Publications by authors named "Zhongqiang Zhang"

31 Publications

CircRNA circ_SEC24A upregulates DNMT3A expression by sponging miR-26b-5p to aggravate osteoarthritis progression.

Int Immunopharmacol 2021 Oct 26;99:107957. Epub 2021 Jul 26.

Department of Sports Medicine, Affiliated Nanhua Hospital, University of South China, Hengyang City, Hunan 421002, China. Electronic address:

Background: Osteoarthritis (OA) is a chronic degenerative disease characterized by degeneration and injury of articular cartilage. Circular RNA_SEC24A (circ_SEC24A; circBase ID: hsa_circ_0005105) is upregulated and promotes multiple tumor processes. However, its role in OA progression remained mostly unknown.

Methods: Quantitative real-time PCR (qRT-PCR) was used to detect the RNA expression of circ_SEC24A, miR-26b-5p and DNA methyltransferase 3 alpha (DNMT3A). Cell proliferation was verified by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) and 5-ethynyl-2'-deoxyuridine (EdU) assays. Flow cytometry was used to detect apoptosis. Western blot was used to detect protein expression of DNMT3A, proliferating cell nuclear antigen (PCNA), extracellular matrix (ECM) proteins (Collagen II and Aggrecan), and ECM degrading enzymes (matrix metalloproteinase-13 [MMP13] and metallopeptidase with thrombospondin type 1 motif 5 [ADAMTS5]). The target relationship between miR-26b-5p and circ_SEC24A or DNMT3A was predicted by Statbase3.0 or TargetScan and confirmed by dual-luciferase reporter assay, RNA pull-down assay and RNA immunoprecipitation.

Results: Circ_SEC24A was upregulated in osteoarthritic cartilage tissues and IL-1β-induced chondrocytes, accompanying with miR-26b-5p downregulation and DNMT3A upregulation. Circ_SEC24A expression was resistant to RNase R digestion and mainly expressed in the cytoplasm. Interfering circ_SEC24A abolished IL-1β-induced effects on proliferation inhibition, apoptosis, and ECM degradation in chondrocytes, but overexpressing circ_SEC24A had the opposite effects. Inhibiting miR-26b-5p counteracted but upregulating miR-26a-5p mimicked the functions of circ_SEC24A silencing. Reinforcing DNMT3A reversed miR-26b-5p overexpression's role in IL-1β-induced chondrocytes. Mechanically, circ_SEC24A and DNMT3A were competitive endogenous RNAs (ceRNAs) for miR-26b-5p.

Conclusion: Circ_SEC24A was a promoting factor for IL-1β-induced OA progression via circ_SEC24A/miR-26b-5p/DNMT3A ceRNA axis.
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http://dx.doi.org/10.1016/j.intimp.2021.107957DOI Listing
October 2021

Electrical energy generation by squeezing a graphene-based aerogel in an electrolyte.

Nanoscale 2021 May 26;13(17):8304-8312. Epub 2021 Apr 26.

Institute of Intelligent Flexible Mechatronics, Jiangsu University, Zhenjiang, 212013, P. R. China.

Mechanical energy harvesters are widely studied because of their diverse applications, such as harvesting ocean wave energy, self-powered wireless sensors, portable power supplies and so on. To be feasible, an energy harvester needs to provide a high output current and voltage, in addition to being environmentally friendly. Hence, in this study, a new energy harvester is developed via reversible deformation of a three-dimensional graphene aerogel which was immersed in a salt solution. The movement of solvated ions in the diffusion layer during the squeezing of the electrode induced the transmission of electrons out of graphene, resulting in electrical energy. The developed harvester can supply a power density of 11.7 W kg and an energy density of 14.3 J kg, in addition to achieving a high energy conversion efficiency of approximately 43.2%. The device can also generate a high open-circuit voltage and short-circuit current when an external compression strain is applied. Moreover, it can be easily scaled up by being connected in series with multiple harvesters. Thus, the proposed energy harvester can not only be widely used for harvesting ocean wave energy, but also for adsorbing pollutants to prevent the pollution of ocean environments.
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http://dx.doi.org/10.1039/d1nr00544hDOI Listing
May 2021

Inhibition of EZH2 enhances the therapeutic effect of 5-FU via PUMA upregulation in colorectal cancer.

Cell Death Dis 2020 12 12;11(12):1061. Epub 2020 Dec 12.

Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.

Although the survival rate of patients with cancer have increased due to the use of current chemotherapeutic agents, adverse effects of cancer therapy remain a concern. The reversal of drug resistance, reduction in harmful side effects and accelerated increase in efficiency have often been addressed in the development of combination therapeutics. Tazemetostat (EPZ-6438), a histone methyltransferase EZH2 selective inhibitor, was approved by the FDA for the treatment of advanced epithelioid sarcoma. However, the effect of tazemetostat on colorectal cancer (CRC) and 5-FU sensitivity remains unclear. In this study, the enhancement of tazemetostat on 5-FU sensitivity was examined in CRC cells. Our findings demonstrated that tazemetostat combined with 5-FU exhibits synergistic antitumor function in vitro and in vivo in CRC cells. In addition, tazemetostat promotes PUMA induction through the ROS/ER stress/CHOP axis. PUMA depletion attenuates the antitumor effect of the combination therapy. Therefore, tazemetostat may be a novel treatment to improve the sensitivity of tumors to 5-FU in CRC therapy. In conclusion, the combination of 5-FU and tazemetostat shows high therapeutic possibility with reduced unfavorable effects.
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http://dx.doi.org/10.1038/s41419-020-03266-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733595PMC
December 2020

The miR-30a-5p/CLCF1 axis regulates sorafenib resistance and aerobic glycolysis in hepatocellular carcinoma.

Cell Death Dis 2020 10 23;11(10):902. Epub 2020 Oct 23.

Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.

