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Ras-related protein Rab-10 (RAB10) is involved in tumorigenesis and progression of hepatocellular carcinoma (HCC). Here, we found RAB10, O-GlcNAc transferase (OGT), and O-GlcNAcylation were upregulated in HCC. In addition, RAB10 protein level was prominently positively correlated with the expression of OGT. O-GlcNAcylation modification of RAB10 was then investigated. Here we showed that RAB10 interacts directly with OGT in HCC cell lines, Meanwhile, O-GlcNAcylation enhanced RAB10 protein stability. Furthermore, knockdown of OGT suppressed aggressive behaviors of HCC in vitro and in vivo, while elevated RAB10 reversed these. Taken together, these results indicated that OGT-mediated O-GlcNAcylation stabilized RAB10, thus accelerating HCC progression.

We empirically examine the impact of industry exchange-traded funds (IETFs) on informed trading and market efficiency. We find that IETF short interest spikes simultaneously with hedge fund holdings on the member stock before positive earnings surprises, reflecting long-the-stock/short-the-ETF activity. This pattern is stronger among stocks with high industry risk exposure. A difference-in-difference analysis on the ETF inception event shows that IETFs reduce post-earnings-announcement drift more among stocks with high industry risk exposure, suggesting that IETFs improve market efficiency. We also find that the short interest ratio of IETFs positively predicts IETF returns, consistent with the hedging role of IETFs.

Over the past four decades, patients with advanced ovarian cancer (OC) has enjoyed greatly improved survival rate considering advances in combined chemotherapy with platinum and paclitaxel. We investigated the association between polymorphisms within glutathione S-transferase genes (GSTM1, GSTT1 and GSTP1) and short- and long-term efficacy of concurrent chemoradiotherapy (CCRT) in advanced OC. Patients with advanced OC and healthy females were selected in our study. Multiplex polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP) were applied to detect homozygous deletions in GSTM1 and GSTT1, as well as codon 105 genetic polymorphisms in GSTP1 exon 5. All the patients with advanced OC were treated with CCRT. Toxicity of chemotherapy, short-term efficacy, recurrence and metastasis, respectively. Long-term survival outcomes were checked with a further examination and all patients were followed up for three years after CCRT.Compared with healthy females, patients with advanced OC showed higher frequencies of GSTT1 non-null genotype and homozygous mutation type GG of GSTP. GSTP1genetic polymorphisms were relevant to neutropenia resulted from CCRT in patients with advanced OC. Compared with patients with GSTT1non-null genotype, those with GSTT1 null genotype appeared to enjoy a better short-term efficacy, lower recurrence and metastasis rate, higher survival rate and longer mean survival time. Compared with patients with GG genotype, those with GSTP1 AA + AG genotype also enjoyed more positive results. Our results reveal that GSTT1 null genotype and GSTP1AA + AG genotype are associated with short- and long-term efficacy of CCRT in advanced OC.

We study how expectations of fund flows causally affect fund performance by exploiting a quasi-natural experiment in the Australian pension system where an unexpected policy change temporarily allowed fund withdrawals from a prespecified date in the future. Using fractions of young members, middle-aged members, and government co-contributions for low-income earners as instrumental variables, we find an insignificant effect of expected fund outflows on performance. A potential explanation is that Australian superannuation funds preemptively engage in liquidity management in response to changes in expectations of future fund flows and this helps to limit direct and indirect costs in the rebalancing process. JEL Classification: G11, G12, G14, G23, G51

Stock exchanges compete for order flow through their fee models. A traditional model pays rebates to liquidity suppliers, and an inverted model pays rebates to liquidity demanders. Using a regulatory intervention to examine the interaction between tick size, restrictions on dark trading, and exchange fees, we show that traders use inverted venues to adjust for suboptimal tick sizes. Increased inverted venue activity improves pricing efficiency and liquidity, especially when the tick size is binding. We show that the sub-tick price improvement offered by inverted venues enhances competition for liquidity provision and increases information impounded into prices through nonmarketable limit orders.

