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1.  Seroconversion to Japanese Encephalitis Virus among U.S. Infantry Forces in Korea 
Japanese encephalitis virus (JEV) is endemic in the Republic of Korea (ROK), posing a medical threat to more than 29,000 U.S. Forces military personnel currently deployed in the ROK. The objective of this study was to provide data on the risk of JEV exposure among U.S. Forces in the ROK. One thousand U.S. Army Soldiers were randomly selected for the study from the cohort of infantry Soldiers deployed in the ROK for a period of at least 330 days from 2008 to 2011. Pre- and post-deployment serum specimens were tested for the presence of JEV antibodies by plaque reduction neutralization test. A total of 2/1,000 (0.2%) U.S. Army Soldiers post-deployment specimens tested positive for JEV antibody. Results from the pre-deployment specimens indicated one true seroconversion and one with titers suggestive of a JEV infection. These results indicate a low, but nonzero risk of JEV exposure among U.S. Army Soldiers in the ROK.
doi:10.4269/ajtmh.15-0307
PMCID: PMC4703268  PMID: 26240157
2.  Tripartite motif containing 62 is a novel prognostic marker and suppresses tumor metastasis via c-Jun/Slug signaling-mediated epithelial-mesenchymal transition in cervical cancer 
Background
TRIM62 (tripartite motif containing 62) has been found to act as a tumor suppressor of several cancers. However, its precise biological role and related mechanism remain unknown in cervical cancer (CC).
Methods
Quantitative Real-time PCR and western blot were adopted to detect the mRNA and protein expression level of TRIM62 in both human CC cell lines and tissues. Immunohistochemistry was used to measure the TRIM62 expression in 30 normal cervical and 189 CC tissues. Univariate and multivariate Cox regression analyses and Kaplan–Meier survival analyses performed to investigate the association between TRIM62 expression and CC patients’ prognosis. The effect of TRIM62 on CC growth and metastasis was studied in vitro and in vivo. Multi-pathway reporter array were utilized to identify the potential signaling manipulated by TRIM62.
Results
TRIM62 was frequently down-regulated in both human CC cells and tissues. Low expression of TRIM62 in CC tissues was associated with aggressive clinicopathological features of CC patients. In addition, TRIM62 was also an independent poor prognostic factor for overall and disease-free survival of CC patients after surgery. Moreover, enforced expression of TRIM62 in CC cells significantly inhibited their abilities of proliferation, migration and invasion in vitro. Besides, subcutaneous xenograft tumor model and xenograft mouse metastatic model respectively displayed that TRIM62 impeded the growth and metastasis of CC in vivo. Furthermore, mechanism study exhibited that TRIM62 could suppress epithelial-mesenchymal transition (EMT) by inhibiting c-Jun/Slug signaling. The inhibitory role of TRIM62 in tumor proliferation might be through regulating cell cycle related proteins CyclinD1 and P27 by targeting c-Jun.
Conclusion
TRIM62 is a potential prognostic biomarker in CC and suppresses metastasis of CC via inhibiting c-Jun/Slug signaling-mediated EMT.
Electronic supplementary material
The online version of this article (doi:10.1186/s13046-016-0445-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13046-016-0445-5
PMCID: PMC5084416  PMID: 27793172
Prognosis; Metastasis; EMT; MAPK; Slug
3.  Characteristics of Plasmonic Bragg Reflectors with Graphene-Based Silicon Grating 
We propose a plasmonic Bragg reflector (PBR) composed of a single-layer graphene-based silicon grating and numerically study its performance. An external voltage gating has been applied to graphene to tune its optical conductivity. It is demonstrated that SPP modes on graphene exhibit a stopband around the Bragg wavelengths. By introducing a nano-cavity into the PBR, a defect resonance mode is formed inside the stopband. We further design multi-defect PBR to adjust the characteristics of transmission spectrum. In addition, through patterning the PBR unit into multi-step structure, we lower the insertion loss and suppress the rippling in transmission spectra. The finite element method (FEM) has been utilized to perform the simulation work.
doi:10.1186/s11671-016-1633-0
PMCID: PMC5031573  PMID: 27654279
Plasmonics; Bragg reflectors; Graphene-based; FEM
4.  QiShenYiQi Attenuates Renal Interstitial Fibrosis by Blocking the Activation of β-Catenin 
PLoS ONE  2016;11(9):e0162873.
Chronic kidney disease (CKD) is becoming a worldwide problem. However, current treatment options are limited. In the current study we showed that QiShenYiQi (QSYQ), a water-ethanol extract from several Chinese medicines, is a potent inhibitor of renal interstitial fibrosis. QSYQ inhibited transforming growth factor-β1 (TGF-β1)-responsive α-smooth muscle actin (α-SMA), collagen I, and fibronectin up-regulation in obstructive nephropathy and cultured cells. Administration of QSYQ also inhibited the established renal interstitial fibrosis in obstructive nephropathy. Interestingly, QSYQ selectively inhibited TGF-β1-induced β-catenin up-regulation and downstream gene transcription. Taken together, our study suggests that QSYQ selectively inhibits TGF-β1-induced β-catenin up-regulation and might have significant therapeutic potential for the treatment of renal fibrosis.
doi:10.1371/journal.pone.0162873
PMCID: PMC5026381  PMID: 27636716
5.  The Cost Implications of Less Tight Versus Tight Control of Hypertension in Pregnancy (CHIPS Trial) 
Hypertension (Dallas, Tex. : 1979)  2016;68(4):1049-1055.
