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1.  miR-195 inhibits tumor progression by targeting RPS6KB1 in human prostate cancer 
Purpose
To investigate the involvement of hsa-microRNA-195-5p (miR-195) in progression and prognosis of human prostate cancer (PCa).
Experimental Design
qRT-PCR was performed to detect miR-195 expression in both PCa cell lines and clinical tissue samples. Its clinical significance was statistically analyzed. The roles of miR-195 and its candidate target gene ribosomal protein S6 kinase, 70kDa, polypeptide 1 (RPS6KB1) in PCa progression were confirmed based on both in vitro and in vivo systems.
Results
MiR-195 downregulation in PCa tissues was significantly associated with high Gleason score (P=0.001), positive metastasis failure (P<0.001) and biochemical recurrence (BCR, P<0.001). Survival analysis identified miR-195 as an independent prognostic factor for BCR-free survival of PCa patients (P=0.022). Then, we confirmed the tumor suppressive role of miR-195 through PCa cell invasion, migration and apoptosis assays in vitro, along with tumor xenografts growth, angiogenesis and invasion in vivo according to both gain-of-function and loss-of-function experiments. Additionally, RPS6KB1 was identified as a novel direct target of miR-195 through proteomic expression profiling combined with bioinformatic target prediction and luciferase reporter assay. Moreover, the re-expression and knockdown of RPS6KB1 could respectively rescue and imitate the effects induced by miR-195. Importantly, RPS6KB1 expression was closely correlated with aggressive progression and poor prognosis in PCa patients as opposed to miR-195. Furthermore, we identified MMP-9, VEGF, BAD and E-cadherin as the downstream effectors of miR-195-RPS6KB1 axis.
Conclusion
The newly identified miR-195-RPS6KB1 axis partially illustrates the molecular mechanism of PCa progression and represents a novel potential therapeutic target for PCa treatment.
doi:10.1158/1078-0432.CCR-15-0217
PMCID: PMC4631653  PMID: 26080838
prostate cancer; microRNA-195; ribosomal protein S6 kinase; 70kDa; polypeptide 1; tumor suppressor; prognosis
2.  Down-regulation of dual-specificity phosphatase 5 predicts poor prognosis of patients with prostate cancer 
Dual-specificity phosphatase 5 (DUSP5), which specifically inactivates the extracellular signal-regulated kinase (ERK) 1/2 within the mitogen-activated protein kinase (MAPK) signaling, has recently been considered to be a tumor suppressor. However, its role in prostate cancer is still elusive. In this study, we performed immunohistochemistry analysis on human tissue microarray (TMA) to detect the DUSP5 protein expression pattern. The results indicated that DUSP5 was down-regulated in the human prostate cancer relative to the adjacent benign tissues (IRS: PCa = 4.29 ± 1.72 versus Benign = 4.89 ± 1.58, P = 0.04). In addition, when we linked the DUSP5 protein levels to the clinicopathological features of the patients, we found that the downregulation of DUSP5 was significantly associated with advanced pathological stage (P = 0.004) and high Gleason score (P = 0.009). Moreover, we attempted to validate these findings and investigate the prognostic value of DUSP5 in a publicly available microarray-based Taylor Dataset. Statistic analysis demonstrated that the downregulation of DUSP5 was closely correlated with high Gleason score (P = 0.011), positive metastasis (P < 0.001) and biochemical recurrence (BCR) (P = 0.016). More importantly, Kaplan-Meier analysis revealed that significant differences between patients with high and low DUSP5 expression level in regard to the BCR-free survival of overall (P = 0.009), non-metastatic (P = 0.006) and patients with Gleason score 7 (P = 0.044). Multivariate analysis by Cox regression indicated that DUSP5 could be an independent predictor for the risk of BCR (HR: 0.41, 95% CI: 0.2-0.82; P = 0.012). In summary, our findings disclose that DUSP5 may be an important tumor suppressor that inhibits the progression of PCa. The downregulation of DUSP5 may accurately predict poor prognosis in PCa patients.
PMCID: PMC4443163  PMID: 26064329
Prostate cancer; dual-specificity phosphatase 5; tumor suppressor; prognosis
3.  Detection of Fungus Infection on Petals of Rapeseed (Brassica napus L.) Using NIR Hyperspectral Imaging 
Scientific Reports  2016;6:38878.
Infected petals are often regarded as the source for the spread of fungi Sclerotinia sclerotiorum in all growing process of rapeseed (Brassica napus L.) plants. This research aimed to detect fungal infection of rapeseed petals by applying hyperspectral imaging in the spectral region of 874–1734 nm coupled with chemometrics. Reflectance was extracted from regions of interest (ROIs) in the hyperspectral image of each sample. Firstly, principal component analysis (PCA) was applied to conduct a cluster analysis with the first several principal components (PCs). Then, two methods including X-loadings of PCA and random frog (RF) algorithm were used and compared for optimizing wavebands selection. Least squares-support vector machine (LS-SVM) methodology was employed to establish discriminative models based on the optimal and full wavebands. Finally, area under the receiver operating characteristics curve (AUC) was utilized to evaluate classification performance of these LS-SVM models. It was found that LS-SVM based on the combination of all optimal wavebands had the best performance with AUC of 0.929. These results were promising and demonstrated the potential of applying hyperspectral imaging in fungus infection detection on rapeseed petals.
doi:10.1038/srep38878
PMCID: PMC5153619  PMID: 27958386
4.  Integrin α7 is a functional cancer stem cell surface marker in oesophageal squamous cell carcinoma 
Nature Communications  2016;7:13568.
