Publications by authors named "Lingyun Xu"

58 Publications

Gold Nanoclusters for NIR-II Fluorescence Imaging of Bones.

Small 2020 10 30;16(43):e2003851. Epub 2020 Sep 30.

Molecular Imaging Program at Stanford (MIPS), Bio-X Program, and Department of Radiology, Stanford University, Palo Alto, CA, 94305, USA.

Fluorescence imaging in the second near-infrared window (NIR-II, 1000-1700 nm) holds great promise for deep tissue visualization. Development of novel clinical translatable NIR-II probes is crucial for realizing the medical applications of NIR-II fluorescence imaging. Herein, the glutathione-capped gold nanoclusters (AuNCs, specifically Au (SG) ) demonstrate highly efficient binding capability to hydroxyapatite in vitro for the first time. Further in vivo NIR-II fluorescence imaging of AuNCs indicate that they accumulate in bone tissues with high contrast and signal-background ratio. AuNCs are also mainly and quickly excreted from body through renal system, showing excellent ribs and thoracic vertebra imaging because of no background signal in liver and spleen. The deep tissue penetration capability and high resolution of AuNCs in NIR-II imaging render their great potential for fluorescence-guided surgery like spinal pedicle screw implantation. Overall, AuNCs are highly promising and clinical translatable NIR-II imaging probe for visualizing bone and bone related abnormalities.
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http://dx.doi.org/10.1002/smll.202003851DOI Listing
October 2020

Downregulation of microRNA-30c-5p was responsible for cell migration and tumor metastasis via COTL1-mediated microfilament arrangement in breast cancer.

Gland Surg 2020 Jun;9(3):747-758

Changzhou No. 2 People's Hospital, Xinglong Lance, Changzhou, China.

Background: Breast cancer metastasis is the main problem that affects the therapy and prognosis of breast cancer patients. Studies have indicated the role of microRNAs in breast cancer regulation, but the mechanisms are largely unknown.

Methods: In this study, we determined the expression of microRNA-30c-5p (miR-30c-5p) and coactosin-like protein 1 () gene in breast cancer tissues, and revealed their effects on breast cancer metastasis regulation. Breast cancer and paracancerous tissues were collected. Reverse transcriptase polymerase chain reaction RT-PCR) was used to analyze the expression of miR-30c-5p and , and breast cancer cell line (MCF-7) was employed to verify the relationship between miR-30c-5p and COTL1. Western blot analysis and immunofluorescence were used for proteins analysis and microfilament observation, respectively. A dual-luciferase reporter gene was used for microRNA-gene interaction assay.

Results: The results showed that the expression of miR-30c-5p decreased, while the expression of COTL1 increased in breast cancer tissues. The results of luciferase reporting gene assay showed that, COTL1 was the target of miR-30c-5p. After miR-30c-5p was upregulated, the expression of COTL1 was reduced, microfilament arrangement was in disorder, and cell migration ability was inhibited. After miR-30c-5p was downregulated, the expression of COTL1 was increased, and the cell migration ability was enhanced. COTL1 protein expression levels were significantly higher in cancer tissues with lymph node metastasis.

Conclusions: These findings indicate that miR-30c-5p/COTL1 pathway regulates breast cancer metastasis and can be used as a potential therapy target.
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http://dx.doi.org/10.21037/gs-20-472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347814PMC
June 2020

Formation of formaldehyde as an artifact peak in head space GC analysis resulting from decomposition of sample diluent DMSO: A GC-MS investigation with deuterated DMSO.

J Pharm Biomed Anal 2020 Sep 24;188:113361. Epub 2020 May 24.

Center of Excellence for Modern Analytical Technologies (CEMAT), Huahai Pharmaceutical Co., Ltd, Xunqiao, Linhai, Zhejiang, 317024, China; Huahai US, Inc., 700 Atrium Drive, Somerset, NJ 08873, USA. Electronic address:

During our method development for residual formaldehyde detection in a drug substance, unusually high levels of formaldehyde were detected when using a mixed solvent of EtOH/DMSO (4:1, v/v) as sample diluent in headspace GC analysis (HS-GC). Initial investigation found that formaldehyde is used in the preparation for one of the starting materials of the drug substance. Nevertheless, there is neither other source of formaldehyde in the manufacturing process of the drug substance, nor would formaldehyde be generated during the process. In the ensuing root cause investigation, it was found that once the solvent DMSO is replaced by other solvent [e.g., N,N-dimethylformamide (DMF)], while keeping other method parameters unchanged in the HS-GC analysis, the level of formaldehyde in the same batch of the drug substance became undetectable (LOD: 3 ppm). All the evidence suggested that the observed formaldehyde in the HS-GC analysis might be due to the decomposition of DMSO, which could be facilitated by the presence of this particular drug substance. In other words, the presence of the drug substance (in the form of HCl salt) would cause a minor decomposition of DMSO to produce formaldehyde. To prove this hypothesis, a GC-MS experiment of the drug substance was conducted in which deuterated DMSO (DMSO-) was used in place of regular DMSO; the expected deuterated derivatization product, i.e., diethoxymethane- (CHOCDOCH), was observed in the HS-GC-MS analysis. Therefore, it became clear that this drug substance facilitates the minor decomposition of DMSO in the HS-GC analysis. In such a case, formaldehyde is an artifact peak, or ghost peak, rather than a true impurity of the drug substance. The false positive results of formaldehyde were also found in other four compounds (three drug substances and one reagent) which are all in the form of HCl or HBr salts, suggesting that generation of formaldehyde from DMSO could be a widely occurred phenomenon in HS-GC analysis of alkyl amines in the form of HCl or HBr salts, when DMSO-containing diluents are used during sample preparation.
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http://dx.doi.org/10.1016/j.jpba.2020.113361DOI Listing
September 2020

The role of titanium-deficient anatase TiO interlayers in boosting lithium-sulfur battery performance: polysulfide trapping, catalysis and enhanced lithium ion transport.

Nanoscale 2020 Feb;12(7):4645-4654

School of Resource and Environmental Sciences, Wuhan University, Wuhan 430072, China. and Shenzhen Research Institute, Wuhan University, Building 403, Hi-tech Park, Nanshan, Shenzhen, 518057, China.