Supplemental Digital Content is available in the text.
The CHIPS randomized controlled trial (Control of Hypertension in Pregnancy Study) found no difference in the primary perinatal or secondary maternal outcomes between planned “less tight” (target diastolic 100 mm Hg) and “tight” (target diastolic 85 mm Hg) blood pressure management strategies among women with chronic or gestational hypertension. This study examined which of these management strategies is more or less costly from a third-party payer perspective. A total of 981 women with singleton pregnancies and nonsevere, nonproteinuric chronic or gestational hypertension were randomized at 14 to 33 weeks to less tight or tight control. Resources used were collected from 94 centers in 15 countries and costed as if the trial took place in each of 3 Canadian provinces as a cost-sensitivity analysis. Eleven hospital ward and 24 health service costs were obtained from a similar trial and provincial government health insurance schedules of medical benefits. The mean total cost per woman–infant dyad was higher in less tight versus tight control, but the difference in mean total cost (DM) was not statistically significant in any province: Ontario ($30 191.62 versus $24 469.06; DM $5723, 95% confidence interval, −$296 to $12 272; P=0.0725); British Columbia ($30 593.69 versus $24 776.51; DM $5817; 95% confidence interval, −$385 to $12 349; P=0.0725); or Alberta ($31 510.72 versus $25 510.49; DM $6000.23; 95% confidence interval, −$154 to $12 781; P=0.0637). Tight control may benefit women without increasing risk to neonates (as shown in the main CHIPS trial), without additional (and possibly lower) cost to the healthcare system.
Clinical Trial Registration—
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01192412.
doi:10.1161/HYPERTENSIONAHA.116.07466
PMCID: PMC5008043  PMID: 27550914
blood pressure; cost analysis; health policy; hypertension; pregnancy; randomized controlled trials
6.  Analysis of the Dynamic Sensitivity of Hemisphere-Shaped Electrostatic Sensors’ Circular Array for Charged Particle Monitoring 
Sensors (Basel, Switzerland)  2016;16(9):1403.
Electrostatic sensor arrays (ESAs) are promising in industrial applications related to charged particle monitoring. Sensitivity is a fundamental and commonly-used sensing characteristic of an ESA. However, the usually used spatial sensitivity, which is called static sensitivity here, is not proper for moving particles or capable of reflecting array signal processing algorithms integrated in an ESA. Besides, reports on ESAs for intermittent particles are scarce yet, especially lacking suitable array signal processing algorithms. To solve the problems, the dynamic sensitivity of ESA is proposed, and a hemisphere-shaped electrostatic sensors’ circular array (HSESCA) along with its application in intermittent particle monitoring are taken as an example. In detail, a sensing model of the HSESCA is built. On this basis, its array signals are analyzed; the dynamic sensitivity is thereupon defined by analyzing the processing of the array signals. Besides, a component extraction-based array signal processing algorithm for intermittent particles is proposed, and the corresponding dynamic sensitivity is analyzed quantitatively. Moreover, simulated and experimental results are discussed, which validate the accuracy of the models and the effectiveness of the relevant approaches. The proposed dynamic sensitivity of ESA, as well as the array signal processing algorithm are expected to provide references in modeling, designing and using ESAs.
doi:10.3390/s16091403
PMCID: PMC5038681  PMID: 27589767
electrostatic sensor array; dynamic sensitivity; hemisphere-shaped electrostatic sensor; circular array; array signal processing algorithm
7.  The Overlooked Fact: Fundamental Need for Spike-In Control for Virtually All Genome-Wide Analyses 
Molecular and Cellular Biology  2016;36(5):662-667.
Genome-wide analyses of changes in gene expression, transcription factor occupancy on DNA, histone modification patterns on chromatin, genomic copy number variation, and nucleosome positioning have become popular in many modern laboratories, yielding a wealth of information during health and disease states. However, most of these studies have overlooked an inherent normalization problem that must be corrected with spike-in controls. Here we describe the reason why spike-in controls are so important and explain how to appropriately design and use spike-in controls for normalization. We also suggest ways to retrospectively renormalize data sets that were wrongly interpreted due to omission of spike-in controls.
doi:10.1128/MCB.00970-14
PMCID: PMC4760223  PMID: 26711261
8.  Modeling Human Leukemia Immunotherapy in Humanized Mice 
EBioMedicine  2016;10:101-108.
