preparation of minor ginsenosides C-Mc, C-Y, F2, and C-K from American ginseng PPD-ginsenoside using special ginsenosidase type-I from Aspergillus niger g.848 
Journal of Ginseng Research  2014;39(3):221-229.
Minor ginsenosides, those having low content in ginseng, have higher pharmacological activities. To obtain minor ginsenosides, the biotransformation of American ginseng protopanaxadiol (PPD)-ginsenoside was studied using special ginsenosidase type-I from Aspergillus niger g.848.
DEAE (diethylaminoethyl)-cellulose and polyacrylamide gel electrophoresis were used in enzyme purification, thin-layer chromatography and high performance liquid chromatography (HPLC) were used in enzyme hydrolysis and kinetics; crude enzyme was used in minor ginsenoside preparation from PPD-ginsenoside; the products were separated with silica-gel-column, and recognized by HPLC and NMR (Nuclear Magnetic Resonance).
The enzyme molecular weight was 75 kDa; the enzyme firstly hydrolyzed the C-20 position 20-O-β-D-Glc of ginsenoside Rb1, then the C-3 position 3-O-β-D-Glc with the pathway Rb1→Rd→F2→C-K. However, the enzyme firstly hydrolyzed C-3 position 3-O-β-D-Glc of ginsenoside Rb2 and Rc, finally hydrolyzed 20-O-L-Ara with the pathway Rb2→C-O→C-Y→C-K, and Rc→C-Mc1→C-Mc→C-K. According to enzyme kinetics, Km and Vmax of Michaelis–Menten equation, the enzyme reaction velocities on ginsenosides were Rb1 > Rb2 > Rc > Rd. However, the pure enzyme yield was only 3.1%, so crude enzyme was used for minor ginsenoside preparation. When the crude enzyme was reacted in 3% American ginseng PPD-ginsenoside (containing Rb1, Rb2, Rc, and Rd) at 45°C and pH 5.0 for 18 h, the main products were minor ginsenosides C-Mc, C-Y, F2, and C-K; average molar yields were 43.7% for C-Mc from Rc, 42.4% for C-Y from Rb2, and 69.5% for F2 and C-K from Rb1 and Rd.
Four monomer minor ginsenosides were successfully produced (at low-cost) from the PPD-ginsenosides using crude enzyme.
PMCID: PMC4506373  PMID: 26199553
Aspergillus niger g.848; Panax quinquefolius; ginsenosidase type-I; minor ginsenosides; protopanaxadiol-type ginsenosides
15.  Clinicopathologic and prognostic relevance of ARID1A protein loss in colorectal cancer 
World Journal of Gastroenterology : WJG  2014;20(48):18404-18412.
AIM: To explore the association between AT-rich interactive domain 1A (ARID1A) protein loss by immunohistochemistry and both clinicopathologic characteristics and prognosis in patients with colorectal cancer.
METHODS: We retrospectively collected clinicopathologic data and archived paraffin-embedded primary colorectal cancer samples from 209 patients, including 111 patients with colon cancer and 98 patients with rectal cancer. The tumor stage ranged from stage I to stage IV according to the 7th edition of the American Joint Committee on Cancer tumor-node-metastasis (TNM) staging system. All patients underwent resection of primary colorectal tumors. The expression of ARID1A protein in primary colorectal cancer tissues was examined by immunohistochemical staining. The clinicopathologic association and survival relevance of ARID1A protein loss in colorectal cancer were analyzed.
RESULTS: ARID1A loss by immunohistochemistry was not rare in primary colorectal cancer tumors (25.8%). There were 7.4%, 24.1%, 22.2% and 46.3% of patients with ARID1A loss staged at TNM stage I, II, III and IV, respectively, compared with 20.0%, 22.6%, 27.7% and 29.7% of patients without ARID1A loss staged at TNM stage I, II, III and IV, respectively. In patients with ARID1A loss, the distant metastasis rate was 46.3%. However, only 29.7% of patients without ARID1A loss were found to have distant metastasis. In terms of pathologic differentiation, there were 25.9%, 66.7% and 7.4% with poorly, moderately and well differentiated tumors in patients with ARID1A loss, and 14.2%, 72.3% and 13.5% with poorly, moderately and well differentiated tumors in patients without ARID1A loss, respectively. ARID1A loss was associated with late TNM stage (P = 0.020), distant metastasis (P = 0.026), and poor pathological classification (P = 0.035). However, patients with positive ARID1A had worse overall survival compared to those with negative ARID1A in stage IV colorectal cancer (HR = 2.49, 95%CI: 1.13-5.51).