Despite the high theoretical energy density, lithium-sulfur (Li-S) batteries are currently facing two major problems, i.e., the shuttle of polysulfides and sluggish redox kinetics. Recent research has shown that electrocatalysts such as Pt and CoS2 can catalyze the polysulfide redox reaction and hence improve the kinetics and cycle performance of Li-S batteries. The current work demonstrates that a cheaper, lightweight and green alternative, i.e., titanium-deficient anatase TiO2 (TDAT) not only possesses a strong lithium polysulfide (LiPS) trapping ability via chemical interactions but also catalyzes the sulfur-sulfide redox reaction. Moreover, the TDAT-PE separator also shows high lithium conductivity, fast lithium diffusion, and facile lithium transference. As a result, the Li-S batteries with the TDAT modified PE interlayer show markedly higher sulfur utilization and capacity, rate and cycle performances. An average capacity fading of only 0.025% per cycle is achieved during the 1000 cycle durability test. This work presents a commercially viable, multifunctional interlayer capable of boosting the performance of Li-S batteries.
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http://dx.doi.org/10.1039/c9nr10349jDOI Listing
February 2020

Targeting Forward and Reverse EphB4/EFNB2 Signaling by a Peptide with Dual Functions.

Sci Rep 2020 01 16;10(1):520. Epub 2020 Jan 16.

Departments of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas, 77054, United States.

The tyrosine kinase receptor EphB4 is frequently overexpressed in ovarian and other solid tumors and is involved in interactions between tumor cells and the tumor microenvironment, contributing to metastasis. Trans-interaction between EphB4 and its membrane-bound ligand ephrin B2 (EFNB2) mediates bi-directional signaling: forward EFNB2-to-EphB4 signaling suppresses tumor cell proliferation, while reverse EphB4-to-EFNB2 signaling stimulates the invasive and angiogenic properties of endothelial cells. Currently, no small molecule-based, dual-function, EphB4-binding peptides are available. Here, we report our discovery of a bi-directional ephrin agonist peptide, BIDEN-AP which, when selectively internalized via receptor-mediated endocytosis, suppressed invasion and epithelial-mesenchymal transition of ovarian cancer cells. BIDEN-AP also inhibited endothelial migration and tube formation. In vivo, BIDEN-AP and its nanoconjugate CCPM-BIDEN-AP significantly reduced growth of orthotopic ovarian tumors, with CCPM-BIDEN-AP displaying greater antitumor potency than BIDEN-AP. Both BIDEN-AP and CCPM-BIDEN-AP compromised angiogenesis by downregulating epithelial-mesenchymal transition and angiogenic pathways. Thus, we report a novel EphB4-based therapeutic approach against ovarian cancer.
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http://dx.doi.org/10.1038/s41598-020-57477-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965176PMC
January 2020

Improved detection of prostate cancer using a magneto-nanosensor assay for serum circulating autoantibodies.

PLoS One 2019 12;14(8):e0221051. Epub 2019 Aug 12.

Department of Radiology, Molecular Imaging Program at Stanford, Bio-X Program, Stanford University School of Medicine, Stanford, California, United States of America.

Purpose: To develop a magneto-nanosensor (MNS) based multiplex assay to measure protein and autoantibody biomarkers from human serum for prostate cancer (CaP) diagnosis.

Materials And Methods: A 4-panel MNS autoantibody assay and a MNS protein assay were developed and optimized in our labs. Using these assays, serum concentration of six biomarkers including prostate-specific antigen (PSA) protein, free/total PSA ratio, as well as four autoantibodies against Parkinson disease 7 (PARK7), TAR DNA-binding protein 43 (TARDBP), Talin 1 (TLN1), and Caldesmon 1 (CALD1) and were analyzed. Human serum samples from 99 patients (50 with non-cancer and 49 with clinically localized CaP) were evaluated.

Results: The MNS assay showed excellent performance characteristics and no cross-reactivity. All autoantibody assays showed a statistically significant difference between CaP and non-cancer samples except for PARK7. The most significant difference was the combination of the four autoantibodies as a panel in addition to the free/total PSA ratio. This combination had the highest area under the curve (AUC)- 0.916 in ROC analysis.

Conclusions: Our results suggest that this autoantibody panel along with PSA and free PSA have potential to segregate patients without cancer from those with prostate cancer with higher sensitivity and specificity than PSA alone.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221051PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690541PMC
March 2020

Upregulation of the long non-coding RNA CBR3-AS1 predicts tumor prognosis and contributes to breast cancer progression.

Gene X 2019 Jun 25;2:100014. Epub 2019 Mar 25.

Department of Radiotherapy, Jiangyin People's Hospital, Affiliated Hospital of Southeast University, Jiangyin, 214400, China.

Breast cancer is the most common female malignancy and the major cause of cancer-related death in women. Long non-coding RNAs (lncRNAs), as oncogenic or tumor suppressor factor, involved in the development and progression of various cancers. In this study, we sought to investigate the function of lncRNA CBR3-AS1 in breast cancer. We evaluated the expression pattern of CBR3-AS1 in breast cancer tissues and cell lines, explored the correlation between CBR3-AS1 expression and the survival time of breast cancer patients, and probed the effect of CBR3-AS1 on tumor progression of breast cancer through loss-of-function and gain-of-function strategies. Our results showed that CBR3-AS1 was overexpressed in breast cancer tissues and cell lines and predicted the prognosis of breast cancer patients. And CBR3-AS1 exerted biological function as an oncogenic lncRNA, involved in the regulation of cell proliferation, colony formation, apoptosis and tumor growth in breast cancer. Taken together, CBR3-AS1 was up-regulated in breast cancer and promoted the risk of breast cancer. It may be a novel therapeutic target and potential prognostic marker for breast cancer.
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http://dx.doi.org/10.1016/j.gene.2019.100014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285981PMC
June 2019

Sperm-associated antigen 5 is a potential biomarker for poor prognosis in breast cancer.

Oncol Lett 2019 Jan 19;17(1):1146-1152. Epub 2018 Nov 19.

Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China.