Non-CG methylation has been associated with stemness regulation in embryonic stem cells. By comparing differentially expressed genes affected by non-CG methylation between tumour and corresponding non-tumour tissues in oesophageal squamous cell carcinoma (OSCC), we find that Integrin α7 (ITGA7) is characterized as a potential cancer stem cell (CSC) marker. Clinical data show that a high frequency of ITGA7+ cells in OSCC tissues is significantly associated with poor differentiation, lymph node metastasis and worse prognosis. Functional studies demonstrate that both sorted ITGA7+ cells and ITGA7 overexpressing cells display enhanced stemness features, including elevated expression of stemness-associated genes and epithelial–mesenchymal transition features, as well as increased abilities to self-renew, differentiate and resist chemotherapy. Mechanistic studies find that ITGA7 regulates CSC properties through the activation of the FAK-mediated signalling pathways. As knockdown of ITGA7 can effectively reduce the stemness of OSCC cells, ITGA7 could be a potential therapeutic target in OSCC treatment.
There is still no consensus on tumour type-specific cancer stem cell markers. Here, the authors demonstrate that ITGA7 is a potential functional marker of oesophageal cancer stem cells involved in the resistance to chemotherapy and metastasis through activation of FAK-mediated signalling.
doi:10.1038/ncomms13568
PMCID: PMC5150658  PMID: 27924820
5.  The coexpression and prognostic significance of c-MET, fibroblast growth factor receptor 2, and human epidermal growth factor receptor 2 in resected gastric cancer: a retrospective study 
OncoTargets and therapy  2016;9:5919-5929.
Molecular-targeted therapy against tyrosine kinase receptors (RTKs) plays an important role in gastric cancer (GC) treatment. Understanding the correlation between RTK coexpression could better guide clinical drug use. In the present study, the coexpression status of c-MET, fibroblast growth factor receptor 2 (FGFR2), and human epidermal growth factor receptor 2 (HER2) in human GC and their clinical significance in clinical therapy were explored. Immunohistochemical (IHC) staining, quantitative real-time polymerase chain reaction and fluorescent in situ hybridization were performed in 143 cases of GC who had undergone gastrectomy without preoperative chemoradiotherapy. Their association with clinicopathological features and clinical prognosis was analyzed. The frequencies of c-MET, FGFR2, and HER2 overexpression were 47.6% (68/143), 34.3% (49/143), and 10.5% (15/143), respectively. In the RTK coexpression study, 30.1% of patients (43/143) were positive for only one RTK, 25.8% (37/143) were positive for two RTKs, 3.5% (5/143) had triple-positive status, and 40.6% (58/143) had triple-negative status. In survival analysis, the overexpression of c-MET, FGFR2, and HER2 were significantly associated with overall survival (OS) (P=0.018, 0.004, and 0.049, respectively). In coexpression analysis, patients with triple-positive GC had the poorest OS (P=0.013). In conclusion, RTK coexpression is significantly associated with poor clinical outcome in GC.
doi:10.2147/OTT.S111778
PMCID: PMC5045911  PMID: 27729801
c-MET; FGFR2; HER2; gastric cancer; coexpression; survival; target therapy
6.  Feasibility Study of the Permeability and Uptake of Mesoporous Silica Nanoparticles across the Blood-Brain Barrier 
PLoS ONE  2016;11(8):e0160705.
Drug delivery into the brain is impeded by the blood-brain-barrier (BBB) that filters out the vast majority of drugs after systemic administration. In this work, we assessed the transport, uptake and cytotoxicity of promising drug nanocarriers, mesoporous silica nanoparticles (MSNs), in in vitro models of the BBB. RBE4 rat brain endothelial cells and Madin-Darby canine kidney epithelial cells, strain II, were used as BBB models. We studied spherical and rod-shaped MSNs with the following modifications: bare MSNs and MSNs coated with a poly(ethylene glycol)-poly(ethylene imine) (PEG-PEI) block copolymer. In transport studies, MSNs showed low permeability, whereas the results of the cellular uptake studies suggest robust uptake of PEG-PEI-coated MSNs. None of the MSNs showed significant toxic effects in the cell viability studies. While the shape effect was detectable but small, especially in the real-time surface plasmon resonance measurements, coating with PEG-PEI copolymers clearly facilitated the uptake of MSNs. Finally, we evaluated the in vivo detectability of one of the best candidates, i.e. the copolymer-coated rod-shaped MSNs, by two-photon in vivo imaging in the brain vasculature. The particles were clearly detectable after intravenous injection and caused no damage to the BBB. Thus, when properly designed, the uptake of MSNs could potentially be utilized for the delivery of drugs into the brain via transcellular transport.