CONCLUSION: ARID1A protein loss is associated with clinicopathologic characteristics in colorectal cancer patients and with survival in stage IV patients.
PMCID: PMC4277979  PMID: 25561809
AT-rich interactive domain 1A; Switching defective/sucrose non-fermenting complexes; Colorectal cancer; Clinicopathologic characteristics; Prognosis
16.  Identification of differentially expressed genes regulated by transcription factors in glioblastomas by bioinformatics analysis 
Molecular Medicine Reports  2014;11(4):2548-2554.
The present study aimed to identify differentially expressed genes (DEGs) regulated by transcription factors (TFs) in glioblastoma, by conducting a bioinformatics analysis. The results of the present study may provide potential therapeutic targets that are involved in the development of glioblastoma. The GSE4290 raw data set was downloaded from the Gene Expression Omnibus database, and consisted of 23 non-tumor samples and 77 glioblastoma (grade 4) tumor samples. Robust Multichip Averaging was used to identify DEGs between the glioblastoma and non-tumor samples. Functional enrichment analysis of the DEGs was also performed. Based on the TRANSFAC® database, TFs associated with the glioblastoma gene expression profile were used to construct a regulatory network. Furthermore, trimmed subnets were identified according to calculated Z-scores. A total of 676 DEGs were identified, of which 190 were upregulated and 496 were downregulated. Gene Ontology analysis demonstrated that the majority of these DEGs were functionally enriched in synaptic transmission, regulation of vesicle-mediated transport and ion-gated channel activity. In addition, the enriched Kyoto Encyclopedia of Genes and Genomes pathway included neuroactive ligand-receptor interaction, calcium signaling pathway, p53 signaling pathway and cell cycle. Based on the TRANSFAC® database, transcriptional regulatory networks with 2,246 nodes and 4,515 regulatory pairs were constructed. According to the Z-scores, the following candidate TFs were identified: TP53, SP1, JUN, STAT3 and SPI1; alongside their downstream DEGs. TP53 was the only differentially expressed TF. These candidate TFs and their downstream DEGs may have important roles in the progression of glioblastoma, and could be potential biomarkers for clinical treatment.
PMCID: PMC4337481  PMID: 25514975
glioblastoma; differentially expressed gene; function enrichment analysis; weighted regulatory network; trimmed subnet
17.  The Cyclic Peptide Ecumicin Targeting ClpC1 Is Active against Mycobacterium tuberculosis In Vivo 
Drug-resistant tuberculosis (TB) has lent urgency to finding new drug leads with novel modes of action. A high-throughput screening campaign of >65,000 actinomycete extracts for inhibition of Mycobacterium tuberculosis viability identified ecumicin, a macrocyclic tridecapeptide that exerts potent, selective bactericidal activity against M. tuberculosis in vitro, including nonreplicating cells. Ecumicin retains activity against isolated multiple-drug-resistant (MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis. The subcutaneous administration to mice of ecumicin in a micellar formulation at 20 mg/kg body weight resulted in plasma and lung exposures exceeding the MIC. Complete inhibition of M. tuberculosis growth in the lungs of mice was achieved following 12 doses at 20 or 32 mg/kg. Genome mining of lab-generated, spontaneous ecumicin-resistant M. tuberculosis strains identified the ClpC1 ATPase complex as the putative target, and this was confirmed by a drug affinity response test. ClpC1 functions in protein breakdown with the ClpP1P2 protease complex. Ecumicin markedly enhanced the ATPase activity of wild-type (WT) ClpC1 but prevented activation of proteolysis by ClpC1. Less stimulation was observed with ClpC1 from ecumicin-resistant mutants. Thus, ClpC1 is a valid drug target against M. tuberculosis, and ecumicin may serve as a lead compound for anti-TB drug development.
PMCID: PMC4335914  PMID: 25421483
18.  Lauren classification combined with HER2 status is a better prognostic factor in Chinese gastric cancer patients 
BMC Cancer  2014;14:823.
Lauren-classification and human epidermal growth factor receptor 2 (HER2) status are two important pathological features of gastric cancer patients. The prognostic value of HER2 in gastric cancer remains controversial. Intestinal type gastric cancer has better prognosis and higher HER2 positive proportion. What is the interaction between these two factors? We hypothesized that a combination of Lauren-classification and human epidermal growth factor receptor 2 (HER2) status (L-H status) might be more meaningful than either factor alone.