The currently available human tumor xenograft models permit modeling of human cancers in vivo, but in immunocompromised hosts. Here we report a humanized mouse (hu-mouse) model made by transplantation of human fetal thymic tissue plus hematopoietic stem cells transduced with a leukemia-associated fusion gene MLL-AF9. In addition to normal human lymphohematopoietic reconstitution as seen in non-leukemic hu-mice, these hu-mice showed spontaneous development of B-cell acute lymphoblastic leukemia (B-ALL), which was transplantable to secondary recipients with an autologous human immune system. Using this model, we show that lymphopenia markedly improves the antitumor efficacy of recipient leukocyte infusion (RLI), a GVHD-free immunotherapy that induces antitumor responses in association with rejection of donor chimerism in mixed allogeneic chimeras. Our data demonstrate the potential of this leukemic hu-mouse model in modeling leukemia immunotherapy, and suggest that RLI may offer a safe treatment option for leukemia patients with severe lymphopenia.
Highlights
•NSG mice grafted with thymus/oncogenic HSC develop human immune system and leukemia.•Leukemia transfer to mice with autologous immunity suffices to model immunotherapy.•Lymphopenia enhances RLI-mediated HVGR and anti-leukemia activity in mixed chimeras.
This study establishes a humanized mouse model with human immunity and autologous leukemia. Using this model, the authors demonstrate that lymphopenia promotes the rejection of donor hematopoietic chimerism and the associated anti-leukemia response by recipient leukocyte infusion in mixed allogeneic chimeras.
doi:10.1016/j.ebiom.2016.06.028
PMCID: PMC5006579  PMID: 27394641
Humanized mice; Leukemia; Lymphopenia; Mixed-lineage leukemia fusion gene; Recipient leukocyte infusion
9.  Are Photosynthetic Characteristics and Energetic Cost Important Invasive Traits for Alien Sonneratia Species in South China? 
PLoS ONE  2016;11(6):e0157169.
A higher photosynthesis and lower energetic cost are recognized as important characteristics for invasive species, but whether these traits are also important for the ability of alien mangrove species to become invasive has seldom been reported. A microcosm study was conducted to compare the photosynthetic characteristics, energetic cost indices and other growth traits between two alien species (Sonneratia apetala and S. caseolaris) and four native mangrove species over four seasons in a subtropical mangrove nature reserve in Shenzhen, South China. The aim of the study was to evaluate the invasive potential of Sonneratia based on these physiological responses. The annual average net photosynthetic rate (Pn), stomatal conductance (Gs) and total carbon assimilation per unit leaf area (Atotal) of the two alien Sonneratia species were significantly higher than the values of the native mangroves. In contrast, the opposite results were obtained for the leaf construction cost (CC) per unit dry mass (CCM) and CC per unit area (CCA) values. The higher Atotal and lower CC values resulted in a 72% higher photosynthetic energy-use efficiency (PEUE) for Sonneratia compared to native mangroves, leading to a higher relative growth rate (RGR) of the biomass and height of Sonneratia with the respective values being 51% and 119% higher than those of the native species. Higher photosynthetic indices for Sonneratia compared to native species were found in all seasons except winter, whereas lower CC values were found in all four seasons. The present findings reveal that alien Sonneratia species may adapt well and become invasive in subtropical mangrove wetlands in Shenzhen due to their higher photosynthetic characteristics coupled with lower costs in energy use, leading to a higher PEUE. The comparison of these physiological responses between S. apetala and S. caseolaris reveal that the former species is more invasive than the latter one, thus requiring more attention in future.
doi:10.1371/journal.pone.0157169
PMCID: PMC4902315  PMID: 27286250
10.  Detuned Plasmonic Bragg Grating Sensor Based on a Defect Metal-Insulator-Metal Waveguide 
A nanoscale Bragg grating reflector based on the defect metal-insulator-metal (MIM) waveguide is developed and numerically simulated by using the finite element method (FEM). The MIM-based structure promises a highly tunable broad stop-band in transmission spectra. The narrow transmission window is shown to appear in the previous stop-band by changing the certain geometrical parameters. The central wavelengths can be controlled easily by altering the geographical parameters. The development of surface plasmon polarition (SPP) technology in metallic waveguide structures leads to more possibilities of controlling light at deep sub-wavelengths. Its attractive ability of breaking the diffraction limit contributes to the design of optical sensors.
doi:10.3390/s16060784
PMCID: PMC4934210  PMID: 27240381
plasmonics; Bragg grating sensor; metal-insulator-metal; finite element method
11.  The comparisons of phenotype and genotype between CADASIL and CADASIL-like patients and population-specific evaluation of CADASIL scale in China 
Background
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of hereditary stroke disorder caused by mutations in the NOTCH3 gene. Although CADASIL scale is a widely used tool to screen clinically suspected CADASIL patients, the differential effects of this scale in various populations remain unknown.
Methods
92 CADASIL-like patients and 24 CADASIL patients were selected based on CADASIL scale and gene tests. The clinical, genetic and radiological characteristics were analyzed.