doi:10.1371/journal.pone.0160705
PMCID: PMC4993362  PMID: 27547955
7.  A Novel Agent Enhances the Chemotherapeutic Efficacy of Doxorubicin in MCF-7 Breast Cancer Cells 
We have previously demonstrated that DT-010, a novel conjugate of danshensu (DSS) and tetramethylpyrazine (TMP), displays anti-tumor effects in breast cancer cells both in vitro and in vivo. In the present study, we investigated whether DT-010 enhances the chemotherapeutic effect of doxorubicin (Dox) in MCF-7 breast cancer cells and exerts concurrent cardioprotective benefit at the same time. Our findings showed that DT-010 was more potent than TMP, DSS, or their combination in potentiating Dox-induced toxicity in MCF-7 cells. Co-treatment with DT-010 and Dox increased apoptosis in MCF-7 cells relative to Dox alone. Further study indicated that glycolytic capacity, glycolytic reserve and lactate level of MCF-7 cells were significantly inhibited after DT-010 treatment. DT-010 also increased the expression of the pro-survival protein GRP78, which was inhibited by co-treatment with Dox. Both endoplasmic reticulum stress inhibitor 4-PBA and knockdown of the expression of GRP78 protein potentiated DT-010-mediated apoptosis in MCF-7 cells. Moreover, DT-010 inhibited Dox-induced cardiotoxicity in H9c2 myoblasts. In conclusion, DT-010 and Dox confer synergistic anti-tumor effect in MCF-7 breast cancer cells through downregulation of the glycolytic pathway and inhibition of the expression of GRP78. Meanwhile, DT-010 also protects against Dox-induced cardiotoxicity.
doi:10.3389/fphar.2016.00249
PMCID: PMC4979254  PMID: 27559313
danshensu; tetramethylpyrazine; doxorubicin; breast cancer; glycolysis; GRP78 protein
8.  Expression of hepaCAM inhibits bladder cancer cell proliferation via a Wnt/β-catenin-dependent pathway in vitro and in vivo 
Cancer Biology & Therapy  2015;16(10):1502-1513.
We previously established that hepatocyte cell adhesion molecule (hepaCAM), a typical structure of immunoglobulin (Ig)-like adhesion molecules, inhibited the proliferation and the progression of cultured human bladder cancer cells. As increasing evidence reveals that aberrant activation of canonical Wnt pathway is involved in the pathogenesis of bladder cancer, and β-catenin serves as a pivotal molecule of Wnt pathway. Then, we explored whether the anti-proliferation effect of hepaCAM was associated with Wnt/β-catenin pathway in human bladder cancer cells. The negative correlation between hepaCAM and β-catenin in transitional cell carcinoma of bladder (TCCB) was found. Follow by, studied the effect of hepaCAM on the key elements of Wnt pathway. Here, Our researches showed that hepaCAM played a central role in modulating the Wnt/β-catenin signaling pathway by interfering nuclear protein levels of β-catenin, leading to down-regulate transcriptional activity of LEF/TCF and its target genes c-Myc and cyclinD1. Mechanistically, we demonstrated that hepaCAM-activated GSK3β led to elevate the phosphorylation of β-catenin, contributing to the aberrant translocation of β-catenin. In addition, Anti-proliferation and associated molecular mechanisms of hepaCAM were demonstrated by using vivo experiment. In conclusion, our reports uncover that expression of hepaCAM suppresses the proliferation of bladder cancer cells through a Wnt/β-catenin-dependent signaling pathway in vitro and in vivo.
doi:10.1080/15384047.2015.1071732
PMCID: PMC4846132  PMID: 26192362
bladder cancer, HepaCAM, T24, Wnt/β-catenin
9.  Possible contribution of IMRT in postoperative radiochemotherapy for rectal cancer: analysis on 1798 patients by prediction model 
Oncotarget  2016;7(29):46536-46544.
The evidence for adjuvant therapy in locally advanced rectal cancer after TME surgery is sparse. The aim of this study was to identify predicting factors of overall survival (OS) in these patients and combine them into a nomogram for individualized treatment. 1798 patients with pathologically staged II/III rectal adenocarcinoma treated by radical TME surgery from a single center's database were reviewed. The nomogram was derived by Cox proportional hazards regression. Its performance was assessed by concordance index and calibration curve in internal validation with bootstrapping. Pooled Cox model analysis identified age, sex, grade of histology, pathological T and N stage, residual tumor, concurrent radiochemotherapy (RTCT), adjuvant chemotherapy cycles (CT), radiotherapy (RT) unexpected interruption days and intensity-modulated radiation therapy (IMRT) as significant covariates for 5-year OS (P<0.05). Postoperative RTCT, CT and IMRT all improved OS. The proposed model can predict 5-year OS with a C-index of 0.7105. IMRT significantly benefited OS in multivariate analysis (p=0.0441).
In conclusion, our nomogram can predict 5-year OS after TME surgery for locally advanced rectal cancer with simple and effective advantage. This model may provide not only baseline OS estimate but also a tool for candidates selecting of adjuvant treatment in prospective studies.
doi:10.18632/oncotarget.10228
PMCID: PMC5216815  PMID: 27340785
rectal cancer; nomogram; survival; postoperative radiochemotherapy; intensity-modulated radiation therapy
10.  HBx-induced MiR-1269b in NF-κB dependent manner upregulates cell division cycle 40 homolog (CDC40) to promote proliferation and migration in hepatoma cells 
Background
Occurrence and progression of hepatocellular carcinoma (HCC) are associated with hepatitis B virus (HBV) infection. miR-1269b is up-regulated in HCC cells and tissues. However, the regulation of miR-1269b expression by HBV and the mechanism underlying the oncogenic activity of miR-1269b in HCC are unclear.
Methods
Reverse transcription quantitative PCR (RT-qPCR) was used to measure the expression of miR-1269b and target genes in HCC tissues and cell lines. Western blot analysis was used to assess the expression of miR-1269b target genes and related proteins. Using luciferase reporter assays and EMSA, we identified the factors regulating the transcriptional level of miR-1269b. Colony formation, flow cytometry and cell migration assays were performed to evaluate the phenotypic changes caused by miR-1269b and its target in HCC cells.
