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1.  Primary tumor PET/CT [18F]FDG uptake is an independent predictive factor for regional lymph node metastasis in patients with non-small cell lung cancer 
Cancer Imaging  2013;12(3):566-572.
Abstract
Aim: To investigate the correlation between [18F]fluorodeoxyglucose (FDG) uptake in a primary tumor and pathologic N stages, and to further analyze the possible risk factors contributing to the regional lymph node metastasis. Patients and methods: Eighty patients with non-small cell lung cancer (NSCLC) who underwent positron emission tomography/computed tomography were enrolled in the study. The FDG uptake in the primary tumor was compared for the different N staging groups and further correlation was performed. The degree of FDG uptake in the primary tumor and other possible variables related to the incidence of lymph node metastasis were examined by univariate and logistic multivariate analysis. FDG uptake was quantitated using the maximum standardized uptake value (SUVmax). Results: Statistically significant differences were found in the SUVmax of the primary tumors among different N staging groups (F = 4.124, P = 0.023), and the correlation between them was also statistically significant (r = 0.438, P = 0.000). Univariate analysis showed that blood tumor markers, primary tumor size, histologic grade, and SUVmax of the primary tumor were significantly associated with lymph node involvement. Logistic multivariate analysis showed that blood tumor makers and SUVmax of primary tumor might be considered as significant predictive factors for lymph node metastasis in patients with NSCLC. Conclusion: Our results show that there is a significant relationship between the SUVmax of the primary tumor and the pathologic N stage of NSCLC. FDG uptake by the primary tumor may be an independent predictor of regional lymph node metastasis in patients with NSCLC.
doi:10.1102/1470-7330.2012.0040
PMCID: PMC3569669  PMID: 23399986
Non-small cell lung cancer; FDG; PET/CT; standardized uptake value; staging; lymph node metastasis; risk factor
2.  HIF-1α -1790G>A polymorphism significantly increases the risk of digestive tract cancer: A meta-analysis 
AIM: To investigate the association between hypoxia-inducible factor-1α (HIF-1α) polymorphisms (-1772C>T and -1790G>A) and the risk of digestive tract cancer.
METHODS: A total of 13 eligible studies were retrieved from PubMed, EMBASE, and the China National Knowledge Infrastructure database. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the strength of the associations.
RESULTS: By pooling the eligible studies, we found that the HIF-1α -1772C>T polymorphism was not associated with the risk of developing digestive tract cancer (dominant comparison, OR: 1.156; 95%CI: 0.839-1.593; Pheterogeneity = 0.007), and no significant association was found in the Asian population or the Caucasian population. However, for the -1790G>A polymorphism, carriers of the variant -1790A allele had a significantly increased risk of digestive tract cancer compared with those with the wildtype -1790G allele (dominant comparison, OR: 3.252; 95%CI: 1.661-6.368; Pheterogeneity < 0.001). Additionally, this increased risk of digestive cancer was only detected in Asians; there was no significant association in Caucasians.
CONCLUSION: This meta-analysis demonstrates that the HIF-1α -1790G>A polymorphism is associated with a significantly increased risk of digestive tract cancer, while the -1772C>T polymorphism is not.
doi:10.3748/wjg.v21.i5.1641
PMCID: PMC4316108  PMID: 25663785
Hypoxia-inducible factor-1α; Digestive tract cancer; Polymorphisms; Cancer risk; Meta-analysis
3.  New Approach to Investigate the Cytotoxicity of Nanomaterials Using Single Cell Mechanics 
The journal of physical chemistry. B  2014;118(5):1246-1255.
Current in vitro methods to assess nanomaterial cytotoxicity involve various assays to monitor specific cellular dysfunction, such as metabolic imbalance or inflammation. Although high throughput, fast, and animal-free, these in vitro methods suffer from unreliability and lack of relevance to in vivo situations. New approaches, especially with the potential to reliably relate to in vivo studies directly, are in critical need. This work introduces a new approach, single cell mechanics, derived from atomic force microscopy-based single cell compression. The single cell based approach is intrinsically advantageous in terms of being able to directly correlate to in vivo investigations. Its reliability and potential to measure cytotoxicity is evaluated using known systems: zinc oxide (ZnO) and silicon dioxide (SiO2) nanoparticles (NP) on human aortic endothelial cells (HAECs). This investigation clearly indicates the reliability of single cell compression. For example, ZnO NPs cause significant changes in force vs relative deformation profiles, whereas SiO2 NPs do not. New insights into NPs–cell interactions pertaining to cytotoxicity are also revealed from this single cell mechanics approach, in addition to a qualitative cytotoxicity conclusion. The advantages and disadvantages of this approach are also compared with conventional cytotoxicity assays.
doi:10.1021/jp410764f
PMCID: PMC3980960  PMID: 24417356
4.  NADPH oxidase p47phox siRNA attenuates adventitial fibroblasts proliferation and migration in apoE(-/-) mouse 
Background
Reactive oxide species (ROS) derived from NADPH oxidases is involved in atherosclerosis. However, as a key component of NADPH oxidase, how p47phox regulates NADPH oxidases activity, ROS production and adventitial fibroblasts (AFs) function remains unclear.