We collected 838 gastric cancer patients at all stages who had received treatment in our cancer center. This study was registered in the website of ClinicalTrials.Gov, with the number NCT01927146. We divided the patients into six groups according to their L-H status: Group A, HER2 negative and intestinal type; Group B, HER2 positive and intestinal type; Group C, HER2 negative and diffuse type; Group D, HER2 positive and diffuse type; Group E, HER2 negative and mixed type; and Group F, HER2 positive and mixed type.
Diffuse type and intestinal type accounted for 51.0% and 33.9%, respectively. The proportion of HER2 positive patients was 11.2%, 25.4%, 2.1% and 10.2% in the whole patient group, intestinal, diffuse and mixed type, respectively. Median overall survival was 34.0 months, 25.3 months, 27.6 months, 19.2 months, 25.9 months and 26.4 months in the six groups patients, P = 0.053. There was a significant difference in survival among the first four groups (P < 0.001). HER2 was an independent prognostic factor in the intestinal type and in stage I + II patients, but not in the diffuse type or stage III + IV patients. L-H status was an independent prognostic factor in patients at all stages. For the diffuse and intestinal types, the multivariate analysis showed that HER2 was not an independent prognostic factor, while Lauren classification and L-H status were. Moreover, L-H status was a better prognostic factor than the Lauren classification.
L-H status is a prognostic factor in diffuse and intestinal type patients, but not in the mixed type. Patients with HER2 negative and intestinal type had the best survival, while patients with HER2 positive status and diffuse type had the worst survival.
PMCID: PMC4289219  PMID: 25380654
Gastric cancer; Lauren classification; Human epidermal growth factor receptor 2; Prognosis
19.  A survival analysis comparing women with ovarian low-grade serous carcinoma to those with high-grade histology 
OncoTargets and therapy  2014;7:1891-1899.
Ovarian low-grade serous carcinoma (LGSC) and high-grade serous carcinoma have distinct molecular profiles, clinical behaviors, and treatment responses. The survival advantage for patients with low-grade carcinoma compared with patients with high-grade histology remains controversial. We retrospectively reviewed the medical charts of 381 patients with ovarian serous carcinoma at Peking Union Medical College Hospital from 2007 to 2010. Patients were classified into two groups according to MD Anderson two-tier system: 35 (9.2%) cases with LGSC and 346 with high-grade serous carcinoma. Patients with low-grade serous ovarian cancer had a significantly younger age at diagnosis (46 versus 56 years, P=0.046), and their median progression-free survival (PFS) and overall survival values were 35.0 and 54.0 months, respectively. A multivariate analysis showed that, for serous ovarian cancer, the histological grade was a significant prognostic factor for PFS but not for overall survival (P=0.022 and P=0.0566, respectively). When stratified by the existence of a residual disease, patients with low-grade disease who underwent cytoreductive surgery without macroscopic residual disease (>1 cm) had a significantly improved median PFS time (36.0 months) compared with that of patients with high-grade carcinoma who received optimal cytoreductive surgery (16.0 months, P=0.017). Conversely, patients with low-grade and high-grade carcinoma who were left with macroscopic residue (>1 cm) experienced a similarly shorter median PFS (10.0 and 13.0 months, respectively, P=0.871). The International Federation of Gynecology and Obstetrics stage and residual disease were significant prognostic factors of low-grade carcinoma, while positive ascites was associated with a worse PFS value. Our data showed that LGSC is a different entity from high-grade carcinoma and that LGSC was associated with improved PFS after optimal cytoreductive surgery but not suboptimal operation.
PMCID: PMC4206388  PMID: 25342912
ovarian carcinoma; low-grade serous carcinoma; high-grade serous carcinoma; prognosis
20.  The target therapy of ovarian clear cell carcinoma 
OncoTargets and therapy  2014;7:1647-1652.
Clear cell adenocarcinoma (CCC) of the ovary accounts for 10% of epithelial ovarian cancer and is a distinct entity from other epithelial ovarian carcinomas. It arises from the endometriosis. CCC has specific biological and clinical behavior. Compared with other histological types, CCC shows a chemoresistant phenotype, which leads to poorer prognosis. Thus, development of new target-based therapies remains an unmet need for these patients. Mutations in the gene ARID1A have been found to occur in high frequency in CCC. The majority of these mutations lead to a loss of expression of the ARID1A protein, which is a subunit of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex and considered as a bona fide tumor suppressor. Upregulation of the PIK3/AKT/mTOR pathway, particularly through mutations of PIK3CA and inactivation of PTEN, is involved in tumorigenesis of CCC. Targeting angiogenesis, the Met protooncogene pathway, and HER2 are also discussed in this review.
