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1.  Vitamin-responsive Mesoporous Nanocarrier with DNA Aptamer-mediated Cell Targeting 
A smart drug delivery system with cancer cell targeting and bioresponsive controlled drug release has been constructed by taking advantage of the protein-capped mesoporous nanovalve and a DNA aptamer.
doi:10.1039/c3cc41072b
PMCID: PMC3676747  PMID: 23589821
2.  SLCO3A1, a Novel Crohn’s Disease-Associated Gene, Regulates NF-κB Activity and Associates with Intestinal Perforation 
PLoS ONE  2014;9(6):e100515.
Background & Aims
To date, only one gene (TNFSF15) has been identified and validated as a Crohn’s disease (CD)-associated gene in non-Caucasian populations. This study was designed to identify novel CD-associated single nucleotide polymorphisms (SNPs)/genes and to validate candidate genes using a functional assay.
Methods
SNPs from 16 CD patients and 16 age- and sex-matched control patients were analyzed using Illumina platform analysis. Subsequently, we expanded the study and followed 53 CD patients and 41 control patients by Sequenom MassArray analysis. Quantitative PCR and immunohistochemical staining were performed to assess mRNA and protein expression of the candidate gene on tissue isolated from CD patients. Genotype was correlated with CD phenotypes. Finally, the candidate gene was cloned and its effect on NF-κB activity assessed using a reporter luciferase assay.
Results
SLCO3A1 (rs207959) reached statistical significance in the first-stage analysis (P = 2.3E-02) and was further validated in the second-stage analysis (P = 1.0E-03). Genotype and phenotype analysis showed that the rs207959 (T) allele is a risk allele that alters SLCO3A1 mRNA expression and is associated with intestinal perforation in CD patients. Higher levels of mRNA and protein expression of SLCO3A1 were seen in CD patients compared with the control group. Overexpression of SLCO3A1 induced increased NF-κB activity and increased phosphorylation of P65, ERK, and JNK. Nicotine augmented the activation of NF-κB in the presence of SLCO3A1.
Conclusions
SLCO3A1, a novel CD-associated gene, mediates inflammatory processes in intestinal epithelial cells through NF-κB transcription activation, resulting in a higher incidence of bowel perforation in CD patients.
doi:10.1371/journal.pone.0100515
PMCID: PMC4063938  PMID: 24945726
3.  Magnetic resonance cholangiopancreatography study of pancreaticobiliary maljunction and pancreaticobiliary diseases 
AIM: To discuss the imaging anatomy about pancreaticobiliary ductal union, occurrence rate of pancreaticobiliary maljunction (PBM) and associated diseases in a Chinese population by using magnetic resonance cholangiopancreatography (MRCP).
METHODS: Data were collected from 694 patients who underwent MRCP from January 2010 to December 2012. Three hundred and ninety-three patients were male and 301 patients were female. The age range was 16-92 years old and the average age was 51.8 years. The recruitment indication of all cases was patients who had clinical symptoms, such as abdominal pain, jaundice, nausea and vomiting, which thus were clinically suspected as relative pancreaticobiliary diseases. All cases were examined by MRCP using single-shot fast spin-echo sequences. In order to obtain MRCP images, the maximum intensity projection was used.
RESULTS: According to the anatomy of pancreaticobiliary ductal union based on our analysis of MRCP images, all cases were classified into normal type and abnormal type according to the position of pancreaticobiliary ductal union. The abnormal type could be further divided into P-B type, B-P type and the duodenum type. By analyzing the incidence of biliary stone and inflammation, pancreatitis, biliary duct tumors and pancreatic tumors between normal and abnormal types, significant differences existed. The abnormal group was more likely to suffer from pancreaticobiliary diseases. Comparing three different types of PBM that were associated with pancreaticobiliary diseases by using Fisher’s method, the result showed that there was no significant difference in the incidence of biliary stones, cholecystitis and pancreatic tumors. The incidence of pancreatitis in B-P type and P-B type was higher than that in duodenum type; the incidence of biliary duct tumor in B-P type was higher than that in P-B type; the incidence of biliary duct tumor in duodenum type was lower than that in P-B type. The incidence of congenital choledochus dilatation in normal type and abnormal type was similar, and there was no significant difference between the two types.
CONCLUSION: Types of PBM are closely related to the occurrence of pancreaticobiliary diseases. MRCP has important clinical value in the early diagnosis and preventive treatment of pancreaticobiliary diseases.
doi:10.3748/wjg.v20.i22.7005
PMCID: PMC4051944  PMID: 24944495
Pancreaticobiliary maljunction; Magnetic resonance cholangiopancreatography; Biliary tract; Pancreas; Magnetic resonance imaging
4.  Selective Small Molecule Compounds Increase BMP-2 Responsiveness by Inhibiting Smurf1-mediated Smad1/5 Degradation 
Scientific Reports  2014;4:4965.