We provide empirical evidence that the decentralized cryptocurrency exchange can help reach the decentralized consensus of cryptocurrency value. We focus on Binance (the largest centralized cryptocurrency exchange) and Uniswap (the largest decentralized cryptocurrency exchange), and show that investors on Binance and Uniswap trade in response to prices on the two exchanges. More importantly, we find that the size of Uniswap user base exerts an asymmetric impact on investors’ trading. When its size increases, Uniswap user base exerts a larger impact on investors’ trading on Binance towards the Uniswap price, compared to the opposite direction. With a quasi-exogenous shock on Uniswap user base, we establish the causal impact of Uniswap user base on trading. Our results suggest that Uniswap as a decentralized exchange can reflect the consensus of cryptocurrency value that investors believe in because of blockchain’s transparency and trustworthiness. Our findings imply that the decentralized infrastructure built on blockchain and smart contracts can provide an alternative solution to cases where a consensus underwritten by a credible central party is not feasible or too costly to obtain.

Tempol (4-hydroxy-2,2,6,6-Tetramethylpiperidine-1-oxyl, TPL), a nitroxide compound, inhibits proliferation and increases the vulnerability of cancer cells to apoptosis induced by cytotoxic agents. However, the molecular mechanism of TPL inhibiting cancer cell proliferation has not been fully understood. In this study, we evaluated the metabolic effect of TPL on cancer cells and explored its cancer therapeutic potential. Extracellular flow assays showed that TPL inhibited cellular basal and maximal oxygen consumption rates of mitochondrial. 13C metabolic flux analysis showed that TPL treatment had minimal effect on glycolysis. However, we found that TPL inhibits glutamine metabolism by interfering with the oxidative tricarboxylic acid cycle (TCA) process and reductive glutamine process. We found that the inhibitory effect of TPL on metabolism occurs mainly on the step from citrate to α-ketoglutarate or vice versa. We also found that activity of isocitrate dehydrogenase IDH1 and IDH2, the key enzymes in TCA, were inhibited by TPL treatment. In xenograft mouse model, TPL treatment reduced tumor growth by inhibiting cellular proliferation of xenograft tumors. Thus, we provided a mechanism of TPL inhibiting cancer cell proliferation by interfering with glutamine utilization that is important for survival and proliferation of cancer cells. The study may help the development of a therapeutic strategy of TPL combined with other anticancer medicines.

Nitric oxide (NO), an important chemical messenger, serves a dual role in tumor progression. Nitric oxide synthase isoform 1 (NOS1) was observed to be increasingly expressed in various types of cancer, and its expression has been associated with tumor progression. However, the level of NOS1 expression and the associated functions of NOS1 in human ovarian cancer remain undefined. Using gene expression profiles of ovarian cancer from the Gene Expression Omnibus (GEO) database, the present study revealed that NOS1 was increasingly expressed in ovarian cancer tissues. The present study investigated the level of NOS1 expression and its effects on in vitro cell function, including proliferation, migration and invasion as well as chemoresistance to cispatin (DDP) treatment in OVCAR3 cells. Reverse transcription-quantitative polymerase chain reaction demonstrated that the level of NOS1 mRNA expression varied in different ovarian cancer lines. However, immunoblotting indicated that the level of NOS1 protein expression was constitutively high in ovarian cancer cell lines. Treatment with NOS inhibitor NG-nitro-L-arginine methyl ester or transfection with NOS1 short hairpin RNA significantly inhibited cell proliferation, migration and invasion compared with the control, whereas the sensitivity of OVCAR3 cells to DDP treatment was increased. The results of the present study indicated that NOS1 promoted the function of ovarian cancer cells, including proliferation, invasion and chemoresistance, providing a potential target for ovarian cancer therapeutic.