Results
We demonstrated that the expression levels of pre-miR-1269b and miR-1269b in HBV-positive HepG2.2.15 cells were dramatically increased compared with HBV-negative HepG2 cells. HBx was shown to facilitate translocation of NF-κB from the cytoplasm to the nucleus, and NF-κB binds to the promoter of miR-1269b to enhance its transcription. miR-1269b targets and up-regulates CDC40, a cell division cycle 40 homolog. CDC40 increases cell cycle progression, cell proliferation and migration. Rescue experiment indicated that CDC40 promotes malignancy induced by miR-1269b in HCC cells.
Conclusion
We found that HBx activates NF-κB to promote the expression of miR1269b, which augments CDC40 expression, contributing to malignancy in HCC. Our findings provide insights into the mechanisms underlying HBV-induced hepatocarcinogenesis.
doi:10.1186/s12967-016-0949-y
PMCID: PMC4924318  PMID: 27349221
HCC; HBx; NF-κB; miR-1269b; CDC40
11.  Sorafenib inhibits macrophage-mediated epithelial-mesenchymal transition in hepatocellular carcinoma 
Oncotarget  2016;7(25):38292-38305.
Tumor-associated macrophages, crucial components of the microenvironment in hepatocellular carcinoma, hamper anti-cancer immune responses. The aim of the present study was to investigate the effect of sorafenib on the formation of the tumor microenvironment, especially the relationship between polarized macrophages and hepatocytes. Macrophage infiltration was reduced in patients with hepatocellular carcinoma who were treated with sorafenib. In vitro, sorafenib abolished polarized macrophage-induced epithelial mesenchymal transition (EMT) and migration of hepatocellular carcinoma cells but not normal hepatocytes. Moreover, sorafenib attenuated HGF secretion in polarized macrophages, and decreased plasma HGF in patients with hepatocellular carcinoma. Additionally, sorafenib abolished the polarized macrophage-induced activation of the HGF receptor Met in hepatocellular carcinoma cells. Our findings suggest that sorafenib inhibits polarized macrophage-induced EMT in hepatocellular carcinoma cells via the HGF-Met signaling pathway. These results contribute to our understanding of the immunological mechanisms that underlie the protective effects of sorafenib in hepatocellular carcinoma therapy.
doi:10.18632/oncotarget.9438
PMCID: PMC5122390  PMID: 27203677
hepatocellular carcinoma; epithelial-mesenchymal transition; sorafenib; HGF; Met
12.  Hyperspectral Imaging for Determining Pigment Contents in Cucumber Leaves in Response to Angular Leaf Spot Disease 
Scientific Reports  2016;6:27790.
Hyperspectral imaging technique was employed to determine spatial distributions of chlorophyll (Chl), and carotenoid (Car) contents in cucumber leaves in response to angular leaf spot (ALS). Altogether, 196 hyperspectral images of cucumber leaves with five infection severities of ALS were captured by a hyperspectral imaging system in the range of 380–1,030 nm covering 512 wavebands. Mean spectrum were extracted from regions of interest (ROIs) in the hyperspectral images. Partial least square regression (PLSR) models were used to develop quantitative analysis between the spectra and the pigment contents measured by biochemical analyses. In addition, regression coefficients (RCs) in PLSR models were employed to select important wavelengths (IWs) for modelling. It was found that the PLSR models developed by the IWs provided the optimal measurement results with correlation coefficient (R) of prediction of 0.871 and 0.876 for Chl and Car contents, respectively. Finally, Chl and Car distributions in cucumber leaves with the ALS infection were mapped by applying the optimal models pixel-wise to the hyperspectral images. The results proved the feasibility of hyperspectral imaging for visualizing the pigment distributions in cucumber leaves in response to ALS.
doi:10.1038/srep27790
PMCID: PMC4901261  PMID: 27283050
13.  Laser-Induced Breakdown Spectroscopy Coupled with Multivariate Chemometrics for Variety Discrimination of Soil 
Scientific Reports  2016;6:27574.
The aim of this work was to analyze the variety of soil by laser-induced breakdown spectroscopy (LIBS) coupled with chemometrics methods. 6 certified reference materials (CRMs) of soil samples were selected and their LIBS spectra were captured. Characteristic emission lines of main elements were identified based on the LIBS curves and corresponding contents. From the identified emission lines, LIBS spectra in 7 lines with high signal-to-noise ratio (SNR) were chosen for further analysis. Principal component analysis (PCA) was carried out using the LIBS spectra at 7 selected lines and an obvious cluster of 6 soils was observed. Soft independent modeling of class analogy (SIMCA) and least-squares support vector machine (LS-SVM) were introduced to establish discriminant models for classifying the 6 types of soils, and they offered the correct discrimination rates of 90% and 100%, respectively. Receiver operating characteristic (ROC) curve was used to evaluate the performance of models and the results demonstrated that the LS-SVM model was promising. Lastly, 8 types of soils from different places were gathered to conduct the same experiments for verifying the selected 7 emission lines and LS-SVM model. The research revealed that LIBS technology coupled with chemometrics could conduct the variety discrimination of soil.
doi:10.1038/srep27574
PMCID: PMC4899786  PMID: 27279284
14.  Fluoxetine synergizes with temozolomide to induce the CHOP-dependent endoplasmic reticulum stress-related apoptosis pathway in glioma cells 
Oncology Reports  2016;36(2):676-684.
