bluuebunny/crossref_metadata_2025 huggingface dataset:
Toward Global Comparability of Sexual Orientation Data in Official Statistics: A Conceptual Framework of Sexual Orientation for Health Data Collection in New Zealand’s Official Statistics System
Authors: Pega Frank , Gray Alistair , Veale Jaimie F. , Binson Diane , Sell Randell L.
Published: June 2013

Objective.Effectively addressing health disparities experienced by sexual minority populations requires high-quality official data on sexual orientation. We developed a conceptual framework of sexual orientation to improve the quality of sexual orientation data in New Zealand’s Official Statistics System.Methods.We reviewed conceptual and methodological literature, culminating in a draft framework. To improve the framework, we held focus groups and key-informant interviews with sexual minority stakeholders and producers and consumers of official statistics. An advisory board of experts provided additional guidance.Results.The framework proposes working definitions of the sexual orientation topic and measurement concepts, describes dimensions of the measurement concepts, discusses variables framing the measurement concepts, and outlines conceptual grey areas.Conclusion.The framework proposes standard definitions and concepts for the collection of official sexual orientation data in New Zealand. It presents a model for producers of official statistics in other countries, who wish to improve the quality of health data on their citizens.
Influence of Sleep and Sleep Deprivation on Ictal and Interictal Epileptiform Activity
Authors: Díaz-Negrillo Antonio
Published: June 2013

Sleep is probably one of the most important physiological factors implicated both in epileptic seizures and interictal epileptiform discharges. The neurophysiology concerning the relationship between sleep and epilepsy is well described in the literature; however, the pathological events that culminate in the seizures are poorly explored. The present paper intends to make a rigorous approach to the main mechanisms involved in this reciprocal relation. Knowledge of sleep and sleep deprivation effects in epilepsy stands as crucial in the understanding of how seizures are produced, their possible lines of treatment, and future research.
History-Dependent Patterns in Randomly Perturbed Nematic Liquid Crystals
Authors: Ranjkesh A. , Ambrožič M. , Cordoyiannis G. , Kutnjak Z. , Kralj S.
Published: June 2013

We study the characteristics of nematic structures in a randomly perturbed nematic liquid crystal (LC) phase. We focus on the impact of the samples history on the universal behavior. The obtained results are of interest for every randomly perturbed system exhibiting a continuous symmetry-breaking phase transition. A semimicroscopic lattice simulation is used where the LC molecules are treated as cylindrically symmetric, rod-like objects interacting via a Lebwohl-Lasher (LL) interaction. Pure LC systems exhibit a first order phase transition into the orientationally ordered nematic phase atT=Tcon lowering the temperatureT. The orientational ordering of LC molecules is perturbed by the quenched, randomly distributed rod-likeimpuritiesof concentrationp. Their orientation is randomly distributed, and they are coupled with the LC molecules via an LL-type interaction. Only concentrations below the percolation threshold are considered. The key macroscopic characteristics of perturbed LC structures in the symmetry-broken nematic phase are analyzed for two qualitatively different histories atT≪Tc. We demonstrate that, for a weak enough interaction among the LC molecules andimpurities, qualitatively different history-dependent states could be obtained. These states could exhibit either short-range, quasi-long-range, or even long-range order.
Determination of Copper in Different Ethanolic Matrices Using a Chloropropyl Silica Gel Modified with a Nanostructured Cubic Octa(3‐aminopropyl)octasilsesquioxane
Authors: Do Carmo Devaney Ribeiro , De Oliveira Bicalho Urquisa , a Silveira Tayla Fernanda , Filho Newton Luiz Dias , Lataro Paim Leonardo
Published: June 2013