Sperm-associated antigen 5 (SPAG5) is currently considered to serve a role in promoting tumor cell growth and is overexpressed in several types of human cancer. However, to the best of our knowledge, the association of SPAG5 with molecular subtypes of patients with breast cancer (BC) remains to be fully investigated. Reverse transcription-quantitative polymerase chain reaction and immunohistochemistry on tissue microarrays were used in the current study to detect the expression levels of SPAG5 mRNA and protein, respectively, in BC. The association between SPAG5 mRNA and protein levels, and clinical characteristics and prognostic information were investigated. SPAG5 mRNA and protein levels were identified to be higher in BC tissues compared with matched adjacent nontumor tissues. High expression level of SPAG5 protein was associated with tumor size, histological grade, estrogen receptor expression, Ki-67 expression, lymph node status, tumor-node-metastasis (TNM) stage and the triple-negative BC subtype. In addition, high expression level of SPAG5 protein was associated with a poor prognosis in patients with BC. In summary, the current study suggests that SPAG5 is a novel and useful prognostic biomarker in BC.
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http://dx.doi.org/10.3892/ol.2018.9729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312992PMC
January 2019

Efficient and Robust Direct Image Registration Based on Joint Geometric and Photometric Lie Algebra.

IEEE Trans Image Process 2018 Dec 10;27(12):6010-6024. Epub 2018 Aug 10.

This paper considers the joint geometric and photometric image registration problem. The inverse compositional (IC) algorithm and the efficient second-order minimization (ESM) algorithm are two typical efficient methods applied to the geometric registration problem. Their efficiency stems from the utilization of the group structure of geometric transformations. To allow for photometric variations, the dual IC algorithm (DIC) proposed by Bartoli performs joint geometric and photometric image registration by extending the IC algorithm. The group structures of both geometric and photometric transformations are exploited. Despite the robustness to large photometric variations, DIC is vulnerable to large geometric deformations. The ESM algorithm is extended by Silveira et al. to address photometric variations. In their approach, the photometric transformations are modeled in Euclidean space. Their approach is robust to relatively large geometric and photometric transformations; however, it is not efficient for large photometric variations. We propose a new efficient and robust image registration method by exploiting the non-Euclidean Lie group structure of joint geometric and photometric transformations for both grayscale and color images. The image registration is formulated as a nonlinear least squares problem. In our method, the geometric and photometric transformations are jointly parameterized by their corresponding Lie algebras. Based on this parameterization approach, the second-order approximation strategy of ESM is employed to optimize the joint geometric and photometric parameters. The error function in the nonlinear least squares problem is approximated by a second-order Taylor expansion with respect to joint geometric and photometric parameters without computing the Hessian matrix. For further efficiency, independent convergence criteria for geometric and photometric parameters are used in the iterative optimization process. The superiority of our proposed method over the previous methods, in terms of efficiency, accuracy, and robustness, is demonstrated through extensive experiments on synthetic and real data.
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http://dx.doi.org/10.1109/TIP.2018.2864895DOI Listing
December 2018

A blood biomarker for monitoring response to anti-EGFR therapy.

Cancer Biomark 2018 ;22(2):333-344

Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA.

Background And Objective: To monitor therapies targeted to epidermal growth factor receptors (EGFR) in non-small cell lung cancer (NSCLC), we investigated Peroxiredoxin 6 (PRDX6) as a biomarker of response to anti-EGFR agents.

Methods: We studied cells that are sensitive (H3255, HCC827) or resistant (H1975, H460) to gefitinib. PRDX6 was examined with either gefitinib or vehicle treatment using enzyme-linked immunosorbent assays. We created xenograft models from one sensitive (HCC827) and one resistant cell line (H1975) and monitored serum PRDX6 levels during treatment.

Results: PRDX6 levels in cell media from sensitive cell lines increased significantly after gefitinib treatment vs. vehicle, whereas there was no significant difference for resistant lines. PRDX6 accumulation over time correlated positively with gefitinib sensitivity. Serum PRDX6 levels in gefitinib-sensitive xenograft models increased markedly during the first 24 hours of treatment and then decreased dramatically during the following 48 hours. Differences in serum PRDX6 levels between vehicle and gefitinib-treated animals could not be explained by differences in tumor burden.

Conclusions: Our results show that changes in serum PRDX6 during the course of gefitinib treatment of xenograft models provide insight into tumor response and such an approach offers several advantages over imaging-based strategies for monitoring response to anti-EGFR agents.
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http://dx.doi.org/10.3233/CBM-171149DOI Listing
October 2018

JWA suppresses the invasion of human breast carcinoma cells by downregulating the expression of CXCR4.

Mol Med Rep 2018 Jun 11;17(6):8137-8144. Epub 2018 Apr 11.

Department of Breast Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.

Breast cancer is the second leading cause of cancer‑associated mortality, and metastatic breast cancer is responsible for 90% of patient mortalities. Given that JWA represses the proliferation, invasion and metastasis of a number of other human tumor cells, including melanoma, esophageal, hepatocellular and gastric carcinomas, via mitogen‑activated protein kinase or integrin signaling, the present study investigated the expression and function of JWA in human breast cancers. The results showed that the expression level of JWA was significantly reduced in human primary breast cancers when compared with the paired adjacent tissues. Downregulating JWA enhanced, while overexpressing JWA suppressed, the migration and invasion abilities of the two breast cancer cell lines, MDA‑MB‑468 and MDA‑MB‑231, without affecting their proliferations in vitro. In addition, JWA negatively regulated the surface expression of CXCR4 in the two cell lines via proteasome degradation, though not via transcriptional inhibition. Functionally, normalizing the disturbed expressions of CXCR4 largely reversed the inhibitory effect of JWA on cell invasion. These data demonstrated that JWA suppressed the migration/invasion of breast carcinoma cells by downregulating the expression of CXCR4, and suggested that JWA may harbor prognostic and therapeutic potential in patients with breast cancer.
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http://dx.doi.org/10.3892/mmr.2018.8866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983986PMC
June 2018

D Rhamnose β-hederin inhibits migration and invasion of human breast cancer cell line MDA-MB-231.

Biochem Biophys Res Commun 2018 01 14;495(1):775-780. Epub 2017 Nov 14.

