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1.  Knockdown of Long Non-Coding RNA UCA1 Increases the Tamoxifen Sensitivity of Breast Cancer Cells through Inhibition of Wnt/β-Catenin Pathway 
PLoS ONE  2016;11(12):e0168406.
Acquired resistance to tamoxifen remains a major obstacle in breast cancer (BC) treatment, since the underlying mechanism has not been fully elucidated. The long non-coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) has been recently shown to be dysregulated and plays important roles in progression of breast cancer. In the present study, we aimed to investigate the biological role and clinical significance of UCA1 in BC drug resistance. Hence, we used quantitative PCR assay to evaluate the UCA1 expression in tissues from patients with BC as well as established tamoxifen-resistant BC cell lines in vitro. We tested the viability, invasive ability and apoptosis rate in MCF-7 and T47D cells using MTT assay, transwell assay and flow cytometry assay, respectively. The influence of UCA1 on tumorigenesis was monitored by in vivo mice xenograft model. The activation of Wnt/β-catenin signaling pathway was evaluated by immunofluorescence assay, western blot assay and luciferase reporter assay, respectively. We found that the expression of UCA1 positively correlated with the pathological grade and mortality of breast cancer patients, moreover, expressions of UCA1 was increased significantly in the tamoxifen-resistant cell lines compared with the wild type parental cells. Ectopic expression of UCA1 promoted cell survival and resistance to tamoxifen treatment, whereas inhibition of UCA1 enhanced tamoxifen sensitivity of BC cells and induced more apoptotic cells. In addition, tamoxifen-resistant cells exhibited increased Wnt signaling activation as measured by the TOP/FOP Wnt luciferase reporter assay and β-catenin protein level compared with parental MCF-7 and T47D cells, respectively. In line with these data, UCA1 depletion attenuated the activity of Wnt/β-catenin pathway activation and the tumorigenicity of the tamoxifen-resistant BC cells. Taken together, our data highlights the pivotal role of UCA1-Wnt/β-catenin signaling pathway in the tamoxifen resistance in breast cancer, which could be targeted to improve the effectiveness and efficacy of tamoxifen treatment in breast cancer.
doi:10.1371/journal.pone.0168406
PMCID: PMC5158064  PMID: 27977766
2.  Fossil record of stem groups employed in evaluating the chronogram of insects (Arthropoda: Hexapoda) 
Scientific Reports  2016;6:38939.
Insecta s. str. (=Ectognatha), comprise the largest and most diversified group of living organisms, accounting for roughly half of the biodiversity on Earth. Understanding insect relationships and the specific time intervals for their episodes of radiation and extinction are critical to any comprehensive perspective on evolutionary events. Although some deeper nodes have been resolved congruently, the complete evolution of insects has remained obscure due to the lack of direct fossil evidence. Besides, various evolutionary phases of insects and the corresponding driving forces of diversification remain to be recognized. In this study, a comprehensive sample of all insect orders was used to reconstruct their phylogenetic relationships and estimate deep divergences. The phylogenetic relationships of insect orders were congruently recovered by Bayesian inference and maximum likelihood analyses. A complete timescale of divergences based on an uncorrelated log-normal relaxed clock model was established among all lineages of winged insects. The inferred timescale for various nodes are congruent with major historical events including the increase of atmospheric oxygen in the Late Silurian and earliest Devonian, the radiation of vascular plants in the Devonian, and with the available fossil record of the stem groups to various insect lineages in the Devonian and Carboniferous.
doi:10.1038/srep38939
PMCID: PMC5154178  PMID: 27958352
3.  Hydrogen sulphide exacerbates acute pancreatitis by over‐activating autophagy via AMPK/mTOR pathway 
Abstract
Previously, we have shown that hydrogen sulphide (H2S) might be pro‐inflammatory during acute pancreatitis (AP) through inhibiting apoptosis and subsequently favouring a predominance of necrosis over apoptosis. In this study, we sought to investigate the detrimental effects of H2S during AP specifically with regard to its regulation on the impaired autophagy. The incubated levels of H2S were artificially intervened by an administration of sodium hydrosulphide (NaHS) or DL‐propargylglycine (PAG) after AP induction. Accumulation of autophagic vacuoles and pre‐mature activation of trypsinogen within acini, which indicate the impairment of autophagy during AP, were both exacerbated by treatment with NaHS but attenuated by treatment with PAG. The regulation that H2S exerted on the impaired autophagy during AP was further attributed to over‐activation of autophagy rather than hampered autophagosome–lysosome fusion. To elucidate the molecular mechanism that underlies H2S‐mediated over‐activation of autophagy during AP, we evaluated phosphorylations of AMP‐activated protein kinase (AMPK), AKT and mammalian target of rapamycin (mTOR). Furthermore, Compound C (CC) was introduced to determine the involvement of mTOR signalling by evaluating phosphorylations of downstream effecters including p70 S6 kinase (P70S6k) and UNC‐51‐Like kinase 1 (ULK1). Our findings suggested that H2S exacerbated taurocholate‐induced AP by over‐activating autophagy via activation of AMPK and subsequently, inhibition of mTOR. Thus, an active suppression of H2S to restore over‐activated autophagy might be a promising therapeutic approach against AP‐related injuries.
doi:10.1111/jcmm.12928
PMCID: PMC5134374  PMID: 27419805
acute pancreatitis; hydrogen sulphide; impaired autophagy; AMPK; mTOR
4.  Potential of Lactobacillus plantarum CCFM639 in Protecting against Aluminum Toxicity Mediated by Intestinal Barrier Function and Oxidative Stress 
Nutrients  2016;8(12):783.