The chloropropyl silica gel was modified with octa(3‐aminopropyl)octasilsesquioxane and characterized by Fourier transform infrared (FTIR) spectroscopy, nuclear magnetic resonance (NMR), spectroscopies, and surface and area porosity. The specific sorption capacity of metallic ions (Cu2+ and Ni2+) increases in the following solvent order: water < ethanol 42% < ethanol < ketone. The high values of the constant (K) in the order of 103 L mol−1 suggested the high adsorbent capacity of the modified silica (SGAPC) for Cu2+ and Ni2+. SGAPC was applied to a separation column and shows recoveries of around 100% of copper in samples of sugar cane spirit, vodka, ginger brandy, and ethanol fuel.
Extraction of S‐ and N‐Compounds from the Mixture of Hydrocarbons by Ionic Liquids as Selective Solvents
Authors: Gabrić Beata , Sander Aleksandra , Cvjetko Bubalo Marina , Macut Dejan
Published: June 2013

Liquid‐liquid extraction is an alternative method that can be used for desulfurization and denitrification of gasoline and diesel fuels. Recent approaches employ different ionic liquids as selective solvents, due to their general immiscibility with gasoline and diesel, negligible vapor pressure, and high selectivity to sulfur‐ and nitrogen‐containing compounds. For that reason, five imidazolium‐based ionic liquids and one pyridinium‐based ionic liquid were selected for extraction of thiophene, dibenzothiophene, and pyridine from two model solutions. The influences of hydrodynamic conditions, mass ratio, and number of stages were investigated. Increasing the mass ratio of ionic liquid/model fuel and multistage extraction promotes the desulfurization and denitrification abilities of the examined ionic liquids. All selected ionic liquids can be reused and regenerated by means of vacuum evaporation.
Data Visualization Using Rational Trigonometric Spline
Authors: Bashir Uzma , Ali Jamaludin Md.
Published: June 2013

This paper describes the use of trigonometric spline to visualize the given planar data. The goal of this work is to determine the smoothest possible curve that passes through its data points while simultaneously satisfying the shape preserving features of the data. Positive, monotone, and constrained curve interpolating schemes, by using aC1piecewise rational cubic trigonometric spline with four shape parameters, are developed. Two of these shape parameters are constrained and the other two are set free to preserve the inherited shape features of the data as well as to control the shape of the curve. Numerical examples are given to illustrate the worth of the work.
A New Filled Function Method with One Parameter for Global Optimization
Authors: Wei Fei , Wang Yuping
Published: June 2013

The filled function method is an effective approach to find the global minimizer of multidimensional multimodal functions. The conventional filled functions are numerically unstable due to exponential or logarithmic term and sensitive to parameters. In this paper, a new filled function with only one parameter is proposed, which is continuously differentiable and proved to satisfy all conditions of the filled function definition. Moreover, this filled function is not sensitive to parameter, and the overflow can not happen for this function. Based on these, a new filled function method is proposed, and it is numerically stable to the initial point and the parameter variable. The computer simulations indicate that the proposed filled function method is efficient and effective.
Optimal Bandwidth Scheduling of Networked Learning Control System Based on Nash Theory and Auction Mechanism
Authors: Yan Xiang , Li Hongbo , Wang Lide , Shen Ping
Published: June 2013

This paper addresses the optimal bandwidth scheduling problem for a double-layer networked learning control system (NLCS). To deal with this issue, auction mechanism is employed, and a dynamic bandwidth scheduling methodology is proposed to allocate the bandwidth for each subsystem. A noncooperative game fairness model is formulated, and the utility function of subsystems is designed. Under this framework, estimation of distribution algorithm (EDA) is used to obtain Nash equilibrium for NLCS. Finally, simulation and experimental results are given to demonstrate the effectiveness of the proposed approach.
Aspergillus awamoriFeeding Modifies Lipid Metabolism in Rats
Authors: Saleh Ahmed A. , Ohtsuka Akira , Yamamoto Masahiro , Hayashi Kunioki
Published: June 2013

