bluuebunny/crossref_metadata_2025 huggingface dataset:
Hispolon from Phellinus linteus Induces G0/G1 Cell Cycle Arrest and Apoptosis in NB4 Human Leukaemia Cells
Authors: Chen Yi-Chuan , Chang Heng-Yuan , Deng Jeng-Shyan , Chen Jian-Jung , Huang Shyh-Shyun , Lin I-Hsin , Kuo Wan-Lin , Chao Wei , Huang Guan-Jhong
Published: November 2013

Hispolon (a phenolic compound isolated from Phellinus linteus) has been shown to possess strong antioxidant, anti-inflammatory, anticancer, and antidiabetic properties. In this study, we investigated the antiproliferative effect of hispolon on human hepatocellular carcinoma NB4 cells using the MTT assay, DNA fragmentation, DAPI (4, 6-diamidino-2-phenylindole dihydrochloride) staining, and flow cytometric analysis. Hispolon inhibited the cellular growth of NB4 cells in a dose-dependent manner through the induction of cell cycle arrest at G0/G1 phase measured using flow cytometric analysis and apoptotic cell death, as demonstrated by DNA laddering. Exposure of NB4 cells to hispolon-induced apoptosis-related protein expressions, such as the cleavage form of caspase 3, caspase 8, caspase 9, poly (ADP ribose) polymerase, and the proapoptotic Bax protein. Western blot analysis showed that the protein levels of extrinsic apoptotic proteins (Fas and FasL), intrinsic related proteins (cytochrome c), and the ratio of Bax/Bcl-2 were increased in NB4 cells after hispolon treatment. Hispolon-induced G0/G1-phase arrest was associated with a marked decrease in the protein expression of p53, cyclins D1, and cyclins E, and cyclin-dependent kinases (CDKs) 2, and 4, with concomitant induction of p21waf1/Cip1 and p27Kip1. We conclude that hispolon induces both of extrinsic and intrinsic apoptotic pathways in NB4 human leukemia cells in vitro.
LATTICES OF COUPLED CAVITIES AS PHOTONIC SIMULATORS FOR TOPOLOGICAL PHENOMENA IN CONDENSED MATTER PHYSICS
Authors: YANNOPAPAS VASSILIOS
Published: November 2013

We review several two- and three-dimensional metamaterial designs which serve as photonic simulators of topological phenomena in condensed matter physics. Based on a coupled-mode theory we show that lattices of interacting cavities can simulate Haldane lattices which exhibit one-way guided modes and mode coalescence in the absence of external magnetic field. Furthermore, periodic holey metals filled with a magnetoelectric material exhibit a nonreciprocal photonic band structure in the optical regime. Lastly, we show that a three-dimensional lattice of interacting cavities respecting time-reversal symmetry and a certain point-group symmetry can simulate a topological crystalline insulator.
CHAOTIC BEHAVIOR AND ITS CONTROL IN THE SINGLE-WALL CARBON NANOTUBE
Authors: FANG JIANSHU
Published: November 2013

Using the direct perturbation technique, we obtained a general perturbed solution of single-wall carbon nanotube (SWNT). We also provided two necessary and sufficient conditions for boundedness of the perturbed solution. Theoretical analysis results and the corresponding numerical results showed that the perturbed solution of the SWNT was unbounded in generally, which indicated the chaotic behavior of the system. Moreover, we were able to control the chaos of the carbon nanotube by adjusting the system parameters.
TACKLING NEGATIVELY CORRELATED GLOBAL AND LOCAL EXTERNALITIES — AN ECONOMIC STUDY OF MULTIPLE GASES ISSUE IN CLIMATE CHANGE
Authors: YANG ZILI , MENON SURABI
Published: November 2013

In this paper, we examine the relationship between CO 2 and SO 2 (including carbonaceous aerosols) mitigations in a framework of correlated global and local externalities. The framework is set up in a revised RICE model [Nordhaus, WD and Z Yang (1996). A regional dynamic general-equilibrium model of alternative climate-change strategies. American Economic Review, 86(4), 741–765], which we labeled as the RICES model (stands for RICE with [Formula: see text]). In RICES model, we pioneer the empirical modeling of negatively correlated global and local externalities through negative radiative forcing of aerosols. Through simulating different scenarios, we quantify the impacts of local pollution control efforts at mitigating SO 2 emissions on climate change and indicate the policy implications of correlations between CO 2 and SO 2 emissions.
Paeoniflorin abrogates DSS-induced colitis via a TLR4-dependent pathway
Authors: Zhang Jingjing , Dou Wei , Zhang Eryun , Sun Aning , Ding Lili , Wei Xiaohui , Chou Guixin , Mani Sridhar , Wang Zhengtao
Published: November 2013

Paeonia lactiflora Pall is one of the most well-known herbs in China, Korea, and Japan for more than 1,200 years. Paeoniflorin, the major bioactive component of peony root, has recently been reported to have anticolitic activity. However, the underlying molecular mechanism is unclear. The present study was to explore the possible mechanism of paeoniflorin in attenuating dextran sulfate sodium (DSS)-induced colitis. Pre- and coadministration of paeoniflorin significantly reduced the severity of colitis and resulted in downregulation of several inflammatory parameters in the colon, including the activity of myeloperoxidase (MPO), the levels of TNF-α and IL-6, and the mRNA expression of proinflammatory mediators (MCP-1, Cox2, IFN-γ, TNF-α, IL-6, and IL-17). The decline in the activation of NF-κB p65, ERK, JNK, and p38 MAPK correlated with a decrease in mucosal Toll-like receptor 4 (TLR4) but not TLR2 or TLR5 expression. In accordance with the in vivo results, paeoniflorin downregulated TLR4 expression, blocked nuclear translocation of NF-κB p65, and reduced the production of IL-6 in LPS-stimulated mouse macrophage RAW264.7 cells. Transient transfection assay performed in LPS-stimulated human colon cancer HT-29 cells indicated that paeoniflorin inhibits NF-κB transcriptional activity in a dose-dependent manner. TLR4 knockdown and overexpression experiments demonstrated a requirement for TLR4 in paeoniflorin-mediated downregulation of inflammatory cytokines. Thus, for the first time, the present study indicates that paeoniflorin abrogates DSS-induced colitis via decreasing the expression of TLR4 and suppressing the activation of NF-κB and MAPK pathways.
Effect of growth hormone on aging connective tissue in muscle and tendon: gene expression, morphology, and function following immobilization and rehabilitation
Authors: Boesen A. P. , Dideriksen K. , Couppé C. , Magnusson S. P. , Schjerling P. , Boesen M. , Aagaard P. , Kjaer M. , Langberg H.
Published: November 2013