The ubiquitin ligase Smad ubiquitination regulatory factor-1 (Smurf1) negatively regulates bone morphogenetic protein (BMP) pathway by ubiquitinating certain signal components for degradation. Thus, it can be an eligible pharmacological target for increasing BMP signal responsiveness. We established a strategy to discover small molecule compounds that block the WW1 domain of Smurf1 from interacting with Smad1/5 by structure based virtual screening, molecular experimental examination and cytological efficacy evaluation. Our selected hits could reserve the protein level of Smad1/5 from degradation by interrupting Smurf1-Smad1/5 interaction and inhibiting Smurf1 mediated ubiquitination of Smad1/5. Further, these compounds increased BMP-2 signal responsiveness and the expression of certain downstream genes, enhanced the osteoblastic activity of myoblasts and osteoblasts. Our work indicates targeting Smurf1 for inhibition could be an accessible strategy to discover BMP-sensitizers that might be applied in future clinical treatments of bone disorders such as osteopenia.
doi:10.1038/srep04965
PMCID: PMC4021816  PMID: 24828823
5.  Development of the mesencephalic trigeminal nucleus requires a paired homeodomain transcription factor, Drg11 
The mesencephalic trigeminal nucleus (Me5) innervates muscle spindles and is responsible for receiving and transmitting proprioception from the oro-facial region. Molecular mechanisms underlying the development of the Me5 are poorly understood. Evidence is provided here that transcription factor Drg11 is required for Me5 development. Drg11 was expressed in the Me5 cells of the embryonic and early postnatal mouse brains, and the Me5 cells were absent in Drg11−/− mice at birth. The absence of the Me5 cells in Drg11−/− mice appeared to be caused by increased cell death in the Me5 during embryonic development. In postnatal Drg11−/− mice, Me5 cell innervation of masseter muscle spindles was undetectable, while robust trigeminal motoneuron innervation of masseter muscle fibers was detected. The postnatal bodyweight of Drg11−/− mice was notably less than that of wild-type mice, and this might result, in part, from disruption of the oro-facial proprioceptive afferent pathway. Taken together, our results demonstrate an essential role for Drg11 in the development of the Me5.
doi:10.1016/j.mcn.2007.03.011
PMCID: PMC4012274  PMID: 17482477
Drg11; Transcription factor; Mesencephalic trigeminal nucleus; Development; Cell survival
6.  Bone Microstructure and Regional Distribution of Osteoblast and Osteoclast Activity in the Osteonecrotic Femoral Head 
PLoS ONE  2014;9(5):e96361.
Objective
To detect and compare the bone microstructure and osteoblast and osteoclast activity in different regions of human osteonecrotic femoral heads.
Methods
Osteonecrotic femoral heads were obtained from 10 patients (6 males, 4 females; Ficat IV) undergoing total hip arthroplasty between 2011 and 2013. The samples were divided into subchondral bone, necrotic, sclerotic, and healthy regions based on micro-computed tomography (CT) images. The bone microstructure, micromechanics, and osteoblast and osteoclast activity were assessed using micro-CT, pathology, immunohistochemistry, nanoindentation, reverse transcription polymerase chain reaction (RT-PCR), tartrate-resistant acid phosphatase staining and Western blotting.
Results
(1) The spatial structure of the bone trabeculae differed markedly in the various regions of the osteonecrotic femoral heads. (2) The elastic modulus and hardness of the bone trabeculae in the healthy and necrotic regions did not differ significantly (P >0.05). (3) The subchondral bone and necrotic region were positive on TRAP staining, while the other regions were negative. (4) On immunohistochemical staining, RANK and RANKL staining intensities were increased significantly in the subchondral bone and necrotic region compared with the healthy region, while RUNX2 and BMP2 staining intensities were increased significantly in the sclerotic region compared with the necrotic region. (5) OPG, RANK, RANKL, RUNX2, BMP2, and BMP7 protein levels were greater in the necrotic and sclerotic region than in subchondral bone and the healthy region.
Conclusion
The micromechanical properties of bone trabeculae in the necrotic region did not differ significantly from the healthy region. During the progress of osteonecrosis, the bone structure changed markedly. Osteoclast activity increased in subchondral bone and the necrotic region while osteoblast activity increased in the sclerotic region. We speculate that the altered osteoblast and osteoclast activity leads to a reduction in macroscopic mechanical strength.
doi:10.1371/journal.pone.0096361
PMCID: PMC4011745  PMID: 24800992
7.  Diagnosis of Kikuchi-Fujimoto Disease: A Comparison between Open Biopsy and Minimally Invasive Ultrasound-Guided Core Biopsy 
PLoS ONE  2014;9(5):e95886.