Results
Based on the CADASIL scale, we first screened 116 suspected CADASIL patients, and detected 20 mutations in 24 CADASIL-patients (Specificity: 20.69 %). Surprisingly, we found that transient ischemic attack/stroke, migraine, cognitive decline, psychiatric disturbances and early onset age in CADASIL scale showed no differences between the CADASIL and the CADASIL-like patients (p > 0.05). Instead, recurrent cerebral ischemic events (58.33 %, p = 0.028) and positive family histories (p < 0.05) were more frequently observed in CADASIL patients. Moreover, compared with CADASIL-like patients (21.74 %), CADASIL patients demonstrated higher percentage of temporal pole involvements (58.33 %, p = 0.001), but not the external capsule involvements (66.67 %, p = 0.602), in MRI imaging. Further, we found that vascular risk factors could occur in both CADASIL patients and CADASIL-like patients, and therefore could not be used as the markers to differentiate the two groups in our study (p > 0.05). By performing DSA analysis, we for the first time identified dysplasia of cerebral blood vessels in CADASIL patients, which were detected more frequently in CADASIL patients (41.67 %) in comparison with CADASIL-like patients (8.69 %, p <0.01).
Conclusion
Our data suggested that the efficacy of CADASIL scale to diagnose the disease varied with specific populations. Recurrent cerebral ischemic events, temporal pole involvements (but not the external capsule) in MRI imaging and dysplasia of cerebral blood vessels in DSA may be the new potential risk factors of the CADASIL scale suitable for Chinese patients. Gene testing by encephalopathy gene panel is expected to improve the accuracy of CADASIL differential diagnosis and increase the understanding of this disease in the future.
doi:10.1186/s10194-016-0646-5
PMCID: PMC4875019  PMID: 27206574
CADASIL; Small vessel disease; Phenotype; Genotype; CADASIL scale
12.  Synergistic strengthening effect of nanocrystalline copper reinforced with carbon nanotubes 
Scientific Reports  2016;6:26258.
In this study, a novel multi-walled carbon nanotubes reinforced nanocrystalline copper matrix composite with super high strength and moderate plasticity was synthesized. We successfully overcome the agglomeration problem of the carbon nanotubes and the grain growth problem of the nanocrystalline copper matrix by combined use of the electroless deposition and spark plasma sintering methods. The yield strength of the composite reach up to 692 MPa, which is increased by 2 and 5 times comparing with those of the nanocrystalline and coarse copper, respectively. Simultaneously, the plasticity of the composite was also significantly increased in contrast with that of the nanocrystalline copper. The increase of the density of the carbon nanotubes after coating, the isolation effect caused by the copper coating, and the improvement of the compatibility between the reinforcements and matrix as well as the effective control of the grain growth of the copper matrix all contribute to improving the mechanical properties of the composite. In addition, a new strengthening mechanism, i.e., the series-connection effect of the nanocrystalline copper grains introduced by carbon nanotubes, is proposed to further explain the mechanical behavior of the nanocomposite.
doi:10.1038/srep26258
PMCID: PMC4869099  PMID: 27185503
13.  Enhancement of anti-tumor effects of 5-fluorouracil on hepatocellular carcinoma by low-intensity ultrasound 
Background
Hepatocellular carcinoma (HCC) accounts for 75 % of liver cancers and is the second most lethal cancer, associated with its multiple etiologies, poor prognosis and resistance to chemotherapy drugs. Chemotherapy treatment on HCC suffers low efficacy of drug uptake and can produce a range of side effects. Here we report an investigation on the effect of a combined treatment on human hepatocellular carcinoma BEL-7402 cells using low-intensity ultrasound (US) and 5-fluorouracil (5-FU).
Methods
The uptake of 5-FU was measured by the high-performance liquid chromatography (HPLC). DNA damage was detected by the comet assay. MTT assay was used to examine cell viability. Intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (Δψm) were respectively detected by the fluorescent probes DCFH-DA or JC-1. Endogenous apoptosis-associated proteins were analyzed by the western blot and immunohistochemistry. Histopathological changes were evaluated by the hematoxylin and eosin (H&E) staining. Cell apoptosis was evaluated by the TUNEL and flow cytometry assays. Cell proliferation was measured using the immunohistochemical staining of PCNA.
Results
Our results showed that low-intensity US (1.1 MHz, 1.0 W/cm2, 10 % duty cycle) significantly enhanced the uptake of 5-FU, 5-FU-mediated DNA damage and reactive oxygen species (ROS) generation. The increased ROS production up-regulated the p53 protein level, which led to the up-regulation of Bax and down-regulation of Bcl-2. The enhancement of ROS generation and the activation of the apoptosis-associated proteins further triggered the collapse of mitochondrial membrane potential, released cytochrome c from mitochondria into cytosol and activated the mitochondria-caspase pathway, and cell apoptosis. Such enhanced effects could be partially blocked by the ROS scavenger N-acetylcysteine (NAC). Overall, low-intensity US combined with 5-FU led to an effective inhibition of tumor growth and prolonged overall survival of BEL-7402 HCC-bearing nude mice by more than 15 % compared with 5-FU treatment alone.
Conclusions
Our results showed that low-intensity ultrasound combined with 5-FU produced much enhanced synergistic anti-tumor effects via enhanced ROS production in treating HCC.