In the present study, an experiment was conducted to show thatA. awamorimodifies lipid metabolism in mammals. A total number of 24 rats at 6 weeks of age were divided into 2 groups (10% and 30% fat dietary groups), and each group was further divided into control and experimental groups (6 rats per group). Rats in the experimental groups were given diets containing 0.05%A. awamori. The diets were administered for 3 weeks to evaluate the effects ofA. awamorion growth, plasma lipid profile, and the expressions of genes related to lipid metabolism in the liver. After the rats were fedA. awamori, body weight gain was increased, while food intake was decreased; therefore, food efficiency was increased in bothA. awamorigroups. Plasma triglycerides, LDL cholesterol, and glucose levels were decreased, but plasma HDL cholesterol levels were increased. Furthermore, saturated fatty acids were decreased while; unsaturated fatty acids were increased in the liver. The liver mRNA levels of FAS, ACC, delta-6-desaturase, and HMG-CoA reductase were increased, while the mRNA level of LDL receptor was decreased. From these data, it is proposed thatA. awamoricould be used as an effective probiotic to prevent lifestyle-related diseases in humans.
Controversial Issues on EEG after Sleep Deprivation for the Diagnosis of Epilepsy
Authors: Giorgi Filippo Sean , Maestri Michelangelo , Guida Melania , Di Coscio Elisa , Carnicelli Luca , Perini Daria , Pizzanelli Chiara , Iudice Alfonso , Bonanni Enrica
Published: June 2013

EEG after sleep deprivation (SD-EEG) is widely used in many epilepsy centers as an important tool in the epilepsy diagnosis process. However, after more than 40 years of use, there are a number of issues which still need to be clarified concerning its features and role. In particular, the many scientific papers addressing its role in epilepsy diagnosis often differ remarkably from each other in terms of the type of patients assessed, their description and study design. Furthermore, also the length and the type of EEG performed after SD, as well as the length of SD itself, vary dramatically from one study to another. In this paper we shortly underscore the abovementioned differences among the different reports, as well as some interpretations of the findings obtained in the different studies. This analysis emphasizes, if needed, how SD-EEG still represents a crucial step in epilepsy diagnosis, and how additional, controlled studies might further shape its precise diagnostic/prognostic role.
AcanthamoebaKeratitis: A 12-Year Experience Covering a Wide Spectrum of Presentations, Diagnoses, and Outcomes
Authors: Page Michael A. , Mathers William D.
Published: June 2013

Purpose. To review characteristics of confocal microscopy, clinical presentation, and clinical outcome in 372 cases ofAcanthamoebakeratitis (AK) from 1999 to 2011.Methods. A retrospective case review was performed on 372 cases of AK diagnosed by confocal microscopy (CFM) at a single institution in Portland, Oregon, from 1999 to 2011. A numbered grading system was devised for describing the relative microscopic severity of the AK infections detected.Results. “grade 1,” 94 as “grade 2,” 40 as “grade 3,” and 62 as “grade 4.” Peak incidences occurred during 2000–2002 and 2005–2007. Seasonal variation was noted, with a peak during summer months. For the 231 cases with complete records, 64% indicated a history of soft contact lens use. Nine progressed to multiple failed penetrating keratoplasties (PKPs) or enucleation.Conclusion. We report an average of 31 new cases of AK per year from 1999 to 2011. This figure equates to 10.3 new cases/1,000,000/year for the Portland metropolitan area. Patients diagnosed with AK exhibited a wide spectrum of clinical and microscopic characteristics. Soft contact lens use remained the single largest risk factor.
LMI-Based Stability Criteria for Discrete-Time Neural Networks with Multiple Delays
Authors: Xu Hui , Wu Ranchao
Published: June 2013