PMCID: PMC4181630  PMID: 25285014
ARID1A; PIK3/AKT/mTOR pathway; angiogenesis; Met protooncogene pathway; HER2
21.  Women Ornament Themselves for Intrasexual Competition near Ovulation, but for Intersexual Attraction in Luteal Phase 
PLoS ONE  2014;9(9):e106407.
The present study examined women's attentional bias toward ornamental objects in relation to their menstrual phase as well as to motivations of intersexual courtship or intrasexual competition. In Experiment 1, 33 healthy heterosexual women were tested in a bias-assessment visual cuing task twice: once on a high-fertility day (during the ovulatory phase) and once on a low-fertility day (during the luteal phase). They paid greater attention to pictures of ornamental objects than to pictures of non-ornamental objects near ovulation, but not during the luteal phase, suggesting an ornamental bias during the high-fertility phase. In Experiment 2, before the visual cuing task, 40 participants viewed 10 same-sex or opposite-sex facial photographs with either high or low attractiveness as priming tasks to activate the intrasexual competition or intersexual courtship motives. Results showed that women's ornamental bias was dependent on the interaction of menstrual phase and mating motive. Specifically, the ornamental bias was observed on the high-fertility day when the subjects were primed with high-attractive same-sex images (intrasexual competition) and was observed on the low-fertility day when they were primed with high-attractive opposite-sex photographs (intersexual courtship). In conclusion, the present findings confirm the hypothesis that, during the high-fertility phase, women have an attentional bias toward ornamental objects and further support the hypothesis that the ornamental bias is driven by intrasexual competition motivation near ovulation, but driven by intersexual courtship motivation during the luteal phase.
PMCID: PMC4152269  PMID: 25180577
22.  Allosteric heat shock protein 70 inhibitors rapidly rescue synaptic plasticity deficits by reducing aberrant tau 
Biological psychiatry  2013;74(5):367-374.
The microtubule associated protein tau accumulates in neurodegenerative diseases known as tauopathies, the most common being Alzheimer’s disease (AD). One way to treat these disorders may be to reduce abnormal tau levels through chaperone manipulation, thus subverting synaptic plasticity defects caused by tau’s toxic accretion.
Tauopathy models were used to study the impact of YM-01 on tau. YM-01 is an allosteric promoter of triage functions of the most abundant variant of the Hsp70 family in the brain, Hsc70. The mechanisms by which YM-01 modified Hsc70 activity and tau stability were evaluated with biochemical methods, cell cultures and primary neuronal cultures from tau transgenic mice. YM-01 was also administered to acute brain slices of tau mice; changes in tau stability and electrophysiological correlates of learning and memory were measured.
Tau levels were rapidly and potently reduced in vitro and ex vivo upon treatment with nanomolar concentrations of YM-01. Consistent with Hsc70 having a key role in this process, over-expression of Hsp40 (DNAJB2), an Hsp70 co-chaperone, suppressed YM-01 activity. In contrast to its effects in pathogenic tauopathy models, YM-01 had little activity in ex vivo brain slices from normal, wildtype mice unless microtubules were disrupted, suggesting that Hsc70 acts preferentially on abnormal pools of free tau. Finally, treatment with YM-01 increased long-term potentiation in from tau transgenic brain slices.
Therapeutics that exploit the ability of chaperones to selectively target abnormal tau can rapidly and potently rescue the synaptic dysfunction that occurs in AD and other tauopathies.
PMCID: PMC3740016  PMID: 23607970
tau; Alzheimer’s disease; chaperones; Hsc70; rhodocyanine; YM-01
23.  Long-term follow-up results in patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents: results from a single high-volume PCI centre 
BMJ Open  2014;4(8):e004892.
To assess both short-term and long-term prognosis in consecutive patients with coronary heart disease treated with drug-eluting stents in a high-volume percutaneous coronary intervention (PCI) centre.
Observational cohort study.
A hospital in the Henan province, China, between 2009 and 2011.
A total of 2533 patients were enrolled. Patients with ST-elevation myocardial infarction (STEMI) treated with urgent PCI accounted for 3.9% of cases; patients with STEMI treated with delayed PCI accounted for 20.5% of cases; patients with stable angina accounted for 16.5% of cases; and patients with non-ST elevation acute coronary syndrome (NSTE-ACS) accounted for 58.6% of cases.