Electronic supplementary material
The online version of this article (doi:10.1186/s13046-016-0349-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s13046-016-0349-4
PMCID: PMC4840943  PMID: 27102814
Low-intensity ultrasound; 5-fluorouracil; Anti-tumor effects; Hepatocellular carcinoma; Reactive oxygen species
14.  Low expression of Aldo–keto reductase 1B10 is a novel independent prognostic indicator for nasopharyngeal carcinoma 
Cell & Bioscience  2016;6:18.
Background
Nasopharyngeal carcinoma (NPC) is one of the most common human head and neck cancers with high incidence in Southern China, Southeast Asia and North Africa. Because of its nonspecific symptoms, the early diagnosis of NPC is very difficult. The 5-year survival rate is not ideal in spite of great innovations in radiation and chemotherapy treatments. Highly sensitive and specific prognostic biomarkers are eager for NPC clinical diagnosis. To find specific target molecules is very important for individualized treatment. Aldo–keto reductase B10 (AKR1B10) is closely related to tumorigenesis and tumor development, and however, its expression level in NPC tissues is not clear.
Results
AKR1B10 expression levels were validated in benign, para-cancerous nasopharyngeal and NPC tissues by immunohistochemical evaluation. AKR1B10 was positively expressed in 42 (82.4 %) of 51 benign specimens, and 235 (98.7 %) of 238 para-carcinoma specimens. This percentage was significantly higher than 44.5 % (133/299) in nasopharyngeal carcinoma tissue (p < 0.01). AKR1B10 mRNA quantitative levels detected by real-time quantitative RT-PCR in 90 NPC tissue samples (0.10 ± 0.21) were significantly lower than that in 15 benign tissue samples (1.03 ± 1.12) (p < 0.01). AKR1B10 expression levels in NPC were correlated negatively with T-classification, lymph node metastasis (p < 0.05). We established nasopharyngeal cancer monoclonal cells CNE-2/AKR1B10 with AKR1B10 stable expression and CNE-2/vector cells without AKR1B10 expression by using a modified lentivirus-mediated method, and found that AKR1B10 inhibited the proliferation of CNE-2/AKR1B10 cells by using MTT assay and flow cytometry, and cell migration by in vitro scratch test.
Conclusion
Taken together, our data suggest that low expression of AKR1B10 is an independent prognostic indicator in nasopharyngeal carcinoma, and that AKR1B10 may be involved in regulating the proliferation and migration of nasopharyngeal cancer cells.
doi:10.1186/s13578-016-0082-x
PMCID: PMC4779195  PMID: 26949513
AKR1B10; Nasopharyngeal carcinoma; Metastasis; Prognostic marker; Low expression
15.  miR‐222 attenuates cisplatin‐induced cell death by targeting the PPP2R2A/Akt/mTOR Axis in bladder cancer cells 
Abstract
Increased miR‐222 levels are associated with a poor prognosis in patients with bladder cancer. However, the role of miR‐222 remains unclear. In the present study, we found that miR‐222 enhanced the proliferation of both the T24 and the 5637 bladder cancer cell lines. Overexpression of miR‐222 attenuated cisplatin‐induced cell death in bladder cancer cells. miR‐222 activated the Akt/mTOR pathway and inhibited cisplatin‐induced autophagy in bladder cancer cells by directly targeting protein phosphatase 2A subunit B (PPP2R2A). Blocking the activation of Akt with LY294002 or mTOR with rapamycin significantly prevented miR‐222‐induced proliferation and restored the sensitivity of bladder cancer cells to cisplatin. These findings demonstrate that miR‐222 modulates the PPP2R2A/Akt/mTOR axis and thus plays a critical role in regulating proliferation and chemotherapeutic drug resistance. Therefore, miR‐222 may be a novel therapeutic target for bladder cancer.
doi:10.1111/jcmm.12760
PMCID: PMC4759461  PMID: 26800397
microRNA‐222; bladder cancer; cisplatin
16.  saRNA-guided Ago2 targets the RITA complex to promoters to stimulate transcription 
Cell Research  2016;26(3):320-335.
Small activating RNAs (saRNAs) targeting specific promoter regions are able to stimulate gene expression at the transcriptional level, a phenomenon known as RNA activation (RNAa). It is known that RNAa depends on Ago2 and is associated with epigenetic changes at the target promoters. However, the precise molecular mechanism of RNAa remains elusive. Using human CDKN1A (p21) as a model gene, we characterized the molecular nature of RNAa. We show that saRNAs guide Ago2 to and associate with target promoters. saRNA-loaded Ago2 facilitates the assembly of an RNA-induced transcriptional activation (RITA) complex, which, in addition to saRNA-Ago2 complex, includes RHA and CTR9, the latter being a component of the PAF1 complex. RITA interacts with RNA polymerase II to stimulate transcription initiation and productive elongation, accompanied by monoubiquitination of histone 2B. Our results establish the existence of a cellular RNA-guided genome-targeting and transcriptional activation mechanism and provide important new mechanistic insights into the RNAa process.
doi:10.1038/cr.2016.22
PMCID: PMC4783471  PMID: 26902284
RNAa; promoter; transcription; RNAP II; Argonaute; Ago2; saRNA; promoter-targeted RNA; RITA
17.  Human melanoma immunotherapy using tumor antigen-specific T cells generated in humanized mice 
Oncotarget  2016;7(6):6448-6459.