Aluminum (Al) is a ubiquitous metal that can seriously harm the health of animals and humans. In our previous study, we demonstrated that Lactobacillus plantarum CCFM639 can decrease Al burden in the tissues of mice by inhibiting intestinal Al absorption. The main aim of the present research was to investigate whether the protection by the strain is also associated with enhancement of the intestinal barrier, alleviation of oxidative stress and modulation of the inflammatory response. In an in vitro cell model, two protection modes (intervention and therapy) were examined and the results indicated that L. plantarum CCFM639 alleviated Al-induced cytotoxicity. In a mouse model, L. plantarum CCFM639 treatment was found to significantly alleviate oxidative stress in the intestinal tract, regulate the function of the intestinal mucosal immune system, restore the integrity of tight junction proteins and maintain intestinal permeability. These results suggest that in addition to Al sequestration, L. plantarum CCFM639 can also inhibit Al absorption by protecting the intestinal barrier, alleviating Al-induced oxidative stress and inflammatory response. Therefore, L. plantarum CCFM639 has the potential to be a dietary supplement ingredient that provides protection against Al-induced gut injury.
doi:10.3390/nu8120783
PMCID: PMC5188438  PMID: 27918411
probiotic; lactic acid bacteria; Lactobacillus plantarum; aluminum; protection; gut health
5.  A novel process of viral vector barcoding and library preparation enables high-diversity library generation and recombination-free paired-end sequencing 
Scientific Reports  2016;6:37563.
Detailed characterization and mapping of oligonucleotide function in vivo is generally a very time consuming effort that only allows for hypothesis driven subsampling of the full sequence to be analysed. Recent advances in deep sequencing together with highly efficient parallel oligonucleotide synthesis and cloning techniques have, however, opened up for entirely new ways to map genetic function in vivo. Here we present a novel, optimized protocol for the generation of universally applicable, barcode labelled, plasmid libraries. The libraries are designed to enable the production of viral vector preparations assessing coding or non-coding RNA function in vivo. When generating high diversity libraries, it is a challenge to achieve efficient cloning, unambiguous barcoding and detailed characterization using low-cost sequencing technologies. With the presented protocol, diversity of above 3 million uniquely barcoded adeno-associated viral (AAV) plasmids can be achieved in a single reaction through a process achievable in any molecular biology laboratory. This approach opens up for a multitude of in vivo assessments from the evaluation of enhancer and promoter regions to the optimization of genome editing. The generated plasmid libraries are also useful for validation of sequencing clustering algorithms and we here validate the newly presented message passing clustering process named Starcode.
doi:10.1038/srep37563
PMCID: PMC5118689  PMID: 27874090
6.  Functional Region Annotation of Liver CT Image Based on Vascular Tree 
BioMed Research International  2016;2016:5428737.
Anatomical analysis of liver region is critical in diagnosis and treatment of liver diseases. The reports of liver region annotation are helpful for doctors to precisely evaluate liver system. One of the challenging issues is to annotate the functional regions of liver through analyzing Computed Tomography (CT) images. In this paper, we propose a vessel-tree-based liver annotation method for CT images. The first step of the proposed annotation method is to extract the liver region including vessels and tumors from the CT scans. And then a 3-dimensional thinning algorithm is applied to obtain the spatial skeleton and geometric structure of liver vessels. With the vessel skeleton, the topology of portal veins is further formulated by a directed acyclic graph with geometrical attributes. Finally, based on the topological graph, a hierarchical vascular tree is constructed to divide the liver into eight segments according to Couinaud classification theory and thereby annotate the functional regions. Abundant experimental results demonstrate that the proposed method is effective for precise liver annotation and helpful to support liver disease diagnosis.
doi:10.1155/2016/5428737
PMCID: PMC5116550  PMID: 27891516
7.  Understanding Doping, Vacancy, Lattice Stability, and Superconductivity in KxFe2− ySe2  
Advanced Science  2016;3(10):1600098.