It is unknown whether loss in musculotendinous tissue during inactivity can be counteracted by growth hormone (GH), and whether GH accelerate rehabilitation in aging individuals. Elderly men (65–75 yr; n = 12) had one leg immobilized 2 wk followed by 6 wk of retraining and were randomly assigned to daily injections of recombinant GH (rhGH; n = 6) or placebo (Plc; n = 6). Cross-sectional area (CSA), muscle strength (MVC), and biomechanical properties of m. quadriceps and patellar tendon were determined. Muscle and tendon biopsies were analyzed for gene expressions (mRNA) of collagen (COL1A1/3A1) and insulin-like growth factors (IGF-1Ea/Ec). Fibril morphology was analyzed by transmission electron microscope (TEM). In tendon, CSA and biomechanical properties did not change following immobilization, but an increase in CSA was found after 6 wk of rehabilitation in both groups. The changes were more pronounced when GH was injected. Furthermore, tendon stiffness increased in the GH group. Muscle CSA declined after immobilization in the Plc but not in the GH group. Muscle CSA increased during retraining, with a significantly larger increase in the GH group compared with the Plc group. Both a time and a group effect were seen for IGF-1Ea/Ec and COL1A1/3A1 mRNA expression in muscle, with a difference between GH and Plc. IGF-1Ea/Ec and COL-1A1/3A1 mRNA expression increased in muscle following immobilization and retraining in subjects receiving GH, whereas an increase in IGF-1Ec mRNA expression was seen in the Plc group only after retraining. In conclusion, in elderly humans, GH seems to have a matrix stabilizing effect during inactivity and rehabilitation by stimulating collagen expression in the musculotendinous tissue and increasing tendon CSA and stiffness.
Design and Performance Evaluation of a Very Low Flow Coefficient Centrifugal Compressor
Authors: Wang Yongsheng , Lin Feng , Nie Chaoqun , Engeda Abraham
Published: November 2013

Very low flow coefficient centrifugal compressors are often applied as the last stages of multistage compressors. Due to the lower volume flow rate, the flow channels in the impeller and diffuser are so narrow that friction loss becomes the main factor, which leads to lower efficiency than that of other stages in the same compressors. In addition, most of design methods are generally based on medium flow coefficient centrifugal compressors. Taking on researches on the low flow coefficient centrifugal compressors is significant and necessary. One-dimensional (1D) code, consisting of design and analysis parts, is developed in this study to provide basic geometric data and predict the entire performance of centrifugal compressor. Three-dimensional geometry of the impeller is built. CFD simulation is carried out as well to be compared with 1D prediction. With the continuous geometry adjustment, the final performance of the centrifugal compressor will be fixed once the performance discrepancy between CFD and one-dimensional code is acceptable. The details on the flow field within impeller will be presented through CFD.
Coordination in the Decentralized Assembly System with Dual Supply Modes
Authors: Guan Xu , Liu Mengqi
Published: November 2013

This paper investigates a decentralized assembly system that consists of one assembler and two independent suppliers; wherein one supplier is perfectly reliable for the production, while the other generates yield uncertainty. Facing the random market demand, the assembler has to order the components from one supplier in advance and meanwhile requires the other supplier to deliver the components under VMI mode. We construct a Nash game between the supplier and the assembler so as to derive their equilibrium procurement/production strategies. The results show that the channel’s performance is highly undermined by the decentralization between players and also the combination of two supply modes. Compared to the centralized system, we propose an advance payment contract to perfectly coordinate the supply chain performance. The numerical examples indicate some management implications on the supply mode comparison and sensitivity analysis.
AR Model-Based Direction-of-Arrival Estimation of Coherent Signals in the Presence of Unknown Mutual Coupling
Authors: Sha Zhi-Chao , Liu Zhang-Meng , Huang Zhi-Tao , Zhou Yi-Yu
Published: November 2013

This paper addresses the problem of direction-of-arrival (DOA) estimation of coherent signals in the presence of unknown mutual coupling, and an autoregression (AR) model-based method is proposed. The effects of mutual coupling can be eliminated by the inherent mechanism of the proposed algorithm, so the DOAs can be accurately estimated without any calibration sources. After the mixing matrix is estimated by independent component analysis (ICA), several parameter equations are established upon the mixing matrix. Finally, all DOAs of coherent signals are estimated by solving these equations. Compared with traditional methods, the proposed method has higher angle resolution and estimation accuracy. Simulation results demonstrate the effectiveness of the algorithm.
Improved Efficiency of Flexible Organic Light-Emitting Diodes by Insertion of Ultrathin SiO2Buffer Layers
Authors: Huang Chien-Jung , Chen Kan-Lin , Sze Po-Wen , Chen Wen-Ray , Meen Teen-Hang , Wu Shi-Lun
Published: November 2013