HCC (hepatocellular carcinoma) is a major health threat for the Chinese population and has poor prognosis because of strong resistance to chemotherapy in patients. For instance, a considerable challenge for the treatment of HCC is sorafenib resistance. The aberrant glucose metabolism in cancer cells aerobic glycolysis is associated with resistance to chemotherapeutic agents. Drug-resistance cells and tumors were exposed to sorafenib to establish sorafenib-resistance cell lines and tumors. Western blotting and real-time PCR or IHC staining were used to analyze the level of CLCF1 in the sorafenib resistance cell lines or tumors. The aerobic glycolysis was analyzed by ECAR assay. The mechanism mediating the high expression of CLCF1 in sorafenib-resistant cells and its relationships with miR-130-5p was determined by bioinformatic analysis, dual luciferase reporter assays, real-time PCR, and western blotting. The in vivo effect was evaluated by xenografted with nude mice. The relation of CLCF1 and miR-30a-5p was determined in patients' samples. In this study, we report the relationship between sorafenib resistance and increased glycolysis in HCC cells. We also show the vital role of CLCF1 in promoting glycolysis by activating PI3K/AKT signaling and its downstream genes, thus participating in glycolysis in sorafenib-resistant HCC cells. Furthermore, we also show that miR-30a-5p directly targets CLCF1 and that sorafenib-mediated suppression of miR-30a-5p results in the upregulation of CLCF1 in HCC cells resistant to sorafenib. We also found that when a cholesterol modified agomiR-30a-5p was delivered systemically to mice harboring sorafenib-resistant HCC tumors, tumor growth decreased significantly. There is an uncharacterized mechanism of biochemical resistance to hormone therapies orchestrated by the miR-30a-5p/CLCF1 axis to mediate sorafenib resistance and aerobic glycolysis in HCC. Therefore, this study indicates that targeting the miR-30a-5p/CLCF1 axis may hold promise for therapeutic intervention in HCC sorafenib resistance patients.
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http://dx.doi.org/10.1038/s41419-020-03123-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584607PMC
October 2020

Surface slip on rotating graphene membrane enables the temporal selectivity that breaks the permeability-selectivity trade-off.

Sci Adv 2020 Aug 19;6(34):eaba9471. Epub 2020 Aug 19.

Institute of Intelligent Flexible Mechatronics, Jiangsu University, Zhenjiang 212013, P.R. China.

Membrane separation technology is dictated by the permeability-selectivity trade-off rule, because selectivity relies on membrane pore size being smaller than that of hydrated ions. We discovered a previously unknown mechanism that breaks the permeability-selectivity trade-off in using a rotating nanoporous graphene membrane with pores of 2 to 4 nanometers in diameter. The results show that the rotating membrane exhibits almost 100% salt rejection even when the pore size is larger than that of hydrated ions, and the surface slip at the liquid/graphene interface of rotating membrane enables concurrent ultra-selectivity and unprecedented high permeability. A novel concept of "temporal selectivity" is proposed to attribute the unconventional selectivity to the time difference between the ion's penetration time through the pore and the bypass time required for ion's sliding across the pore. The newly discovered temporal selectivity overcomes the limitation imposed by pore size and provokes a novel theory in designing high-performance membranes.
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http://dx.doi.org/10.1126/sciadv.aba9471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438089PMC
August 2020

Graft IL-33 regulates infiltrating macrophages to protect against chronic rejection.

J Clin Invest 2020 10;130(10):5397-5412

Department of Surgery and.

Alarmins, sequestered self-molecules containing damage-associated molecular patterns, are released during tissue injury to drive innate immune cell proinflammatory responses. Whether endogenous negative regulators controlling early immune responses are also released at the site of injury is poorly understood. Herein, we establish that the stromal cell-derived alarmin interleukin 33 (IL-33) is a local factor that directly restricts the proinflammatory capacity of graft-infiltrating macrophages early after transplantation. By assessing heart transplant recipient samples and using a mouse heart transplant model, we establish that IL-33 is upregulated in allografts to limit chronic rejection. Mouse cardiac transplants lacking IL-33 displayed dramatically accelerated vascular occlusion and subsequent fibrosis, which was not due to altered systemic immune responses. Instead, a lack of graft IL-33 caused local augmentation of proinflammatory iNOS+ macrophages that accelerated graft loss. IL-33 facilitated a metabolic program in macrophages associated with reparative and regulatory functions, and local delivery of IL-33 prevented the chronic rejection of IL-33-deficient cardiac transplants. Therefore, IL-33 represents what we believe is a novel regulatory alarmin in transplantation that limits chronic rejection by restraining the local activation of proinflammatory macrophages. The local delivery of IL-33 in extracellular matrix-based materials may be a promising biologic for chronic rejection prophylaxis.
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http://dx.doi.org/10.1172/JCI133008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524467PMC
October 2020

A Novel Cytocompatibility Strengthening Strategy of Ultrafine-Grained Pure Titanium.

ACS Appl Mater Interfaces 2019 Dec 13;11(51):47680-47694. Epub 2019 Dec 13.

Jiangsu Collaborative Innovation Center of Photovoltaic Science and Engineering , Changzhou University , Changzhou 213164 , China.

Ultrafine-grained pure (UFG) titanium processed by equal channel angular pressing possesses mechanical properties comparable to those of Ti-6Al-4V and features more favorable friction resistance, biocompatibility, and corrosion resistance than does commercially pure (CP) titanium. Nevertheless, UFG titanium is still a bio-inert material with a lack of bone-inducing ability. Here, TiO-hydroxyapatite (TiO-HA) coatings were fabricated on CP titanium and UFG titanium through combining micro-arc oxidation and hydrothermal treatment together to improve their cytocompatibility. The results indicate that, compared with conventional coatings that use CP titanium as the substrate, such coatings formed on the UFG titanium possess additional hydrophilicity and in vitro cytocompatibility. The fantastic hierarchical structure of the UFG TiO-HA coating (UG-MH coating), including microscale and nanoscale pores and short column-shaped and sheet-shaped HA grains with varying geometric shapes, excellent hydrophilicity, and high polar force, enhances the mutual effects between the osteoblasts and titanium implant since it provides an adequate microenvironment for the ingrowth of osteoblasts, inducing osteoblast adhesion, proliferation, and differentiation. The UG-MH coating has a synergistic effect due to its fantastic hydrophilic hierarchical structure and high polar force on the up-regulated expression of cytoskeletal actin proteins as well as osteocalcin, protein kinase C (PKC), nuclear factor of activated T-cells (NFAT), and Wnt5, enabling osteoblasts to differentiate via the Wnt calcium-dependent signaling pathway. This study highlights the idea that the modified UFG titanium will be more suitable than CP titanium in dental and orthopedic applications.
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http://dx.doi.org/10.1021/acsami.9b13554DOI Listing
December 2019

Unidirectional Self-Driving Liquid Droplet Transport on a Monolayer Graphene-Covered Textured Substrate.

ACS Appl Mater Interfaces 2019 Aug 29;11(31):28562-28570. Epub 2019 Jul 29.

Department of Civil and Environmental Engineering , University of California , Berkeley , California 94720-1710 , United States.