Methods
p47phox in aortic arteries of apoE(-/-) mice fed with hyperlipid diet was detected by immunohistochemistry. NADPH oxidase activity, superoxide anion (O2−) generation and p47phox expression were analyzed in primary AFs treated by diphenyleneiodonium (DPI). The proliferation and migration of AFs were also analyzed.
Results
p47phox expression was low in the aortic adventitia but high in the site of intimal injury with continuous hyperlipidic diet. Compared to AFs from wild-type mice, AFs derived from apoE(-/-) mice exhibited elevated NADPH oxidase activity, O2− production and higher mRNA and protein levels of p47phox, correlated with increased capability of proliferation and migration. DPI inhibited NADPH oxidase activity and AFs proliferation and migration in a dose-dependent manner. In addition, siRNA mediated knockdown of p47phox attenuated the proliferation and migration of AFs derived from apoE(-/-) mice.
Conclusion
p47phox plays a critical role in the regulation of adventitial fibroblast proliferation and migration and may be a new therapeutic target for neointimal hyperplasia.
doi:10.1186/s12967-015-0407-2
PMCID: PMC4312606  PMID: 25628043
NADPH oxidase; p47phox; Adventitia fibroblasts; Atherosclerosis; ApoE(-/-)
5.  SPOCK1 as a potential cancer prognostic marker promotes the proliferation and metastasis of gallbladder cancer cells by activating the PI3K/AKT pathway 
Molecular Cancer  2015;14(1):12.
Background
Gallbladder cancer (GBC) is a leading cause of cancer-related death worldwide, and its prognosis remains poor, with 5-year survival of approximately 5%. In this study, we analyzed the involvement of a novel proteoglycan, Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1), in the tumor progression and prognosis of human GBC.
Methods
SPOCK1 expression levels were measured in fresh samples and stored specimens of GBC and adjacent nontumor tissues. The effect of SPOCK1 on cell growth, DNA replication, migration and invasion were explored by Cell Counting Kit-8, colony formation, EdU retention assay, wound healing, and transwell migration assays, flow cytometric analysis, western blotting, and in vivo tumorigenesis and metastasis in nude mice.
Results
SPOCK1 mRNA and protein levels were increased in human GBC tissues compared with those in nontumor tissues. Immunohistochemical analysis indicated that SPOCK1 levels were increased in tumors that became metastatic, compared with those that did not, which was significantly associated with histological differentiation and patients with shorter overall survival periods. Knockdown of SPOCK1 expression by lentivirus-mediated shRNA transduction resulted in significant inhibition of GBC cell growth, colony formation, DNA replication, and invasion in vitro. The knockdown cells also formed smaller xenografted tumors than control GBC cells in nude mice. Overexpression of SPOCK1 had the opposite effects. In addition, SPOCK1 promoted cancer cell migration and epithelial-mesenchymal transition by regulating the expression of relevant genes. We found that activation of the PI3K/Akt pathway was involved in the oncogenic functions of SPOCK1 in GBC.
Conclusions
SPOCK1 activates PI3K/Akt signaling to block apoptosis and promote proliferation and metastasis by GBC cells in vitro and in vivo. Levels of SPOCK1 increase with the progression of human GBC. SPOCK1 acts as an oncogene and may be a prognostic factor or therapeutic target for patients with GBC.
Electronic supplementary material
The online version of this article (doi:10.1186/s12943-014-0276-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12943-014-0276-y
PMCID: PMC4320842  PMID: 25623055
Gallbladder cancer; SPOCK1; Tumor progression; RNA interference; Epithelial-mesenchymal transition
6.  Toroidal-Spiral Particles for Codelivery of Anti-VEGFR-2 Antibody and Irinotecan: A Potential Implant to Hinder Recurrence of Glioblastoma Multiforme 
Biomacromolecules  2014;15(3):756-762.
Heterogeneous toroidal-spiral particles (TSPs) were generated by polymer droplet sedimentation, interaction, and cross-linking. TSPs provide a platform for encapsulation and release of multiple compounds of different sizes and physicochemical properties. As a model system, we demonstrate the encapsulation and independently controlled release of an anti-VEGFR-2 antibody and irinotecan for the treatment of glioblastoma multiforme. The anti-VEGFR-2 antibody was released from the TS channels and its binding to HUVECs was confirmed by confocal microscopy and flow cytometry, suggesting active antibody encapsulation and release. Irinotecan, a small molecule drug, was released from the dense polymer matrix of poly(ethylene glycol) diacrylate (MW ∼ 700 g/mol; PEGDA 700). Released irinotecan inhibited the proliferation of U251 malignant glioma cells. Since the therapeutic compounds are released through different pathways, specifically diffusion through the polymer matrix versus TS channels, the release rate can be controlled independently through the design of the structure and material of particle components.
doi:10.1021/bm401550r
PMCID: PMC3983134  PMID: 24460101
7.  Genetic Characterization of Shigella flexneri Isolates in Guizhou Province, China 
PLoS ONE  2015;10(1):e0116708.