We study how expectations of fund flows causally affect fund performance by exploiting a quasi-natural experiment in the Australian pension system where an unexpected policy change temporarily allowed fund withdrawals from a pre-specified date in the future. Using fractions of young members, middle-aged members, and government co-contributions for low income earners as instrumental variables, we find an insignificant effect of expected fund outflows on fund performance. A potential explanation is that Australian superannuation funds preemptively engage in liquidity management in response to changes in expectations of future fund flows and that this helps to limit direct and indirect costs in the rebalancing process.

Using bond transaction data from TRACE from 2005 to 2015, we investigate the impact of pre-trade transparency on over-the-counter bond markets, and find that NYSE pre-trade transparency reduces US corporate bond transaction costs by $846 million per year. NYSE pre-trade transparent bonds also maintain smaller standard deviation in bid-ask spreads and institutional investors face smaller bid-ask spreads when trading the pre-trade transparent bonds, suggesting that pre-trade transparency tends to favor traders rather than dealers by enhancing traders' bargaining capability.

BackgroundThe dysfunction of type I interferon (IFN) signaling is an important mechanism of immune escape and metastasis in tumors. Increased NOS1 expression has been detected in melanoma, which correlated with dysfunctional IFN signaling and poor response to immunotherapy, but the specific mechanism has not been determined. In this study, we investigated the regulation of NOS1 on the interferon response and clarified the relevant molecular mechanisms.MethodsAfter stable transfection of A375 cells with NOS1 expression plasmids, the transcription and expression of IFNα-stimulated genes (ISGs) were assessed using pISRE luciferase reporter gene analysis, RT-PCR, and western blotting, respectively. The effect of NOS1 on lung metastasis was assessed in melanoma mouse models. A biotin-switch assay was performed to detect the S-nitrosylation of HDAC2 by NOS1. ChIP-qPCR was conducted to measure the binding of HDAC2, H4K16ac, H4K5ac, H3ac, and RNA polymerase II in the promoters of ISGs after IFNα stimulation. This effect was further evaluated by altering the expression level of HDAC2 or by transfecting the HDAC2-C262A/C274A site mutant plasmids into cells. The coimmunoprecipitation assay was performed to detect the interaction of HDAC2 with STAT1 and STAT2. Loss-of-function and gain-of-function approaches were used to examine the effect of HDAC2-C262A/C274A on lung metastasis. Tumor infiltrating lymphocytes were analyzed by flow cytometry.ResultsHDAC2 is recruited to the promoter of ISGs and deacetylates H4K16 for the optimal expression of ISGs in response to IFNα treatment. Overexpression of NOS1 in melanoma cells decreases IFNα-responsiveness and induces the S-nitrosylation of HDAC2-C262/C274. This modification decreases the binding of HDAC2 with STAT1, thereby reducing the recruitment of HDAC2 to the ISG promoter and the deacetylation of H4K16. Moreover, expression of a mutant form of HDAC2, which cannot be nitrosylated, reverses the inhibition of ISG expression by NOS1 in vitro and decreases NOS1-induced lung metastasis and inhibition of tumor infiltrating lymphocytes in a melanoma mouse model.ConclusionsThis study provides evidence that NOS1 induces dysfunctional IFN signaling to promote lung metastasis in melanoma, highlighting NOS1-induced S-nitrosylation of HDAC2 in the regulation of IFN signaling via histone modification.