An ultrathin hole-injection buffer layer (HBL) using silicon dioxide (SiO2) by electron beam evaporation in flexible organic light-emitting diode (FOLED) has been fabricated. While the current of the device at constant driving voltage decreases as increasing SiO2thickness. Compared to the different thicknesses of the buffer layer, the FOLED with the buffer layer of 4 nm showed the highest luminous efficiency. The atomic force microscopy (AFM) investigation of indium tin oxide (ITO)/SiO2topography reveals changes at the interface between SiO2and N,N′-bis-(1-naphthl)-diphenyl-1,1′-bipheny-4,4′-diamine (NPB), resulting in ultrathin SiO2layers being a clear advantage for a FOLED. However, the SiO2can be expected to be a good buffer layer material and thus enhance the emission performance of the FOLED.
CYP19Genetic Polymorphism HaplotypeAASAIs Associated with a Poor Prognosis in Premenopausal Women with Lymph Node-Negative, Hormone Receptor-Positive Breast Cancer
Authors: Kuo Sung-Hsin , Yang Shi-Yi , Lien Huang-Chun , Lo Chiao , Lin Ching-Hung , Lu Yen-Sen , Cheng Ann-Lii , Chang King-Jeng , Huang Chiun-Sheng
Published: November 2013

Given the critical role ofCYP19in estrogen synthesis, we investigated the influence ofCYP19gene polymorphisms on the clinical outcome of lymph node- (LN-) negative, hormone receptor- (HR-) positive early breast cancers. Genotyping for theCYP19polymorphisms rs4646 (A/C), rs1065779 (A/C),CYP19(TTTA)n (short allele/long (S/L) allele using the 7 TTTA repeat polymorphism as the cut-off), and rs1870050 (A/C) was performed on 296 patients with LN-negative, HR-positive breast cancers. All patients received adjuvant hormonal therapy. Associations were examined between these 4 genotypes and 6 common haplotypes ofCYP19and distant disease-free survival (DDFS), disease-free survival (DFS), and overall survival (OS). Patients were divided into the 6 subhaplotypes ofCCLA(41.1%),AASA(17.1%),CASA(11.9%),CCLC(8.9%),CCSA(7.5%),AASC(8.9%), and others (4.6%). In premenopausal patients, haplotypeAASAwas significantly associated with a poor DDFS (adjusted hazard ratio (aHR), 3.3;P=0.001), DFS (aHR, 2.5;P=0.0008), and OS (aHR, 2.9;P=0.0004) after adjusting for age, tumor size, tumor grade, estrogen receptor status, progesterone receptor status, chemotherapy, pathology, adjuvant hormone therapy, menopausal status, and radiotherapy. Furthermore, haplotypeAASAremained a negative prognostic factor for premenopausal patients receiving adjuvant chemotherapy in terms of DDFS (aHR, 4.5;P=0.0005), DFS (HR, 3.2;P=0.003), and OS (HR, 6.4;P=0.0009). However, in postmenopausal patients, haplotypeAASAwas not associated with a poor prognosis, whereas theAASChaplotype was significantly associated with a poor DFS (aHR, 3.1;P=0.03) and OS (aHR, 4.4;P=0.01). Our results indicate that, in patients with LN-negative, HR-positive breast cancers, genetic polymorphism haplotypeAASAis associated with poor survival of premenopausal women but does not affect survival of postmenopausal women.
The Infrared Radiation Temperature Characteristic of Acupoints of Mammary Gland Hyperplasia Patients
Authors: Zheng Juanjuan , Zhao Yi , Wang Yafang , Hu Shengfang , Lu Ping , Shen Xueyong
Published: November 2013

Objective. To ascertain pathological information on hyperplasia of mammary glands (HMG) of patients via the infrared radiation temperature of acupoints.Method. Patients with HMG and healthy controls were tested using an infrared thermal imager.Results. In controls, no significant difference in temperature was observed between points with the same name (P>0.05). The temperature of all tested points was found to be higher in the group with HMG than in that of the healthy controls, except for the left and right Zusanli (ST36). The temperature of the right Rugen (ST18), Guanyuan (CV4), Qihai (CV6), and Hegu (LI4) reached a statistically significant heightened level (P=0.046~P<0.001). The temperature of the Zusanli (ST36) and Hegu (LI4) present on the right side was significantly higher than that of the left (P=0.001andP=0.004, resp.), while the temperature of the left Youmen (KI21) was significantly higher than that of the right (P=0.008).Conclusion. The temperature of the bilateral acupoints in healthy controls was symmetrical, and the raised temperatures observed of the Rugen (ST18), Guanyuan (CV4), Qihai (CV6), and Hegu (LI4) acupoints of HMG patients and the imbalance of the temperature of the bilateral acupoints Zusanli (ST36), Youmen (KI21), and Hegu (LI4) carried special pathological information about HMG disease.
Effects of Wenxin Keli on the Action Potential and L-Type Calcium Current in Rats with Transverse Aortic Constriction-Induced Heart Failure
Authors: Chen Yu , Li Yang , Guo Lili , Chen Wen , Zhao Mingjing , Gao Yonghong , Wu Aiming , Lou Lixia , Wang Jie , Liu Xiaoqiu , Xing Yanwei
Published: November 2013

Objective. We investigated the effects of WXKL on the action potential (AP) and the L-type calcium current (ICa-L) in normal and hypertrophied myocytes.Methods. Forty male rats were randomly divided into two groups: the control group and the transverse aortic constriction- (TAC-) induced heart failure group. Cardiac hypertrophy was induced by TAC surgery, whereas the control group underwent a sham operation. Eight weeks after surgery, single cardiac ventricular myocytes were isolated from the hearts of the rats. The APs andICa-Lwere recorded using the whole-cell patch clamp technique.Results. The action potential duration (APD) of the TAC group was prolonged compared with the control group and was markedly shortened by WXKL treatment in a dose-dependent manner. The current densities of theICa-Lin the TAC group treated with 5 g/L WXKL were significantly decreased compared with the TAC group. We also determined the effect of WXKL on the gating mechanism of theICa-Lin the TAC group. We found that WXKL decreased theICa-Lby accelerating the inactivation of the channels and delaying the recovery time from inactivation.Conclusions. The results suggest that WXKL affects the AP and blocked theICa-L, which ultimately resulted in the treatment of arrhythmias.
Bifurcations and Stability of Nondegenerated Homoclinic Loops for Higher Dimensional Systems
Authors: Jin Yinlai , Li Feng , Xu Han , Li Jing , Zhang Liqun , Ding Benyan
Published: November 2013