Shigella flexneri is one of the major etiologic causes of shigellosis in Guizhou Province, China. However, the genetic characteristics of circulating isolates are unknown. Phenotypic and molecular profiles of 60 S. flexneri isolates recovered in Guizhou between 1972 to 1982 and 2008 to 2010 were determined. Nine serotypes (1a, 2a, 3a, 1b, 2b, X, Y, 4av and Yv) were identified. Multi-locus sequence typing differentiated the isolates into 20 sequence types (STs); 18 were novel. Four STs, ST 129, ST 100, ST 126 and ST 18, were most abundant, accounting for 65% of the isolates. Thirty-nine NotI-pulsed field gel electrophoresis patterns (pulsotypes, PTs) were observed; eight PTs were represented by more than one isolate with six isolates sharing the PT 13 profile. Multi-locus variable-nucleotide tandem-repeat analysis recognized 44 different types (MTs); seven MTs were represented by more than one isolate and MT 1 was most commonly encountered. Correlation between genetic relationships and serotypes was observed among the isolates studied; the majority of isolates belonging to the same serotype from different years clustered together based on the molecular data. These clustered isolates were also from similar geographical origins. These results enhance our understanding of genetic relationships between S. flexneri in Guizhou Province and can be used to help understand the changing etiology of shigellosis in China.
doi:10.1371/journal.pone.0116708
PMCID: PMC4305296  PMID: 25617838
8.  Baicalein Inhibits Progression of Gallbladder Cancer Cells by Downregulating ZFX 
PLoS ONE  2015;10(1):e0114851.
Baicalein, a widely used Chinese herbal medicine, has multiple pharmacological activities. However, the precise mechanisms of the anti-proliferation and anti-metastatic effects of baicalein on gallbladder cancer (GBC) remain poorly understood. Therefore, the aim of this study was to assess the anti-proliferation and anti-metastatic effects of baicalein and the related mechanism(s) on GBC. In the present study, we found that treatment with baicalein induced a significant inhibitory effect on proliferation and promoted apoptosis in GBC-SD and SGC996 cells, two widely used gallbladder cancer cell lines. Additionally, treatment with baicalein inhibited the metastasis of GBC cells. Moreover, we demonstrated for the first time that baicalein inhibited GBC cell growth and metastasis via down-regulation of the expression level of Zinc finger protein X-linked (ZFX). In conclusion, our studies suggest that baicalein may be a potential phytochemical flavonoid for therapeutics of GBC and ZFX may serve as a molecular marker or predictive target for GBC.
doi:10.1371/journal.pone.0114851
PMCID: PMC4305301  PMID: 25617627
9.  Reprogramming Human Endothelial to Hematopoietic Cells Requires Vascular Induction 
Nature  2014;511(7509):312-318.
Summary
Generating engraftable human hematopoietic cells from autologous tissues promises new therapies for blood diseases. Directed differentiation of pluripotent stem cells yields hematopoietic cells that poorly engraft. Here, we devised a method to phenocopy the vascular-niche microenvironment of hemogenic cells, thereby enabling reprogramming of human endothelial cells (ECs) into engraftable hematopoietic cells without transition through a pluripotent intermediate. Highly purified non-hemogenic human umbilical vein-ECs (HUVECs) or adult dermal microvascular ECs (hDMECs) were transduced with transcription factors (TFs), FOSB, GFI1, RUNX1, and SPI1 (FGRS), and then propagated on serum-free instructive vascular niche monolayers to induce outgrowth of hematopoietic colonies containing cells with functional and immunophenotypic features of multipotent progenitor cells (MPP). These reprogrammed ECs- into human-MPPs (rEC-hMPPs) acquire colony-forming cell (CFC) potential and durably engraft in immune-deficient mice after primary and secondary transplantation, producing long-term rEC-hMPP-derived myeloid (granulocytic/monocytic, erythroid, megakaryocytic) and lymphoid (NK, B) progeny. Conditional expression of FGRS transgenes, combined with vascular-induction, activates endogenous FGRS genes endowing rEC-hMPPs with a transcriptional and functional profile similar to self-renewing MPPs. Our approach underscores the role of inductive cues from vascular-niche in orchestrating and sustaining hematopoietic specification and may prove useful for engineering autologous hematopoietic grafts to treat inherited and acquired blood disorders.
doi:10.1038/nature13547
PMCID: PMC4159670  PMID: 25030167
10.  Detection for pathway effect contributing to disease in systems epidemiology with a case–control design 
BMJ Open  2015;5(1):e006721.