Kikuchi-Fujimoto disease (KFD) is a self-limited disease without any need of surgical treatments. Sampling of tissue is the only invasive procedure during the clinical course. However, the standard sampling procedure with accuracy, minimal invasiveness, and esthetic maintenance has not been established yet. In this study, a retrospective review of clinical utility and pathological presentations of the ultrasound-guided core biopsy (USCB) and the open biopsy (OB) in consecutive KFD patients. From 2010 to 2012, 34 consecutive patients were enrolled. USCB was performed in 11 patients, and OB was done in 26 patients. KFD was confirmed in 82% cases by USCB. Similar pathological presentations were found both in the specimens of USCB and OB. In the three patients who had received both USCB and OB, KFD was confirmed by USCB in one case, while two by OB. Sampling errors were found both in USCB and OB. For diagnosing KFD, USCB can serve as the first-line diagnostic tool. OB can be applied only in the failed cases of USCB.
doi:10.1371/journal.pone.0095886
PMCID: PMC4008434  PMID: 24787483
8.  Poly(ADP-Ribose) Polymerase 1 Promotes Oxidative-Stress-Induced Liver Cell Death via Suppressing Farnesoid X Receptor α 
Molecular and Cellular Biology  2013;33(22):4492-4503.
Farnesoid X receptor α (FXR) is highly expressed in the liver and regulates the expression of various genes involved in liver repair. In this study, we demonstrated that activated poly(ADP-ribose) polymerase 1 (PARP1) promoted hepatic cell death by inhibiting the expression of FXR-dependent hepatoprotective genes. PARP1 could bind to and poly(ADP-ribosyl)ate FXR. Poly(ADP-ribosyl)ation dissociated FXR from the FXR response element (FXRE), present in the promoters of target genes, and suppressed FXR-mediated gene transcription. Moreover, treatment with a FXR agonist attenuated poly(ADP-ribosyl)ation of FXR and promoted FXR-dependent gene expression. We further established the CCl4-induced acute liver injury model in wild-type and FXR-knockout mice and identified an essential role of FXR poly(ADP-ribosyl)ation in CCl4-induced liver injury. Thus, our results identified poly(ADP-ribosyl)ation of FXR by PARP1 as a key step in oxidative-stress-induced hepatic cell death. The molecular association between PARP1 and FXR provides new insight into the mechanism, suggesting that inhibition of PARP1 could prevent liver injury.
doi:10.1128/MCB.00160-13
PMCID: PMC3838191  PMID: 24043304
9.  Ectopic Expression of a Maize Hybrid Down-Regulated Gene ZmARF25 Decreases Organ Size by Affecting Cellular Proliferation in Arabidopsis 
PLoS ONE  2014;9(4):e94830.
Heterosis is associated with differential gene expression between hybrids and their parental lines, and the genes involved in cell proliferation played important roles. AtARF2 is a general cell proliferation repressor in Arabidopsis. In our previous study, two homologues (ZmARF10 and ZmARF25) of AtARF2 were identified in maize, but their relationship with heterosis was not elucidated. Here, the expression patterns of ZmARF10 and ZmARF25 in seedling leaves of maize hybrids and their parental lines were analyzed. The results of qRT-PCR exhibited that ZmARF25 was down-regulated in leaf basal region of hybrids. Moreover, overexpression of ZmARF25 led to reduced organ size in Arabidopsis, which was mainly due to the decrease in cell number, not cell size. In addition, the cell proliferation related genes AtANT, AtGIF1 and AtGRF5 were down-regulated in 35S::ZmARF25 transgenic lines. Collectively, we proposed that the down-regulation of ZmARF25 in maize hybrid may accelerate cell proliferation and promote leaf development, which, in turn, contributes to the observed leaf size heterosis in maize.
doi:10.1371/journal.pone.0094830
PMCID: PMC3995674  PMID: 24756087
10.  Breast cancer molecular subtypes of Uygur and Han in Xinjiang of China 
Purpose: To compare the difference between Uygur and Han patients with breast cancer in molecular subtype. Methods: 4 immunohistochemical (IHC) markers (ER, PR, HER-2 and KI-67) were used to divide Uygur and Han breast cancer patients into 4 subtypes (Luminal A, Luminal B, HER-2 over expression and Basal-like), respectively. statistical analysis were used to evaluate difference in molecular subtype characteristics by race, tumor size, age of onset, menstruation and birth status, histological grade and lymph node metastasis. Results: There is no statistical difference on the molecular subtypes between Han and Uygur. But some characteristics about four subtypes between Han and Uygur have statistical difference like age onset of the Her-2 overexpression cases, subtypes of age less than 35 years, menarche age of the Basal-like cases and tumor size of the Luminal A cases. Between Han and Uygur there is statistical difference on the menarche age, number of childbirths, and tumor size. The HER-2 overexpression and Basal-like subtypes were more likely to be grade III tumors both of Han and Uygur. Between 4 molecular subtypes of Han there have statistical difference in number of metastasis lymph nodes. Conclusions: Our result shows that there are some significant differences between Uygur and Han in the pathological features as well as molecular subtypes. Correct understanding the difference of breast cancer between Uygur and Han can provide guidance for clinical practice.