By using the foundational solutions of the linear variational equation of the unperturbed system along the homoclinic orbit as the local current coordinates system of the system in the small neighborhood of the homoclinic orbit, we discuss the bifurcation problems of nondegenerated homoclinic loops. Under the nonresonant condition, existence, uniqueness, and incoexistence of 1-homoclinic loop and 1-periodic orbit, the inexistence ofk-homoclinic loop andk-periodic orbit is obtained. Under the resonant condition, we study the existence of 1-homoclinic loop, 1-periodic orbit, 2-fold 1-periodic orbit, and two 1-periodic orbits; the coexistence of 1-homoclinic loop and 1-periodic orbit. Moreover, we give the corresponding existence fields and bifurcation surfaces. At last, we study the stability of the homoclinic loop for the two cases of non-resonant and resonant, and we obtain the corresponding criterions.
Supported Zinc Oxide Photocatalyst for Decolorization and Mineralization of Orange G Dye Wastewater under UV365 Irradiation
Authors: Chang Ming-Chin , Shu Hung-Yee , Tseng Tien-Hsin , Hsu Hsin-Wen
Published: November 2013

To solve the environmental challenge of textile wastewater, a UV/ZnO photocatalytic system was proposed. The objective of this study was to prepare a photocatalytic system by utilizing both cold cathode fluorescent light (CCFL) UV irradiation and steel mesh supported ZnO nanoparticles in a closed reactor for the degradation of azo dye C.I. Orange G (OG). Various operating parameters such as reaction time, preparation temperature, mixing speed, ZnO dosage, UV intensity, pH, initial dye concentration, and service duration were studied. Results presented efficient color and total organic carbon (TOC) removal of the OG azo dye by the designed photocatalytic system. The optimal ZnO dosage for color removal was 60 g m−2. An alkaline pH of 11.0 was sufficient for photocatalytic decolorization and mineralization. The rate of color removal decreased with the increase in the initial dye concentration. However, the rate of color removal increased with the increase in the UV intensity. The steel mesh supported ZnO can be used repeatedly over 10 times without losing the color removal efficiency for 120 min reaction time. Results of Fourier transform infrared (FTIR) and ion chromatography (IC) indicated the breakage of N=N bonds and formation of sulfate, nitrate, and nitrite as the major and minor products. The observation indicated degradation of dye molecules.
TheD-Property of Finite Unions oft-Metrizable Spaces and Certain Function Spaces
Authors: Zhang Xin , Guo Hongfeng
Published: November 2013

The additivity ofD-property is studied ont-metrizable spaces and certain function spaces. It is shown that a space of countable tightness is aD-space provided that it is the union of finitely manyt-metrizable subspaces, or function spacesCp(Xi)where eachXiis LindelöfΣ.
Direct Numerical Simulation of Concentration and Orientation Distribution of Fibers in a Mixing Layer
Authors: Zhou Kun , Yang Wei , He Zhu , Xiao Ming
Published: November 2013

The concentration and orientation of suspended fibers in a mixing layer are investigated numerically. Two cases (diffusive and nondiffusive) are investigated for the fiber concentration distribution. The fine structures of the instantaneous distributions under these two cases are very different due to molecular diffusion. Sharp front of concentration is observed in the nondiffusive case. However, there is no obvious difference in the mean concentration between the two cases. With regard to the orientation, a fiber may rotate periodically or approach an asymptotic orientation, which is determined by a determinant defined with the stain rate. The symmetric part of the strain rate tends to make a fiber align to an asymptotic orientation, while the antisymmetric part drives a fiber to rotate. When a fluid parcel passes through a region with relatively high shear rate, fibers carried by the fluid parcel are most likely to rotate incessantly. On the other hand, in the region of relatively high extension rate, fibers tend to align to some asymptotic orientation. Generally, fibers tend to align with the shear plane. This fact has significant implications in predicting the rheological properties of fiber suspension flows.
On Complete Convergence for Weighted Sums ofρ*-Mixing Random Variables
Authors: Shen Aiting , Wang Xinghui , Zhu Huayan
Published: November 2013

We prove the strong law of large numbers for weighted sums∑i=1n‍aniXi, which generalizes and improves the corresponding one for independent and identically distributed random variables andφ-mixing random variables. In addition, we present some results on complete convergence for weighted sums ofρ*-mixing random variables under some suitable conditions, which generalize the corresponding ones for independent random variables.
Global Robust Exponential Stability and Periodic Solutions for Interval Cohen-Grossberg Neural Networks with Mixed Delays
Authors: Du Yanke , Xu Rui
Published: November 2013

A class of interval Cohen-Grossberg neural networks with time-varying delays and infinite distributed delays is investigated. By employing H-matrix and M-matrix theory, homeomorphism techniques, Lyapunov functional method, and linear matrix inequality approach, sufficient conditions are established for the existence, uniqueness, and global robust exponential stability of the equilibrium point and the periodic solution to the neural networks. Our results improve some previously published ones. Finally, numerical examples are given to illustrate the feasibility of the theoretical results and further to exhibit that there is a characteristic sequence of bifurcations leading to a chaotic dynamics, which implies that the system admits rich and complex dynamics.
Requirements for Aurora-A in Tissue Regeneration and Tumor Development in Adult Mammals
Authors: Pérez de Castro Ignacio , Aguirre-Portolés Cristina , Fernández-Miranda Gonzalo , Cañamero Marta , Cowley Dale O. , Van Dyke Terry , Malumbres Marcos
Published: November 2013