Although temozolomide (TMZ) is the most effective chemotherapy agent for glioma, chemotherapy resistance has limited its clinical use. Fluoxetine (FLT), which is widely used in cancer-related depression, has exhibited potent anticancer properties in different cancer cell types. The aim of this study was i) to evaluate the antitumor mechanism of FLT, and ii) to further evaluate the effects of a combination of FLT and TMZ on glioma cells. Glioma cell lines were exposed to FLT and/or TMZ. Cell viability and apoptosis were examined by CCK-8 assay, flow cytometry and caspase-3 activity assay, respectively. The expression of endoplasmic reticulum-stress (ERS) apoptosis-related proteins was measured using real-time PCR and western blotting. Synergism between the two drugs was evaluated by the combination index (CI) through CompuSyn software. FLT significantly and dose-dependently inhibited the proliferation of various glioma cell lines, and rat glioma C6 cells had a highly sensitive response to the addition of FLT. FLT treatment increased the early apoptosis rate, induced typical apoptotic morphology in the C6 cells and activated caspase-3 with no change in the mitochondrial membrane potential. Further study showed that FLT activated the ERS marker, CHOP. This induction was associated with activation of the PERK-eIF2α-ATF4 and ATF6 cascade. Concomitantly, GADD34, a downstream molecule of CHOP, was also increased. Combined FLT and TMZ treatment showed a synergistic cytotoxic effect in the C6 glioma cells. Knockdown of CHOP expression abolished the synergistic effect of FLT and TMZ in the C6 cells, which suggests that FLT may sensitize glioma cells to TMZ through activation of the CHOP-dependent apoptosis pathway. These results revealed that FLT induced glioma cell apoptosis and sensitized glioma cells to TMZ through activation of the CHOP-dependent apoptosis pathway. The present study provides a primary basis for using the combination of these drugs in patients with advanced glioma.
doi:10.3892/or.2016.4860
PMCID: PMC4933544  PMID: 27278525
glioma; fluoxetine; temozolomide; apoptosis; CHOP
15.  Derivation of Porcine Embryonic Stem-Like Cells from In Vitro-Produced Blastocyst-Stage Embryos 
Scientific Reports  2016;6:25838.
Efficient isolation of embryonic stem (ES) cells from pre-implantation porcine embryos has remained a challenge. Here, we describe the derivation of porcine embryonic stem-like cells (pESLCs) by seeding the isolated inner cell mass (ICM) from in vitro-produced porcine blastocyst into α-MEM with basic fibroblast growth factor (bFGF). The pESL cells kept the normal karyotype and displayed flatten clones, similar in phenotype to human embryonic stem cells (hES cells) and rodent epiblast stem cells. These cells exhibited alkaline phosphatase (AP) activity and expressed pluripotency markers such as OCT4, NANOG, SOX2, SSEA-4, TRA-1-60, and TRA-1-81 as determined by both immunofluorescence and RT-PCR. Additionally, these cells formed embryoid body (EB), teratomas and also differentiated into 3 germ layers in vitro and in vivo. Microarray analysis showed the expression of the pluripotency markers, PODXL, REX1, SOX2, KLF5 and NR6A1, was significantly higher compared with porcine embryonic fibroblasts (PEF), but expression of OCT4, TBX3, REX1, LIN28A and DPPA5, was lower compared to the whole blastocysts or ICM of blastocyst. Our results showed that porcine embryonic stem-like cells can be established from in vitro-produced blastocyst-stage embryos, which promote porcine naive ES cells to be established.
doi:10.1038/srep25838
PMCID: PMC4865852  PMID: 27173828
16.  The Vanderbilt Memory & Aging Project: Study Design and Baseline Cohort Overview 
Background
Vascular health factors frequently co-occur with Alzheimer’s disease (AD). A better understanding of how systemic vascular and cerebrovascular health intersects with clinical and pathological AD may inform prevention and treatment opportunities.
Objective
To establish the Vanderbilt Memory & Aging Project, a case-control longitudinal study investigating vascular health and brain aging, and describe baseline methodology and participant characteristics.
Methods
From September 2012 to November 2014, 335 participants age 60–92 were enrolled, including 168 individuals with mild cognitive impairment (MCI, 73 ± 8 years, 41% female) and 167 age-, sex-, and race-matched cognitively normal controls (NC, 72 ± 7 years, 41% female). At baseline, participants completed a physical and frailty examination, fasting blood draw, neuropsychological assessment, echocardiogram, cardiac MRI, and brain MRI. A subset underwent 24-hour ambulatory blood pressure monitoring and lumbar puncture for cerebrospinal fluid (CSF) collection.
Results
As designed, participant groups were comparable for age (p = 0.31), sex (p = 0.95), and race (p = 0.65). MCI participants had greater Framingham Stroke Risk Profile scores (p = 0.008), systolic blood pressure values (p = 0.008), and history of left ventricular hypertrophy (p = 0.04) than NC participants. As expected, MCI participants performed worse on all neuropsychological measures (p-values<0.001), were more likely to be APOE ε4 carriers (p = 0.02), and had enhanced CSF biomarkers, including lower Aβ42 (p = 0.02), higher total tau (p = 0.004), and higher p-tau (p = 0.02) compared to NC participants.
Conclusion
Diverse sources of baseline and longitudinal data will provide rich opportunities to investigate pathways linking vascular and cerebrovascular health, clinical and pathological AD, and neurodegeneration contributing to novel strategies to delay or prevent cognitive decline.
doi:10.3233/JAD-150914
PMCID: PMC4866875  PMID: 26967211
Alzheimer’s disease; biomarkers; brain MRI; cardiac MRI; mild cognitive impairment; vascular risk factors
17.  Interim analysis of postoperative chemoradiotherapy with capecitabine and oxaliplatin versus capecitabine alone for pathological stage II and III rectal cancer: a randomized multicenter phase III trial 
Oncotarget  2016;7(18):25576-25584.