Metal‐intercalated iron selenides are a class of superconductors that have received much attention but are less understood in comparison with their FeAs‐based counterparts. Here, the controversial issues such as Fe vacancy, the real phase responsible for superconductivity, and lattice stability have been addressed based on first‐principles calculations. New insights into the distinct features in terms of carrier doping have been revealed.
doi:10.1002/advs.201600098
PMCID: PMC5096254  PMID: 27840799
density functional calculations; metal‐intercalated iron selenides; phase diagrams; superconductors
8.  Comprehensive proteomic analysis of developing protein bodies in maize (Zea mays) endosperm provides novel insights into its biogenesis 
Journal of Experimental Botany  2016;67(22):6323-6335.
Highlight
Proteomic analysis of developing maize protein bodies (PBs) reveals an unexpected diversity and complexity of PB proteins, and provides a roadmap for the transport and translation of mRNAs of zein genes, and the assembly of PBs.
Prolamins, the major cereal seed storage proteins, are sequestered and accumulated in the lumen of the endoplasmic reticulum (ER), and are directly assembled into protein bodies (PBs). The content and composition of prolamins are the key determinants for protein quality and texture-related traits of the grain. Concomitantly, the PB-inducing fusion system provides an efficient target to produce therapeutic and industrial products in plants. However, the proteome of the native PB and the detailed mechanisms underlying its formation still need to be determined. We developed a method to isolate highly purified and intact PBs from developing maize endosperm and conducted proteomic analysis of intact PBs of zein, a class of prolamine protein found in maize. We thus identified 1756 proteins, which fall into five major categories: metabolic pathways, response to stimulus, transport, development, and growth, as well as regulation. By comparing the proteomes of crude and enriched extractions of PBs, we found substantial evidence for the following conclusions: (i) ribosomes, ER membranes, and the cytoskeleton are tightly associated with zein PBs, which form the peripheral border; (ii) zein RNAs are probably transported and localized to the PB–ER subdomain; and (iii) ER chaperones are essential for zein folding, quality control, and assembly into PBs. We futher confirmed that OPAQUE1 (O1) cannot directly interact with FLOURY1 (FL1) in yeast, suggesting that the interaction between myosins XI and DUF593-containing proteins is isoform-specific. This study provides a proteomic roadmap for dissecting zein PB biogenesis and reveals an unexpected diversity and complexity of proteins in PBs.
doi:10.1093/jxb/erw396
PMCID: PMC5181578  PMID: 27789589
Endosperm; prolamin; protein body; proteomic; storage protein; Zea mays.
9.  Simvastatin induces cell cycle arrest and inhibits proliferation of bladder cancer cells via PPARγ signalling pathway 
Scientific Reports  2016;6:35783.
Simvastatin is currently one of the most common drugs for old patients with hyperlipidemia, hypercholesterolemia and atherosclerotic diseases by reducing cholesterol level and anti-lipid properties. Importantly, simvastatin has also been reported to have anti-tumor effect, but the underlying mechanism is largely unknown. We collected several human bladder samples and performed microarray. Data analysis suggested bladder cancer (BCa) was significantly associated with fatty acid/lipid metabolism via PPAR signalling pathway. We observed simvastatin did not trigger BCa cell apoptosis, but reduced cell proliferation in a dose- and time-dependent manner, accompanied by PPARγ-activation. Moreover, flow cytometry analysis indicated that simvastatin induced cell cycle arrest at G0/G1 phase, suggested by downregulation of CDK4/6 and Cyclin D1. Furthermore, simvastatin suppressed BCa cell metastasis by inhibiting EMT and affecting AKT/GSK3β. More importantly, we found that the cell cycle arrest at G0/G1 phase and the alterations of CDK4/6 and Cyclin D1 triggered by simvastatin could be recovered by PPARγ-antagonist (GW9662), whereas the treatment of PPARα-antagonist (GW6471) shown no significant effects on the BCa cells. Taken together, our study for the first time revealed that simvastatin inhibited bladder cancer cell proliferation and induced cell cycle arrest at G1/G0 phase via PPARγ signalling pathway.
doi:10.1038/srep35783
PMCID: PMC5078845  PMID: 27779188
10.  New Initiation Modes for Directed Carbonylative C–C Bond Activation: Rhodium-Catalyzed (3 + 1 + 2) Cycloadditions of Aminomethylcyclopropanes 
Journal of the American Chemical Society  2016;138(41):13501-13504.
Under carbonylative conditions, neutral Rh(I)-systems modified with weak donor ligands (AsPh3 or 1,4-oxathiane) undergo N-Cbz, N-benzoyl, or N-Ts directed insertion into the proximal C–C bond of aminomethylcyclopropanes to generate rhodacyclopentanone intermediates. These are trapped by N-tethered alkenes to provide complex perhydroisoindoles.
doi:10.1021/jacs.6b08608
PMCID: PMC5073370  PMID: 27709913
11.  Immunomodulatory Effects of Different Lactic Acid Bacteria on Allergic Response and Its Relationship with In Vitro Properties 
PLoS ONE  2016;11(10):e0164697.