Aurora-A is a kinase involved in the formation and maturation of the mitotic spindle and chromosome segregation. This kinase is frequently overexpressed in human cancer, and its activity may confer resistance to antitumoral drugs such as Taxol. Inhibition of Aurora-A results in mitotic defects, and this kinase is considered as an attractive therapeutic target for cancer. Nevertheless, the specific requirements for this kinase in adult mammalian tissues remain unclear. Conditional genetic ablation of Aurora-A in adult tissues results in polyploid cells that display a DNA-damage–like response characterized by the upregulation of p53 and the cell-cycle inhibitor p21Cip1. This is accompanied by apoptotic, differentiation, or senescence markers in a tissue-specific manner. Therapeutic elimination of Aurora-A prevents the progression of skin and mammary gland tumors. However, this is not due to significant levels of apoptosis or senescence, but because Aurora-A–deficient tumors accumulate polyploid cells with limited proliferative potential. Thus, Aurora-A is required for tumor formation in vivo, and the differential response observed in various tissues might have relevant implications in current therapeutic strategies aimed at inhibiting this kinase in the treatment of human cancer. Cancer Res; 73(22); 6804–15. ©2013 AACR.
The Transcription Factor IRF8 Counteracts BCR-ABL to Rescue Dendritic Cell Development in Chronic Myelogenous Leukemia
Authors: Watanabe Tomoya , Hotta Chie , Koizumi Shin-ichi , Miyashita Kazuho , Nakabayashi Jun , Kurotaki Daisuke , Sato Go R. , Yamamoto Michio , Nakazawa Masatoshi , Fujita Hiroyuki , Sakai Rika , Fujisawa Shin , Nishiyama Akira , Ikezawa Zenro , Aihara Michiko , Ishigatsubo Yoshiaki , Tamura Tomohiko
Published: November 2013

BCR-ABL tyrosine kinase inhibitors (TKI) have dramatically improved therapy for chronic myelogenous leukemia (CML). However, several problems leading to TKI resistance still impede a complete cure of this disease. IFN regulatory factor-8 (IRF8) is a transcription factor essential for the development and functions of immune cells, including dendritic cells. Irf8−/− mice develop a CML-like disease and IRF8 expression is downregulated in patients with CML, suggesting that IRF8 is involved in the pathogenesis of CML. In this study, by using a murine CML model, we show that BCR-ABL strongly inhibits a generation of dendritic cells from an early stage of their differentiation in vivo, concomitant with suppression of Irf8 expression. Forced expression of IRF8 overrode BCR-ABL (both wild-type and T315I-mutated) to rescue dendritic cell development in vitro, indicating that the suppression of Irf8 causes dendritic cell deficiency. Gene expression profiling revealed that IRF8 restored the expression of a significant portion of BCR-ABL–dysregulated genes and predicted that BCR-ABL has immune-stimulatory potential. Indeed, IRF8-rescued BCR-ABL–expressing dendritic cells were capable of inducing CTLs more efficiently than control dendritic cells. Altogether, our findings suggest that IRF8 is an attractive target in next-generation therapies for CML. Cancer Res; 73(22); 6642–53. ©2013 AACR.
MAPK Kinase 3 Is a Tumor Suppressor with Reduced Copy Number in Breast Cancer
Authors: MacNeil Adam J. , Jiao Shun-Chang , McEachern Lori A. , Yang Yong Jun , Dennis Amanda , Yu Haiming , Xu Zhaolin , Marshall Jean S. , Lin Tong-Jun
Published: November 2013

Cancers are initiated as a result of changes that occur in the genome. Identification of gains and losses in the structure and expression of tumor-suppressor genes and oncogenes lies at the root of the understanding of cancer cell biology. Here, we show that the mitogen–activated protein kinase (MAPK) MKK3 suppresses the growth of breast cancer, in which it varies in copy number. A pervasive loss of MKK3 gene copy number in patients with breast cancer is associated with an impairment of MKK3 expression and protein level in malignant tissues. To assess the functional role of MKK3 in breast cancer, we showed in an animal model that MKK3 activity is required for suppression of tumor growth. Active MKK3 enhanced expression of the cyclin-dependent kinase inhibitors p21Cip1/Waf1 and p27Kip1, leading to increased cell-cycle arrest in G1 phase of the cell cycle. Our results reveal the functional significance of MKK3 as a tumor suppressor and improve understanding of the dynamic role of the MAPK pathway in tumor progression. Cancer Res; 74(1); 162–72. ©2013 AACR.
Small-Molecule Intramimics of Formin Autoinhibition: A New Strategy to Target the Cytoskeletal Remodeling Machinery in Cancer Cells
Authors: Lash L. Leanne , Wallar Bradley J. , Turner Julie D. , Vroegop Steven M. , Kilkuskie Robert E. , Kitchen-Goosen Susan M. , Xu H. Eric , Alberts Arthur S.
Published: November 2013