Microcystins-LR (MC-LR), a cyanobacterial toxins, initiate apoptosis in normal and tumor cells. Nitric oxide produced by iNOS is necessary for MC-LR-induced apoptosis. However, the underlying mechanism of NO mediated MC-LR cytotoxicity remains unclear. Here, we performed in vitro experiments on MC-LR cytotoxicity associated with NO induced S-nitrosyation of GAPDH in human colon cancer cells SW480. MTT assay indicated that MC-LR decreased the cellular viability by high concentration (>1 μM). Flow cytometer assay revealed that apoptosis was core mode for MC-LR cytotoxicity. Griess assay showed that MC-LR exposure increased the release of NO through the function of NOS1 and NOS2 in SW480 cells. In turn, NO stress induced the S-nitrosylated modification of GAPDH leading to its nuclear translocation following Siah1 binding. CHIP assay showed that the nuclear GADPH increased P53 transcript of a panner of apoptosis related genes. Moreover, apoptosis induced by MC-LR could be reduced by GAPDH or si-Siah1 or NOSs inhibitor, L-NAME. Thus, our study verified a molecular mechanism of NO/GAPDH/Siah1 cascade in MC-LR mediated apoptosis in colorectal cancer cells, providing a further understanding the in vitro molecular mechanism of MC-LR colorectal toxicity.

It was brought to the attention of the Editors that there had been an accidental duplication of the western blot images during the preparation of Figs. 1b and c. The authors were notified about the error and have supplied the correct image for Fig. 1c (below). We apologize for any inconvenience this may have caused readers.

This paper examines how the relative tick size influences market liquidity and the biodiversity of trader interactions. Using unique NYSE order-level data, we find that a larger relative tick size benefits High-Frequency Trading (HFT) firms that make markets on the NYSE: they leave orders in the book longer, trade more aggressively, and have higher profit margins. The effects of a larger relative tick size on the market are more complex. In a one-tick spread environment, a larger relative tick size results in greater depth and more volume; in a multi-tick environment, the opposite outcome prevails. The negative impact on depth and volume in the multi-tick environment is consistent with greater adverse selection coming from increased undercutting of limit orders by informed HFT market makers. Our work suggests why a one-size-fits-all spread policy is unlikely to be optimal, and we propose an alternative policy.

In this paper, I evaluate how a centralized market impacts the opacity of an over-the-counter (OTC) market. I show that a competitive centralized market provides an incentive for dealers in the OTC market to reduce opacity, whereas a noncompetitive centralized market does not. Competition between the competitive centralized market and the OTC market forces dealers in the latter to reduce opacity. With the noncompetitive centralized market, opportunities for collusion provide an incentive for dealers to increase opacity. Specifically, the natural monopoly market maker in the noncompetitive centralized market coordinates his spread according to dealers’ spreads to profit from opacity.

Stock exchanges compete for order flow through their fee models. A traditional model pays rebates to liquidity suppliers, and an inverted model pays rebates to liquidity demanders. Using a regulatory intervention to examine the interaction between tick size, restrictions on dark trading, and exchange fees we show that traders use inverted venues to adjust for suboptimal tick sizes. Increased inverted venue activity improves pricing efficiency and liquidity, especially when the tick size is binding. We show that the sub-tick price improvement offered by inverted venues enhances competition for liquidity provision and increases information impounded into prices through non-marketable limit orders.