PMCID: PMC4057871  PMID: 24955192
Breast; molecular; subtypes; race
11.  Increased Risk of Ischemic Stroke after Hyperosmolar Hyperglycemic State: A Population-Based Follow-Up Study 
PLoS ONE  2014;9(4):e94155.
Background
Although much attention has been focused on the association between chronic hyperglycemia and cerebrovascular diseases in type 2 diabetes mellitus (DM) patients, there is no data regarding the risk of ischemic stroke after a hyperosmolar hyperglycemic state (HHS) attack. The objective of this study was to investigate the risk of ischemic stroke in type 2 DM patients after an HHS attack.
Methods
From 2004 to 2008, this retrospective observational study was conducted on a large cohort of Taiwanese using Taiwan’s National Health Insurance Research Database (NHIRD). We identified 19,031 type 2 DM patients who were discharged with a diagnosis of HHS and 521,229 type 2 DM patients without an HHS diagnosis. Using the propensity score generated from logistic regression models, conditional on baseline covariates, we matched 19,031 type 2 DM patients with an HHS diagnosis with the same number from the comparison cohort. The one-year cumulative rate for ischemic stroke was estimated using the Kaplan-Meier method. After adjusting covariates, Cox proportional hazard regression was used to compute the adjusted one-year rate of ischemic stroke.
Results
Of the patients sampled, 1,810 (9.5%) of the type 2 DM patients with HHS and 996 (5.2%) of the comparison cohort developed ischemic stroke during the one-year follow-up period. After adjusting for covariates, the adjusted HR for developing ischemic stroke during the one-year follow-up period was 1.8 (95% C.I., 1.67 to 1.95, P<0.001) for type 2 DM patients with HHS compared with those without HHS.
Conclusion
Although DM is a well-recognized risk factor for atherosclerosis, type 2 DM patients that have suffered a HHS attacks are at an increased risk of developing ischemic stroke compared with those without HHS.
doi:10.1371/journal.pone.0094155
PMCID: PMC3979762  PMID: 24714221
12.  Tumors of the angle of Treitz: A single-center experience 
AIM: To explore the feasibility and oncologic outcomes of segmental jejunal resection on the left side of the mesenteric vessels in patients with tumors of the angle of Treitz using data from a single center.
METHODS: Thirteen patients with tumors of the angle of Treitz who underwent surgery at our institution were prospectively followed. A segmental jejunal resection on the left side of the mesenteric vessels was performed in all patients. Formalin-fixed and paraffin-embedded tumor samples were examined. The primary end point of this analysis was disease-free survival.
RESULTS: In this study, there were 8 males and 5 females (mean age, 50.1 years; range, 36-74 years). The mean tumor size was 8.1 cm (range, 3.2-15 cm). Histologic examination showed 11 gastrointestinal stromal tumors (GISTs) and 2 adenocarcinomas. Five of the GIST patients presented with potential low risk, and 6 presented with intermediate and high risk, according to the National Institutes of Health criteria. One potentially high-risk patient showed tumor progression at 46 mo and died 52 mo after surgery. One patient with locally advanced adenocarcinoma received neoadjuvant chemotherapy and adjuvant radiotherapy, but the disease progressed, and the patient died 9 mo after surgery. One GIST patient without progression died 16 mo after surgery because of a postoperative intestinal obstruction. The median overall survival rate was 84.6 mo, and the median disease-free survival rate was 94.5 mo.
CONCLUSION: The overall survival of patients with tumors of the angle of Treitz was encouraging even when the tumor size was relatively large. A segmental resection on the left side of the mesenteric vessels is considered to be a reliable and curative option for tumors of the angle of Treitz.
doi:10.3748/wjg.v20.i13.3628
PMCID: PMC3974531  PMID: 24707147
Gastrointestinal stromal tumor; Adenocarcinoma; Angle of Treitz; Surgical treatment; Prognosis
13.  Double-bundle anatomical versus single-bundle isometric medial patellofemoral ligament reconstruction for patellar dislocation 
International Orthopaedics  2013;37(4):617-624.
Purpose
The purpose of this study was to evaluate reconstruction of the medial patellofemoral ligament (MPFL) using the double-bundle anatomical or single-bundle isometric procedure with respect to the patients’ clinical outcomes.