Although the cancer cell cytoskeleton is a clinically validated target, few new strategies have emerged for selectively targeting cell division by modulating the cytoskeletal structure, particularly ways that could avoid the cardiotoxic and neurotoxic effects of current agents such as taxanes. We address this gap by describing a novel class of small-molecule agonists of the mammalian Diaphanous (mDia)-related formins, which act downstream of Rho GTPases to assemble actin filaments, and their organization with microfilaments to establish and maintain cell polarity during migration and asymmetric division. GTP-bound Rho activates mDia family members by disrupting the interaction between the DID and DAD autoregulatory domains, which releases the FH2 domain to modulate actin and microtubule dynamics. In screening for DID–DAD disruptors that activate mDia, we identified two molecules called intramimics (IMM-01 and -02) that were sufficient to trigger actin assembly and microtubule stabilization, serum response factor-mediated gene expression, cell-cycle arrest, and apoptosis. In vivo analysis of IMM-01 and -02 established their ability to slow tumor growth in a mouse xenograft model of colon cancer. Taken together, our work establishes the use of intramimics and mDia-related formins as a new general strategy for therapeutic targeting of the cytoskeletal remodeling machinery of cancer cells. Cancer Res; 73(22); 6793–803. ©2013 AACR.
Helicobacter pylori Seropositivities and Risk of Pancreatic Carcinoma
Authors: Risch Harvey A. , Lu Lingeng , Kidd Mark S. , Wang Jing , Zhang Wei , Ni Quanxing , Gao Yu-Tang , Yu Herbert
Published: November 2013

Background: Pathophysiologic actions of Helicobacter pylori colonization on gastric acidity have been hypothesized to modulate the effect of pancreatic carcinogens, through CagA-negative organism strain type, hyperchlorhydria and increased risk of pancreatic cancer, or CagA-positive strain, hypochlorhydria and decreased risk of pancreatic cancer. We aimed to determine H. pylori strain–specific associations with pancreatic cancer in a population in which colonization by CagA-positive strains is common.

Methods: We carried out a large population-based case–control study of pancreatic carcinoma in Shanghai, China. Venipuncture specimens were obtained from a representative sample of 761 case patients and 794 randomly selected control subjects matched by category of age and gender. Antibody seropositivity for H. pylori and its virulence protein CagA were determined by commercial enzyme-linked immunosorbent IgG assays.

Results: Compared with individuals seronegative for both H. pylori and CagA, decreased pancreas-cancer risk was seen for CagA seropositivity [adjusted OR, 0.68; 95% confidence interval (CI), 0.54–0.84], whereas some increased risk was suggested for CagA-negative H. pylori seropositivity (OR, 1.28; 95% CI, 0.76–2.13). No risk interactions were observed between CagA seropositivity and gender, cigarette smoking, or age-21 body mass index.

Conclusions: Similar to what has been seen in animal models, our results provide suggestive evidence in humans for the involvement of gastric acidity, through its bidirectional modification according to colonization by H. pylori CagA strain type, in the risk of pancreatic carcinoma.

Impact:H. pylori colonization may have diverse effects on cancer risk, depending on the organism strain type as well as on the particular cancer site. Cancer Epidemiol Biomarkers Prev; 23(1); 172–8. ©2013 AACR.
The Host and the Flora
Authors: Nuding S. , Antoni L. , Stange E.F.
Published: November 2013

To prevent bacterial overgrowth, colonization of the epithelium and subsequent translocation, the gastrointestinal tract maintains an effective mucosal barrier. Besides mucus the most important components of this protective system are epithelial antimicrobial peptides such as defensins, the cathelicidin LL-37, lysozyme, phospholipase A, and proteins with additional antimicrobial properties such as ubiquicidin, ribosomal proteins or histones. Commensal species may tolerate intestinal antimicrobial peptides, for example Bacteroides ssp. or Parabacteroides ssp. as major species in the human colon were highly resistant to the constitutive defensin HBD-1 and only susceptible to the inducible defensin HBD-3. Reduction of disulfide bonds is an important mechanism activating HBD-1. As several studies show, alterations in the expression of antimicrobial peptides directly influence the composition of the intestinal flora. Correspondingly, an increased production of defensins or inhibition of the processing of mouse defensins to their active form led to a quantitative shift of luminal and mucosal bacterial species. On the other hand, microorganisms also modulate the synthesis of host defensins by induction or inhibition of specific peptides. Lactobacilli, the probiotic strain Escherichia coli Nissle and Salmonella enteritica stimulate HBD-2 expression, whereas Shigella flexneri downregulates the synthesis of HBD-1, HBD-3 and LL-37. Thus, the proper balance between the luminal flora and the mucosa is a permanently dynamic, sensitive and host-specific relationship.
Adverse Events of Tumor Necrosis Factor Inhibitors
Authors: Fellermann Klaus
Published: November 2013

Background/Aims: Adverse events in anti-TNF treatment can be divided into allergic reactions with an acute and delayed onset, infectious complications in relation to the underlying disease, and without. Last but not least, there is the unresolved question of tumor induction and propagation. All of these may account for morbidity and eventually mortality. Methods: Literature-based review to update current knowledge about safety and adverse events of TNF blockers. Results: Major drawbacks are infectious complications with the use of anti-TNF-α antibodies. The risk is increased in inflammatory bowel disease in general and in the perioperative setting of Crohn's disease patients. The number of tuberculosis cases has decreased since meticulous testing prior to treatment start is mandatory. An excess mortality that has been reported from referral centers is neither documented in randomized controlled trials nor in real-life settings. Regarding malignancies, lymphoma and skin cancer are a concern. The incidence of lymphoma may be raised, but this has also been debated with the use of thiopurines. Skin cancer, especially melanoma, is more common in inflammatory bowel disease and may be associated with the use of biologics. Overall, most studies do not address the influence of active inflammation or co-administration of other drugs. Hence, the risk attributable to TNF blockers alone is currently ill-defined. Conclusion: Treatment with anti-TNF-α antibodies is an option with substantial risks. Most problems can be prevented by thorough workup of the patient.
Antibiotics and Inflammatory Bowel Diseases
Authors: Scribano Maria Lia , Prantera Cosimo
Published: November 2013