Discrete neural models are of great importance in numerical simulations and practical implementations. In the current paper, a discrete model of continuous-time neural networks with variable and distributed delays is investigated. By Lyapunov stability theory and techniques such as linear matrix inequalities, sufficient conditions guaranteeing the existence and global exponential stability of the unique equilibrium point are obtained. Introduction of LMIs enables one to take into consideration the sign of connection weights. To show the effectiveness of the method, an illustrative example, along with numerical simulation, is presented.
A Probabilistic Damage Identification Approach for Structures under Unknown Excitation and with Measurement Uncertainties
Authors: Lei Ying , Su Ying , Shen Wenai
Published: June 2013

Recently, an innovative algorithm has been proposed by the authors for the identification of structural damage under unknown external excitations. However, identification accuracy of this proposed deterministic algorithm decreases under high level of measurement noise. A probabilistic approach is therefore proposed in this paper for damage identification considering measurement noise uncertainties. Based on the former deterministic algorithm, the statistical values of the identified structural parameters are estimated using the statistical theory and a damage index is defined. The probability of identified structural damage is further derived based on the reliability theory. The unknown external excitations to the structure are also identified by statistical evaluation. A numerical example of the identification of structural damage of a multistory shear-type building and its unknown excitation shows that the proposed probabilistic approach can accurately identify structural damage and the unknown excitations using only partial measurements of structural acceleration responses contaminated by intensive measurement noises.
Some Properties of Convolved k-Fibonacci Numbers
Authors: Ramírez José L.
Published: June 2013

We define the convolved k-Fibonacci numbers as an extension of the classical convolved Fibonacci numbers. Then we give some combinatorial formulas involving the k-Fibonacci and k-Lucas numbers. Moreover we obtain the convolved k-Fibonacci numbers from a family of Hessenberg
matrices.
Puerarin Suppress Apoptosis of Human Osteoblasts via ERK Signaling Pathway
Authors: Liu Ling-juan , Liu Li-qun , Bo Tao , Li Shi-jun , Zhu Zhen , Cui Rong-rong , Mao Ding-an
Published: June 2013

Puerarin, the main isoflavone glycoside extracted from Radix Puerariae, is an isoflavone traditional Chinese herb. Previous studies have demonstrated that puerarin could regulate osteoblast proliferation and differentiation to promote bone formation. However, the effect of puerarin on the process of human osteoblasts (hOBs) apoptosis is still unclear. In this study, we detected the function of puerarin on serum-free-induced cell apoptosis using ELISA and TUNEL arrays and then found that the mortality of hOBs was significantly decreased after exposure to 10−10–10−6 M puerarin and reached the maximal antiapoptotic effect at the concentration of 10−8 M. In addition, compared with the control group, puerarin notably increased the Bcl-2 protein levels while it decreased the Bax protein levels in the hOBs in a dose-dependent way. 10−7 M puerarin decreased the Bax/Bcl-2 ratio with a maximal decrease to 0.08. Moreover, puerarin activated ERK signaling pathways in hOBs, and the antiapoptotic effect induced by puerarin was abolished by incubation of ERK inhibitor PD98059. Similarly, the estrogen receptor antagonist ICI182780 also suppressed the inhibitory effect of puerarin on hOBs apoptosis. In conclusion, puerarin could prevent hOBs apoptosis via ERK signaling pathway, which might be effective in providing protection against bone loss and bone remolding associated with osteoporosis.
Multistability and Multiperiodicity for a General Class of Delayed Cohen-Grossberg Neural Networks with Discontinuous Activation Functions
Authors: Du Yanke , Li Yanlu , Xu Rui
Published: June 2013

A general class of Cohen-Grossberg neural networks with time-varying delays, distributed delays, and discontinuous activation functions is investigated. By partitioning the state space, employing analysis approach and Cauchy convergence principle, sufficient conditions are established for the existence and locally exponential stability of multiple equilibrium points and periodic orbits, which ensure thatn-dimensional Cohen-Grossberg neural networks withk-level discontinuous activation functions can haveknequilibrium points orknperiodic orbits. Finally, several examples are given to illustrate the feasibility of the obtained results.
Matrix Metalloproteinases: Inflammatory Regulators of Cell Behaviors in Vascular Formation and Remodeling
Authors: Chen Qishan , Jin Min , Yang Feng , Zhu Jianhua , Xiao Qingzhong , Zhang Li
Published: June 2013