A major factor hindering the exploration of adoptive immunotherapy in preclinical settings is the limited availability of tumor-reactive human T cells. Here we developed a humanized mouse model that permits large-scale production of human T cells expressing the engineered melanoma antigen MART-1-specific TCR. Humanized mice, made by transplantation of human fetal thymic tissue and CD34+ cells virally-transduced with HLA class I-restricted melanoma antigen (MART-1)-specific TCR gene, showed efficient development of MART-1-TCR+ human T cells with predominantly CD8+ cells. Importantly, MART-1-TCR+CD8+ T cells developing in these mice were capable of mounting antigen-specific responses in vivo, as evidenced by their proliferation, phenotypic conversion and IFN-γ production following MART-1 peptide immunization. Moreover, these MART-1-TCR+CD8+ T cells mediated efficient killing of melanoma cells in an HLA/antigen-dependent manner. Adoptive transfer of in vitro expanded MART-1-TCR+CD8+ T cells induced potent antitumor responses that were further enhanced by IL-15 treatment in melanoma-bearing recipients. Finally, a short incubation of MART-1-specific T cells with rapamycin acted synergistically with IL-15, leading to significantly improved tumor-free survival in recipients with metastatic melanoma. These data demonstrate the practicality of using humanized mice to produce potentially unlimited source of tumor-specific human T cells for experimental and preclinical exploration of cancer immunotherapy. This study also suggests that pretreatment of tumor-reactive T cells with rapamycin in combination with IL-15 administration may be a novel strategy to improve the efficacy of adoptive T cell therapy.
doi:10.18632/oncotarget.7044
PMCID: PMC4872726  PMID: 26824989
animal model; immunotherapy; melanoma; TCR; T cells; Immunology and Microbiology Section; Immune response; Immunity
18.  Structural Abnormalities in Childhood Absence Epilepsy: Voxel-Based Analysis Using Diffusion Tensor Imaging 
Purpose: Childhood absence epilepsy (CAE) is a common syndrome of idiopathic generalized epilepsy. However, little is known about the brain structural changes in this type of epilepsy, especially in the default mode network (DMN) regions. This study aims at using the diffusion tensor imaging (DTI) technique to quantify structural abnormalities of DMN nodes in CAE patients.
Method: DTI data were acquired in 14 CAE patients (aged 8.64 ± 2.59 years, seven females and seven males) and 16 age- and sex-matched healthy controls. The data were analyzed using voxel-based analysis (VBA) and statistically compared between patients and controls. Pearson correlation was explored between altered DTI metrics and clinical parameters. The difference of brain volumes between patients and controls were also tested using unpaired t-test.
Results: Patients showed significant increase of mean diffusivity (MD) and radial diffusivity (RD) in left medial prefrontal cortex (MPFC), and decrease of fractional anisotropy (FA) in left precuneus and axial diffusivity (AD) in both left MPFC and precuneus. In correlation analysis, MD value from left MPFC was positively associated with duration of epilepsy. Neither the disease duration nor the seizure frequency showed significant correlation with FA values. Between-group comparison of brain volumes got no significant difference.
Conclusion: The findings indicate that structural impairments exist in DMN regions in children suffering from absence epilepsy and MD values positively correlate with epilepsy duration. This may contribute to understanding the pathological mechanisms of chronic neurological deficits and promote the development of new therapies for this disorder.
doi:10.3389/fnhum.2016.00483
PMCID: PMC5039196  PMID: 27733824
childhood absence epilepsy; diffusion tensor imaging; voxel-based analysis; default mode network; structural impairment
19.  TALENs-mediated gene disruption of FLT3 in leukemia cells: Using genome-editing approach for exploring the molecular basis of gene abnormality 
Scientific Reports  2015;5:18454.
Novel analytic tools are needed to elucidate the molecular basis of leukemia-relevant gene mutations in the post-genome era. We generated isogenic leukemia cell clones in which the FLT3 gene was disrupted in a single allele using TALENs. Isogenic clones with mono-allelic disrupted FLT3 were compared to an isogenic wild-type control clone and parental leukemia cells for transcriptional expression, downstream FLT3 signaling and proliferation capacity. The global gene expression profiles of mutant K562 clones and corresponding wild-type controls were compared using RNA-seq. The transcriptional levels and the ligand-dependent autophosphorylation of FLT3 were decreased in the mutant clones. TALENs-mediated FLT3 haplo-insufficiency impaired cell proliferation and colony formation in vitro. These inhibitory effects were maintained in vivo, improving the survival of NOD/SCID mice transplanted with mutant K562 clones. Cluster analysis revealed that the gene expression pattern of isogenic clones was determined by the FLT3 mutant status rather than the deviation among individual isogenic clones. Differentially expressed genes between the mutant and wild-type clones revealed an activation of nonsense-mediated decay pathway in mutant K562 clones as well as an inhibited FLT3 signaling. Our data support that this genome-editing approach is a robust and generally applicable platform to explore the molecular bases of gene mutations.
doi:10.1038/srep18454
PMCID: PMC4680874  PMID: 26669855
20.  PLK2 phosphorylates and inhibits enriched TAp73 in human osteosarcoma cells 
Cancer Medicine  2015;5(1):74-87.