Jiangsu Breast Disease Center, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China. Electronic address:

Many natural products have been shown to have inhibitory effects on the metastatic process of various cancers including breast cancer. An active triterpenoid saponin D Rhamnose β-hederin (DRβ-H) from Clematis ganpiniana, has been known induce the apoptosis of breast cancer cells, but the effect of DRβ-H on the metastasis of breast cancer cells is largely unknown. In this study, we demonstrated that a non-cytotoxic concentration of DRβ-H markedly suppressed wound healing migration, migration through the chamber and invasion through the matrigel. In addition, DRβ-H regulated expression of RNPC1, E-cadherin proteins of MDA-MB-231 cells. Furthermore, RNPC1 knockdown decreased the DRβ-H-induced up-regulation of RNPC1 and E-Cadherin in MDA-MB-231 cells. RNPC1 knockdown reduced the anti-metastasis activities of DRβ-H, meaning that the up-rugulation of RNPC1 by DRβ-H is essential for its anti-metastatis activities. These results suggest that DRβ-H might be a potential therapeutic candidate for the treatment of breast cancer metastasis.
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http://dx.doi.org/10.1016/j.bbrc.2017.11.081DOI Listing
January 2018

Fast Noncircular 2D-DOA Estimation for Rectangular Planar Array.

Sensors (Basel) 2017 Apr 12;17(4). Epub 2017 Apr 12.

Electronic and Information School of Yangtze University, Jingzhou 434023, China.

A novel scheme is proposed for direction finding with uniform rectangular planar array. First, the characteristics of noncircular signals and Euler's formula are exploited to construct a new real-valued rectangular array data. Then, the rotational invariance relations for real-valued signal space are depicted in a new way. Finally the real-valued propagator method is utilized to estimate the pairing two-dimensional direction of arrival (2D-DOA). The proposed algorithm provides better angle estimation performance and can discern more sources than the 2D propagator method. At the same time, it has very close angle estimation performance to the noncircular propagator method (NC-PM) with reduced computational complexity.
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http://dx.doi.org/10.3390/s17040840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5422201PMC
April 2017

miR-17 as a diagnostic biomarker regulates cell proliferation in breast cancer.

Onco Targets Ther 2017 27;10:543-550. Epub 2017 Jan 27.

Department of Thyroid and Breast Surgery, Shanghai No 10 People's Hospital, Clinical College of Nanjing Medical University, Shanghai, People's Republic of China.

Background: MicroRNAs (miRNAs) have been shown to be involved in the initiation and progression of cancers in the literature. In this study, we aimed to evaluate the clinicopathological role of miR-17 in breast cancer.

Materials And Methods: The expression of miR-17 was measured in 132 breast cancer tissues and paired adjacent normal tissues by using real-time quantitative polymerase chain reaction. The association between miR-17 expression levels and clinicopathological parameters was also analyzed. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and flow cytometry assays were used to investigate the role of miR-17 in the regulation of breast cancer cells.

Results: The expression of miR-17 was remarkably increased in breast cancer tissues and cell lines. Clinical association analysis revealed that a high expression of miR-17 was prominently associated with poor survival time in breast cancer. Overexpression of miR-17 promoted cell proliferation and induced tumor growth.

Conclusion: Our findings clarified that the upregulation of miR-17 played a vital role in breast cancer progression and suggested that miR-17 could be used as a prognostic biomarker for breast cancer.
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http://dx.doi.org/10.2147/OTT.S127723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5293507PMC
January 2017

Adsorptive removal of fluoride from drinking water using porous starch loaded with common metal ions.

Carbohydr Polym 2017 Mar 23;160:82-89. Epub 2016 Dec 23.

School of Tea & Food Science and Technology, Anhui Agricultural University/State Key Laboratory of Tea Plant Biology and Utilization, Hefei 230036, Anhui, People's Republic of China. Electronic address:

In this study, porous corn starch was loaded with Zr, Al, Fe or La to produce the composites PS-Zr, PS-Al, PS-Fe and PS-La. Fluoride adsorption from water was tested at different biosorbent dosages, contact times, solution pH values and initial fluoride concentrations. The biosorbents were characterized by microscopy and spectroscopy. PS-Zr was shown superior defluoridation capacity over a pH range of 3.0-9.0. The adsorption process could be described by the Langmuir isotherm model and the Lagergren pseudo-second-order kinetic model. The maximum fluoride adsorption capacity calculated to be for PS-Zr was 25.41mg/g. Our results revealed that PS-Zr could be employed as an effective biosorbent for removal of fluoride from drinking water.
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http://dx.doi.org/10.1016/j.carbpol.2016.12.052DOI Listing
March 2017

Autophagy-deficient Kupffer cells promote tumorigenesis by enhancing mtROS-NF-κB-IL1α/β-dependent inflammation and fibrosis during the preneoplastic stage of hepatocarcinogenesis.

Cancer Lett 2017 03 20;388:198-207. Epub 2016 Dec 20.

Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China. Electronic address:

As a cellular degradation mechanism, autophagy exerts crucial and complicated effects on HCC development. Liver non-parenchymal cells, including hepatic resident macrophage Kupffer cells, also play important roles in this process. However, most associated studies have focused on the influence of the autophagy level in hepatic cells and HCC cells, but not liver non-parenchymal cells. Based on our previous study, we confirmed that Atg5 silence in the liver during the preneoplastic stage facilitated liver fibrosis, inflammation and, ultimately, tumorigenesis. We further found that autophagy deficiency promotes the production of inflammatory and fibrogenic factors in macrophages. Moreover, Kupffer cell depletion rescued the tumor-promoting effect of autophagy deficiency during the preneoplastic stage. In autophagy-deficient macrophages, mitochondrial ROS mediated inflammation- and fibrosis-promoting effects by increasing IL1α/β production via enhancing NF-κB-associated pathways. Both blocking of mitochondrial ROS and blocking the IL1 receptor stopped the promotion of fibrosis, inflammation and tumorigenesis resulting from Atg5 knockdown during the preneoplastic stage. In conclusion, autophagy-deficient Kupffer cells promote liver fibrosis, inflammation and, finally, hepatocarcinogenesis during the preneoplastic stage by enhancing mitochondrial ROS- NF-κB-IL1α/β pathways.
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http://dx.doi.org/10.1016/j.canlet.2016.12.004DOI Listing
March 2017

Real-Time Robust Tracking for Motion Blur and Fast Motion via Correlation Filters.

Sensors (Basel) 2016 Sep 7;16(9). Epub 2016 Sep 7.

Key Laboratory of Opto-Electronic Information Processing, Chinese Academy of Sciences, Shenyang 110016, China.