Some studies reported that probiotic could relieve allergy-induced damage to the host, but how to get a useful probiotic is still a challenge. In this study, the protective effects of three lactic acid bacteria (La, Lp and Lc) were evaluated in a mouse model, and its relationship with the in vitro properties was analyzed. The in vitro results indicated that La with the capacity to inhibit IL-4 production could have a better anti-allergy effect in vivo than two others. However, the animal trials showed that all LAB strains could alleviate allergen-induced airway inflammation. Among them, LAB strain Lp had a better effect in inhibiting allergic response through a modulation of Th1/Th2 balance and an increase of regulatory T cells. This difference could be explained by that different LAB strains have a strain-specific effect on gut microbiota closely associated with host immune responses. Finally, this study did not only obtain an effective anti-allergy probiotic strain via animal study, but also indicate that probiotic-induced effect on intestinal microbiota should be considered as an important screening index, apart from its inherent characteristics.
doi:10.1371/journal.pone.0164697
PMCID: PMC5072832  PMID: 27764153
12.  Maize ZmVPP5 is a truncated Vacuole H+‐PPase that confers hypersensitivity to salt stress 
Abstract
In plants, Vacuole H+‐PPases (VPPs) are important proton pumps and encoded by multiple genes. In addition to full‐length VPPs, several truncated forms are expressed, but their biological functions are unknown. In this study, we functionally characterized maize vacuole H+‐PPase 5 (ZmVPP5), a truncated VPP in the maize genome. Although ZmVPP5 shares high sequence similarity with ZmVPP1, ZmVPP5 lacks the complete structure of the conserved proton transport and the inorganic pyrophosphatase‐related domain. Phylogenetic analysis suggests that ZmVPP5 might be derived from an incomplete gene duplication event. ZmVPP5 is expressed in multiple tissues, and ZmVPP5 was detected in the plasma membrane, vacuole membrane and nuclei of maize cells. The overexpression of ZmVPP5 in yeast cells caused a hypersensitivity to salt stress. Transgenic maize lines with overexpressed ZmVPP5 also exhibited the salt hypersensitivity phenotype. A yeast two‐hybrid analysis identified the ZmBag6‐like protein as a putative ZmVPP5‐interacting protein. The results of bimolecular luminescence complementation (BiLC) assay suggest an interaction between ZmBag6‐like protein and ZmVPP5 in vivo. Overall, this study suggests that ZmVPP5 might act as a VPP antagonist and participate in the cellular response to salt stress. Our study of ZmVPP5 has expanded the understanding of the origin and functions of truncated forms of plant VPPs.
doi:10.1111/jipb.12462
PMCID: PMC5071666  PMID: 26728417
Maize; salt stress; vacuole H+‐PPases; ZmBag6‐like protein; ZmVPP5
13.  Robust ultra-low-friction state of graphene via moiré superlattice confinement 
Nature Communications  2016;7:13204.
Two-dimensional (2D) materials possess outstanding lubrication property with their thicknesses down to a few atomic layers, but they are easily susceptible to sliding induced degradation or ubiquitous chemical modification. Maintaining the superior lubricating performance of 2D materials in a harsh working environment is highly desirable yet grandly challenging. Here we show that by proper alignment of graphene on a Ge(111) substrate, friction of graphene could be well preserved at an ultra-low level even after fluorination or oxidation. This behaviour is experimentally found to be closely related to the suppression of molecular-level deformation of graphene within the moiré superlattice structure. Atomistic simulations reveal that the formation of an interconnected meshwork with enhanced interfacial charge density imposes a strong anchoring effect on graphene even under chemical modification. Modulating molecular-level deformation by interfacial confinements may offer a unique strategy for tuning the mechanical or even chemical properties of 2D materials.
Two-dimensional materials show remarkable lubrication properties, yet chemical modifications may hinder such capabilities. Here, the authors show that when graphene is aligned on a Ge(111) substrate, ultra-low friction can be preserved even after graphene fluorination or oxidation.
doi:10.1038/ncomms13204
PMCID: PMC5075778  PMID: 27759019
14.  Enhanced Emission of Quantum System in Si-Ge Nanolayer Structure 
It is very interesting that the enhanced peaks near 1150 and 1550 nm are observed in the photoluminescence (PL) spectra in the quantum system of Si-Ge nanolayer structure, which have the emission characteristics of a three-level system with quantum dots (QDs) pumping and emission of quasi-direct-gap band, in our experiment. In the preparing process of Si-Ge nanolayer structure by using a pulsed laser deposition method, it is discovered that the nanocrystals of Si and Ge grow in the (100) and (111) directions after annealing or electron beam irradiation. The enhanced PL peaks with multi-longitudinal-mode are measured at room temperature in the super-lattice of Si-Ge nanolayer quantum system on SOI.
doi:10.1186/s11671-016-1682-4
PMCID: PMC5069211  PMID: 27757943
Quantum system; Si-Ge nanolayer structure; (100) and (111) direction; Super-lattice
15.  Capsaicin mediates caspases activation and induces apoptosis through P38 and JNK MAPK pathways in human renal carcinoma 
BMC Cancer  2016;16:790.