The aim of this study is to present an interim analysis of a phase III trial (NCT00714077) of postoperative concurrent capecitabine and radiotherapy with or without oxaliplatin for pathological stage II and III rectal cancer. Patients with pathologically confirmed stage II and III rectal cancer were randomized to either radiotherapy with concurrent capecitabine (Cap-RT group) or with capecitabine and oxaliplatin (Capox-RT group). The primary endpoint was 3-year disease-free survival rate (DFS). The 3-year DFS rate was 73.9% in the Capox-RT group and 71.6% in the Cap-RT group (HR 0.92, p = 0.647), respectively. No significant difference was observed in overall survival, cumulative incidence of local recurrence and distant metastasis between the two groups (p > 0.05). More grade 3–4 acute toxicity was observed in the Capox-RT group than in the Cap-RT group (38.1% vs. 29.2%, p = 0.041). Inclusion of oxaliplatin in the capecitabine-based postoperative regimen did not improve DFS but increased toxicities for pathological stage II and III rectal cancer in this interim analysis.
doi:10.18632/oncotarget.8226
PMCID: PMC5041927  PMID: 27014909
rectal cancer; postoperative chemoradiotherapy; capecitabine; oxaliplatin; phase 3 trial
18.  Analyzing the Chinese landscape in anti-diabetic drug research: leading knowledge production institutions and thematic communities 
Chinese Medicine  2016;11:13.
Background
The discovery of anti-diabetic drugs is an active Chinese medicine research area. This study aims to map out anti-diabetic drug research in China using a network-based systemic approach based on co-authorship of academic publications. We focused on identifying leading knowledge production institutions, analyzing interactions among them, detecting communities with high internal associations, and exploring future research directions.
Methods
Target articles published in 2009–2013 under the topic “diabetes” and subject category “pharmacology & pharmacy,” with “China,” “Taiwan,” “Hong Kong,” or “Macao” (or “Macau”) in the authors’ address field were retrieved from the science citation index expanded database and their bibliographic information (e.g., article title, authors, keywords, and authors’ affiliation addresses) analyzed. A social network approach was used to construct an institutional collaboration network based on co-publications. Gephi software was used to visualize the network and relationships among institutes were analyzed using centrality measurements. Thematic analysis based on article keywords and Rsc value was applied to reveal the research hotspots and directions of network communities.
Results
The top 50 institutions were identified; these included Shanghai Jiao Tong University, National Taiwan University, Peking University, and China Pharmaceutical University. Institutes from Taiwan tended to cooperate with institutes outside Taiwan, but those from mainland China showed low interest in external collaboration. Fourteen thematic communities were detected with the Louvain algorithm and further labeled by their high-frequency and characteristic keywords, such as Chinese medicines, diabetic complications, oxidative stress, pharmacokinetics, and insulin resistance. The keyword Chinese medicines comprised a range of Chinese medicine-related topics, including berberine, flavonoids, Astragaluspolysaccharide, emodin, and ginsenoside. These keywords suggest potential fields for further anti-diabetic drug research. The correlation of −0.641 (P = 0.013) between degree centrality and the Rsc value of non-core keywords indicates that communities concentrating on rare research fields are usually isolated by others and have a lower chance of collaboration.
Conclusion
With a better understanding of the Chinese landscape in anti-diabetic drug research, researchers and scholars looking for experts and institutions in a specific research area can rapidly spot their target community, then select the most appropriate potential collaborator and suggest preferential research directions for future studies.
Electronic supplementary material
The online version of this article (doi:10.1186/s13020-016-0084-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13020-016-0084-y
PMCID: PMC4812608  PMID: 27030797
Greater China; Anti-diabetes drug; Chinese medicines; Research collaboration networks; Network analysis
19.  CD68 and interleukin 13, prospective immune markers for esophageal squamous cell carcinoma prognosis prediction 
Oncotarget  2016;7(13):15525-15538.
Purpose
Oncology immunity was reported to play a key role in cancer development and progression, so we investigated the prediction role of several immune markers in esophageal squamous cell carcinoma (ESCC) patients after operation in this study.
Patients and Methods
66 primary ESCC tumor tissues and four sets of tissue microarrays including 705 primary ESCC tumor tissues from four centers were collected and analyzed. Expressions of several immune markers in ESCC tumor tissue were detected with immunohistochemistry staining. Their distribution densities were analyzed with InForm™ 2.0.1 software. All statistic analyses were performed with SPSS16.0 and Stata version 10.0.
Results
Survival analyses assessed by Kaplan-Meier plots and log-rank tests demonstrated that densities of CD68 and interleukin 13 (IL-13) in tumor stroma were positively correlated with the overall survival of ESCC patients after operation (p < 0.01 for CD68, p < 0.001 for IL-13). Further, a model based on tumor stroma densities of CD68 and IL-13 was constructed and it could significantly classify patients with poor or good prognosis. This model could further identify high-risk group and low-risk group at the same Tumor lymph Nodes Metastases (TNM) stage. Lastly, a more accuracy model based on TNM stage, densities of CD68 and IL-13 was constructed to predict the prognosis of ESCC patient after operation.