Primary outcomes
Death, major adverse cardiac and cerebrovascular events (MACCE: death/myocardial infarction/stroke), and target vessel revascularisation.
Follow-up after a median of 29.8 months was obtained for 2533 patients (92.6%). The mortality rate during hospitalisation was highest in the urgent PCI group (p<0.001). During follow-up, although the incidences of death and MACCE were highest in the urgent PCI group, no significant differences were observed among the different groups. The incidences of cardiac death and myocardial infarction were significantly higher in the paclitaxel-eluting stent (PES) group than in the sirolimus-eluting stent (SES) group. Independent predictors of death during follow-up were age, left ventricular ejection function <40%, diabetes mellitus, prior coronary artery bypass graft and chronic total occlusion.
PCI patients with STEMI had the worst hospital and long-term prognosis. The mortality rate after hospital increased markedly in patients with NSTE-ACS. SESs seem to be more effective than PESs.
PMCID: PMC4127920  PMID: 25113554
24.  Effect of sun ginseng potentiation on epirubicin and paclitaxel-induced apoptosis in human cervical cancer cells 
Journal of Ginseng Research  2014;39(1):22-28.
Sun ginseng (SG), a specific formulation of quality-controlled red ginseng, contains approximately equal amounts of three major ginsenosides (RK1, Rg3, and Rg5), which reportedly has antitumor-promoting activities in animal models.
MTT assay was used to assess whether SG can potentiate the anticancer activity of epirubicin or paclitaxel in human cervical adenocarcinoma HeLa cells, human colon cancer SW111C cells, and SW480 cells; apoptosis status was analyzed by annexin V-FITC and PI and analyzed by flow cytometry; and apoptosis pathway was studied by analysis of caspase-3, -8, and -9 activation, mitochondrial accumulation of Bax and Bak, and cytochrome c release.
SG remarkably enhances cancer cell death induced by epirubicin or paclitaxel in human cervical adenocarcinoma HeLa cells, human colon cancer SW111C cells, and SW480 cells. Results of the mechanism study highlighted the cooperation between SG and epirubicin or paclitaxel in activating caspase-3 and -9 but not caspase-8. Moreover, SG significantly increased the mitochondrial accumulation of both Bax and Bak triggered by epirubicin or paclitaxel as well as the subsequent release of cytochrome c in the targeted cells.
SG significantly potentiated the anticancer activities of epirubicin and paclitaxel in a synergistic manner. These effects were associated with the increased mitochondrial accumulation of both Bax and Bak that led to an enhanced cytochrome c release, caspase-9/-3 activation, and apoptosis. Treating cancer cells by combining epirubicin and paclitaxel with SG may prove to be a novel strategy for enhancing the efficacy of the two drug types.
PMCID: PMC4268562  PMID: 25535473
apoptosis; caspase-9; sun ginseng; synergistic effect
25.  The synthesis and characterization of monodispersed chitosan-coated Fe3O4 nanoparticles via a facile one-step solvothermal process for adsorption of bovine serum albumin 
Nanoscale Research Letters  2014;9(1):296.
Preparation of magnetic nanoparticles coated with chitosan (CS-coated Fe3O4 NPs) in one step by the solvothermal method in the presence of different amounts of added chitosan is reported here. The magnetic property of the obtained magnetic composite nanoparticles was confirmed by X-ray diffraction (XRD) and magnetic measurements (VSM). Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) allowed the identification of spherical nanoparticles with about 150 nm in average diameter. Characterization of the products by Fourier transform infrared spectroscopy (FTIR) demonstrated that CS-coated Fe3O4 NPs were obtained. Chitosan content in the obtained nanocomposites was estimated by thermogravimetric analysis (TGA). The adsorption properties of the CS-coated Fe3O4 NPs for bovine serum albumin (BSA) were investigated under different concentrations of BSA. Compared with naked Fe3O4 nanoparticles, the CS-coated Fe3O4 NPs showed a higher BSA adsorption capacity (96.5 mg/g) and a fast adsorption rate (45 min) in aqueous solutions. This work demonstrates that the prepared magnetic nanoparticles have promising applications in enzyme and protein immobilization.
PMCID: PMC4070400  PMID: 24994954
Magnetic nanoparticles; Chitosan; Solvothermal; BSA adsorption

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