Methods
In this retrospective study, we evaluated the clinical outcome of double-bundle anatomical versus single-bundle isometric reconstruction of the MPFL for patellar dislocation patients. Sixty-three patients were included in this study from August 2004 to January 2008. From August 2004 to September 2006, MPFL reconstruction using a single-bundle isometric technique was performed in 21 patients (26 knees). Since October 2006, the double-bundle anatomical reconstruction of the MPFL has been used as the routine surgical procedure. It was performed in 37 patients (44 knees). Fifty-eight patients (70 knees) could be followed up. According to the different techniques, we divided the patients into two groups: group D with double-bundle anatomical reconstruction (37 patients) and group S with single-bundle isometric reconstruction (21 patients). Clinical evaluation consisted of the number with a patellar re-dislocation, patellar apprehension sign, Kujala score, subjective questionnaire score, the patella lateral shift rate and patellar tilt angle measured by cross-sectional CT scan.
Results
According to the Kujala score and the subjective questionnaire score, the outcome of the double-bundle group was better than the outcome of the single-bundle group especially in the long-term. Patellar re-dislocation occurred in three patients in the group S, while no re-dislocation occurred in the group D. In total, 26.9 % of group S was considered to have patellar instability, compared to 4.54 % of the group D. After operation, the patellar tilt angle (PTA) and the patella lateral shift rate (PLSR) were restored to the normal range, with statistical significance (P < 0.05) compared to the preoperative state.
Conclusion
Single- and double-bundle reconstruction of the MPFL can both effectively restore patella stability and improve knee function. However, outcomes in the follow-up period showed that the double-bundle surgery procedure was much better than in single-bundle surgery.
doi:10.1007/s00264-013-1788-6
PMCID: PMC3609965  PMID: 23371425
14.  Enrichment of provitamin A content in wheat (Triticum aestivum L.) by introduction of the bacterial carotenoid biosynthetic genes CrtB and CrtI  
Journal of Experimental Botany  2014;65(9):2545-2556.
Summary
Co-expression of CrtB and CrtI enhanced carotenoid in endosperm through upregulation of the endogenous carotenogenic genes. Our results also indicate important roles of LCYB and HYD in wheat carotenoid biosynthesis.
Carotenoid content is a primary determinant of wheat nutritional value and affects its end-use quality. Wheat grains contain very low carotenoid levels and trace amounts of provitamin A content. In order to enrich the carotenoid content in wheat grains, the bacterial phytoene synthase gene (CrtB) and carotene desaturase gene (CrtI) were transformed into the common wheat cultivar Bobwhite. Expression of CrtB or CrtI alone slightly increased the carotenoid content in the grains of transgenic wheat, while co-expression of both genes resulted in a darker red/yellow grain phenotype, accompanied by a total carotenoid content increase of approximately 8-fold achieving 4.76 μg g–1 of seed dry weight, a β-carotene increase of 65-fold to 3.21 μg g–1 of seed dry weight, and a provitamin A content (sum of α-carotene, β-carotene, and β-cryptoxanthin) increase of 76-fold to 3.82 μg g–1 of seed dry weight. The high provitamin A content in the transgenic wheat was stably inherited over four generations. Quantitative PCR analysis revealed that enhancement of provitamin A content in transgenic wheat was also a result of the highly coordinated regulation of endogenous carotenoid biosynthetic genes, suggesting a metabolic feedback regulation in the wheat carotenoid biosynthetic pathway. These transgenic wheat lines are not only valuable for breeding wheat varieties with nutritional benefits for human health but also for understanding the mechanism regulating carotenoid biosynthesis in wheat endosperm.
doi:10.1093/jxb/eru138
PMCID: PMC4036513  PMID: 24692648
Bacterial phytoene synthase (CrtB); bacterial phytoene desaturase (CrtI); carotenoid β-hydroxylase (HYD); lycopene β-cyclase (LCYB); provitamin A; particle bombardment; transgenic wheat.
15.  Involvement of ephrin receptor A4 in pancreatic cancer cell motility and invasion 
Oncology Letters  2014;7(6):2165-2169.
Ephrin (EPH) receptors can be classified into EPHA and EPHB receptors and are important in diverse cellular processes. EPHA4, a member of the EPHA receptors, has been demonstrated to be elevated in various human cancers and involved in the tumor progression. However, the role of EPHA4 in pancreatic cancer cells remains unclear. Therefore, the present study transfected Panc-1 and BxPC-3 cells with small interfering RNA (siRNA) to knockdown the expression of EPHA4. Wound healing and invasion assays were then performed to assess the effect of EPHA4 knockdown on the motility and invasion of pancreatic cancer cells. The results demonstrated that the knockdown of EPHA4 by siRNA inhibits the motility and invasion of pancreatic cancer cells. Furthermore, gelatin zymography assay showed that EPHA4 may regulate the activity of matrix metalloproteinase (MMP)-2. In addition, the knockdown of EPHA4 increased the expression of epithelial (E)-cadherin, as well as decreased the expression of Snail. Overall, these results suggested that EPHA4 may promote the motility and invasion of pancreatic cancer cells via the upregulation of MMP-2 and Snail, as well as the downregulation of E-cadherin. Thus, EPHA4 may act as a useful target for the treatment of pancreatic cancer.