Conclusion
Combining the TNM staging system and densities of CD68 and IL-13 could substantially improve the prognosis prediction accuracy of ESCC patient after operation, which might be an excellent tool for selecting patients for individualized therapy in future.
doi:10.18632/oncotarget.6900
PMCID: PMC4941258  PMID: 26771842
ESCC; IL-13; macrophage; prognosis; CD68
20.  Gut microbiota-involved mechanisms in enhancing systemic exposure of ginsenosides by coexisting polysaccharides in ginseng decoction 
Scientific Reports  2016;6:22474.
Oral decoctions of traditional Chinese medicines (TCMs) serve for therapeutic and prophylactic management of diseases for centuries. Small molecules and polysaccharides are the dominant chemicals co-occurred in the TCM decoction. Small molecules are well-studied by multidisciplinary elaborations, whereas the role of polysaccharides remains largely elusive. Here we explore a gut microbiota-involved mechanism by which TCM polysaccharides restore the homeostasis of gut microbiota and consequently promote the systemic exposure of concomitant small molecules in the decoction. As a case study, ginseng polysaccharides and ginsenosides in Du-Shen-Tang, the decoction of ginseng, were investigated on an over-fatigue and acute cold stress model. The results indicated that ginseng polysaccharides improved intestinal metabolism and absorption of certain ginsenosides, meanwhile reinstated the perturbed holistic gut microbiota, and particularly enhanced the growth of Lactobacillus spp. and Bacteroides spp., two major metabolic bacteria of ginsenosides. By exploring the synergistic actions of polysaccharides with small molecules, these findings shed new light on scientization and rationalization of the classic TCM decoctions in human health care.
doi:10.1038/srep22474
PMCID: PMC4774164  PMID: 26932472
21.  Emodin ameliorates cisplatin-induced apoptosis of rat renal tubular cells in vitro by activating autophagy 
Acta Pharmacologica Sinica  2016;37(2):235-245.
Aim:
A previous report shows that emodin extracted from the Chinese herbs rhubarb and giant knotweed rhizome can ameliorate the anticancer drug cisplatin-induced injury of HEK293 cells. In this study, we investigated whether and how emodin could protect renal tubular epithelial cells against cisplatin-induced nephrotoxicity in vitro.
Methods:
The viability and apoptosis of normal rat renal tubular epithelial cells (NRK-52E) were detected using formazan assay and flow cytometry analysis, respectively. The expression levels of cleaved caspase-3, autophagy maker LC3 I/II, and AMPK/mTOR signaling pathway-related proteins were measured with Western blot analysis. The changes of morphology and RFP-LC3 fluorescence were observed under microscopy.
Results:
Cisplatin (10-50 μmol/L) dose-dependently induced cell damage and apoptosis in NRK-52E cells, whereas emodin (10 and 100 μmol/L) significantly ameliorated cisplatin-induced cell damage, apoptosis and caspase-3 cleavage. Emodin dose-dependently increased LC3-II levels and induced RFP-LC3-containing punctate structures in NRK-52E cells. Furthermore, the protective effects of emodin were abolished by bafilomycin A1 (10 nmol/L), and mimicked by rapamycin (100 nmol/L). Moreover, emodin increased the phosphorylation of AMPK and suppressed the phosphorylation of mTOR. The AMPK inhibitor compound C (10 μmol/L) not only abolished emodin-induced autophagy activation, but also emodin-induced anti-apoptotic effects.
Conclusion:
Emodin ameliorates cisplatin-induced apoptosis of rat renal tubular cells in vitro through modulating the AMPK/mTOR signaling pathways and activating autophagy. Emodin may have therapeutic potential for the prevention of cisplatin-induced nephrotoxicity.
doi:10.1038/aps.2015.114
PMCID: PMC4753365  PMID: 26775661
cisplatin; nephrotoxicity; apoptosis; rat renal tubular cells; emodin; autophagy; bafilomycin A1; rapamycin; AMPK; mTOR; compound C
22.  Coding Properties of Mouse Retinal Ganglion Cells with Dual-Peak Patterns with Respect to Stimulus Intervals 
How visual information is encoded in spikes of retinal ganglion cells (RGCs) is essential in visual neuroscience. In the present study, we investigated the coding properties of mouse RGCs with dual-peak patterns with respect to visual stimulus intervals. We first analyzed the response properties, and observed that the latencies and spike counts of the two response peaks in the dual-peak pattern exhibited systematic changes with the preceding light-OFF interval. We then applied linear discriminant analysis (LDA) to assess the relative contributions of response characteristics of both peaks in information coding regarding the preceding stimulus interval. It was found that for each peak, the discrimination results were far better than chance level based on either latency or spike count, and were further improved by using the combination of the two parameters. Furthermore, the best discrimination results were obtained when latencies and spike counts of both peaks were considered in combination. In addition, the correct rate for stimulation discrimination was higher when RGC population activity was considered as compare to single neuron's activity, and the correct rate was increased with the group size. These results suggest that rate coding, temporal coding, and population coding are all involved in encoding the different stimulus-interval patterns, and the two response peaks in the dual-peak pattern carry complementary information about stimulus interval.
doi:10.3389/fncom.2016.00075
PMCID: PMC4949255  PMID: 27486396
retinal ganglion cell; dual-peak response; response latency; spike count; linear discriminant analysis; information coding; stimulus interval
23.  Effects of Altered Intra-abdominal Pressure on the Upper Airway Collapsibility in a Porcine Model 
Chinese Medical Journal  2015;128(23):3204-3210.