Abnormal angiogenesis and vascular remodeling contribute to pathogenesis of a number of disorders such as tumor, arthritis, atherosclerosis, restenosis, hypertension, and neurodegeneration. During angiogenesis and vascular remodeling, behaviors of stem/progenitor cells, endothelial cells (ECs), and vascular smooth muscle cells (VSMCs) and its interaction with extracellular matrix (ECM) play a critical role in the processes. Matrix metalloproteinases (MMPs), well-known inflammatory mediators are a family of zinc-dependent proteolytic enzymes that degrade various components of ECM and non-ECM molecules mediating tissue remodeling in both physiological and pathological processes. MMPs including MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, and MT1-MMP, are stimulated and activated by various stimuli in vascular tissues. Once activated, MMPs degrade ECM proteins or other related signal molecules to promote recruitment of stem/progenitor cells and facilitate migration and invasion of ECs and VSMCs. Moreover, vascular cell proliferation and apoptosis can also be regulated by MMPs via proteolytically cleaving and modulating bioactive molecules and relevant signaling pathways. Regarding the importance of vascular cells in abnormal angiogenesis and vascular remodeling, regulation of vascular cell behaviors through modulating expression and activation of MMPs shows therapeutic potential.
TheLω-Compactness inLω-Spaces
Authors: Chen Shui-Li , Huang Jin-Lan
Published: June 2013

The concepts ofαω-remote neighborhood family,γω-cover, andLω-compactness are defined inLω-spaces. The characterizations ofLω-compactness are systematically discussed. Some important properties ofLω-compactness such asω-closed heredity, arbitrarily multiplicative property, and preserving invariance underω-continuous mappings are obtained. Finally, the Alexanderω-subbase lemma and the Tychonoff product theorem with respect toLω-compactness are given.
Performance Analysis of a Two-Hop MIMO Mobile-to-Mobile via Stratospheric-Relay Link Employing Hierarchical Modulation
Authors: Nomikos Nikolaos , Michailidis Emmanouel T. , Vouyioukas Demosthenes , Kanatas Athanasios G.
Published: June 2013

Next generation wireless communication networks intend to take advantage of the integration of terrestrial and aerospace infrastructures. Besides, multiple-input multiple-output (MIMO) architecture is the key technology, which has brought the wireless gigabit vision closer to reality. In this direction, high-altitude platforms (HAPs) could act as relay stations in the stratosphere transferring information from an uplink to a downlink MIMO channel. This paper investigates the performance of a novel transmission scheme for the delivery of mobile-to-mobile (M-to-M) services via a stratospheric relay. It is assumed that the source, relay, and destination nodes are equipped with multiple antennas and that amplify-and-forward (AF) relaying is adopted. The performance is analyzed through rigorous simulations in terms of the bit-error rate (BER) by using a recently proposed 3D geometry-based reference model in spatially correlated flat-fading MIMO channels, employing a hierarchical broadcast technique and minimum mean square error (MMSE) receivers.
The Benefits and Detriments of Macrophages/Microglia in Models of Multiple Sclerosis
Authors: Rawji Khalil S. , Yong V. Wee
Published: June 2013