Controllable directional transport of liquid droplets on a functionalized surface has been a challenge in the field of microfluidics because it does not require energy supply, and the physical mechanism of such self-driving transport exhibits extraordinary contribution to fundamental understanding of some biological processes and the design of microfluidic apparatus. In this paper, we report a novel design of a surface microstructure that can realize unidirectional self-driving liquid mercury (Hg) droplet transport on a graphene-covered copper (Cu) substrate with a three-dimensional surface microstructure. We have demonstrated that a liquid Hg droplet spontaneously propagates on a grooved Cu substrate covered by a monolayer graphene without any external force fields. Classical molecular dynamics results provide a profound insight on the self-driving process of Hg droplets. It shows that the Hg droplet undergoes acceleration, deceleration, and return stages successively from the narrow to wide ends of the gradient groove. Intriguingly, Hg droplets can move continuously and unidirectionally on the three-dimensional graphene-covered surface microstructure when they accumulate enough kinetic energy from the gradient groove to break the energy barrier at the step junctions between the two neighboring unit cells. The design of the zigzag textured surface covered by a monolayer graphene artfully uses the facts; (1) the monolayer graphene can effectively reduce the droplet pinning on the textured surface, (2) the hydrophobic graphene layer reduces the friction between Hg droplets and the substrate, and (3) the textured surface can permeably interact with the droplets through the monolayer graphene to achieve a continuous self-driving process. The findings reported here open a door to explore the graphene-covered functional surface to directional transport of liquid droplets and provide an in-depth understanding of the self-driving mechanism for liquid droplets on graphene-covered textured substrates.
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http://dx.doi.org/10.1021/acsami.9b09219DOI Listing
August 2019

Life-supporting Kidney Xenotransplantation From Genetically Engineered Pigs in Baboons: A Comparison of Two Immunosuppressive Regimens.

Transplantation 2019 10;103(10):2090-2104

Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL.

Background: The aims of this study were to evaluate the efficacy of US Food and Drug Administration-approved drugs in genetically engineered pig-to-baboon kidney xenotransplantation and compare the results with those using an anti-CD40 monoclonal antibody (mAb)-based regimen.

Methods: Ten life-supporting kidney transplants were carried out in baboons using α1,3-galactosyltransferase gene-knockout/CD46 pigs with various other genetic manipulations aimed at controlling coagulation dysregulation. Eight transplants resulted in informative data. Immunosuppressive therapy consisted of induction with antithymocyte globulin and anti-CD20mAb, and maintenance based on either (1) CTLA4-Ig and/or tacrolimus (+rapamycin or mycophenolate mofetil) (GroupA [US Food and Drug Administration-approved regimens], n = 4) or (2) anti-CD40mAb + rapamycin (GroupB, n = 4). All baboons received corticosteroids, interleukin-6R blockade, and tumor necrosis factor-α blockade. Baboons were followed by clinical and laboratory monitoring of kidney function, coagulation, and immune parameters. At euthanasia, morphological and immunohistochemical studies were performed on the kidney grafts.

Results: The median survival in GroupB was 186 days (range 90-260), which was significantly longer than in GroupA; median 14 days (range 12-32) (P < 0.01). Only GroupA baboons developed consumptive coagulopathy and the histopathological features of thrombotic microangiopathic glomerulopathy and interstitial arterial vasculitis.

Conclusions: Recognizing that the pig donors in each group differed in some genetic modifications, these data indicate that maintenance immunosuppression including anti-CD40mAb may be important to prevent pig kidney graft failure.
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http://dx.doi.org/10.1097/TP.0000000000002796DOI Listing
October 2019

Dual-Channel Reconstruction Network for Image Compressive Sensing.

Sensors (Basel) 2019 Jun 4;19(11). Epub 2019 Jun 4.

School of Artificial Intelligence, Xidian University, Xi'an 710071, China.

The existing compressive sensing (CS) reconstruction algorithms require enormous computation and reconstruction quality that is not satisfying. In this paper, we propose a novel Dual-Channel Reconstruction Network (DC-Net) module to build two CS reconstruction networks: the first one recovers an image from its traditional random under-sampling measurements (RDC-Net); the second one recovers an image from its CS measurements acquired by a fully connected measurement matrix (FDC-Net). Especially, the fully connected under-sampling method makes CS measurements represent original images more effectively. For the two proposed networks, we use a fully connected layer to recover a preliminary reconstructed image, which is a linear mapping from CS measurements to the preliminary reconstructed image. The DC-Net module is used to further improve the preliminary reconstructed image quality. In the DC-Net module, a residual block channel can improve reconstruction quality and dense block channel can expedite calculation, whose fusion can improve the reconstruction performance and reduce runtime simultaneously. Extensive experiments manifest that the two proposed networks outperform state-of-the-art CS reconstruction methods in PSNR and have excellent visual reconstruction effects.
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http://dx.doi.org/10.3390/s19112549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6603530PMC
June 2019

An adjustable permeation membrane up to the separation for multicomponent gas mixture.

Sci Rep 2019 May 14;9(1):7380. Epub 2019 May 14.

International Research Center for Computational Mechanics, State Key Laboratory of Structural Analysis for Industrial Equipment, Department of Engineering Mechanics, Faculty of Vehicle Engineering and Mechanics, Dalian University of Technology, Dalian, 116024, P.R. China.

The mixture separation is of fundamental importance in the modern industry. The membrane-based separation technology has attracted considerable attention due to the high efficiency, low energy consumption, etc. However, the tradeoff between the permeability and selectivity is a crucial challenge, which is also difficult to adjust during the separation process. Based on the salt water-filled carbon nanotubes, a separation membrane with the adjustable molecular channels by the electric field is proposed in this work. The separation mechanism is clarified on the basis of the characteristic size of the molecular channel and the overall effective diameter of gas molecules. The molecular dynamics simulation is performed to examine the feasibility and validity of the designed separation membrane. The simulations on the binary gas mixture (H and N) reveal the flow control and high-purity separation as the electric field intensity varies. As for the mixed gas with the three components (H, N and Xe), the successive separations and the switch between the high-efficiency and high-purity separation could be achieved only through adjusting the electric field intensity. This work incorporates the control into the membrane-based separation technology, which provides a novel solution for the complex industrial separation requirement.
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http://dx.doi.org/10.1038/s41598-019-43751-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517568PMC
May 2019

Carbohydrate antigen expression and anti-pig antibodies in New World capuchin monkeys: Relevance to studies of xenotransplantation.