Objectives
Identification of pathway effects responsible for specific diseases has been one of the essential tasks in systems epidemiology. Despite some advance in procedures for distinguishing specific pathway (or network) topology between different disease status, statistical inference at a population level remains unsolved and further development is still needed. To identify the specific pathways contributing to diseases, we attempt to develop powerful statistics which can capture the complex relationship among risk factors.
Setting and participants
Acute myeloid leukaemia (AML) data obtained from 133 adults (98 patients and 35 controls; 47% female).
Results
Simulation studies indicated that the proposed Pathway Effect Measures (PEM) were stable; bootstrap-based methods outperformed the others, with bias-corrected bootstrap CI method having the highest power. Application to real data of AML successfully identified the specific pathway (Treg→TGFβ→Th17) effect contributing to AML with p values less than 0.05 under various methods and the bias-corrected bootstrap CI (−0.214 to −0.020). It demonstrated that Th17–Treg correlation balance was impaired in patients with AML, suggesting that Th17–Treg imbalance potentially plays a role in the pathogenesis of AML.
Conclusions
The proposed bootstrap-based PEM are valid and powerful for detecting the specific pathway effect contributing to disease, thus potentially providing new insight into the underlying mechanisms and ways to study the disease effects of specific pathways more comprehensively.
doi:10.1136/bmjopen-2014-006721
PMCID: PMC4298111  PMID: 25596199
STATISTICS & RESEARCH METHODS; EPIDEMIOLOGY
11.  New Approach to Investigate the Cytotoxicity of Nanomaterials Using Single Cell Mechanics 
The Journal of Physical Chemistry. B  2014;118(5):1246-1255.
Current in vitro methods to assess nanomaterial cytotoxicity involve various assays to monitor specific cellular dysfunction, such as metabolic imbalance or inflammation. Although high throughput, fast, and animal-free, these in vitro methods suffer from unreliability and lack of relevance to in vivo situations. New approaches, especially with the potential to reliably relate to in vivo studies directly, are in critical need. This work introduces a new approach, single cell mechanics, derived from atomic force microscopy-based single cell compression. The single cell based approach is intrinsically advantageous in terms of being able to directly correlate to in vivo investigations. Its reliability and potential to measure cytotoxicity is evaluated using known systems: zinc oxide (ZnO) and silicon dioxide (SiO2) nanoparticles (NP) on human aortic endothelial cells (HAECs). This investigation clearly indicates the reliability of single cell compression. For example, ZnO NPs cause significant changes in force vs relative deformation profiles, whereas SiO2 NPs do not. New insights into NPs–cell interactions pertaining to cytotoxicity are also revealed from this single cell mechanics approach, in addition to a qualitative cytotoxicity conclusion. The advantages and disadvantages of this approach are also compared with conventional cytotoxicity assays.
doi:10.1021/jp410764f
PMCID: PMC3980960  PMID: 24417356
12.  Biomembrane disruption by silica-core nanoparticles: effect of surface functional group measured using a tethered bilayer lipid membrane 
Biochimica et biophysica acta  2013;1838(1):10.1016/j.bbamem.2013.09.007.
Engineered nanomaterials (ENM) have desirable properties that make them well suited for many commercial applications. However, a limited understanding of how ENM’s properties influence their molecular interactions with biomembranes hampers efforts to design ENM that are both safe and effective. This paper describes the use of a tethered bilayer lipid membrane (tBLM) to characterize biomembrane disruption by functionalized silica-core nanoparticles. Electrochemical impedance spectroscopy was used to measure the time trajectory of tBLM resistance following nanoparticle exposure. Statistical analysis of parameters from an exponential resistance decay model was then used to quantify and analyze differences between the impedance profiles of nanoparticles that were unfunctionalized, amine-functionalized, or carboxyl-functionalized. All of the nanoparticles triggered a decrease in membrane resistance, indicating nanoparticle-induced disruption of the tBLM. Hierarchical clustering allowed the potency of nanoparticles for reducing tBLM resistance to be ranked in the order amine > carboxyl ~ bare silica. Dynamic light scattering analysis revealed that tBLM exposure triggered minor coalescence for bare and amine-functionalized silica nanoparticles but not for carboxyl-functionalized silica nanoparticles. These results indicate that the tBLM method can reproducibly characterize ENM-induced biomembrane disruption and can distinguish the BLM-disruption patterns of nanoparticles that are identical except for their surface functional groups. The method provides insight into mechanisms of molecular interaction involving biomembranes and is suitable for miniaturization and automation for high-throughput applications to help assess the health risk of nanomaterial exposure or identify ENM having a desired mode of interaction with biomembranes.
doi:10.1016/j.bbamem.2013.09.007
PMCID: PMC3855902  PMID: 24060565
silica nanoparticle; lipid bilayer; electrochemical impedance; resistance; aggregation
13.  Design, Synthesis and Cytotoxic Activity of Novel Sulfonylurea Derivatives of Podophyllotoxin 
Bioorganic & medicinal chemistry  2013;22(1):204-210.