Background
Renal cell carcinoma (RCC) is one of the tumors most refractory to chemotherapy to date. Therefore, novel therapeutic agents are urgently needed for this disease. Capsaicin (CPS), a natural active ingredient of green and red peppers, and a ligand of transient receptor potential vanilloid type 1 (TRPV1), has been showed potential in suppression of tumorigenesis of several cancers. Nonetheless, the anti-cancer activity of CPS has never been studied in human RCC.
Methods
CCK8 analysis, LDH release activity and ROS generation analysis, flow cytometry analysis, and nuclear staining test were performed to test the influence of CPS in cultured cells in vitro, meanwhile western blot was done to uncover the precise molecular mechanisms. 786-O renal cancer xenografts were builded to investigate the antitumor activity of CPS in vivo.
Results
We found treatment of CPS reduced proliferation of renal carcinoma cells, which could be attenuated by TRPV1 representative antagonist capsazepine (CPZ). CPS induced obvious apoptosis in renal carcinoma cells. These events were associated with substantial up-regulation of pro-apoptotic genes including c-myc, FADD, Bax and cleaved-caspase-3, -8, and -9, while down-regulation of anti-apoptotic gene Bcl2. Besides, CPS-treatment activated P38 and JNK MAPK pathways, yet P38 and JNK inhibitors afforded protection against CPS-induced apoptosis by abolishing activation of caspase-3, -8, and -9. Furthermore, CPS significantly slowed the growth of 786-O renal cancer xenografts in vivo.
Conclusions
Such results reveal that CPS is an efficient and potential drug for management of human RCC.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-016-2831-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-016-2831-y
PMCID: PMC5059898  PMID: 27729033
Capsaicin; Renal cell carcinoma; TRPV1; Caspases; Apoptosis; MAPK
16.  Rrp15 affects cell cycle, proliferation, and apoptosis in NIH3T3 cells 
FEBS Open Bio  2016;6(11):1085-1092.
Riken 2810430M08 (hereinafter referred to as Rrp15) is a newly identified and reported gene from the mouse genome. In our previous work, we found that the gene had a relationship with the proliferation and activation of T cells. Rrp15 protein is highly homologous with RRP15 (budding yeast), which has an important role in ribosomal RNA processing. We explored the potential function of Rrp15 in apoptosis, cell proliferation, and its involvement with RNA in the nucleus. We constructed a knockdown of the Rrp15 gene in NIH3T3 cells and then performed real‐time PCR, western blotting, flow cytometry, and immunofluorescence to determine the function of the Rrp15 gene. Knockdown of the Rrp15 gene suppresses proliferation and induces apoptosis. We also found that the Rrp15 protein was normally distributed in the nucleus and bound to RNA or pre‐RNA in the nucleus. Additionally, Rrp15 altered the activity of the 20S proteasome. Rrp15 promotes proliferation and inhibits apoptosis in NIH3T3 cells and may have a relationship with RNA in the nucleus.
doi:10.1002/2211-5463.12128
PMCID: PMC5095146  PMID: 27833849
cell proliferation and apoptosis; NIH3T3 cell; RNA binding; Rrp15 gene
17.  “Fast-track” and “Minimally Invasive” Surgery for Gastric Cancer 
Chinese Medical Journal  2016;129(19):2294-2300.
Background:
Enhanced recovery after surgery (ERAS) protocols or fast-track (FT) programs enable a shorter hospital stay and lower complication rate. Minimally invasive surgery (MIS) is associated with a lesser trauma and a quicker recovery in many elective abdominal surgeries. However, little is known of the safety and effectiveness made by ERAS protocols combined with MIS for gastric cancer. The purpose of this study was to evaluate the safety and effectiveness made by FT programs and MIS in combination or alone.
Methods:
We summarized an 11-year experience on gastric cancer patients undergoing elective laparotomy or minimally invasive gastric resection in standard cares (SC) or FT programs during January 2004 to December 2014. A total of 984 patients were enrolled and assigned into four groups: open gastrectomies (OG) with SC (OG + SC group, n = 167); OG with FT programs (OG + FT group, n = 277); laparoscopic gastrectomies (LG) with FT programs (LG + FT group, n = 248); and robot-assisted gastrectomies (RG) with FT programs (RG + FT group, n = 292). Patients’ data were collected to evaluate the clinical outcome. The primary end point was the length of postoperative hospital stay.