Xenotransplantation 2019 05 16;26(3):e12498. Epub 2019 Feb 16.

Department of Surgery, Xenotransplantation Program, University of Alabama at Birmingham, Birmingham, Alabama.

Background: Old World non-human primates (OWNHPs) are used for preclinical pig-to-NHP studies. However, like pigs, OWNHPs express Neu5Gc, and therefore do not develop natural anti-Neu5Gc antibodies. New World NHPs (NWNHPs) have been reported not to express Neu5Gc. We investigated the potential of NWNHPs in xenotransplantation research.

Methods: We investigated expression of Gal, Neu5Gc, and Sd antigens on RBCs and PBMCs from humans, selected OWNHPs, and capuchin monkeys (a NWNHP). Serum anti-Gal and anti-Neu5Gc IgM and IgG levels were measured by ELISA. Binding of primate serum IgM and IgG to pig RBCs was measured by flow cytometry.

Results: (a) Neither humans, OWNHPs, or capuchin monkeys expressed Gal on their RBCs, but capuchins expressed Gal on PBMCs. Humans and capuchins did not express Neu5Gc on either RBCs or PBMCs, but OWNHPs expressed Neu5Gc on both cells. Sd was not expressed on any RBCs or PBMCs. (b) By ELISA, human and OWNHP, but not capuchin, sera showed IgM and IgG binding to Gal. Human and capuchin, but not OWNHP, sera demonstrated some binding to Neu5Gc. (c) Anti-Sd IgM/IgG antibodies were detected in OWNHP sera. Knockout of Sd on pig RBCs did not significantly reduce human and capuchin antibody binding.

Conclusion: Capuchin monkeys could be surrogates for humans in experiments using RBCs, islets, neuronal cells, etc, from triple-knockout pigs (but may be too small to be used as recipients of pig organ grafts).
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http://dx.doi.org/10.1111/xen.12498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591082PMC
May 2019

Molecular Dynamics Study on the Reverse Osmosis Using Multilayer Porous Graphene Membranes.

Nanomaterials (Basel) 2018 Oct 9;8(10). Epub 2018 Oct 9.

Micro/Nano Science and Technology Center, Jiangsu University, Zhenjiang 212013, China.

In this study, the reverse osmosis (RO) of a salt solution was investigated using a molecular dynamics method to explore the performance of a multilayer porous graphene membrane. The effects of the salt solution concentration, pressure, layer separation and pore offset on the RO performance of the membrane were investigated and the influences of the number of layers and the gradient structure were determined. The results show that as the salt solution concentration increases, the energy barrier of the water molecules passing through the bilayer porous graphene membranes changes slightly, indicating that the effect of the water flux on the membrane can be ignored. The salt rejection performance of the membrane improves with an increase in the concentration of the salt solution. When the pressure is increased, the energy barrier decreases, the water flux increases and the salt rejection decreases. When the layer separation of the bilayer porous graphene membrane is the same as the equilibrium spacing of the graphene membrane, the energy barrier is the lowest and the membrane water flux is the largest. The energy barrier of the bilayer porous graphene membrane increases with increasing layer separation, resulting in a decrease in the water flux of the membrane. The salt rejection increases with increasing layer separation. The water flux of the membrane decreases as the energy barrier increases with increasing pore offset and the salt rejection increases. The energy barrier effect is more pronounced for a larger number of graphene layers and the water flux of the membrane decreases because it is more difficult for the water molecules to pass through the porous graphene membrane. However, the salt rejection performance improves with the increase in the number of layers. The gradient pore structure enhances the energy barrier effect of the water molecules permeating through the membrane and the water flux of the membrane decreases. The salt rejection performance is improved by the gradient pore structure. The research results provide theoretical guidance for research on the RO performance of porous graphene membranes and the design of porous graphene membranes.
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http://dx.doi.org/10.3390/nano8100805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215223PMC
October 2018

GNA13 promotes tumor growth and angiogenesis by upregulating CXC chemokines via the NF-κB signaling pathway in colorectal cancer cells.

Cancer Med 2018 11 28;7(11):5611-5620. Epub 2018 Sep 28.

Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.

GNA13 has been found overexpressed in various types of cancer, which is related to tumor metastasis and progression. However, the biological functions of GNA13 in colorectal cancer (CRC) progression remain unclear. This study aimed to explore the role of GNA13 in CRC and investigate the mechanism of how GNA13 promotes tumor growth. Interestingly, our findings showed that GNA13 is commonly upregulated in CRC, where these events are associated with a worse histologic grade and poor survival. Increased expression levels of GNA13 promoted cell growth, migration, invasion, and epithelial-mesenchymal transition, whereas GNA13 silencing abrogated these malignant phenotypes. In addition, overexpressing GNA13 in cancer cells increased the levels of the chemokines CXCL1, CXCL2, and CXCL4, which contributed to CRC proliferation and colony formation. Moreover, our mechanistic investigations suggest that the NF-κB/p65 signaling pathway was activated by the increase in GNA13 levels. Inhibiting the NF-κB/p65 pathway with an inhibitor decreased GNA13-induced migration, invasion and CXCL chemokine level increases, indicating the critical role of NF-κB/p65 signaling in mediating the effects of GNA13 in CRC. Together, these results demonstrate a key role of GNA13 overexpression in CRC that contributes to malignant behavior in cancer cells, at least in part through stimulating angiogenesis and increasing the levels of the NF-κB-dependent chemokines CXCL1, CXCL2, and CXCL4.
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http://dx.doi.org/10.1002/cam4.1783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6246959PMC
November 2018

Tim-4 promotes the growth of colorectal cancer by activating angiogenesis and recruiting tumor-associated macrophages via the PI3K/AKT/mTOR signaling pathway.

Cancer Lett 2018 11 14;436:119-128. Epub 2018 Aug 14.

Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China. Electronic address:

T-cell immunoglobulin domain and mucin domain-4 (Tim-4) is overexpressed in several tumors and is correlated with enhanced tumor development and metastasis. In this study, we investigated the physiological alterations and molecular events related to Tim-4 overexpression in a mouse model of colorectal cancer (CRC). In the current study, we observed that Tim-4 is upregulated in CRC tissues compared with neighboring normal tissues. In addition, statistical analysis revealed that elevated Tim-4 expression was strongly linked to distant metastasis, TNM stage and reduced overall survival duration in CRC patients. An orthotopic model was employed to explore the function of Tim-4 in CRC development through the implantation of Tim-4-overexpressing CT26 murine colon adenocarcinoma cells. It was observed that Tim-4 overexpression considerably enhanced CRC tumorigenesis in vivo and promoted angiogenesis through the upregulation of vascular endothelial growth factor (VEGF). In CT26 cells, Tim-4 overexpression increased the aldehyde dehydrogenase-1 (ALDH1) level, indicating an increase in cancer stem cell (CSC)-like properties. Furthermore, we determined that Tim-4 activates PI3K/AKT/mTOR signaling in CRC cells. Tim-4-overexpressing cancer cells recruited tumor-associated macrophages (TAMs), thereby accelerating cancer development. Therefore, our results strongly indicate that Tim-4 overexpression promotes proliferation and tumor stroma remodeling in CRC. PI3K/AKT/mTOR activation might be crucial in Tim-4-linked tumor development. This finding might offer a new strategy for therapeutic intervention.
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http://dx.doi.org/10.1016/j.canlet.2018.08.012DOI Listing
November 2018

A hybrid hierarchical Bayesian model for spatiotemporal surveillance data.

Stat Med 2018 12 23;37(28):4216-4233. Epub 2018 Jul 23.

Department of Mathematical Sciences, Worcester Polytechnic Institute, Worcester, Massachusetts.

Due to the low signal-to-noise ratio and high-dimensional structure, spatiotemporal data analysis is challenging. In outbreak detection, the assumptions for control charts, including independence, normality, and stationarity, are often violated in syndromic surveillance data. We develop a novel hybrid hierarchical Bayesian model through the combination of the Dirichlet process and particle filters to resolve these issues. We use a modified adjacency matrix as the observation matrix in the Markovian state-space model. This methodology achieves dimension reduction and computational efficiency and enjoys a superior detection performance with the ability to incorporate online updating for data streaming applications. Our data set is derived from the Indiana Public Health Emergency Surveillance System. It consists of surveillance data on emergency room visits for influenza-like and respiratory illness from 2008 to 2010. We are able to detect the 2009 H1N1 outbreak as well as the seasonal influenza outbreaks. Numerical results show that our Dirichlet process/particle filter models improve the outbreak detection performance in both simulation and real data analysis.
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http://dx.doi.org/10.1002/sim.7909DOI Listing
December 2018

Is sensitization to pig antigens detrimental to subsequent allotransplantation?

Xenotransplantation 2018 05 14;25(3):e12393. Epub 2018 Apr 14.

Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.

An important question in xenotransplantation is whether an allotransplant can safely be carried out in a patient who has become sensitized to a pig xenograft. To answer this question, we have searched the literature. We primarily limited our review to the clinically relevant pig-to-non-human primate (NHP) model and found five studies that explored this topic. No NHP that had received a pig graft developed antibodies to alloantigens, and in vitro studies indicated no increased humoral and/or cellular alloreactivity. We carried out a small in vitro study ourselves that confirmed this conclusion. There have been three experiments in which patients undergoing dialysis were exposed to wild-type pig kidneys and three clinical studies related to bridging a patient in hepatic failure to liver allotransplantation. Despite the development of anti-pig antibodies, all subsequent organ (kidney or liver) allografts were successful (except possibly in one case). In addition, pig fetal islets were transplanted into patients with kidney allografts; there was no increase in panel-reactive alloantibodies and the kidney grafts continued to function satisfactorily. In conclusion, the limited data suggest that, after sensitization to pig antigens, there is no evidence of antibody-mediated or accelerated cellular rejection of a subsequent allograft.
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http://dx.doi.org/10.1111/xen.12393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005721PMC
May 2018

Immune Responses of HLA Highly Sensitized and Nonsensitized Patients to Genetically Engineered Pig Cells.

Transplantation 2018 05;102(5):e195-e204

Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA.

Background: We investigated in vitro whether HLA highly sensitized patients with end-stage renal disease will be disadvantaged immunologically after a genetically engineered pig kidney transplant.

Methods: Blood was drawn from patients with a calculated panel-reactive antibody (cPRA) 99% to 100% (Gp1, n = 10) or cPRA 0% (Gp2, n = 12), and from healthy volunteers (Gp3, n = 10). Serum IgM and IgG binding was measured (i) to galactose-α1-3 galactose and N-glycolylneuraminic acid glycans by enzyme-linked immunosorbent assay, and (ii) to pig red blood cell, pig aortic endothelial cells, and pig peripheral blood mononuclear cell from α1,3-galactosyltransferase gene-knockout (GTKO)/CD46 and GTKO/CD46/cytidine monophosphate-N-acetylneuraminic acid hydroxylase-knockout (CMAHKO) pigs by flow cytometry. (iii) T-cell and B-cell phenotypes were determined by flow cytometry, and (iv) proliferation of T-cell and B-cell carboxyfluorescein diacetate succinimidyl ester-mixed lymphocyte reaction.

Results: (i) By enzyme-linked immunosorbent assay, there was no difference in IgM or IgG binding to galactose-α1-3 galactose or N-glycolylneuraminic acid between Gps1 and 2, but binding was significantly reduced in both groups compared to Gp3. (ii) IgM and IgG binding in Gps1 and 2 was also significantly lower to GTKO/CD46 pig cells than in healthy controls, but there were no differences between the 3 groups in binding to GTKO/CD46/CMAHKO cells. (iii and iv) Gp1 patients had more memory T cells than Gp2, but there was no difference in T or B cell proliferation when stimulated by any pig cells. The proliferative responses in all 3 groups were weakest when stimulated by GTKO/CD46/CMAHKO pig peripheral blood mononuclear cell.

Conclusions: (i) End-stage renal disease was associated with low antipig antibody levels. (ii) Xenoreactivity decreased with increased genetic engineering of pig cells. (iii) High cPRA status had no significant effect on antibody binding or T-cell and B-cell response.
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http://dx.doi.org/10.1097/TP.0000000000002060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924598PMC
May 2018

Anti-Neu5Gc and anti-non-Neu5Gc antibodies in healthy humans.

PLoS One 2017 17;12(7):e0180768. Epub 2017 Jul 17.

Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, United States of America.