Three series of novel sulfonylurea podophyllotoxin derivatives were designed, synthesized, and evaluated for in vitro cytotoxicity against four tumor cell lines (A-549, DU-145, KB and KBvin). Compounds 14c (IC50: 1.41–1.76 μM) and 14e (IC50: 1.72–2.01 μM) showed superior cytotoxic activity compared with etoposide (IC50: 2.03– >20μM), a clinically available anticancer drug. Significantly, most of the compounds exhibited comparable cytotoxicity against the drug-resistant tumor cell line KBvin, while etoposide lost activity completely. Preliminary structure-activity relationship (SAR) correlations indicated that the 4′-O-methyl functionality in podophyllotoxin analogues may be essential to maintain cytotoxic activity, while an arylsulfonylurea side chain at podophyllotoxin’s 4β position can significantly improve cytotoxic activity.
doi:10.1016/j.bmc.2013.11.035
PMCID: PMC3902999  PMID: 24332656
podophyllotoxin; sulfonylurea; synthesis; cytotoxic activity
14.  The compensation for asynchronous cardiac quiescence in coronary wall MR imaging 
The aim of the present study was to assess the incremental benefit of compensating asynchronous cardiac quiescence in coronary wall MR imaging. With the approval of IRB, black-blood coronary wall MR imaging was performed on 30 older subjects (90 coronary wall segments). For round 1 coronary wall MR imaging, acquisition windows were traditionally set within rest period 4-chamber. Totally 51 of 90 images were ranked as "good" images and resulted in an interpretability rate of 57%. Then, an additional cine-MR was centered at coronary segments to obtain rest period cross-sectional. The rest period overlap (the intersection between rest period 4-chamber and rest period cross-sectional) was measured for each coronary segments. The "good" images had a longer rest period overlap and higher acquisition coincidence rate (the percentage of acquisition window covered by the rest period overlap) than "poor" images. Coronary wall rescans (round 2) were completed at 39 coronary segments that were judged as having "poor" images in round 1 scans. The acquisition windows was set within the rest period overlap. For the round 2 images, 17 of 39 (44%) coronary segments was ranked as "good" images. The overall interpretability rate (68 of 90, 76%) was significantly higher than that of the round 1 images alone. Our data demonstrated that asynchronous cardiac quiescence adversely affects the performance of coronary wall MR imaging. Individualizing acquisition windows based on multi-plane cine-MR imaging helps to compensate for this motion discrepancy and to improve image quality.
doi:10.1007/s10554-013-0318-3
PMCID: PMC3946801  PMID: 24170261
Coronary wall MR imaging; Asynchronous quiescence; Compensation
15.  The interaction between the helicase DHX33 and IPS-1 as a novel pathway to sense double-stranded RNA and RNA viruses in myeloid dendritic cells 
In eukaryotes, there are at least 60 members of the DExD/H helicase family, many of which are able to sense viral nucleic acids. By screening all known family members, we identified the helicase DHX33 as a novel double-stranded RNA (dsRNA) sensor in myeloid dendritic cells (mDCs). The knockdown of DHX33 using small heteroduplex RNA (shRNA) blocked the ability of mDCs to produce type I interferon (IFN) in response to poly I:C and reovirus. The HELICc domain of DHX33 was shown to bind poly I:C. The interaction between DHX33 and IPS-1 is mediated by the HELICc region of DHX33 and the C-terminal domain of IPS-1 (also referred to MAVS and VISA). The inhibition of DHX33 expression by RNA interference blocked the poly I:C-induced activation of MAP kinases, NF-κB and IRF3. The interaction between the helicase DHX33 and IPS-1 was independent of RIG-I/MDA5 and may be a novel pathway for sensing poly I:C and RNA viruses in mDCs.
doi:10.1038/cmi.2013.40
PMCID: PMC4002151  PMID: 24037184
DHX33; helicase; innate immunity; IPS-1; myeloid dendritic cell; viral nucleic acid
16.  Detection of High-Risk Atherosclerotic Plaques with Ultrasound Molecular Imaging of Glycoprotein IIb/IIIa Receptor on Activated Platelets 
Theranostics  2015;5(4):418-430.
Objective: Ultrasound molecular imaging (UMI) of glycoprotein (GP) IIb/IIIa receptor on activated platelets offers a unique means of identifying high-risk atherosclerosis. We hypothesized that contrast-enhanced ultrasound with microbubbles (MBs) targeted to GP IIb/IIIa could be used to detect and quantify activated platelets on the surface of advanced plaques.