Inflammatory bowel diseases are characterized by an altered composition of gut microbiota (dysbiosis) that may contribute to their development. Antibiotics can alter the bacterial flora, and a link between antibiotic use and onset of Crohn's disease (CD), but not ulcerative colitis, has been reported. The hypothesis that Mycobacterium avium subspecies paratuberculosis (MAP) could be an etiologic agent of CD has not been confirmed by a large study on patients treated by an association of antibiotics active against MAP. The observations supporting a role of intestinal microbiota in CD pathogenesis provide the rationale for a therapeutic manipulation of the intestinal flora through the employment of antibiotics. However, current data do not strongly support a therapeutic benefit from antibiotics, and there is still controversy regarding their use as primary therapy for treatment of acute flares of CD, and for postoperative recurrence prevention. Nevertheless, clinical practice and some studies suggest that a subgroup of patients with colonic involvement, early disease, and abnormal laboratory test of inflammation may respond better to antibiotic treatment. Since their long-term use is frequently complicated by a high rate of side effects, the use of antibiotics that work locally appears to be promising.
Clinical Importance of a Fixed Bowel Loop in the Treatment of Necrotizing Enterocolitis
Authors: Muller Anoek , Schurink Maarten , Bos Arend F. , Hulzebos Christian V. , Martijn Albert , Hulscher Jan B.F. , Kooi Elisabeth M.W.
Published: November 2013

Background: The need for surgical treatment in neonates with necrotizing enterocolitis (NEC) is associated with high mortality. Although pneumoperitoneum and progressive disease are generally accepted indications for surgery, it is unclear whether a fixed bowel loop (FBL) should prompt surgery. Objective: To determine the relationship between an FBL, type of treatment, and death in the management of NEC. Methods: Retrospective analysis (January 2000-December 2011) of all neonates with definite NEC in a tertiary neonatal intensive care unit. FBL was defined as a persistent (i.e. >24 h) dilated intestinal segment present on serial abdominal X-rays. Results: NEC was diagnosed in 141 neonates (median gestational age 30 weeks; median birth weight 1,340 g). An FBL was reported in 38 (27%) patients, of whom 18 were treated surgically. Mortality among FBL patients was independent of the type of treatment (surgical versus conservative): 8/18 and 7/20, respectively (p = 0.55). Of the 103 patients without FBL, 37 (36%) were treated surgically, which is comparable to the FBL group. Again, mortality was not related to the type of treatment (surgical versus conservative): 5/37 and 6/66, respectively (p = 0.49). The presence of an FBL was associated with mortality: more patients with an FBL (15/38, 39%) died than without an FBL (11/103, 11%; odds ratio 5.45, 95% confidence interval 2.21-13.45; p < 0.01). Conclusions: In NEC patients, an FBL is associated with increased mortality. On its own it has moderate significance to guide treatment. Nevertheless, because it reflects disease severity, early recognition is important and prompt (surgical) treatment should be considered.
Inappropriate Prescribing as a Predictor for Long-Term Mortality after Hip Fracture
Authors: Gosch M. , Wörtz M. , Nicholas J.A. , Doshi H.K. , Kammerlander C. , Lechleitner M.
Published: November 2013

Background: Hip fracture patients are at a higher risk for death compared to age-matched controls. While the reasons for this increased mortality risk are incompletely understood, medical comorbidities and associated medication prescribing likely play an important role in patient outcomes. Altered drug metabolism, polypharmacy and diminished physiologic reserve may all lead to adverse drug reactions and adverse outcomes. Additionally, underprescribing of efficacious medications may deprive older patients of potential therapeutic benefits. Objective: The aim of our trial was to estimate the impact of inappropriate medication prescribing on the long-term outcome of older hip fracture patients. Methods: The present study is a retrospective cohort study. We included all hip fracture patients who were consecutively admitted to our department from 2000 to 2004. We used the previously published STOPP (Screening Tool of Older Person's Prescriptions) and START (Screening Tool to Alert doctors to Right Treatment) criteria to assess the appropriateness of medication prescribing with an additional focus on osteoporosis medications and the total number of prescriptions. Prescriptions meeting STOPP and START criteria were considered ‘positive items' and correlated with outcomes. Mortality was assessed by cross-referencing with the national death registry of the Tyrolean Institute of Epidemiology. Results: During the study period, a total of 457 patients with hip fracture (mean age 80.61 ± 7.07 years; range 65-98) were evaluated. The mean number of positive combined STOPP and START items per patient was 2 ± 1.3, with ranges from 0 to 6 (STOPP items), 0 to 4 (START items) and 0 to 7 (combined STOPP/START items). Only 44 (9.6%) of patients had no positive STOPP or START items. The mean number of positive items (STOPP, START and combined) was significantly higher in non-survivors than survivors. The all-cause mortality rate at 3 years was lowest in the subjects with 1 or 0 positive items (20.5%; n = 35) and highest among those with >3 positive items (44.4%; n = 63). Inappropriate medication prescribing remained an independent risk factor with an odds ratio of 1.28 (1.07-1.52) after adjustment for sex, age, activities of daily living, comorbidities and nutrition status. Conclusion: Inappropriate medication prescribing is an independent predictor of long-term mortality in older hip fracture patients. It increases the relative risk of mortality in older hip fracture patients by 28%.
IL-25 and IL-25 Receptor Expression on Eosinophils from Subjects with Allergic Asthma
Authors: Tang Wei , Smith Steven G. , Beaudin Sue , Dua Benny , Howie Karen , Gauvreau Gail , O'Byrne Paul M.
Published: November 2013