Our group previously investigated the levels of anti-Gal and anti-nonGal IgM and IgG in a cohort of 75 healthy humans of various backgrounds, and found some significant differences related to factors such as age, gender, ABO blood group, diet, vaccination history, and geographic location during childhood. We have now expanded our cohort (n = 84) to investigate the levels of anti-Neu5Gc and anti-nonGal/nonNeu5Gc antibodies in healthy humans. Anti-nonGal and anti-nonGal/nonNeu5Gc human IgM and IgG binding to pRBCs and pAECs from GTKO/CD46 and GTKO/CD46/Neu5GcKO pigs were measured by flow cytometry. Anti-Gal and anti-Neu5Gc IgM and IgG levels were measured by ELISA. In summary, (i) the great majority (almost 100%) of humans had anti-Neu5Gc IgM and IgG antibodies that bound to pAECs and approximately 50% had anti-Neu5Gc antibodies that bound to pRBCs, (ii) there was significantly less human antibody binding to pig cells that did not express either Gal or Neu5Gc compared with those that did not express Gal alone, (iii) the levels of both IgM and IgG binding to GTKO/CD46/Neu5GcKO pRBCs and pAECs were low, (iv) the level of anti-Neu5Gc IgG was higher in men than women, (v) the level did not change with age or diet, and there was some variability associated with (vi) previous vaccination history and (vii) the geographic region in which the individual spent his or her childhood. Our study confirms that human antibody binding to RBCs and AECs from GTKO/CD46/Neu5GcKO pigs is greatly reduced compared to binding to GTKO/CD46 cells. However, all humans appear to have a low level of antibody that binds to pAECs that is not directed to either Gal or Neu5Gc. Our findings require consideration in planning clinical trials of xenotransplantation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180768PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513429PMC
September 2017

Vertically Oriented 2D Layered Perovskite Solar Cells with Enhanced Efficiency and Good Stability.

Small 2017 09 10;13(33). Epub 2017 Jul 10.

State Key Laboratory of Silicon Materials, MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, P. R. China.

Vertically oriented highly crystalline 2D layered (BA) (MA) Pb I (BA = CH (CH ) NH , MA = CH NH , n = 3, 4) perovskite thin-films are fabricated with the aid of ammonium thiocyanate (NH SCN) additive through one-step spin-coating process. The humidity-stability of the film is certified by the almost unchanged X-ray diffraction patterns after exposed to humid atmosphere (H = 55 ± 5%) for 40 d. The photovoltaic devices with the structure of indium tin oxide(ITO)/poly(3,4-ethylenedioxythiophene):poly(styrene-sulfonate)/(BA) (MA) Pb I (n = 3,4)/[6,6]-phenyl-C -butyric acid methyl ester/Bathocuproine/Ag are fabricated. The devices based on (BA) (MA) Pb I perovskite (n = 3) with the precursor composition of BAI:methylammonium iodide:PbI :NH SCN = 2:2:3:1 (by molar ratio) show an averaged power conversion efficiency (PCE) of 6.82%. In the case of (BA) (MA) Pb I (n = 4), a higher PCE of 8.79% is achieved. Both of the unsealed devices perform unique stability with almost unchanged PCE during the period of storage in purified N glove box. This work provides a simple and effective method to enhance the efficiency of the 2D perovskite solar cell.
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http://dx.doi.org/10.1002/smll.201700611DOI Listing
September 2017

The impact of serum incubation time on IgM/IgG binding to porcine aortic endothelial cells.

Xenotransplantation 2017 07 25;24(4). Epub 2017 May 25.

Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, USA.

The results of the assay for measuring anti-non-Gal antibodies (which affect pig xenograft survival) in recipients are important. Serum incubation time and concentration may be important factors in the extent of antibody binding to the graft. The aim of this in vitro study was to determine the optimal incubation time and serum concentration for measuring anti-non-Gal antibody binding to porcine aortic endothelial cells (pAECs). Pooled human, naive, and sensitized baboon sera were incubated with wild-type, α1,3-galactosyltransferase gene-knockout (GTKO), and GTKO/human CD55 pAECs. IgM/IgG binding to pAECs after varying serum incubation times (0.5, 1, 2, and 3 hour) and concentrations (5, 10, 20, and 40 μL) was determined by flow cytometry. An increase in incubation time from 30 minutes to 2 hour was associated with increases in anti-non-Gal IgM/IgG binding to GTKO and GTKO/hCD55 pAECs of pooled human, naive and sensitized baboon sera (P<.05). Pooled human serum showed a significant increase in anti-non-Gal IgM (1.5 times) and a minimal increase in anti-non-Gal IgG antibody binding. IgM/IgG binding of sensitized baboon serum to GTKO pAECs after 2-hour incubation was 1.5 times and 2 times greater than after 30-minutes incubation, respectively, whereas naïve baboon sera showed minimal (non-significant) increase in anti-non-Gal IgM/IgG antibody binding. With 2-hour incubation, increasing the serum concentration from 5 μL to 20 μL significantly increased antibody binding to non-Gal antigens in pooled human and sensitized baboon serum. With naïve baboon serum, only IgG was significantly increased. Increasing the serum incubation time contributed to improve the sensitivity of detecting anti-non-Gal antibodies, without affecting cell viability in vitro.
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http://dx.doi.org/10.1111/xen.12312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546950PMC
July 2017

Immunological and physiological observations in baboons with life-supporting genetically engineered pig kidney grafts.

Xenotransplantation 2017 03 17;24(2). Epub 2017 Mar 17.

Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.

Background: Genetically engineered pigs could provide a source of kidneys for clinical transplantation. The two longest kidney graft survivals reported to date have been 136 and 310 days, but graft survival >30 days has been unusual until recently.

Methods: Donor pigs (n=4) were on an α1,3-galactosyltransferase gene-knockout (GTKO)/human complement regulatory protein (CD46) background (GTKO/CD46). In addition, the pigs were transgenic for at least one human coagulation regulatory protein. Two baboons received a kidney from a six-gene pig (GroupA) and two from a three-gene pig (GroupB). Immunosuppressive therapy was identical in all four cases and consisted of anti-thymoglobulin (ATG)+anti-CD20mAb (induction) and anti-CD40mAb+rapamycin+corticosteroids (maintenance). Anti-TNF-α and anti-IL-6R mAbs were administered to reduce the inflammatory response. Baboons were followed by clinical/laboratory monitoring of immune/coagulation/inflammatory/physiological parameters. At biopsy or euthanasia, the grafts were examined by microscopy.

Results: The two GroupA baboons remained healthy with normal renal function >7 and >8 months, respectively, but then developed infectious complications. However, no features of a consumptive coagulopathy, eg, thrombocytopenia and reduction of fibrinogen, or of a protein-losing nephropathy were observed. There was no evidence of an elicited anti-pig antibody response, and histology of biopsies taken at approximately 4, 6, and 7 months and at necropsy showed no significant abnormalities. In contrast, both GroupB baboons developed features of a consumptive coagulopathy and required euthanasia on day 12.