doi:10.3892/ol.2014.2011
PMCID: PMC4049679  PMID: 24932309
ephrin receptor A4; invasion; motility; pancreatic cancer; matrix metalloproteinase-2; epithelial-mesenchymal transition
16.  Curcumin attenuates acute inflammatory injury by inhibiting the TLR4/MyD88/NF-κB signaling pathway in experimental traumatic brain injury 
Background
Traumatic brain injury (TBI) initiates a neuroinflammatory cascade that contributes to substantial neuronal damage and behavioral impairment, and Toll-like receptor 4 (TLR4) is an important mediator of thiscascade. In the current study, we tested the hypothesis that curcumin, a phytochemical compound with potent anti-inflammatory properties that is extracted from the rhizome Curcuma longa, alleviates acute inflammatory injury mediated by TLR4 following TBI.
Methods
Neurological function, brain water content and cytokine levels were tested in TLR4-/- mice subjected to weight-drop contusion injury. Wild-type (WT) mice were injected intraperitoneally with different concentrations of curcumin or vehicle 15 minutes after TBI. At 24 hours post-injury, the activation of microglia/macrophages and TLR4 was detected by immunohistochemistry; neuronal apoptosis was measured by FJB and TUNEL staining; cytokines were assayed by ELISA; and TLR4, MyD88 and NF-κB levels were measured by Western blotting. In vitro, a co-culture system comprised of microglia and neurons was treated with curcumin following lipopolysaccharide (LPS) stimulation. TLR4 expression and morphological activation in microglia and morphological damage to neurons were detected by immunohistochemistry 24 hours post-stimulation.
Results
The protein expression of TLR4 in pericontusional tissue reached a maximum at 24 hours post-TBI. Compared with WT mice, TLR4-/- mice showed attenuated functional impairment, brain edema and cytokine release post-TBI. In addition to improvement in the above aspects, 100 mg/kg curcumin treatment post-TBI significantly reduced the number of TLR4-positive microglia/macrophages as well as inflammatory mediator release and neuronal apoptosis in WT mice. Furthermore, Western blot analysis indicated that the levels of TLR4 and its known downstream effectors (MyD88, and NF-κB) were also decreased after curcumin treatment. Similar outcomes were observed in the microglia and neuron co-culture following treatment with curcumin after LPS stimulation. LPS increased TLR4 immunoreactivity and morphological activation in microglia and increased neuronal apoptosis, whereas curcumin normalized this upregulation. The increased protein levels of TLR4, MyD88 and NF-κB in microglia were attenuated by curcumin treatment.
Conclusions
Our results suggest that post-injury, curcumin administration may improve patient outcome by reducing acute activation of microglia/macrophages and neuronal apoptosis through a mechanism involving the TLR4/MyD88/NF-κB signaling pathway in microglia/macrophages in TBI.
doi:10.1186/1742-2094-11-59
PMCID: PMC3986937  PMID: 24669820
Toll-like receptor 4; Curcumin; Traumatic brain injury; Inflammation
17.  Positive Feedback Regulation of Proliferation in Vascular Smooth Muscle Cells Stimulated by Lipopolysaccharide Is Mediated through the TLR 4/Rac1/Akt Pathway 
PLoS ONE  2014;9(3):e92398.
Toll-like receptor 4 (TLR4) are important in inflammation and regulating vascular smooth muscle cells (VSMCs) proliferation, which are related to atherosclerosis and restenosis. We have investigated the mechanisms involved in Lipopolysaccharide (LPS)-induced proliferation of VSMCs. Stimulation of rat aortic VSMCs with LPS significantly increases the proliferation of VSMCs. This effect is regulated by Rac1 (Ras-related C3 botulinum toxin substrate l), which mediates the activation of phosphatidylinositol 3-kinase/Akt (PI3K/Akt) signaling pathways. Inhibition of Rac1 activity by NSC23766 is associated with inhibition of Akt activity. Treatment with NSC23766 or LY294002 significantly decreases LPS-induced TLR4 protein and mRNA expression. The data show that positive feedback regulation of proliferation in VSMCs is mediated through the TLR4/Rac1/Akt pathway.
doi:10.1371/journal.pone.0092398
PMCID: PMC3965409  PMID: 24667766
18.  Diagnostic and Prognostic Implications of a Serum miRNA Panel in Oesophageal Squamous Cell Carcinoma 
PLoS ONE  2014;9(3):e92292.
Background and Aim
Circulating microRNAs (miRNAs) are potential biomarkers for cancer detection; however, little is known about their prognostic impact on oesophageal squamous cell carcinoma (ESCC). The current study aims to uncover novel miRNAs for prognostic biomarkers in ESCC patients.