Visual tracking has extensive applications in intelligent monitoring and guidance systems. Among state-of-the-art tracking algorithms, Correlation Filter methods perform favorably in robustness, accuracy and speed. However, it also has shortcomings when dealing with pervasive target scale variation, motion blur and fast motion. In this paper we proposed a new real-time robust scheme based on Kernelized Correlation Filter (KCF) to significantly improve performance on motion blur and fast motion. By fusing KCF and STC trackers, our algorithm also solve the estimation of scale variation in many scenarios. We theoretically analyze the problem for CFs towards motions and utilize the point sharpness function of the target patch to evaluate the motion state of target. Then we set up an efficient scheme to handle the motion and scale variation without much time consuming. Our algorithm preserves the properties of KCF besides the ability to handle special scenarios. In the end extensive experimental results on benchmark of VOT datasets show our algorithm performs advantageously competed with the top-rank trackers.
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http://dx.doi.org/10.3390/s16091443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5038721PMC
September 2016

Short-term association between particular matter air pollution and pediatric clinical visits for wheezing in a subarea of Shanghai.

Environ Sci Pollut Res Int 2016 Oct 28;23(19):19201-11. Epub 2016 Jun 28.

Department of Pediatrics, South Campus, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 201112, China.

To assess the association between the concentration of ambient particulate matter (PM) and the pediatric clinical visits for wheezing among children under 3 years old, data of daily air pollutants (PM2.5, PM10, NO2, SO2, CO), meteorological reports, along with the number of daily clinical visits of the children with wheezing at the Pediatric Department of Shanghai Renji Hospital (South Campus) were collected from January through December 2014. Correlation between the levels of air pollutants and the number of clinical patients for wheezing were analyzed by a time series analysis with a generalized addictive model (GAM). During the study period, the daily average concentrations of PM2.5, PM10, NO2, SO2, and CO were 51.84 ± 32.51, 72.69 ± 41.15, 43.25 ± 18.07, 17.45 ± 10.42, and 0.82 ± 0.26 μg/m(3), respectively, which were abnormally higher compared to the standard defined by the Chinese Ministry of Environment Protection. The average number of daily clinical patients with wheezing was 23 ± 14 persons/day. The number of clinical visit by children with wheezing was significantly correlated with concentration of PM2.5 or PM10 when the effect of SO2 and NO2 was adjusted (P < 0.05). It was also found that exposure-response relationship was a linear non-threshold mode when it was analyzed by the GAM, and the percent of the clinical visits of children with wheezing increased from 0 to nearly 20 % with every interquartile increase of PM2.5. The visiting number of children at a pediatric outpatient clinic increased due to the increase of PM2.5 in Pujiang, Shanghai, China.
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http://dx.doi.org/10.1007/s11356-016-7066-6DOI Listing
October 2016

A Cystine Knot Peptide Targeting Integrin αvβ6 for Photoacoustic and Fluorescence Imaging of Tumors in Living Subjects.

J Nucl Med 2016 Oct 26;57(10):1629-1634. Epub 2016 May 26.

Department of Radiology, Molecular Imaging Program at Stanford, Canary Center for Cancer Early Detection, Stanford University, Stanford, California; and

Photoacoustic imaging is a nonionizing biomedical imaging modality with higher resolution and imaging depth than fluorescence imaging, which has greater sensitivity. The combination of the 2 imaging modalities could improve the detection of cancer. Integrin αβ is a cell surface marker overexpressed in many different cancers. Here, we report the development and evaluation of a dye-labeled cystine knot peptide, which selectively recognizes integrin αβ with high affinity, for photoacoustic and fluorescence imaging. The new dual-modality probe may find clinical application in cancer diagnosis and intraoperative imaging of integrin αβ-positive tumors.

Methods: An engineered cystine knot peptide, R1, that recognizes integrin αβ was labeled with Atto 740 (A740) and evaluated for its specific cell uptake and its sensitivity threshold. A740-R1 was injected via the tail vein into nude mice xenografted with A431 (integrin αβ-positive) or 293T (integrin αβ-negative) tumors. Photoacoustic and fluorescence scans of tumors were acquired before and at 0.5, 1, 2, and 4 h after injection of A740-R1. Dynamic photoacoustic scans of various normal organs were also acquired. Ex vivo fluorescence imaging of tissues was performed 1 h after injection.

Results: The A740-R1 demonstrated integrin αβ-dependent binding to A431 cells in culture. Sensitivity studies indicated that the probe may potentially detect lesions as small as 1 or 6 mm by fluorescence or photoacoustic imaging, respectively. The photoacoustic and fluorescence signals of A431 xenografts at 1 h after injection were 1.87 ± 0.25 arbitrary units (AU) and 8.27 ± 0.87 AU, respectively. Target specificity was confirmed by low tumor uptake in 293T tumors at 1 h after injection (1.07 ± 0.15 AU and 1.10 ± 0.14 AU for photoacoustic and fluorescence signals, respectively). A740-R1 exhibited hepatobiliary clearance marked by high uptake in the liver, spleen, and intestine but low uptake in the kidneys.

Conclusion: A740-R1 specifically targeted integrin αβ with low nanomolar affinity. A740-R1 was able to detect integrin αβ both in vitro and in vivo by photoacoustic and fluorescence imaging. A740-R1 is able to detect αβ-positive tumors in living subjects and may have clinical application in cancer diagnosis and real-time image-guided surgery.
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http://dx.doi.org/10.2967/jnumed.115.169383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367447PMC
October 2016

AshwaMAX and Withaferin A inhibits gliomas in cellular and murine orthotopic models.

J Neurooncol 2016 Jan 9;126(2):253-64. Epub 2015 Dec 9.

Departments of Radiology and Bioengineering, Stanford University, Palo Alto, CA, USA.