Background: Allergic asthma is an inflammatory airway disease in which Th2 cytokines play an important role. Epithelial-derived interleukin (IL)-25 has been suggested to be important in the maintenance of Th2-type responses. The effects of IL-25 are mediated by the IL-25 receptor, composed of two subunits, IL-17RA and IL-17RB. Eosinophils are effector cells in allergic asthma. The role of IL-25 in eosinophil function is unknown. This study examined the expression of IL-25 and its receptor on eosinophils in allergic asthmatics compared to atopic nonasthmatics and normal controls. Methods: The expression of IL-25, IL-17RA and IL-17RB on eosinophils, and levels of plasma IL-25 were measured in 14 normal control subjects, 15 atopic nonasthmatics and 14 mild allergic asthmatics. Results: The expression of IL-17RB on eosinophils was significantly higher in allergic asthmatics (43.08%, range 33.96-59.98%) than in atopic nonasthmatics (11.98%, range 6.33-27.11%, p = 0.002) and normal controls (17.70%, range 10.97-38.9%, p = 0.01). IL-17RA expression was also significantly higher in the allergic asthmatic group. No differences were observed in the intracellular expression of IL-25. The concentration of IL-25 in plasma was significantly increased in the allergic asthmatics (145 ng/ml, range 64-290 ng/ml) when compared to the normal controls (21 ng/ml, range 0-116 ng/ml, p = 0.012), but not compared to atopic nonasthmatics. There was a significant negative correlation between FEV1 % predicted and the IL-25 level in the plasma (r = -0.443, p = 0.003). Conclusions: The increased IL-25 levels in plasma and the expression of IL-17RA and IL-17RB on eosinophils in allergic asthma patients suggests that IL-25 may activate eosinophils during allergic inflammation.
Objectifying the Conjunctival Provocation Test: Photography-Based Rating and Digital Analysis
Authors: Dogan S. , Astvatsatourov A. , Deserno T.M. , Bock F. , Shah-Hosseini K. , Michels A. , Mösges R.
Published: November 2013

Background: Patients with allergic rhinoconjunctivitis are susceptible to both nasal and ocular symptoms. The conjunctival provocation test (CPT) is an established diagnostic procedure used in allergic rhinoconjunctivitis, particularly to document a patient's current reactivity to allergens. To date, there are no international guidelines defining the CPT. No approved evaluation method exists for interpreting CPT results. This paper aims to establish the digital analysis of macroimages as an objective, validated and standardized method for interpreting CPT results. Methods: In a clinical immunotherapy trial with 155 patients, treatment progress was documented based on the CPT. Local investigators used a symptom score to grade tearing, reddening and the patients' subjective perception of symptoms (mucosal irritation). A central observer rated conjunctival hyperemia via digital photography. Digital image analysis software was utilized to determine conjunctival hyperemia. Results: Spearman's correlation between the local investigators' and the central observer's ratings was r = 0.729 (p < 0.001); the percentage of total agreement was 48% (based on 739 photos). Digital image analysis (based on 48 photos) had a high percentage of total agreement with the central observer's ratings (69%) but a low percentage of total agreement with the investigators' ratings (38%). The corresponding correlations were r = 0.264 and 0.064, respectively. Conclusion: Photography-based rating by a central observer may represent a valuable supplement to the local investigator's assessment for making an objective evaluation of CPT results. Digital image analysis possesses the potential of being an objective evaluation method compared to the wide-spread subjective evaluation by the investigators.
Refractoriness of Intestinal Behçet's Disease with Myelodysplastic Syndrome Involving Trisomy 8 to Medical Therapies - Our Case Experience and Review of the Literature
Authors: Toyonaga Takahiko , Nakase Hiroshi , Matsuura Minoru , Minami Naoki , Yamada Satoshi , Honzawa Yusuke , Hukata Norimasa , Yoshino Takuya , Chiba Tsutomu , Okazaki Kazuichi
Published: November 2013

Background/Aims: Gastrointestinal lesions of Behçet's disease (BD) are often refractory to medical therapy and sometimes result in serious comorbidities such as gastrointestinal perforation and massive bleeding. There are several reports of patients with BD comorbid with myelodysplastic syndrome (MDS) involving trisomy 8 that frequently have intestinal lesions refractory to conventional medical therapy. Little is known about the efficacy of infliximab (IFX) for these intestinal lesions. Methods: We present 2 cases of intestinal BD with MDS involving trisomy 8 who did not respond to IFX, and review previous reports of BD with MDS involving trisomy 8 concerning their responsiveness to conventional medical therapy. Results: Among 31 previously reported cases that received medical treatment for BD, 19 (61.3%) showed temporary improvement of the BD symptoms, 9 (29.0%) deteriorated, and 3 (9.7%) showed no change. All of the 9 cases that showed deterioration had intestinal lesions. Our 2 cases failed to respond to IFX, resulting in a poor prognosis. Conclusions: IFX might not be effective for improving intestinal BD comorbid with MDS involving trisomy 8. Trisomy 8 is associated with the BD prognosis and refractoriness to conventional medical therapy.
Intraocular Invasion of Adult T-Cell Leukemia Cells without Systemic Symptoms after Cataract Surgery
Authors: Maruyama Kazuichi , Nagata Kenji , Kojima Kentaro , Inaba Toru , Sugita Sunao , Mochizuki Manabu , Kinoshita Shigeru
Published: November 2013

Adult T-cell leukemia (ATL) is an aggressive lymphoid proliferation associated with the human T-lymphotropic virus type I (HTLV-I). The intraocular invasion of ATL is a rare event. A 75-year-old man without any systemic disease underwent uneventful cataract surgery of the right eye. On postoperative day 6, the patient presented with blurred vision due to severe vitreous opacity in the right eye. Analysis of the vitreous fluid revealed a suspected ATL infection based on the flow cytometric analysis. Moreover, cytological examination of the vitreous specimen revealed flower cell infiltration, and HTLV-1 DNA was detected by PCR analysis of the vitreous sample. Monoclonal T-cell receptor chain rearrangement was also detected by PCR. Thorough analysis of a vitreous sample is essential for vitrectomy in vitreous opacity of unknown cause. Flow cytometric, cytological, and PCR analysis of vitreous samples is beneficial for determining the cause of this kind of severe illness.