Results:
The OG + SC group showed the longest postoperative hospital stay (mean: 12.3 days, median: 11 days, interquartile range [IQR]: 6–16 days), while OG + FT, LG + FT, and RG + FT groups recovered faster (mean: 7.4, 6.4, and 6.6 days, median: 6, 6, and 6 days, IQR: 3–9, 4–8, and 3–9 days, respectively, all P < 0.001). The postoperative rehabilitation parameters such as flatus time after surgery (4.7 ± 0.9, 3.1 ± 0.8, 3.0 ± 0.9, and 3.1 ± 0.9 days) followed the same manner. After 30 postoperative days’ follow-up, the total incidence of complications was 9.6% in OG + SC group, 10.1% in OG + FT group, 8.1% in LG + FT group, and 10.3% in RG + FT group. The complications showed no significant differences between the four groups (all P > 0.05).
Conclusions:
ERAS protocols alone could significantly bring fast recovery after surgery regardless of the surgical technique. MIS further reduces postoperative hospital stay. It is safe and effective to apply ERAS protocols combined with MIS for gastric cancer.
doi:10.4103/0366-6999.190659
PMCID: PMC5040014  PMID: 27647187
Enhanced Recovery after Surgery; Fast-track Surgery; Gastrectomy; Minimally Invasive Surgery; Optimized Care
18.  Pluronic-based micelle encapsulation potentiates myricetin-induced cytotoxicity in human glioblastoma cells 
As one of the natural herbal flavonoids, myricetin has attracted much research interest, mainly owing to its remarkable anticancer properties and negligible side effects. It holds great potential to be developed as an ideal anticancer drug through improving its bioavailability. This study was performed to investigate the effects of Pluronic-based micelle encapsulation on myricetin-induced cytotoxicity and the mechanisms underlying its anticancer properties in human glioblastoma cells. Cell viability was assessed using a methylthiazol tetrazolium assay and a real-time cell analyzer. Immunoblotting and quantitative reverse transcriptase polymerase chain reaction techniques were used for determining the expression levels of related molecules in protein and mRNA. The results indicated that myricetin-induced cytotoxicity was highly potentiated by the encapsulation of myricetin. Mitochondrial apoptotic pathway was demonstrated to be involved in myricetin-induced glioblastoma cell death. The epidermal growth factor receptor (EGFR)/PI3K/Akt pathway located in the plasma membrane and cytosol and the RAS-ERK pathway located in mitochondria served as upstream and downstream targets, respectively, in myricetin-induced apoptosis. MiR-21 inhibitors interrupted the expression of EGFR, p-Akt, and K-Ras in the same fashion as myricetin-loaded mixed micelles (MYR-MCs) and miR-21 expression were dose-dependently inhibited by MYR-MCs, indicating the interaction of miR-21 with MYR-MCs. This study provided evidence supportive of further development of MYR-MC formulation for preferentially targeting mitochondria of glioblastoma cells.
doi:10.2147/IJN.S114302
PMCID: PMC5055108  PMID: 27757032
myricetin; glioblastoma; EGFR; miR-21; mitochondrial apoptosis; mixed micelles; anticancer; drug delivery
19.  Genetic polymorphism of the Nrf2 promoter region is associated with vitiligo risk in Han Chinese populations 
Abstract
The nuclear factor erythroid‐derived two‐like 2‐antioxidant response element (Nrf2‐ARE) pathway and its downstream antioxidant enzyme heme oxygenase‐1 (HMOX1 or HO‐1) play essential roles in H2O2‐induced oxidative damage in human melanocytes. However, the link between Nrf2 promoter polymorphisms and susceptibility to oxidative stress‐related diseases such as vitiligo is unknown. This study evaluated the association of the Nrf2 and HO‐1 genes polymorphisms with vitiligo susceptibility. In this case–control study of 1136 Han Chinese vitiligo patients and 1200 controls, Nrf2 (rs35652124 and rs6721961) and HO‐1 (rs2071746) genes were genotyped by PCR‐restriction fragment length polymorphism analysis. Overall, a significantly decreased risk of vitiligo was found to be associated with Nrf2 rs35652124 CC and combined (CT+CC) genotypes [odds ratio (OR) 0.64, 95% confidence interval (CI) 0.50–0.83 and OR, 0.84, 95% CI 0.71–0.99, respectively], as well as among subgroups: female, onset age ≤20 and never smoker. We subsequently found that Nrf2 rs35652124 C allele had higher transcriptional activity in the luciferase reporter assay compared with Nrf2 rs35652124 T allele. Furthermore, we investigated serum HO‐1 activity was associated with the rs35652124 CT+CC genotype and lower in patients than in controls (P = 0.024). Logistic regression analysis showed a dose–response relationship between lower vitiligo risk and increased HO‐1 activity in rs35652124 CT+CC genotype carriers (P trend < 0.05). These findings indicate that the C allele of rs35652124 located in the promoter region of Nrf2 gene is associated with protective effect on vitiligo in a Han Chinese population.
doi:10.1111/jcmm.12874
PMCID: PMC5020638  PMID: 27222475
vitiligo; SNP; Nrf2
20.  Controllable Edge Oxidation and Bubbling Exfoliation Enable the Fabrication of High Quality Water Dispersible Graphene 
Scientific Reports  2016;6:34127.