Glioblastoma multiforme (GBM) is an aggressive, malignant cancer Johnson and O'Neill (J Neurooncol 107: 359-364, 2012). An extract from the winter cherry plant (Withania somnifera ), AshwaMAX, is concentrated (4.3 %) for Withaferin A; a steroidal lactone that inhibits cancer cells Vanden Berghe et al. (Cancer Epidemiol Biomark Prev 23: 1985-1996, 2014). We hypothesized that AshwaMAX could treat GBM and that bioluminescence imaging (BLI) could track oral therapy in orthotopic murine models of glioblastoma. Human parietal-cortical glioblastoma cells (GBM2, GBM39) were isolated from primary tumors while U87-MG was obtained commercially. GBM2 was transduced with lentiviral vectors that express Green Fluorescent Protein (GFP)/firefly luciferase fusion proteins. Mutational, expression and proliferative status of GBMs were studied. Intracranial xenografts of glioblastomas were grown in the right frontal regions of female, nude mice (n = 3-5 per experiment). Tumor growth was followed through BLI. Neurosphere cultures (U87-MG, GBM2 and GBM39) were inhibited by AshwaMAX at IC50 of 1.4, 0.19 and 0.22 µM equivalent respectively and by Withaferin A with IC50 of 0.31, 0.28 and 0.25 µM respectively. Oral gavage, every other day, of AshwaMAX (40 mg/kg per day) significantly reduced bioluminescence signal (n = 3 mice, p < 0.02, four parameter non-linear regression analysis) in preclinical models. After 30 days of treatment, bioluminescent signal increased suggesting onset of resistance. BLI signal for control, vehicle-treated mice increased and then plateaued. Bioluminescent imaging revealed diffuse growth of GBM2 xenografts. With AshwaMAX, GBM neurospheres collapsed at nanomolar concentrations. Oral treatment studies on murine models confirmed that AshwaMAX is effective against orthotopic GBM. AshwaMAX is thus a promising candidate for future clinical translation in patients with GBM.
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http://dx.doi.org/10.1007/s11060-015-1972-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5597337PMC
January 2016

A Magnetic Bead-Based Sensor for the Quantification of Multiple Prostate Cancer Biomarkers.

PLoS One 2015 30;10(9):e0139484. Epub 2015 Sep 30.

Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, California, United States of America; Bioengineering, Materials Science & Engineering, Bio-X, Stanford University, Stanford, California, United States of America.

Novel biomarker assays and upgraded analytical tools are urgently needed to accurately discriminate benign prostatic hypertrophy (BPH) from prostate cancer (CaP). To address this unmet clinical need, we report a piezeoelectric/magnetic bead-based assay to quantitate prostate specific antigen (PSA; free and total), prostatic acid phosphatase, carbonic anhydrase 1 (CA1), osteonectin, IL-6 soluble receptor (IL-6sr), and spondin-2. We used the sensor to measure these seven proteins in serum samples from 120 benign prostate hypertrophy patients and 100 Gleason score 6 and 7 CaP using serum samples previously collected and banked. The results were analyzed with receiver operator characteristic curve analysis. There were significant differences between BPH and CaP patients in the PSA, CA1, and spondin-2 assays. The highest AUC discrimination was achieved with a spondin-2 OR free/total PSA operation--the area under the curve was 0.84 with a p value below 10(-6). Some of these data seem to contradict previous reports and highlight the importance of sample selection and proper assay building in the development of biomarker measurement schemes. This bead-based system offers important advantages in assay building including low cost, high throughput, and rapid identification of an optimal matched antibody pair.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0139484PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589536PMC
March 2016

Novel Radiotracer for ImmunoPET Imaging of PD-1 Checkpoint Expression on Tumor Infiltrating Lymphocytes.

Bioconjug Chem 2015 Oct 10;26(10):2062-9. Epub 2015 Sep 10.

Radiology, School of Medicine, ‡Bioengineering and §Materials Science and Engineering, Stanford University , Stanford, California 94305, United States.

Immune checkpoint signaling through the programmed death 1 (PD-1) axis to its ligand (PD-L1) significantly dampens anti-tumor immune responses. Cancer patients treated with checkpoint inhibitors that block this suppressive signaling have exhibited objective response rates of 20-40% for advanced solid tumors, lymphomas, and malignant melanomas. This represents a tremendous advance in cancer treatment. Unfortunately, all patients do not respond to immune checkpoint blockade. Recent findings suggest that patients with tumor infiltrating lymphocytes (TILs) expressing PD-1 may be most likely to respond to αPD-1/PD-L1 checkpoint inhibitors. There is a compelling need for diagnostic and prognostic imaging tools to assess the PD-1 status of TILs in vivo. Here we have developed a novel immunoPET tracer to image PD-1 expressing TILs in a transgenic mouse model bearing melanoma. A (64)Cu labeled anti-mouse antibody (IgG) PD-1 immuno positron emission tomography (PET) tracer was developed to detect PD-1 expressing murine TILs. Quality control of the tracer showed >95% purity by HPLC and >70% immunoreactivity in an in vitro cell binding assay. ImmunoPET scans were performed over 1-48 h on Foxp3+.LuciDTR4 mice bearing B16-F10 melanoma tumors. Mice receiving anti-PD-1 tracer (200 ± 10 μCi/10-12 μg/200 μL) revealed high tracer uptake in lymphoid organs and tumors. BLI images of FoxP3(+) CD4(+) Tregs known to express PD-1 confirmed lymphocyte infiltration of tumors at the time of PET imaging. Biodistribution measurements performed at 48 h revealed a high (11×) tumor to muscle uptake ratio of the PET tracer (p < 0.05). PD-1 tumors exhibited 7.4 ± 0.7%ID/g tracer uptake and showed a 2× fold signal decrease when binding was blocked by unlabeled antibody. To the best of our knowledge this data is the first report to image PD-1 expression in living subjects with PET. This radiotracer has the potential to assess the prognostic value of PD-1 in preclinical models of immunotherapy and may ultimately aid in predicting response to therapies targeting immune checkpoints.
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http://dx.doi.org/10.1021/acs.bioconjchem.5b00318DOI Listing
October 2015

Tamoxifen and risk of contralateral breast cancer among women with inherited mutations in BRCA1 and BRCA2: a meta-analysis.

Breast Cancer 2015 Jul 30;22(4):327-34. Epub 2015 May 30.

Department of Breast Surgery, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.