Patients and Methods
We initially screened the expression of 754 serum miRNAs using TaqMan Low Density Array in two pooled samples respectively from 28 ESCC and 28 normal controls. Markedly upregulated miRNAs in ESCC and some miRNAs reported to be differently expressed in ESCC tissue were then validated individually by RT-qPCR in another 83 patients and 83 controls arranged in two phases. The changes of the selected miRNAs during the esophagectomy and their prognostic value were examined.
Results
Seven serum miRNAs were found to be significantly higher in ESCC than in controls; namely, miR-25, miR-100, miR-193-3p, miR-194, miR-223, miR-337-5p and miR-483-5p (P<0.0001), and the area under the receiver-operating-characteristic (ROC) curve (AUC) for the seven-miRNA panel was 0.83 (95% CI 0.75–0.90). Most of these miRNAs declined markedly in postoperative samples versus preoperative samples (P<0.05). Moreover, high level of miR-25 was significantly correlated with shorter overall survival in patients (P = 0.027). Cox regression analysis identified lymph node metastasis, miR-25 and miR-100 as the independent risk factors for overall survival (hazard ratio (HR) 2.98 [1.36–6.55], P = 0.006; HR 3.84 [1.02–14.41], P = 0.029; HR 4.18 [1.21–14.50], P = 0.024, respectively).
Conclusion
The seven serum miRNAs could potentially serve as novel biomarkers for ESCC; moreover, specific miRNAs such as miR-25 and miR-100 can predict poor survival in ESCC.
doi:10.1371/journal.pone.0092292
PMCID: PMC3961321  PMID: 24651474
19.  Measurement and Analysis of P2P IPTV Program Resource 
The Scientific World Journal  2014;2014:101702.
With the rapid development of P2P technology, P2P IPTV applications have received more and more attention. And program resource distribution is very important to P2P IPTV applications. In order to collect IPTV program resources, a distributed multi-protocol crawler is proposed. And the crawler has collected more than 13 million pieces of information of IPTV programs from 2009 to 2012. In addition, the distribution of IPTV programs is independent and incompact, resulting in chaos of program names, which obstructs searching and organizing programs. Thus, we focus on characteristic analysis of program resources, including the distributions of length of program names, the entropy of the character types, and hierarchy depth of programs. These analyses reveal the disorderly naming conventions of P2P IPTV programs. The analysis results can help to purify and extract useful information from chaotic names for better retrieval and accelerate automatic sorting of program and establishment of IPTV repository. In order to represent popularity of programs and to predict user behavior and popularity of hot programs over a period, we also put forward an analytical model of hot programs.
doi:10.1155/2014/101702
PMCID: PMC3977418  PMID: 24772008
20.  Genetic Variants at 10p11 Confer Risk of Tetralogy of Fallot in Chinese of Nanjing 
PLoS ONE  2014;9(3):e89636.
A recent genome-wide association study (GWAS) has identified a new subset of susceptibility loci of Tetralogy of Fallot (TOF), one form of cyanotic congenital heart disease (CHD), on chromosomes 10p11, 10p14, 12q24, 13q31, 15q13 and 16q12 in Europeans. In the current study, we conducted a case-control study in a Chinese population including 1,010 CHD cases [atrial septal defect (ASD), ventricular septal defect (VSD) and TOF] and 1,962 controls to evaluate the associations of these loci with risk of CHD. We found that rs2228638 in NRP1 on 10p11 was significantly increased the risk of TOF (OR = 1.52, 95% CI = 1.13–2.04, P = 0.006), but not in other subgroups including ASD and VSD. In addition, no significant associations were observed between the other loci and the risk of ASD, VSD or TOF. Our results suggested that the genetic variants on 10p11 may serve as candidate markers for TOF susceptibility in Chinese population.
doi:10.1371/journal.pone.0089636
PMCID: PMC3940663  PMID: 24594544
21.  Polycomb group protein EZH2-mediated E-cadherin repression promotes metastasis of oral tongue squamous cell carcinoma 
Molecular carcinogenesis  2011;52(3):229-236.
Enhancer of zeste homolog 2 (EZH2) is a critical component of the polycomb-repressive complex 2 (PRC2) that regulates many essential biological processes, including embryogenesis and many developmental events. The oncogenic role of EZH2 has recently been implicated in several cancer types. In this study, we first confirmed that the over-expression of EZH2 is a frequent event in oral tongue squamous cell carcinoma (OTSCC). We further demonstrated that EZH2 over-expression is correlated with advanced stages of the disease and is associated with lymph node metastasis. Statistical analysis revealed that EZH2 over-expression was correlated with reduced overall survival. Furthermore, over-expression of EZH2 was correlated with reduced expression of tumor suppressor gene E-cadherin. These observations were confirmed in vitro, in which knockdown of EZH2 induced E-cadherin expression and reduced cell migration and invasion. In contrast, ectopic transfection of EZH2 led to reduced E-cadherin expression and enhanced cell migration and invasion. Furthermore, EZH2 may act on cell migration in part by suppressing the E-cadherin expression. Taken together, these data suggest that EZH2 plays major roles in the progression of OTSCC, and may serve as a biomarker or therapeutic target for patients at risk of metastasis.
doi:10.1002/mc.21848
PMCID: PMC3400713  PMID: 22161744
EZH2; E-cadherin; metastasis; prognosis; squamous cell carcinoma
22.  Characterization of ELISA Detection of Broad-spectrum Anti- Epstein-Barr Virus Antibodies Associated with Nasopharyngeal Carcinoma 
Journal of medical virology  2012;85(3):524-529.