Conclusions: The combination of (i) a graft from a specific six-gene genetically modified pig, (ii) an effective immunosuppressive regimen, and (iii) anti-inflammatory therapy prevented immune injury, a protein-losing nephropathy, and coagulation dysfunction for >7 months. Although the number of experiments is very limited, our impression is that expression of human endothelial protein C receptor (±CD55) in the graft is important if coagulation dysregulation is to be avoided.
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http://dx.doi.org/10.1111/xen.12293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5397334PMC
March 2017

Molecular electron acceptors for efficient fullerene-free organic solar cells.

Phys Chem Chem Phys 2017 Feb;19(5):3440-3458

MOE Key Laboratory of Macromolecular Synthesis and Functionalization, State Key Laboratory of Silicon Materials, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, P. R. China.

Nowadays, organic solar cells (OSCs) with efficiencies over 10% have been achieved through the elaborate design of electron donors and fullerene acceptors. However, the drawbacks of fullerene acceptors, like poor absorption, limited chemical and energetic tunabilities, high-cost purification and morphological instability, have become the bottlenecks for the further improvement of OSCs. To overcome the mentioned shortages from fullerene, research studies on non-fullerene electron acceptors have boomed. To date, the highest efficiency of fullerene-free OSCs has been pushed to be 12%, which surpasses that of fullerene-based OSCs. In this perspective, we focus on summarizing the development of small molecule electron acceptors designed to replace the fullerene derivatives. Since it has been revealed that the search for matched donor:acceptor pairs is important for accomplishing high efficiencies, we therefore divide electron acceptors into several categories according to the donors used in fullerene-free OSCs. After the introduction of these acceptors, we outline the designing rules as well as perspectives for the development of non-fullerene acceptors. We believe that the development of non-fullerene electron acceptors will make organic photovoltaics closer to practical applications.
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http://dx.doi.org/10.1039/c6cp07465kDOI Listing
February 2017

Matrine‑induced apoptosis in Hep3B cells via the inhibition of MDM2.

Mol Med Rep 2017 Jan 7;15(1):442-450. Epub 2016 Dec 7.

Department of Organ Transplantation and General Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China.

Matrine, an alkaloid component derived from the Sophora root, can inhibit cancer cell proliferation and induce autophagy via p53 associated pathways. However, numerous tumor cells lack functional p53 and little is known about the effect of matrine on the p53‑deficient/mutant cancer cells. The present study aimed to assess anticancer effects of matrine in p53‑deficient human Hep3B hepatoma cells. The present results demonstrated that matrine caused Hep3B cell apoptosis by suppressing gene expression of minute double‑mutant (MDM)2. Notably, it was revealed that matrine inhibited MDM2 at the transcriptional level in a time‑ and dose‑dependent manner. This MDM2 inhibition resulted in induction of the p53 family member, p73; however, the functions of p73 were not induced since matrine‑induced p73 failed to activate its target genes, p21 and p53 upregulated modulator of apoptosis. The matrine‑induced downregulation of MDM2 led to an inhibition of inhibitor of apoptosis protein 3, which might serve a critical role in matrine‑induced apoptosis in MDM2‑overexpressing Hep3B cells. Finally, combination therapy of matrine with 100 µM epotoside successfully killed more Hep3B cells, suggesting that matrine can sensitize p53‑deficient Hep3B cells to epotoside‑induced apoptosis.
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http://dx.doi.org/10.3892/mmr.2016.5999DOI Listing
January 2017

Polymorphic Phase-Dependent Optical and Electrical Properties of a Diketopyrrolopyrrole-Based Small Molecule.

ACS Appl Mater Interfaces 2016 Aug 2;8(32):20916-27. Epub 2016 Aug 2.

State Key Laboratory of Silicon Materials, MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University , 38 Zheda Road, Hangzhou 310027, P. R. China.

Four different polymorphic conformations of diethyl 5,5'-[5,5'-[2,5-bis(2-ethylhexyl)-3,6-dioxo-2,3,5,6-tetrahydropyrrolo[3,4-c]pyrrole-1,4-diyl]bis(thiophene-5,2-diyl)]difuran-2-carboxylate (DPP-(CF)2), namely, DPP-(CF)2-α, DPP-(CF)2-β, DPP-(CF)2-γ, and DPP-(CF)2-ω, were identified from X-ray diffraction analysis conducted on their thin films and single crystals. Highly crystalline and well-textured thin films of these four polymorphs were successfully prepared via postgrowth solvent vapor and thermal annealing treatments to investigate the polymorphic phase-dependent optical and electrical properties of DPP-(CF)2. Interestingly, during the phase transition from DPP-(CF)2-α to DPP-(CF)2-ω, the optical band gap decreases from 1.75 to 1.5 eV because of the enhanced π-π interaction between the neighboring molecules. Except for DPP-(CF)2-γ, the other three phases show ambipolar charge transport. Although DPP-(CF)2-β and DPP-(CF)2-γ exhibit a similar way of packing, a small increment in the π-π-stacking distance (0.006 Å) and twist conformation of the grafted electron-donating moieties of DPP-(CF)2-γ are found to reduce its hole mobility.
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http://dx.doi.org/10.1021/acsami.6b05084DOI Listing
August 2016

Long non-coding RNA CCAT2 functions as an oncogene in hepatocellular carcinoma, regulating cellular proliferation, migration and apoptosis.

Oncol Lett 2016 Jul 16;12(1):132-138. Epub 2016 May 16.

Department of Organ Transplantation and General Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China.

An increasing number of studies have demonstrated that the dysregulation of long non-coding RNAs (lncRNAs) may serve an important role in tumor progression. Previous studies have reported that the lncRNA, colon cancer associated transcript 2 (CCAT2), was highly expressed in various tumors. However, the function of CCAT2 in hepatocellular carcinoma (HCC) has not yet been elucidated. The aim of the present study was to identify novel oncogene lncRNAs and investigate their physiological function and mechanism in HCC. Using reverse transcription-quantitative polymerase chain reaction, it was observed that CCAT2 was upregulated in HCC tissues and human HCC cell lines. Furthermore, the impacts of CCAT2 on cell proliferation, migration and apoptosis were analyzed using cell migration, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and enzyme-linked immunosorbent assay analysis respectively. The overexpression of CCAT2 using a synthesized vector significantly promoted cell migration and proliferation, and inhibited apoptosis of HCC cells . The suppression of CCAT2 expression resulted in opposing effects. To the best of our knowledge, the present study is the first to demonstrate that CCAT2 functions as a oncogene in HCC. Further investigation is required to clarify the molecular mechanisms of this lncRNA in HCC development.
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http://dx.doi.org/10.3892/ol.2016.4580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906942PMC
July 2016

Controllable deformation of salt water-filled carbon nanotubes using an electric field with application to molecular sieving.