The central nervous system (CNS) is immune privileged with access to leukocytes being limited. In several neurological diseases, however, infiltration of immune cells from the periphery into the CNS is largely observed and accounts for the increased representation of macrophages within the CNS. In addition to extensive leukocyte infiltration, the activation of microglia is frequently observed. The functions of activated macrophages/microglia within the CNS are complex. In three animal models of multiple sclerosis (MS), namely, experimental autoimmune encephalomyelitis (EAE) and cuprizone- and lysolecithin-induced demyelination, there have been many reported detrimental roles associated with the involvement of macrophages and microglia. Such detriments include toxicity to neurons and oligodendrocyte precursor cells, release of proteases, release of inflammatory cytokines and free radicals, and recruitment and reactivation of T lymphocytes in the CNS. Many studies, however, have also reported beneficial roles of macrophages/microglia, including axon regenerative roles, assistance in promoting remyelination, clearance of inhibitory myelin debris, and the release of neurotrophic factors. This review will discuss the evidence supporting the detrimental and beneficial aspects of macrophages/microglia in models of MS, provide a discussion of the mechanisms underlying the dichotomous roles, and describe a few therapies in clinical use in MS that impinge on the activity of macrophages/microglia.
The Characteristics and Significance of Locally Infiltrating B Cells in Lupus Nephritis and Their Association with Local BAFF Expression
Authors: Sun Chuan-Yin , Shen Yan , Chen Xiao-Wei , Yan Yu-Cheng , Wu Feng-Xia , Dai Ming , Li Ting , Yang Cheng-De
Published: June 2013

Introduction.Dysfunction of the B lymphocyte is considered to be involved in the pathogenesis of lupus nephritis (LN). Intrarenal B cells have been found in several forms of inflammatory kidney disease. B-cell activating factor (BAFF) regulates B lymphocyte proliferation and survival, and contributes to human autoimmune disease. Their role in renal inflammation is not well defined.Methods.Clinical parameters and renal biopsies from 62 LN patients were prospectively analyzed. We performed standard immunohistochemistry on serial paraffin tissue sections using monoclonal antibodies to CD20 and BAFF to investigate the characteristics and significance of locally infiltrating B cells and local BAFF expression in patients with LN.Results.Intrarenal B cells and/or BAFF were mainly distributed in the renal interstitium. Compared to the LN-non-B-cell/BAFF expression group, proteinuria (g/24 hour), blood urea nitrogen, serum creatinine levels, LN renal activity, and chronicity indices, were all significantly greater in the LN-B-cell/BAFF expression groups. The expression of BAFF was strongly associated with the quantity of B-cell infiltrate in the interstitium.Conclusion.As BAFF expression was strongly associated with B-cell infiltration, we hypothesize that altered B-cell differentiation and tolerance induced by excess BAFF may be central to the pathogenesis of LN.
Fault Detection for Non-Gaussian Stochastic Systems with Time-Varying Delay
Authors: Li Tao , Zhang Kai , Zheng Bo-Chao
Published: June 2013

Fault detection (FD) for non-Gaussian stochastic systems with time-varying delay is studied. The available information for the addressed problem is the input and the measured output probability density functions (PDFs) of the system. In this framework, firstly, by constructing an augmented Lyapunov functional, which involves some slack variables and a tuning parameter, a delay-dependent condition for the existence of FD observer is derived in terms of linear matrix inequality (LMI) and the fault can be detected through a threshold. Secondly, in order to improve the detection sensitivity performance, the optimal algorithm is applied to minimize the threshold value. Finally, paper-making process example is given to demonstrate the applicability of the proposed approach.
Some Generalized Difference Sequence Spaces Defined by Ideal Convergence and Musielak-Orlicz Function
Authors: Bakery Awad A. , Mohamed Elsayed Abdelbayen Elnour , Ahmed Mohamed Alamin
Published: June 2013

In the present paper we introduced the ideal convergence of generalized difference sequence spaces combining de La Vallée-Poussin mean and Musielak-Orlicz function overn-normed spaces. We also study some topological properties and inclusion relation between these spaces.
Influence of Gut Microbiota on Subclinical Inflammation and Insulin Resistance
Authors: Carvalho Bruno Melo , Abdalla Saad Mario Jose
Published: June 2013