Given the greatly elevated risks of contralateral breast cancer (CBC) observed in breast cancer patients who carry mutation in BRCA1 or BRCA2, the present meta-analysis was addressed to determine whether adjuvant tamoxifen treatment for breast cancer is associated with reduced CBC risk for these patients. We searched the database of PubMed for eligible studies about the effectiveness of tamoxifen on CBC risk among BRCA1/2 mutation carriers, and we calculated the pooled relative risks (RRs) for CBC risk along with 95 % confidence intervals (CIs). Fixed- or random-effects model was conducted according to study heterogeneity. Four non-overlapping studies met the inclusion criteria for the meta-analysis. Tamoxifen was found to be significantly associated with reduced risk of CBC among BRCA1/2 mutation carriers (summary RR = 0.56, 95 % CI = 0.41-0.76). Similar findings were observed in BRCA1 mutation carriers (summary RR = 0.47, 95 % CI = 0.37-0.60) and BRCA2 mutation carriers (summary RR = 0.39, 95 % CI = 0.28-0.54), respectively. In conclusion, tamoxifen significantly reduces the incidence of CBC among BRCA1/2 mutation carriers with primary unilateral breast cancer. It can reasonably be offered to breast cancer patients with BRCA1 or BRCA2 mutation for the prevention of CBC. Further studies are required to get a more precise estimation of the benefits and harms of tamoxifen in these patients.
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http://dx.doi.org/10.1007/s12282-015-0619-6DOI Listing
July 2015

MMP13 Regulates Aggressiveness of Pediatric Multiple Myeloma Through VEGF-C.

Cell Physiol Biochem 2015 11;36(2):509-16. Epub 2015 May 11.

Department of Pediatrics, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.

Background/aims: Even though the blood and lymphatic vascular systems are both involved in the occurrence of cancer metastases, it is believed that lymphatic system is primarily responsible for the initial metastasis. Nevertheless, the molecular mechanisms underlying lymphangiogenesis of multiple myeloma (MM), especially in pediatric period, have not been clarified.

Methods: Here we studied vascular endothelial growth factor C (VEGF-C) and matrix metalloproteinase 13 (MMP13) in pediatric MM patients. We overexpressed or inhibited VEGF-C in MM cells to study their effects on MMP13, and vice versa. A specific inhibitor for PI3k/Akt signaling pathway was used to examine the role of PI3k/Akt signaling in this regulatory axis.

Results: Both VEGF-C and MMP13 significantly upregulated in MM with lymph-node metastases. A strong correlation between VEGF-C and MMP13 were detected in MM specimen. Using a human MM line 8226, we found that VEGF-C was regulated by MMP13 in MM cells, but not vice versa. Moreover, a specific PI3k/Akt inhibitor significantly abolished the effect of MMP13 on VEGF-C activation.

Conclusion: Since VEGF-C is a well-known growth factor for lymphatic vessels, our data suggest that MMP13 may activate VEGF-C to promote cancer cell metastasis through lymphatic vascular systems in pediatric MM.
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http://dx.doi.org/10.1159/000430116DOI Listing
February 2016

Bacterial lysate increases the percentage of natural killer T cells in peripheral blood and alleviates asthma in children.

Pharmacology 2015 26;95(3-4):139-44. Epub 2015 Mar 26.

Department of Pediatrics, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Aims: To assess the efficacy of conventional treatment combined with bacterial lysate [OM-85 Broncho-Vaxom (BV)] in the prevention of asthma in children as well as its influence on the number of natural killer T (NKT) cells and their cytokine production.

Materials And Methods: Sixty children diagnosed with asthma were divided into either a BV-treated group (with oral OM-85 BV) or a conventional inhaled corticosteroid (ICS) group. The numbers of NKT cells and CD4+ NKT cells were measured in the peripheral blood by flow cytometry. The levels of IFN-γ, IL-4, and IL-10 after the blood cells had been cultured with an NKT cell agonist were detected by ELISA.

Results: After therapy, asthma attacks were significantly decreased compared with before therapy in both groups. However, after therapy, respiratory tract infections were reduced compared with before therapy in the BV-treated group only. Additionally, the frequency of asthma attacks and use of antibiotics in the BV-treated group were lower than in the ICS group. With BV treatment, the numbers of peripheral blood NKT cells and CD4+ NKT cells were higher after therapy than before therapy. After therapy, the ratio of IFN-γ/IL-4 and IL-10 levels were increased in the BV-treated group, whereas IL-4 was reduced in the BV-treated group compared with the ICS group.

Conclusion: BV combined with conventional asthma treatment can prevent recurrent respiratory tract infections and suppress the severity of asthma attacks, possibly by altering the rates and cytokines of NKT cells.
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http://dx.doi.org/10.1159/000377683DOI Listing
January 2016

The efficacy and safety of subcutaneous immunotherapy in mite-sensitized subjects with asthma: a meta-analysis.

Respir Care 2015 Feb 11;60(2):269-78. Epub 2014 Nov 11.

Department of Pediatrics, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Background: Subcutaneous immunotherapy (SCIT) is widely used in the management of allergic diseases such as allergic asthma. We aimed to conduct a systematic review and meta-analysis to evaluate the efficacy and safety of SCIT in mite-sensitized subjects with asthma.

Methods: Literature from January 1990 to February 2013 on the efficacy and safety of SCIT for mite-sensitized asthma patients was searched in electronic databases, including the Cochrane Library, MEDLINE, Embase, PubMed, China Knowledge Resource Integrated Database, Wanfang, and Vendor Information Pages. Data were extracted from randomized controlled trials (RCTs) according to the selection criteria by 2 investigators independently. The quality of included trials was evaluated according to the Jadad scale standard.

Results: A total of 796 subjects from 19 different RCTs were included in this analysis. SCIT significantly reduced the asthma symptom scores (standardized mean difference of -0.94, 95% CI -1.58 to -0.29, P=.004) and the asthma medication scores (standardized mean difference of -1.06, 95% CI -1.70 to -0.42, P=.001) compared with the control group. However, there were no significant differences between subjects receiving SCIT and the control group in lung function (peak expiratory flow, percent-of-predicted FEV1, percent-of-predicted FVC) and specific antibody (allergen-specific immunoglobulin E) levels of blood serum (P>.05). In the studies containing data on safety, the incidences of systemic and local adverse reactions were 9.1% (8/88) and 17.2% (23/134), respectively, in subjects treated with SCIT, and no severe adverse events were reported.

Conclusions: Our results suggest that SCIT is helpful in alleviating symptoms and reducing medication used in mite-sensitive asthma subjects, but with no improvement in lung function. The safety of SCIT is acceptable.
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http://dx.doi.org/10.4187/respcare.03399DOI Listing
February 2015

Isolation and mutational analysis of circulating tumor cells from lung cancer patients with magnetic sifters and biochips.

Lab Chip 2014 Jan;14(1):78-88

Department of Materials Science and Engineering, Stanford University, Stanford, CA 94305, USA.