// Linlin Li 1, 2, 3, * , Lingqun Zhu 1, * , Bingtao Hao 1, 2, 3 , Wenwen Gao 1 , Qianli Wang 1 , Keyi Li 1 , Meng Wang 1 , Mengqiu Huang 1 , Zhengjun Liu 4 , Qiaohong Yang 5, 6 , Xiqing Li 7 , Zhuo Zhong 8 , Wenhua Huang 9 , Guanghui Xiao 1 , Yang Xu 1, 2, 3 , Kaitai Yao 1 , Qiuzhen Liu 1, 2, 3 1 Cancer Research Institute, Southern Medical University, Guangzhou 510515, China 2 Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research, Guangzhou 510515, China 3 Guangzhou Key Laboratory of Tumor Immunology Research, Southern Medical University, Guangzhou 510515, China 4 Department of Vascular Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China 5 School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China 6 Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA 7 Department of Oncology, Henan Provincial People’s Hospital, Zhengzhou 450003, Henan, China 8 Department of Oncology, Guangzhou Hospital of Integrated Traditional and Western Medicine, Guangzhou 510800, China 9 Department of Human Anatomy, Southern Medical University, Guangzhou 510515, China * These authors have contributed equally to this work Correspondence to: Qiuzhen Liu, email: liuqiuzhen@126.com Kaitai Yao, email: yao.kaitai@hotmail.com Keywords: nitric oxide, iNOS, Warburg effect, PKM2, EGFR/ERK2 Received: October 19, 2016 Accepted: March 15, 2017 Published: March 23, 2017 ABSTRACT Aerobic glycolysis is essential for tumor growth and survival. Activation of multiple carcinogenic signals contributes to metabolism reprogramming during malignant transformation of cancer. Recently nitric oxide has been noted to promote glycolysis but the mechanism remains elusive. We report here the dual role of nitric oxide in glycolysis: low/physiological nitric oxide (≤ 100 nM) promotes glycolysis for ATP production, oxidative defense and cell proliferation of ovary cancer cells, whereas excess nitric oxide (≥ 500 nM) inhibits it. Nitric oxide has a positive effect on glycolysis by inducing PKM2 nuclear translocation in an EGFR/ERK2 signaling-dependent manner. Moreover, iNOS induced by mild inflammatory stimulation increased glycolysis and cell proliferation by producing low doses of nitric oxide, while hyper inflammation induced iNOS inhibited it by producing excess nitric oxide. Finally, iNOS expression is abnormally increased in ovarian cancer tissues and is correlated with PKM2 expression. Overexpression of iNOS is associated with aggressive phenotype and poor survival outcome in ovarian cancer patients. Our study indicated that iNOS/NO play a dual role of in tumor glycolysis and progression, and established a bridge between iNOS/NO signaling pathway and EGFR/ERK2/PKM2 signaling pathway, suggesting that interfering glycolysis by targeting the iNOS/NO/PKM2 axis may be a valuable new therapeutic approach of treating ovarian cancer.

Autophagy is a cellular survival mechanism that involves the catabolic degradation of damaged proteins and organelles during periods of metabolic stress, and when overly stimulated, commonly contributes to cell death. Nitric oxide (NO), a potent cellular messenger, participates in a complex mechanism which assists in controlling autophagy. However, the mechanism by which endogenous NO formed by distinct isoforms of nitric oxide synthase (NOS) helps to regulate autophagy in cancer cells remains unclear. Here we report that NOS1 reduces excessive levels of autophagy and promotes the survival of nasopharyngeal carcinoma cells. We found that inhibition of NOS1 increased cell death resulting from siRNA or the use of pharmacologic agents; and this effect was reversed by the autophagy inhibitor, chloroquine. The role of NOS1 in the autophagy process depended on the activation of AKT/mTOR signaling by S-nitrosylation of phosphatase and tensin homolog (PTEN) proteins. The mechanism by which NOS1 modifies PTEN protein might involve a direct interaction between these two molecules. Moreover, in an in vivo study, the NOS1 inhibitor N(G)-nitro-L-arginine methyl ester activated AKT/mTOR signaling and promoted autophagy in xenograph tumors. Our studies demonstrated that NOS1 prevents excessive autophagy via S-nitrosylation of PTEN, and activation of the AKT/mTOR signaling pathway. PTEN and the AKT/mTOR signaling pathway are promising targets for improving the chemotherapeutic treatment of cancer.

The effects of organic chloride-PVC and inorganic chloride-NaCl on Cd partitioning during sludge incineration with adding Cd(CH3COO)2 . 2H2O to the real sludge were investigated using a simulated tubular incineration furnace. And transformation and distribution of Cd were studied in different sludge incineration operation conditions. The results indicated that the partitioning of Cd tended to be enhanced in the fly ash and fule gas as the chloride content increasing. The migration and transformation of Cd-added sludge affected by different chloride were not obvious with the increasing of chloride content. With increasing temperature, organic chloride (PVC) and inorganic chloride (NaC1) can reduce the Cd distribution in the bottom ash. However, the effect of chlorides, the initial concentration and incineration time on Cd emissions had no significant differences. Using SEM-EDS and XRD technique, different Cd compounds including CdCl2, Na2CdCl4, K2CdCl6, K2CdSiO4 and NaCdO2 were formed in the bottom ash and fly ash after adding NaCl to the sludge. In contrast, after adding PVC to the sludge, the Na2CdCl4 and CdCl2 were the main forms of Cd compounds, at the same time, K4CdCI6 and K6CdO4 were also formed. The two different mechanisms of chlorides effects on Cd partitioning were affected by the products of Cd compound types and forms.