Despite significant progresses made on mass production of chemically exfoliated graphene, the quality, cost and environmental friendliness remain major challenges for its market penetration. Here, we present a fast and green exfoliation strategy for large scale production of high quality water dispersible few layer graphene through a controllable edge oxidation and localized gas bubbling process. Mild edge oxidation guarantees that the pristine sp2 lattice is largely intact and the edges are functionalized with hydrophilic groups, giving rise to high conductivity and good water dispersibility at the same time. The aqueous concentration can be as high as 5.0 mg mL−1, which is an order of magnitude higher than previously reports. The water soluble graphene can be directly spray-coated on various substrates, and the back-gated field effect transistor give hole and electron mobility of ~496 and ~676 cm2 V−1 s−1, respectively. These results achieved are expected to expedite various applications of graphene.
doi:10.1038/srep34127
PMCID: PMC5036305  PMID: 27666869
21.  Diffusion and perfusion weighted magnetic resonance imaging for tumor volume definition in radiotherapy of brain tumors 
Accurate target volume delineation is crucial for the radiotherapy of tumors. Diffusion and perfusion magnetic resonance imaging (MRI) can provide functional information about brain tumors, and they are able to detect tumor volume and physiological changes beyond the lesions shown on conventional MRI. This review examines recent studies that utilized diffusion and perfusion MRI for tumor volume definition in radiotherapy of brain tumors, and it presents the opportunities and challenges in the integration of multimodal functional MRI into clinical practice. The results indicate that specialized and robust post-processing algorithms and tools are needed for the precise alignment of targets on the images, and comprehensive validations with more clinical data are important for the improvement of the correlation between histopathologic results and MRI parameter images.
doi:10.1186/s13014-016-0702-y
PMCID: PMC5031292  PMID: 27655356
Brain tumors; Diffusion; Perfusion; Radiotherapy; Tumor volume definition
22.  Echocardiographic Follow-up of Robotic Mitral Valve Repair for Mitral Regurgitation due to Degenerative Disease 
Chinese Medical Journal  2016;129(18):2199-2203.
Background:
Mitral valve (MV) repair can now be carried out through small incisions with the use of robotic assistance. Previous reports have demonstrated the excellent clinical result of robotic MV repair for degenerative mitral regurgitation (MR). However, there has been limited information regarding the echocardiographic follow-up of these patients. The present study was therefore to evaluate the echocardiographic follow-up outcomes after robotic MV repair in patients with MR due to degenerative disease of the MV.
Methods:
A retrospective analysis was undertaken using data from the echocardiographic database of our department. Between March 2007 and February 2015, 84 patients with degenerative MR underwent robotic MV repair. The repair techniques included leaflet resection in 67 patients (79.8%), artificial chordae in 20 (23.8%), and ring annuloplasty in 79 (94.1%). Eighty-one (96.4%) of the 84 patients were eligible for echocardiographic follow-up assessment, and no patients were lost to follow-up.
Results:
At a median echocardiographic follow-up of 36.0 months (interquartile range 14.3–59.4 months), four patients (4.9%) developed recurrent mild MR, and no patients had more than mild MR. Mean MR grade, left atrial diameter (LAD), left ventricular end-diastolic diameter (LVEDD), and left ventricular ejection fraction (LVEF) were significantly decreased when compared with preoperative values. Mean MR grade decreased from 3.96 ± 0.13 to 0.17 ± 0.49 (Z = −8.456, P < 0.001), LAD from 43.8 ± 5.9 to 35.5 ± 3.8 mm (t = 15.131, P < 0.001), LVEDD from 51.0 ± 5.0 to 43.3 ± 2.2 mm (t = 14.481, P < 0.001), and LVEF from 67.3 ± 7.0% to 63.9 ± 5.1% (t = 4.585, P < 0.001).
Conclusion:
Robotic MV repair for MR due to degenerative disease is associated with a low rate of recurrent MR, and a significant improvement in MR grade, LAD, and LVEDD, but a significant decrease in LVEF at echocardiographic follow-up.
doi:10.4103/0366-6999.189909
PMCID: PMC5022341  PMID: 27625092
Degenerative Disease; Mitral Regurgitation; Mitral Valve Repair
23.  An allosteric interaction links USP7 to deubiquitination and chromatin targeting of UHRF1 
Cell reports  2015;12(9):1400-1406.