Obesity is the main condition that is correlated with the appearance of insulin resistance, which is the major link among its comorbidities, such as type 2 diabetes, nonalcoholic fatty liver disease, cardiovascular and neurodegenerative diseases, and several types of cancer. Obesity affects a large number of individuals worldwide; it degrades human health and quality of life. Here, we review the role of the gut microbiota in the pathophysiology of obesity and type 2 diabetes, which is promoted by a bacterial diversity shift mediated by overnutrition. Whole bacteria, their products, and metabolites undergo increased translocation through the gut epithelium to the circulation due to degraded tight junctions and the consequent increase in intestinal permeability that culminates in inflammation and insulin resistance. Several strategies focusing on modulation of the gut microbiota (antibiotics, probiotics, and prebiotics) are being experimentally employed in metabolic derangement in order to reduce intestinal permeability, increase the production of short chain fatty acids and anorectic gut hormones, and promote insulin sensitivity to counteract the inflammatory status and insulin resistance found in obese individuals.
Rational Combination of a MEK Inhibitor, Selumetinib, and the Wnt/Calcium Pathway Modulator, Cyclosporin A, in Preclinical Models of Colorectal Cancer
Authors: Spreafico Anna , Tentler John J. , Pitts Todd M. , Tan Aik Choon , Gregory Mark A. , Arcaroli John J. , Klauck Peter J. , McManus Martine C. , Hansen Ryan J. , Kim Jihye , Micel Lindsey N. , Selby Heather M. , Newton Timothy P. , McPhillips Kelly L. , Gustafson Daniel L. , DeGregori James V. , Messersmith Wells A. , Winn Robert A. , Eckhardt S. Gail
Published: June 2013

Purpose: The mitogen-activated protein kinase (MAPK) pathway is a crucial regulator of cell proliferation, survival, and resistance to apoptosis. MEK inhibitors are being explored as a treatment option for patients with KRAS-mutant colorectal cancer who are not candidates for EGFR-directed therapies. Initial clinical results of MEK inhibitors have yielded limited single-agent activity in colorectal cancer, indicating that rational combination strategies are needed.

Experimental Design: In this study, we conducted unbiased gene set enrichment analysis and synthetic lethality screens with selumetinib, which identified the noncanonical Wnt/Ca++ signaling pathway as a potential mediator of resistance to the MEK1/2 inhibitor selumetinib. To test this, we used shRNA constructs against relevant WNT receptors and ligands resulting in increased responsiveness to selumetinib in colorectal cancer cell lines. Further, we evaluated the rational combination of selumetinib and WNT pathway modulators and showed synergistic antiproliferative effects in in vitro and in vivo models of colorectal cancer.

Results: Importantly, this combination not only showed tumor growth inhibition but also tumor regression in the more clinically relevant patient-derived tumor explant (PDTX) models of colorectal cancer. In mechanistic studies, we observed a trend toward increased markers of apoptosis in response to the combination of MEK and WntCa++ inhibitors, which may explain the observed synergistic antitumor effects.

Conclusions: These results strengthen the hypothesis that targeting both the MEK and Wnt pathways may be a clinically effective rational combination strategy for patients with metastatic colorectal cancer. Clin Cancer Res; 19(15); 4149–62. ©2013 AACR.
microRNA 223 Is Upregulated in the Multistep Progression of Barrett's Esophagus and Modulates Sensitivity to Chemotherapy by Targeting PARP1
Authors: Streppel Mirte Mayke , Pai Shweta , Campbell Nathaniel R. , Hu Chaoxin , Yabuuchi Shinichi , Canto Marcia Irene , Wang Jean S. , Montgomery Elizabeth A. , Maitra Anirban
Published: June 2013

Purpose: Recent microarray and RNA-sequencing studies have uncovered aberrantly expressed microRNAs (miRNA) in Barrett's esophagus–associated esophageal adenocarcinoma. The functional significance of these miRNAs in esophageal adenocarcinoma initiation and progression is largely unknown.