Nanotechnology 2016 Aug 23;27(31):315702. Epub 2016 Jun 23.

State Key Laboratory of Structural Analysis for Industrial Equipment, Department of Engineering Mechanics, Faculty of Vehicle Engineering and Mechanics, Dalian University of Technology, Dalian 116024, People's Republic of China.

Precisely controlling the deformation of carbon nanotubes (CNTs) has practical application in the development of nanoscale functional devices, although it is a challenging task. Here, we propose a novel method to guide the deformation of CNTs through filling them with salt water and applying an electric field. With the electric field along the axial direction, the height of CNTs is enlarged by the axial electric force due to the internal ions and polar water molecules. Under an electric field with two mutually orthogonal components, the transverse electric force could further induce the bending deformation of CNTs. Based on the classical rod and beam theories, two mechanical models are constructed to verify and quantitatively describe the relationships between the tension and bending deformations of CNTs and the electric field intensity. Moreover, by means of the electric field-driven tension behavior of CNTs, we design a stretchable molecular sieve to control the flow rate of mixed gas and collect a single high-purity gas. The present work opens up new avenues in the design and fabrication of nanoscale controlling units.
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http://dx.doi.org/10.1088/0957-4484/27/31/315702DOI Listing
August 2016

Dopant-Free Hole-Transporting Material with a C3h Symmetrical Truxene Core for Highly Efficient Perovskite Solar Cells.

J Am Chem Soc 2016 Mar 18;138(8):2528-31. Epub 2016 Feb 18.

MOE Key Laboratory of Macromolecular Synthesis and Functionalization, State Key Laboratory of Silicon Materials, Department of Polymer Science and Engineering, Zhejiang University , Hangzhou 310027, P. R. China.

Herein we present a new structural design of hole-transporting material, Trux-OMeTAD, which consists of a C3h Truxene-core with arylamine terminals and hexyl side-chains. This planar, rigid, and fully conjugated molecule exhibits excellent hole mobility and desired surface energy to the perovskite uplayer. Perovskite solar cells fabricated using the p-i-n architecture with Trux-OMeTAD as the p-layer, show a high PCE of 18.6% with minimal hysteresis.
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http://dx.doi.org/10.1021/jacs.6b00039DOI Listing
March 2016

Clinical efficacy of second-generation tyrosine kinase inhibitors in imatinib-resistant gastrointestinal stromal tumors: a meta-analysis of recent clinical trials.

Drug Des Devel Ther 2014 30;8:2061-7. Epub 2014 Oct 30.

Department of General Surgery, Second Xiangya Hospital of Central South University, Changsha, People's Republic of China.

Background: Primary and secondary resistance to imatinib, a selective receptor tyrosine kinase inhibitor (TKI), is a serious clinical problem in the control of advanced gastrointestinal stromal tumors (GIST). Here we report on a meta-analysis we performed to evaluate the efficacy of second-generation TKIs in the treatment of patients with imatinib-resistant GIST.

Methods: Randomized controlled trials evaluating the clinical efficacy of second-generation TKIs were identified by searching PubMed and EMBASE from 2000 to February 2014. Outcomes subjected to analysis were progression-free survival and overall survival. Statistical analyses were performed using Review Manager version 5.1.0 (Cochrane Collaboration, Oxford, UK). Weighted hazard ratios (HR) with 95% confidence intervals (CIs) were calculated for the outcomes. Fixed-effects or random-effects models were used, depending on the degree of heterogeneity across the selected studies.

Results: Three randomized controlled trials were selected for meta-analysis. Among imatinib-resistant or imatinib-intolerant patients, 541 received second-generation TKIs (sunitinib, nilotinib, or regorafenib) and 267 controls received placebo or best supportive care. Progression-free survival was significantly improved in the TKI-treated group (HR 0.38; 95% CI 0.24-0.59; P<0.0001). No statistically significant difference was detected in overall survival between the treatment group and the control group (HR 0.85; 95% CI 0.71-1.03; P=0.09). In the subgroup of patients who were resistant or intolerant to both imatinib and sunitinib, TKI therapy (nilotinib or regorafenib) improved progression-free survival (HR 0.40; 95% CI 0.19-0.84; P=0.02) but not overall survival (HR 0.83; 95% CI 0.63-1.08; P=0.17). Regorafenib was shown to be effective in terms of progression-free survival across different subpopulations of patients who were resistant to both imatinib and sunitinib.

Conclusion: Second-generation TKIs (sunitinib, nilotinib, and regorafenib) are effective in improving progression-free survival but not overall survival in patients with GIST who are resistant or intolerant to imatinib or to imatinib and sunitinib. Regorafenib is promising as a third-line treatment option for patients with advanced GIST.
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http://dx.doi.org/10.2147/DDDT.S63840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4219427PMC
August 2015

Size and temperature effects on the viscosity of water inside carbon nanotubes.

Nanoscale Res Lett 2011 Jan 17;6(1):87. Epub 2011 Jan 17.

State Key Laboratory of Structural Analysis for Industrial Equipment, Department of Engineering Mechanics, Faculty of Vehicle Engineering and Mechanics, Dalian University of Technology, Dalian 116023, China.

The influences of the diameter (size) of single-walled carbon nanotubes (SWCNTs) and the temperature on the viscosity of water confined in SWCNTs are investigated by an "Eyring-MD" (molecular dynamics) method. The results suggest that the relative viscosity of the confined water increases with increasing diameter and temperature, whereas the size-dependent trend of the relative viscosity is almost independent of the temperature. Based on the computational results, a fitting formula is proposed to calculate the size- and temperature- dependent water viscosity, which is useful for the computation on the nanoflow. To demonstrate the rationality of the calculated relative viscosity, the relative amount of the hydrogen bonds of water confined in SWCNTs is also computed. The results of the relative amount of the hydrogen bonds exhibit similar profiles with the curves of the relative viscosity. The present results should be instructive for understanding the coupling effect of the size and the temperature at the nanoscale.
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http://dx.doi.org/10.1186/1556-276X-6-87DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3212236PMC
January 2011
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