Methods and Results: A mouse model of advanced atherosclerosis was generated by maintaining apolipoprotein E-deficient (ApoE-/-) mice on a hypercholesterolemic diet (HCD). The three other experimental groups consisted of ApoE-/- and wild-type (C57BL/6) mice fed a normal chow diet and C57BL/6 mice on an HCD diet. Plaque formation was confirmed by histological and immunohistochemical methods using light, fluorescence, and electron microscopy. Mice were injected with a lipid MB-conjugated cyclic Arg-Gly-Asp peptide or nonspecific control peptide, and the abdominal aorta was examined by UMI. The accumulation of GP IIb/IIIa and activated platelets on the surface of atherosclerotic plaques was highest in the ApoE-/-+HCD group, followed by ApoE-/-+chow, C57BL/6+HCD, and C57BL/6+chow groups (P<0.05). Notably, GP IIb/IIIa expression was associated with the vulnerability index and necrotic center/fiber cap ratio (P<0.05), and contrast video intensity from adhered cyclic Arg-Gly-Asp-modified MBs (MB-cRGDs) was correlated with GP IIb/IIIa expression on the plaque surface (P<0.05).
Conclusion: GP IIb/IIIa of activated platelets on the atherosclerotic endothelium is a biomarker for high-risk plaques that can be quantified by UMI using MB-cRGDs, providing a noninvasive means for detecting high-risk plaques and preventing acute cardiovascular events.
doi:10.7150/thno.10020
PMCID: PMC4329504
Atherosclerosis; Microbubbles; Molecular imaging; Platelets; Glycoprotein IIb/IIIa
17.  Electrical Stimulation over Bilateral Occipito-Temporal Regions Reduces N170 in the Right Hemisphere and the Composite Face Effect 
PLoS ONE  2014;9(12):e115772.
Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that can modulate cortical excitability. Although the clinical value of tDCS has been advocated, the potential of tDCS in cognitive rehabilitation of face processing deficits is less understood. Face processing has been associated with the occipito-temporal cortex (OT). The present study investigated whether face processing in healthy adults can be modulated by applying tDCS over the OT. Experiment 1 investigated whether tDCS can affect N170, a face-sensitive ERP component, with a face orientation judgment task. The N170 in the right hemisphere was reduced in active stimulation conditions compared with the sham stimulation condition for both upright faces and inverted faces. Experiment 2 further demonstrated that tDCS can modulate the composite face effect, a type of holistic processing that reflects the obligatory attention to all parts of a face. The composite face effect was reduced in active stimulation conditions compared with the sham stimulation condition. Additionally, the current polarity did not modulate the effect of tDCS in the two experiments. The present study demonstrates that N170 can be causally manipulated by stimulating the OT with weak currents. Furthermore, our study provides evidence that obligatory attention to all parts of a face can be affected by the commonly used tDCS parameter setting.
doi:10.1371/journal.pone.0115772
PMCID: PMC4274090  PMID: 25531112
18.  Association between NME8 Locus Polymorphism and Cognitive Decline, Cerebrospinal Fluid and Neuroimaging Biomarkers in Alzheimer's Disease 
PLoS ONE  2014;9(12):e114777.
Recently, a large meta-analysis of five genome wide association studies (GWAS) identified a novel locus (rs2718058) adjacent to NME8 that played a preventive role in Alzheimer's disease (AD). However, this link between the single nucleotide polymorphism (SNP) rs2718058 and the pathology of AD have not been mentioned yet. Therefore, this study assessed the strength of association between the NME8 rs2718058 genotypes and AD-related measures including the cerebrospinal fluid (CSF) amyloid beta, tau, P-tau concentrations, neuroimaging biomarkers and cognitive performance, in a large cohort from Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We used information of a total of 719 individuals, including 211 normal cognition (NC), 346 mild cognitive impairment (MCI) and 162 AD. Although we didn't observe a positive relationship between rs2718058 and AD, it was significantly associated with several AD related endophenotypes. Among the normal cognitively normal participants, the minor allele G carriers showed significantly associated with higher CDRSB score than A allele carriers (P = 0.021). Occipital gyrus atrophy were significantly associated with NME8 genotype status (P = 0.002), with A allele carriers has more atrophy than the minor allele G carriers in AD patients; lateral ventricle (both right and left) cerebral metabolic rate for glucose (CMRgl) were significantly associated with NME8 genotype (P<0.05), with GA genotype had higher metabolism than GG and AA genotypes in MCI group; the atrophic right hippocampus in 18 months is significantly different between the three group, with GG and AA genotypes had more hippocampus atrophy than GA genotypes in the whole group. Together, our results are consistent with the direction of previous research, suggesting that NME8 rs2718058 appears to play a role in lowering the brain neurodegeneration.
doi:10.1371/journal.pone.0114777
PMCID: PMC4259473  PMID: 25486118
19.  Orally Administered Nano-curcumin to Attenuate Morphine Tolerance: Comparison between Negatively Charged PLGA and Partially and Fully PEGylated Nanoparticles 
Molecular pharmaceutics  2013;10(12):4546-4551.