Abstract
TAp73, a member of the p53 tumor suppressor family, can substitute for p53 function, especially in p53‐null and p53‐mutant cells. However, TAp73 enrichment and phosphorylation change its transcriptional activity. Previously, we found that the antitumor function of TAp73 was reactivated by dephosphorylation. Polo‐like kinase 2 (PLK2) plays an important role in bone development. Using a biological information database and phosphorylation prediction software, we hypothesized that PLK2 phosphorylates TAp73 and inhibits TAp73 function in osteosarcomas. Actually,we determined that PLK2 physically binds to and phosphorylates TAp73 when TAp73 protein abundance is up‐regulated by cisplatin. PLK2‐phosphorylated TAp73 at residue Ser48 within the TA domain; phosphorylation of TAp73 was abolished by mutating this residue. Moreover, PLK2 inhibition combined with cisplatin treatment in osteosarcoma Saos2 cells up‐regulated p21 and puma mRNA expression to a greater extent than cisplatin treatment alone. Inhibiting PLK2 in TAp73‐enriched Saos2 cells resulted in inhibited cell proliferation, increased apoptosis, G1 phase arrest, and decreased cell invasion. However, these changes did not occur in TAp73 knockdown Saos2 cells. In conclusion, these findings reveal a novel PLK2 function in the phosphorylation of TAp73, which prevents TAp73 activity in osteosarcoma cells. Thereby, this research provides an insight into the clinical treatment of malignant tumors overexpressing TAp73.
doi:10.1002/cam4.558
PMCID: PMC4708894  PMID: 26625870
Antitumor; cisplatin; phosphorylation; PLK2; TAp73
21.  Through-Metal-Wall Power Delivery and Data Transmission for Enclosed Sensors: A Review 
Sensors (Basel, Switzerland)  2015;15(12):31581-31605.
The aim of this review was to assess the current viable technologies for wireless power delivery and data transmission through metal barriers. Using such technologies sensors enclosed in hermetical metal containers can be powered and communicate through exterior power sources without penetration of the metal wall for wire feed-throughs. In this review, we first discuss the significant and essential requirements for through-metal-wall power delivery and data transmission and then we: (1) describe three electromagnetic coupling based techniques reported in the literature, which include inductive coupling, capacitive coupling, and magnetic resonance coupling; (2) present a detailed review of wireless ultrasonic through-metal-wall power delivery and/or data transmission methods; (3) compare various ultrasonic through-metal-wall systems in modeling, transducer configuration and communication mode with sensors; (4) summarize the characteristics of electromagnetic-based and ultrasound-based systems, evaluate the challenges and development trends. We conclude that electromagnetic coupling methods are suitable for through thin non-ferromagnetic metal wall power delivery and data transmission at a relatively low data rate; piezoelectric transducer-based ultrasonic systems are particularly advantageous in achieving high power transfer efficiency and high data rates; the combination of more than one single technique may provide a more practical and reliable solution for long term operation.
doi:10.3390/s151229870
PMCID: PMC4721790  PMID: 26694392
through metal wall; power delivery; data transmission; metallic enclosed sensors
22.  Effects of a novel magnetic orthopedic appliance (MOA-III) on the dentofacial complex in mild to moderate skeletal class III children 
Head & Face Medicine  2015;11:34.
Introduction
The objective of this study was to evaluate the changes of skeletal and dental structures in mild to moderate skeletal Class III children following the use of a new magnetic orthopedic appliance (MOA-III).
Methods
A total of 36 patients (14 boys and 22 girls, mean age 9 years and 5 months) who presented with a mild to moderate skeletal Class III jaw discrepancy were treated with MOA-III. Another group of 20 untreated patients (9 boys and 11 girls, mean age 9 years and 2 months) with the same level of deformity served as the control group. The average treatment time was 6.6 months. Radiographs were taken at the same time intervals for both groups. A paired t test was used to determine the significant differences before and after treatment, and a two-sample t test was used to analyze the differences between the treatment and control groups.
Results
The anterior crossbite in all subjects was corrected after MOA-III therapy. The maxillomandibular relationship showed favorable changes (ANB, Wits, overjet increased significantly, P < 0.001). The maxilla was anteriorly positioned (SNA, ptm-A, ptm-S increased significantly, P < 0.001) with clockwise rotation (PP-FH increased, P < 0.001). The mandible showed a slight downward and backward rotation (SNB decreased, P < 0.05, MP-SN, Y-axis increased, P < 0.05). The length of the mandibular body showed no significant changes (Go-Pg, P > 0.05). Significant upper incisor proclination and lower incisor retroclination were observed (UI-NA increased, P < 0.001, LI-NB, FMIA decreased, P < 0.001). The upper lip moved forward, and the lower lip moved backward (UL-EP increased, P < 0.001, LL-EP decreased, P < 0.05). In the control group, most of the parameters showed normal growth, except for some unfavorable mandibular skeletal and soft tissue changes (Go-Pg, Go-Co, MP-SN, N′-SN-Pg′ increased, P < 0.001). Significant positive changes were induced with the MOA-III appliance compared to the untreated group.