Detection and characterization of circulating tumor cells (CTCs) may reveal insights into the diagnosis and treatment of malignant disease. Technologies for isolating CTCs developed thus far suffer from one or more limitations, such as low throughput, inability to release captured cells, and reliance on expensive instrumentation for enrichment or subsequent characterization. We report a continuing development of a magnetic separation device, the magnetic sifter, which is a miniature microfluidic chip with a dense array of magnetic pores. It offers high efficiency capture of tumor cells, labeled with magnetic nanoparticles, from whole blood with high throughput and efficient release of captured cells. For subsequent characterization of CTCs, an assay, using a protein chip with giant magnetoresistive nanosensors, has been implemented for mutational analysis of CTCs enriched with the magnetic sifter. The use of these magnetic technologies, which are separate devices, may lead the way to routine preparation and characterization of "liquid biopsies" from cancer patients.
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http://dx.doi.org/10.1039/c3lc50580dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4144998PMC
January 2014

Acute and subacute toxicity studies on triptolide and triptolide-loaded polymeric micelles following intravenous administration in rodents.

Food Chem Toxicol 2013 Jul 11;57:371-9. Epub 2013 Apr 11.

College of Biological and Pharmaceutical Engineering, Wuhan Polytechnic University, Wuhan 430023, PR China.

Except its anti-tumour effects, triptolide (TP) also shows multiple pharmacological side activities, such as immune-suppressive and male anti-fertility. To increase the therapeutic index of TP, a novel polymeric micelle system containing TP (TP-PM) has been developed to treat tumour. Our previous studies have demonstrated the good anti-tumour efficacy of TP-PM. This paper investigated the acute toxicity in mice and subacute toxicity in rats of TP-PM and TP. Results demonstrated that the LD50 for TP-PM and TP administered intravenously were 1.06 mg/kg and 0.83 mg/kg in mice, respectively. In subacute toxicity study, TP-PM and TP were administered intravenously at the dose levels of 0.1 mg/kg and 0.3 mg/kg for 14 d. Compared to the control, there was significant decrease in the serum AST activities, the testis ACP activities, thymus index, testis index, and significant increase in spleen index, and obvious histopathological changes in rats treated with TP, however, the toxicities of TP-PM on liver, kidney, testis and spleen are slighter than TP. Compared to TP, TP-PM significantly increased the ACP activity of the testis and decreased the MDA level in serum. So, the polymeric micelles may be a novel drug delivery carrier of TP for reducing the toxicities of TP.
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http://dx.doi.org/10.1016/j.fct.2013.03.044DOI Listing
July 2013

The combination effects of acetaminophen and N-acetylcysteine on cytokines production and NF-κB activation of lipopolysaccharide-challenged piglet mononuclear phagocytes in vitro and in vivo.

Vet Immunol Immunopathol 2013 Apr 8;152(3-4):381-8. Epub 2013 Feb 8.

School of Animal Science and Nutritional Engineering, Wuhan Polytechnic University, Wuhan, PR China.

Lipopolysaccharide (LPS) is a known activator of mononuclear phagocytes. LPS activates the pro-inflammatory gene expression and induces the release of mediators/cytokines by TLR4-NF-κB signaling pathway. The purpose of this study was to investigate the effects of acetaminophen (AAP) and N-acetylcysteine (NAC), individually as well as in combination on LPS-induced cytokines production and NF-κB activation in piglets. AAP (0.125-1.0mM) and NAC (0.0625-1.0mM) down-regulate the expression of cytokines and inhibit NF-κB p65 protein transfer from the cytoplasm to the nucleus in vitro. NAC enhances the inhibition action of AAP on cytokines expression in vitro. IL-6 in piglet plasma of the AAP group (mixed feed concentration of 600 mg/kg) was significantly reduced (P<0.05) at 3h after LPS-challenge as compared with the LPS control group. IL-10 also significantly reduced (P<0.05) at 24h after LPS injection. The levels of inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-10) in piglet plasma of the NAC group (mixed feeding concentration of 1200 mg/kg) were significantly lower at 3h after LPS stimulation (P<0.05). IL-10 was significantly decreased in the NAC group at 24h after LPS stimulation (P<0.05). AAP or NAC treated alone could reduce the NF-κB p65 concentration ratio. The levels of cytokines (TNF-α, IL-1β, IL-6, and IL-10) in the group with piglet plasma of AAP (mixed feed concentration of 600 mg/kg) plus NAC (mixed feeding concentration of 1200 mg/kg) group were significantly lower (P<0.05) at 3h after LPS activation. The level of IL-10 in the group with AAP plus NAC was significantly lower (P<0.05) at 24h after LPS stimulation, while the rest of the inflammatory cytokines were returned to the original levels. The NF-κB p65 concentration ratio had significantly reduced (P<0.05) when AAP and NAC were used in combination. In summary, NAC could enhance the anti-inflammatory effects of AAP both in vitro and in vivo.
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http://dx.doi.org/10.1016/j.vetimm.2013.01.013DOI Listing
April 2013

Gamma-aminobutyric acid transporter 1 negatively regulates T cell activation and survival through protein kinase C-dependent signaling pathways.

J Immunol 2009 Sep 10;183(5):3488-95. Epub 2009 Aug 10.

Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Gamma-aminobutyric acid transporter 1 (GAT-1), as the major regulator in maintaining a gamma-aminobutyric acid reservoir in the CNS, plays negative roles in experimental autoimmune encephalomyelitis pathogenesis. Our previous study has revealed that, besides its wide expression in the CNS, GAT-1 expression can be induced on activated T cells triggered by Ag. However, the function of GAT-1 in T cell activation is unclear. In this study, we show that GAT-1 deficiency induces more vigorous cell cycle entry and less cell apoptosis in T cells, thus leading to enhanced cell proliferation. GAT-1 deficiency promotes T cell division and survival by down-regulating cyclin dependent kinase inhibitor p27(kip1), differentially regulating the pro- and anti-apoptotic proteins Bcl-2, Bcl-xl, and Bad and activating transcription factor NF-kappaB through induction of translocation and phosphorylation of protein kinase C (PKC) theta. In addition, our data reveal that GAT-1 expression on T cells is modulated by PKC activation. Taken together, the data show that GAT-1 negatively regulates T cell activation and survival through PKC-dependent signaling pathways.
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http://dx.doi.org/10.4049/jimmunol.0900767DOI Listing
September 2009