We have formulated hydrophobic curcurmin [1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] into stable nanoparticle suspensions (nano-curcumin) to overcome its relatively low bioavailability, high rate of metabolism and rapid elimination and clearance from the body. Employing the curcumin nanoformulations as the platform, we discovered that curcumin has the potential to alleviate morphine tolerance. The two types of stable polymeric nanoparticles - poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol)-b-poly(lactic acid) (PEG-b-PLA) - and the hybrid of the two were generated using flash nanoprecipitation integrated with spray drying. The optimized formulations have high drug loading (>45%), small particles size with narrow distribution, and controlled surface properties. Mice behavioral studies (tail-flick and hot-plate tests) were conducted to verify the effects of nano-curcumin on attenuating morphine tolerance. Significant analgesia was observed in mice during both tail-flick and hot-plate tests using orally administrated nano-curcumin following subcutaneous injections of morphine. However, unformulated curcumin at the same dose showed no effect. Compared with PEGylated nano-curcumin, negatively charged PLGA nanoparticles showed better functionality.
doi:10.1021/mp400358z
PMCID: PMC3939066  PMID: 24195658
polymeric nanoparticles; bioavailability; oral delivery; drug tolerance; pain management
20.  Hierarchical Macro-meso-microporous ZSM-5 Zeolite Hollow Fibers With Highly Efficient Catalytic Cracking Capability 
Scientific Reports  2014;4:7276.
Zeolite fibers have attracted growing interest for a range of new applications because of their structural particularity while maintaining the intrinsic performances of the building blocks of zeolites. The fabrication of uniform zeolite fibers with tunable hierarchical porosity and further exploration of their catalytic potential are of great importance. Here, we present a versatile and facile method for the fabrication of hierarchical ZSM-5 zeolite fibers with macro-meso-microporosity by coaxial electrospinning. Due to the synergistic integration of the suitable acidity and the hierarchical porosity, high yield of propylene and excellent anti-coking stability were demonstrated on the as-prepared ZSM-5 hollow fibers in the catalytic cracking reaction of iso-butane. This work may also provide good model catalysts with uniform wall thickness and tunable porosity for studying a series of important catalytic reactions.
doi:10.1038/srep07276
PMCID: PMC4250908  PMID: 25450726
21.  Failure to process dentin sialophosphoprotein (DSPP) into fragments leads to periodontal defects in mice 
European journal of oral sciences  2013;121(6):10.1111/eos.12088.
Dentin sialophosphoprotein (DSPP) plays a vital role in dentinogenesis. Previously, we showed that, in addition to dentin, DSPP is also highly expressed in the alveolar bone and cellular cementum, and plays a crucial role in maintaining periodontal integrity; Dspp deficient mice demonstrate severe periodontal defects including alveolar bone loss, decreased cementum deposition, abnormal osteocyte morphology in the alveolar bone and apical migration of periodontal ligament. DSPP in dentin and bone is cleaved into NH2-terminal and COOH-terminal fragments. While our previous study showed that the proteolytic processing of DSPP is critical for dentinogenesis, it is unclear whether the posttranslational cleavage of DSPP also plays an essential role in maintaining a healthy periodontium. In this study, we analyzed the periodontal tissues in transgenic mice expressing the uncleavable full-length DSPP in the Dspp knockout (Dspp-KO) background (named “Dspp-KO/D452A-Tg mice”), in comparison with those in the wild-type mice, Dspp-KO mice, and mice expressing the normal DSPP transgene in the Dspp-KO background (designated “Dspp-KO/normal-Tg mice”). We found that transgenic expression of the normal DSPP fully rescued the periodontal defects of the Dspp-KO mice, whereas expressing Dspp-KO/D452A-Tg failed to do so. These results indicate that proteolytic processing of DSPP is essential to periodontal integrity.
doi:10.1111/eos.12088
PMCID: PMC3825804  PMID: 24112131
Alveolar bone; cementoblast; dentin; periodontal ligament; periodontal disease
22.  Generation and characterization of spiking and non-spiking oligodendroglial progenitor cells from embryonic stem cells 
Stem cells (Dayton, Ohio)  2013;31(12):2620-2631.