Epstein-Barr virus (EBV) infection is associated with undifferentiated nasopharyngeal carcinomas (NPC). A distinct seroreactivity pattern to EBV is predictive of subsequent risk of sporadic and familial nasopharyngeal carcinomas. There are currently no accepted screening tools for guiding the clinical management of individuals at high-risk for nasopharyngeal carcinomas, particularly unaffected relatives from nasopharyngeal carcinoma multiplex families. Therefore, the reproducibility of a panel of largely synthetic peptide-based anti-EBV antibody ELISAs was evaluated and their ability to distinguish nasopharyngeal carcinoma cases from controls was explored. IgG and IgA antibodies against 6 different EBV antigens (10 assays, total) were tested on sera from 97 individuals representing the full spectrum of anti-EBV seroprevalence (i.e., healthy individuals with no known EBV seroreactivity, healthy individuals with known EBV seroreactivity, and nasopharyngeal carcinoma cases). Each specimen was tested in triplicate to assess within-batch and across-batch variation, and the triplicate testing was repeated on two separate days. Reproducibility was assessed by the coefficients of variation (CV) and intraclass correlation coefficients (ICC). All markers were detectable in 17% or more of samples. For all but one marker, the overall, within-batch, and across-batch CVs were below 15%, and the ICCs were above 70% for all but three markers. Sensitivity of these markers to detect prevalent nasopharyngeal carcinomas ranged from 22–100%, and among unaffected controls, most distinguished those with and without known seropositivity. In conclusion, a large number of EBV markers can be measured reliably in serum samples using peptide-based anti-EBV ELISAs.
doi:10.1002/jmv.23498
PMCID: PMC3553325  PMID: 23280934
Epstein-Barr virus; EBNA1; VCA; IgA; nasopharyngeal carcinoma; screening
23.  Behind death 
doi:10.3978/j.issn.2072-1439.2014.02.24
PMCID: PMC3949191  PMID: 24624292
24.  Docetaxel extravasation results in significantly delayed and relapsed skin injury: A case report 
Oncology Letters  2014;7(5):1497-1498.
Chemotherapeutic agents can result in extravasation, which is considered to be a serious complication. The increasing number of exposures to different cytotoxic agents experienced by each patient may enhance the prevalence of this complication. Docetaxel is widely used in the treatment of numerous solid tumors. Thus, the current report presents the case of a breast cancer patient who developed a significantly delayed skin reaction one day after docetaxel extravasation, a rare skin manifestation, and relapsed one week subsequently. This unusual clinical presentation is an indicator that practitioners are required to carefully monitor the patient for further cutaneous reactions in the weeks following extravasation to observe any additional adverse reactions.
doi:10.3892/ol.2014.1921
PMCID: PMC3997661  PMID: 24765163
docetaxel; chemotherapy; extravasation
25.  Syllable frequency and word frequency effects in spoken and written word production in a non-alphabetic script 
The effects of word frequency (WF) and syllable frequency (SF) are well-established phenomena in domain such as spoken production in alphabetic languages. Chinese, as a non-alphabetic language, presents unique lexical and phonological properties in speech production. For example, the proximate unit of phonological encoding is syllable in Chinese but segments in Dutch, French or English. The present study investigated the effects of WF and SF, and their interaction in Chinese written and spoken production. Significant facilitatory WF and SF effects were observed in spoken as well as in written production. The SF effect in writing indicated that phonological properties (i.e., syllabic frequency) constrain orthographic output via a lexical route, at least, in Chinese written production. However, the SF effect over repetitions was divergent in both modalities: it was significant in the former two repetitions in spoken whereas it was significant in the second repetition only in written. Due to the fragility of the SF effect in writing, we suggest that the phonological influence in handwritten production is not mandatory and universal, and it is modulated by experimental manipulations. This provides evidence for the orthographic autonomy hypothesis, rather than the phonological mediation hypothesis. The absence of an interaction between WF and SF showed that the SF effect is independent of the WF effect in spoken and written output modalities. The implications of these results on written production models are discussed.
doi:10.3389/fpsyg.2014.00120
PMCID: PMC3927083  PMID: 24600420
spoken production; written production; word frequency effect; syllable frequency effect; Chinese

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