In recent years, the inherent effectiveness of Peer-to-Peer (P2P) networks has been advocated to address scalability issues in large scale Internet-based on-Demand streaming services. Most of existing works adopt Cache-and-Relay (CR) scheme to exploit a cooperative paradigm among peers. In this paper, we mainly present our practical evaluation study of the scalability of the CR scheme by taking into account of more than 20,000,000 collected real traces. Based on trace-driven simulations, we conclude that the CR scheme is not as effective as previously reported in terms of saving server bandwidth.

The decentralized over-the-counter (OTC) market generates a trading network among dealers. We model the driver behind the formation of this inter-dealer network as the need for dealers to share risk. The trade-o¤ between the benefit of risk-sharing and the funding cost of collateral determines the shape of the inter-dealer network. In equilibrium, dealers’ markups and trading volumes increase with the number of links they have to other dealers, whereas dealers’inventory risks decrease as they form links. In addition, when capacity of providing liquidity differentiates dealers, the network formed exhibits the empirically observed core-periphery structure: dealers with large capacity comprise the core of the network, connecting them to all other dealers, while dealers who have small capacity operate at the periphery. The model matches recent empirical findings on the negative relationship between order sizes and markups. More importantly, we show that there may be structural breaks in this negative relationship as variations in order sizes may alter the inter-dealer network. These results suggest that empirical studies on OTC markets should control for the stability of an inter-dealer network to avoid model misspeci…cation.

The results of hydrothermal preparation of BaTiO3 fine powders are reported. The effects of the reaction temperature, the molar ratio of Ba Ti in the precursors, the chemical form of the precursors on the phase composition, the size and the morphology of the products are presented. The higher the temperature, the higher the basicity and the greater the molar ratio of Ba Ti in the precursor, the easier the formation of the perovskite type BaTiO3 crystallite will be. It was found that BaTiO3 microcrystals(150–300 nm) could be synthesized through the hydrothermal reaction of commercial TiO2 with Ba(OH)2 aqueous solution, while the hydrothermal reaction of the newly prepared Ti(OH)4 gel with the Ba(OH)2 solution produced highly crystallized, well dispersed perovskite type BaTiO3 crystallites with very fine (

In this paper, I evaluate how a centralized market impacts the opacity of an over-the-counter (OTC) market. I show that a competitive centralized market provides an incentive for dealers in the OTC market to reduce opacity, whereas a noncompetitive centralized market does not. Competition between the competitive centralized market and the OTC market forces dealers in the latter to reduce opacity. With the noncompetitive centralized market, opportunities for collusion provide an incentive for dealers to increase opacity. Specifically, the natural monopoly market maker in the noncompetitive centralized market coordinates his spread according to dealers’ spreads to profit from opacity.

Using bond transaction data from TRACE, we investigate the impact of pre-trade transparency on over-the-counter markets, and find that NYSE pre-trade transparency reduces US corporate bond transaction costs by 10 basis points. NYSE pre-trade transparent bonds also maintain smaller standard deviation in bid-ask spreads and institutional investors face smaller bid-ask spreads when trading the pre-trade transparent bonds, suggesting that pre-trade transparency tends to favor traders rather than dealers by enhancing traders’ bargaining capability. Pre-trade transparency increases bonds’ values, since bonds with the NYSE pre-trade transparency have significantly lower bond yields than bonds. Our findings are robust to endogeneity of firms’ bond listing decisions on NYSE.