Pluripotent stem cells (PSCs) have been differentiated into oligodendroglial progenitor cells (OPCs), providing promising cell replacement therapies for many CNS disorders. Studies from rodents have shown that brain OPCs express a variety of ion channels, and that a subset of brain OPCs express voltage-gated sodium channel (NaV), mediating the spiking properties of OPCs. However, it is unclear whether PSC-derived OPCs exhibit electrophysiological properties similar to brain OPCs and the role of NaV in the functional maturation of OPCs is unknown. Here, using a mouse embryonic stem cell (mESC) GFP-Olig2 knockin reporter line, we demonstrated that unlike brain OPCs, all of the GFP+/Olig2+ mESC-derived OPCs (mESC-OPCs) did not express functional NaV and failed to generate spikes (hence termed “non-spiking mESC-OPCs”), while expressing the delayed rectifier and inactivating potassium currents. By ectopically expressing NaV1.2 α subunit via viral transduction, we successfully generated mESC-OPCs with spiking properties (termed “spiking mESC-OPCs”). After transplantation into the spinal cord and brain of myelin-deficient shiverer mice, the spiking mESC-OPCs demonstrated better capability in differentiating into MBP expressing oligodendrocytes and in myelinating axons in vivo than the non-spiking mESC-OPCs. Thus, by generating spiking and non-spiking mESC-OPCs, this study reveals a novel function of NaV in OPCs in their functional maturation and myelination, and sheds new light on ways to effectively develop PSC-derived OPCs for future clinical applications.
doi:10.1002/stem.1515
PMCID: PMC3923867  PMID: 23940003
Embryonic stem cell; oligodendroglial progenitor cell; voltage-gated ion channel; action potential; myelination
23.  Use of personalized Dynamic Treatment Regimes (DTRs) and Sequential Multiple Assignment Randomized Trials (SMARTs) in mental health studies 
Shanghai Archives of Psychiatry  2014;26(6):376-383.
Summary
Dynamic treatment regimens (DTRs) are sequential decision rules tailored at each point where a clinical decision is made based on each patient’s time-varying characteristics and intermediate outcomes observed at earlier points in time. The complexity, patient heterogeneity, and chronicity of mental disorders call for learning optimal DTRs to dynamically adapt treatment to an individual’s response over time. The Sequential Multiple Assignment Randomized Trial (SMARTs) design allows for estimating causal effects of DTRs. Modern statistical tools have been developed to optimize DTRs based on personalized variables and intermediate outcomes using rich data collected from SMARTs; these statistical methods can also be used to recommend tailoring variables for designing future SMART studies. This paper introduces DTRs and SMARTs using two examples in mental health studies, discusses two machine learning methods for estimating optimal DTR from SMARTs data, and demonstrates the performance of the statistical methods using simulated data.
doi:10.11919/j.issn.1002-0829.214172
PMCID: PMC4311115  PMID: 25642116
SMART; dynamic treatment regimes; personalized medicine; O-learning; Q-learning; double robust estimation
24.  First imported relapse case of Plasmodium vivax malaria and analysis of its origin by CSP sequencing in Henan Province, China 
Malaria Journal  2014;13(1):448.
In recent years, there has been a substantial increase of imported Plasmodium vivax incidence in Henan Province. As China is in a pre-elimination phase, the surveillance of imported malaria is essential, but there is no good way to distinguish imported cases from indigenous cases. This paper reports a case of a 39-year-old man who acquired P. vivax while staying in Indonesia for one month in 2013, and relapsed in Henan, China in 2014. This was diagnosed as vivax malaria based on rapid diagnostic test, Giemsa-stained peripheral blood smear and Plasmodium species-specific nested PCR. The genetic sequence for the circumsporozoite protein genes was analysed and the genetic variations were compared with a previously constructed database of Chinese isolates. The results from the circumsporozoite protein (CSP) gene sequence analysis centered on the repeat patterns showed that the imported cases had completely different sequences from any subtypes from Chinese isolates, but well matched with the countries travelled by the patient. The imported vivax cases were able to clearly distinguish from the indigenous vivax cases by detecting the CSP gene and were able to confim its origin by genotyping.
doi:10.1186/1475-2875-13-448
PMCID: PMC4251853  PMID: 25416163
Plasmodium vivax; Relapse; Imported; CSP
25.  The Differential Impact of Early Father and Mother Involvement on Later Student Achievement 
Journal of educational psychology  2009;101(2):498-508.
The purpose of this exploratory study was to examine the direct and indirect effects of early parenting on later parental school involvement and student achievement. The sample, pulled from the first and second waves of the Panel Study of Income Dynamics – Child Development Supplement data set, consisted of 390 children ages 2–5 at time 1 and their families. Fathers’ and mothers’ participation in five dimensions of early parenting behaviors were assessed at time 1, while later parental school involvement and student achievement were assessed at time 2. Although early paternal and maternal parenting behaviors were not directly related to later student achievement, differences were revealed in the pattern of relationships between early parenting and later parental school involvement for fathers and mothers. In addition, fathers’ later school involvement was found to be negatively related to student achievement while maternal school involvement was found to be positively related to student achievement. These findings provide partial support for the hypothesized differential relationship between fathers’ and mothers’ early parenting and later student achievement.
doi:10.1037/a0014238
PMCID: PMC4235963  PMID: 25414521

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