Background:
Obstructive sleep apnea is strongly associated with obesity, particularly abdominal obesity common in centrally obese males. Previous studies have demonstrated that intra-abdominal pressure (IAP) is increased in morbid obesity, and tracheal traction forces may influence pharyngeal airway collapsibility. This study aimed to investigate that whether IAP plays a role in the mechanism of upper airway (UA) collapsibility via IAP-related caudal tracheal traction.
Methods:
An abdominal wall lifting (AWL) system and graded CO2 pneumoperitoneum pressure was applied to four supine, anesthetized Guizhou miniature pigs and its effects on tracheal displacement (TD) and airflow dynamics of UA were studied. Individual run data in 3 min obtained before and after AWL and obtained before and after graded pneumoperitoneum pressure were analyzed. Differences between baseline and AWL/graded pneumoperitoneum pressure data of each pig were examined using a Student's t-test or analysis of variance.
Results:
Application of AWL resulted in decreased IAP and significant caudal TD. The average displacement amplitude was 0.44 mm (P < 0.001). There were three subjects showed increased tidal volume (TV) (P < 0.01) and peak inspiratory airflow (P < 0.01); however, the change of flow limitation inspiratory UA resistance (Rua) was not significant. Experimental increased IAP by pneumoperitoneum resulted in significant cranial TD. The average displacement amplitude was 1.07 mm (P < 0.001) when IAP was 25 cmH2O compared to baseline. There were three subjects showed reduced Rua while the TV increased (P < 0.01). There was one subject had decreased TV and elevated Rua (P < 0.001).
Conclusions:
Decreased IAP significantly increased caudal TD, and elevated IAP significantly increased cranial TD. However, the mechanism of UA collapsibility appears primarily mediated by changes in lung volume rather than tracheal traction effect. TV plays an independent role in the mechanism of UA collapsibility.
doi:10.4103/0366-6999.170281
PMCID: PMC4794893  PMID: 26612297
Abdominal Obesity; Intra-abdominal Pressure; Lung Volume; Obstructive Sleep Apnea; Trachea Traction
24.  A Novel Murine Anti-Lactoferrin Monoclonal Antibody Activates Human Polymorphonuclear Leukocytes through Membrane-Bound Lactoferrin and TLR4 
BioMed Research International  2015;2015:285237.
Soluble lactoferrin (LTF) is a versatile molecule that not only regulates the iron homeostasis, but also harbors direct microbicidal and immunomodulating abilities in mammalian body fluids. In contrast, little is known about the function of membrane-bound LTF (mbLTF), although its expression on human polymorphonuclear leukocytes (huPMNs) has been reported for decades. Given that LTF/anti-LTF antibodies represent a potential diagnostic/prognostic biomarker and a therapeutic target in patients with immune disorders, we wished, in the present study, to generate a novel human LTF- (huLTF-) specific mAb suitable for detailed analyses on the expression and function of mbLTF as well as for deciphering the underlying mechanisms. By using the traditional hybridoma cell fusion technology, we obtained a murine IgG1 (kappa) mAb, M-860, against huLTF. M-860 recognizes a conformational epitope of huLTF as it binds to natural, but not denatured, huLTF in ELISA. Moreover, M-860 detects mbLTF by FACS and captures endogenous huLTF in total cell lysates of huPMNs. Functionally, M-860 induces the activation of huPMNs partially through TLR4 but independently of phagocytosis. M-860 is thus a powerful tool to analyze the expression and function of human mbLTF, which will further our understanding of the roles of LTF in health and disease.
doi:10.1155/2015/285237
PMCID: PMC4662965  PMID: 26649297
25.  Complex molecular mechanisms underlying seedling salt tolerance in rice revealed by comparative transcriptome and metabolomic profiling 
Journal of Experimental Botany  2015;67(1):405-419.
Highlight
Comprehensive analyses of phenotypic, metabolic, and transcriptome data from two genotypes with contrasting salt tolerance provided a more complete picture of the molecular mechanisms underlying seedling tolerance in rice.
To understand the physiological and molecular mechanisms underlying seedling salt tolerance in rice (Oryza sativa L.), the phenotypic, metabolic, and transcriptome responses of two related rice genotypes, IR64 and PL177, with contrasting salt tolerance were characterized under salt stress and salt+abscisic acid (ABA) conditions. PL177 showed significantly less salt damage, lower Na+/K+ ratios in shoots, and Na+ translocation from roots to shoots, attributed largely to better salt exclusion from its roots and salt compartmentation of its shoots. Exogenous ABA was able to enhance the salt tolerance of IR64 by selectively decreasing accumulation of Na+ in its roots and increasing K+ in its shoots. Salt stress induced general and organ-specific increases of many primary metabolites in both rice genotypes, with strong accumulation of several sugars plus proline in shoots and allantoin in roots. This was due primarily to ABA-mediated repression of genes for degradation of these metabolites under salt. In PL177, salt specifically up-regulated genes involved in several pathways underlying salt tolerance, including ABA-mediated cellular lipid and fatty acid metabolic processes and cytoplasmic transport, sequestration by vacuoles, detoxification and cell-wall remodeling in shoots, and oxidation–reduction reactions in roots. Combined genetic and transcriptomic evidence shortlisted relatively few candidate genes for improved salt tolerance in PL177.
doi:10.1093/jxb/erv476
PMCID: PMC4682442  PMID: 26512058
ABA; metabolomics; molecular mechanisms; Oryza sativa L; salt tolerance; transcriptome.

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