Conclusions
The MOA-III was effective for the early treatment of a mild to moderate Class III malocclusion in children.
doi:10.1186/s13005-015-0092-7
PMCID: PMC4606506  PMID: 26468063
Magnetic; Twin-block; Angle Class III; Adolescent
23.  Optimal Sequential Diagnostic Strategy Generation Considering Test Placement Cost for Multimode Systems 
Sensors (Basel, Switzerland)  2015;15(10):25592-25606.
Sequential fault diagnosis is an approach that realizes fault isolation by executing the optimal test step by step. The strategy used, i.e., the sequential diagnostic strategy, has great influence on diagnostic accuracy and cost. Optimal sequential diagnostic strategy generation is an important step in the process of diagnosis system construction, which has been studied extensively in the literature. However, previous algorithms either are designed for single mode systems or do not consider test placement cost. They are not suitable to solve the sequential diagnostic strategy generation problem considering test placement cost for multimode systems. Therefore, this problem is studied in this paper. A formulation is presented. Two algorithms are proposed, one of which is realized by system transformation and the other is newly designed. Extensive simulations are carried out to test the effectiveness of the algorithms. A real-world system is also presented. All the results show that both of them have the ability to solve the diagnostic strategy generation problem, and they have different characteristics.
doi:10.3390/s151025592
PMCID: PMC4634445  PMID: 26457709
diagnostic strategy; sequential fault diagnosis; AND/OR graph; multimode system
24.  Phase diagram and spin mixing dynamics in spinor condensates with a microwave dressing field 
Scientific Reports  2015;5:14464.
Spinor condensates immersed in a microwave dressing field, which access both negative and positive values of the net quadratic Zeeman effect, have been realized in a recent experiment. In this report, we study the ground state properties of a spinor condensate with a microwave dressing field which enables us to access both negative and positive values of quadratic Zeeman energy. The ground state exhibits three different phases by varying the magnetization and the net quadratic Zeeman energy for both cases of ferromagnetic and antiferromagnetic interactions. We investigate the atomic-number fluctuations of the ground state and show that the hyperfine state displays super-Poissonian and sub-Poissonian distributions in the different phases. We also discuss the dynamical properties and show that the separatrix has a remarkable relation to the magnetization.
doi:10.1038/srep14464
PMCID: PMC4585920  PMID: 26403676
25.  5-Aminolevulinic Acid-Based Sonodynamic Therapy Induces the Apoptosis of Osteosarcoma in Mice 
PLoS ONE  2015;10(7):e0132074.
Objective
Sonodynamic therapy (SDT) is promising for treatment of cancer, but its effect on osteosarcoma is unclear. This study examined the effect of 5-Aminolevulinic Acid (5-ALA)-based SDT on the growth of implanted osteosarcoma and their potential mechanisms in vivo and in vitro.
Methods
The dose and metabolism of 5-ALA and ultrasound periods were optimized in a mouse model of induced osteosarcoma and in UMR-106 cells. The effects of ALA-SDT on the proliferation and apoptosis of UMR-106 cells and the growth of implanted osteosarcoma were examined. The levels of mitochondrial membrane potential (ΔψM), ROS production, BcL-2, Bax, p53 and caspase 3 expression in UMR-106 cells were determined.
Results
Treatment with 5-ALA for eight hours was optimal for ALA-SDT in the mouse tumor model and treatment with 2 mM 5-ALA for 6 hours and ultrasound (1.0 MHz 2.0 W/cm2) for 7 min were optimal for UMR-106 cells. SDT, but not 5-ALA, alone inhibited the growth of implanted osteosarcoma in mice (P<0.01) and reduced the viability of UMR-106 cells (p<0.05). ALA-SDT further reduced the tumor volumes and viability of UMR-106 cells (p<0.01 for both). Pre-treatment with 5-ALA significantly enhanced the SDT-mediated apoptosis (p<0.01) and morphological changes. Furthermore, ALA-SDT significantly reduced the levels of ΔψM, but increased levels of ROS in UMR-106 cells (p<0.05 or p<0.01 vs. the Control or the Ultrasound). Moreover, ALA-SDT inhibited the proliferation of osteosarcoma cells and BcL-2 expression, but increased levels of Bax, p53 and caspase 3 expression in the implanted osteosarcoma tissues (p<0.05 or p<0.01 vs. the Control or the Ultrasound).
Conclusions
The ALA-SDT significantly inhibited osteosarcoma growth in vivo and reduced UMR-106 cell survival by inducing osteosarcoma cell apoptosis through the ROS-related mitochondrial pathway.
doi:10.1371/journal.pone.0132074
PMCID: PMC4498784  PMID: 26161801

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