The protein stability and chromatin functions of UHRF1 (Ubiquitin-like, containing PHD and RING Finger domains, 1) are regulated in a cell cycle-dependent manner. We report a structural characterization of the complex between UHRF1 and the deubiquitinase USP7. The first two UBL domains of USP7 bind to the polybasic region (PBR) of UHRF1, and this interaction is required for the USP7-mediated deubiquitination of UHRF1. Importantly, we find that the USP7-binding site of UHRF1 PBR overlaps with the region engaging an intramolecular interaction with the N-terminal tandem Tudor domain (TTD). We show that the USP7-UHRF1 interaction perturbs the TTD-PBR interaction of UHRF1, thereby shifting the conformation of UHRF1 from a TTD-“occluded” state to a state open for multivalent histone binding. Consistently, introduction of an USP7-interaction defective mutation to UHRF1 significantly reduces its chromatin association. Together, these results link USP7 interaction to the dynamic deubiquitination and chromatin association of UHRF1.
doi:10.1016/j.celrep.2015.07.046
PMCID: PMC4558366  PMID: 26299963
24.  Ideal glycated hemoglobin cut‐off points for screening diabetes and prediabetes in a Chinese population 
Abstract
Aims/Introduction
The aims of the present study were to evaluate the diagnostic value of fasting plasma glucose, 2‐h postload plasma glucose and glycosylated hemoglobin (HbA1c) measurements in the screening of diabetes and prediabetes, and to determine the cut‐off point of HbA1c in the diagnosis of diabetes and prediabetes in a Chinese population.
Materials and Methods
A total of 7,611 individuals aged 40 years or older, who did not have a prior history of diabetes, were randomly selected in the Changchun area. For each participant, a questionnaire was completed, and a physical examination and an oral glucose tolerance test were carried out. The values of fasting plasma glucose, 2‐h postload plasma glucose and HbA1c were compared by area under the receiver operating characteristic curves. The Youden index was used to identify the optimal cut‐off point of HbA1c in the diagnosis of diabetes and prediabetes.
Results
The prevalence of newly diagnosed diabetes and prediabetes was 12.71% and 29.39%, respectively. In participants with newly diagnosed diabetes, the area under the receiver operating characteristic curve was 0.8368 for fasting plasma glucose, 0.9330 for 2‐h postload plasma glucose and 0.8064 for HbA1c; whereas for prediabetes, these values were 0.8022, 0.9288 and 0.6895, respectively. In addition, an HbA1c threshold of 6.3% showed the highest Youden index (0.4799) for detecting diabetes; furthermore, an HbA1c threshold of 5.8% showed the highest Youden index (0.2866) for detecting prediabetes.
Conclusions
HbA1c ≥6.3% (45 mmol/mol) and between 5.8% and 6.2% (40–44 mmol/mol) were the optimal cut‐off values for the diagnosis of diabetes and prediabetes, respectively, in a Chinese population.
doi:10.1111/jdi.12498
PMCID: PMC5009131  PMID: 27181567
Chinese adults; Receiver operating characteristic curves; Type 2 diabetes mellitus
25.  Cross-sectional study on the relationship between the level of serum cystatin C and blood pressure reverse dipping in hypertensive patients 
BMJ Open  2016;6(9):e011166.
Objective
To investigate the relationship between the level of serum cystatin C (s-CC) and reverse-dipper blood pressure (BP) pattern.
Design
Cross-sectional study.
Setting
Single centre.
Participants
A total of 718 hypertensive patients were eventually recruited from cardiac clinics between 2012 and 2014 in the Second Affiliated Hospital, Xi'an Jiaotong University. They were diagnosed as essential hypertension according to their casual office records of systolic blood pressure (SBP) and/or diastolic blood pressure (DBP). Patients were excluded if they were <18 or >90 years old, under antihypertensive treatment, night workers, suffering from acute stroke or myocardial infarction within the past 6 months, diagnosed as secondary hypertension, sleep apnoea or other sleep disorders, renal failure, cardiac failure, chronic obstructive pulmonary disease, women during pregnancy or intolerant to the ambulatory BP monitoring (ABPM).
Measurement
The selected patients were evaluated with 24 hours ABPM. Peripheral venous blood samples were collected to evaluate the s-CC levels by ELISA.
Methods
The distribution of hypertensive patients with different levels of s-CC among each circadian BP pattern group was analysed using analysis of variance. Multinomial logistic regression analysis was applied to explore the relationship between the relevant variables and ABPM results.
Results
S-CC level in reverse-dipper group (1.19±0.53 mg/L) was increased significantly when compared with dipper group (1.06±0.36 mg/L) (p=0.021). In addition, after multinomial logistic regression analysis, s-CC (OR 1.717; 95% CI 1.033 to 2.854; p=0.037) and diabetes (OR 2.313; 95% CI 1.401 to 3.821; p=0.01) were significantly different between the reverse-dipper group and dipper group. On the other hand, the decline rate of nocturnal SBP (r=−0.117; p=0.002) and DBP (r=−0.089; p=0.018) was negatively correlated with the s-CC level.
Conclusions
The s-CC level was significantly higher in the reverse-dipper group than the dipper group and that s-CC was associated with the reverse-dipper pattern of BP examined with 24 hour ABPM.
doi:10.1136/bmjopen-2016-011166
PMCID: PMC5020748  PMID: 27591018
blood pressure; essential hypertension; reverse dipping; serum cystatin C

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