Experimental Design: Expression levels of miR-199a/b-3p, -199a-5p, -199b-5p, -200b, -200c, -223, and -375 were determined in microdissected tissues from cardiac mucosa, Barrett's esophagus, dysplastic Barrett's esophagus, and esophageal adenocarcinoma using quantitative real-time PCR. miR-223 expression was validated in precursors and esophageal adenocarcinomas from 95 patients with esophageal adenocarcinoma by in situ hybridization (ISH). miR-223 was transfected into two esophageal adenocarcinoma cell lines, and in vitro assays were conducted. Target genes were identified using Illumina microarray, and results were validated in cell lines and human specimens.

Results: miR-199 family members and miR-223 were significantly overexpressed in esophageal adenocarcinoma, however, only miR-223 showed a stepwise increase during esophageal adenocarcinoma carcinogenesis. A similar trend was observed by ISH, which additionally showed that miR-223 is exclusively expressed by the epithelial compartment. miR-223–overexpressing cells had statistically significantly more migratory and invasive potential than scramble sequence–transfected cells. PARP1 was identified as a direct target gene of miR-223 in esophageal adenocarcinoma cells. Increased sensitivity to chemotherapy was observed in cells with enforced miR-223 expression and reduced PARP1.

Conclusions: miR-223 is significantly upregulated during the Barrett's esophagus–dysplasia–esophageal adenocarcinoma sequence. Although high miR-223 levels might contribute to an aggressive phenotype, our results also suggest that patients with esophageal adenocarcinoma with high miR-223 levels might benefit from treatment with DNA-damaging agents. Clin Cancer Res; 19(15); 4067–78. ©2013 AACR.
Modulation of OATP1B-Type Transporter Function Alters Cellular Uptake and Disposition of Platinum Chemotherapeutics
Authors: Lancaster Cynthia S. , Sprowl Jason A. , Walker Aisha L. , Hu Shuiying , Gibson Alice A. , Sparreboom Alex
Published: June 2013

Expression of the human organic anion transporting polypeptides OATP1B1 and OATP1B3 has been previously believed to be restricted to hepatocytes. Here we show that the gene encoding OATP1B3, but not OATP1B1, is abundantly expressed in multiple human solid tumors that include hepatocellular, lung, and ovarian carcinomas. Surprisingly, OATP1B3 gene expression in a panel of 60 human tumor cell lines was linked with sensitivity to multiple cytotoxic agents, including the platinum anticancer drugs cisplatin, carboplatin, and oxaliplatin. In addition, overexpression of OATP1B3 in mammalian cells increased cellular accumulation of platinum agents and decreased cell survival. In mice with a targeted disruption of the ortholog transporter Oatp1b2, the liver-to-plasma ratio of cisplatin was significantly reduced compared with wild-type mice, without concurrent changes in expression profiles of other transporter genes. Our findings indicate an unexpected role for tumoral and host OATP1B-type carriers in the toxicity and disposition of platinum anticancer drugs, and may provide a foundation for understanding the extensive interindividual pharmacodynamic variability seen with these drugs in patients. Mol Cancer Ther; 12(8); 1537–44. ©2013 AACR.
The Bleeding Risk during Warfarin Therapy Is Associated with the Number of Variant Alleles of CYP2C9 and VKORC1 Genes
Authors: Tomek Aleš , Maťoška Václav , Kolářová Tereza , Neumann Jiří , Šrámek Martin , Šarbochová Ivana , Táborský Luděk , Bojar Martin , Goetz Petr , Serebruany Victor L.
Published: June 2013

Background: Warfarin is commonly used for the treatment and prevention of arterial and venous thromboembolism but its use is hindered by the risk of bleeding. The main reason for this risk is a narrow therapeutic index and a wide response variability after warfarin treatment. These shortcomings affect clinical outcomes including bleeding complications and may be associated with variant polymorphisms in the CYP2C9 and VKORC1 genes. Aim: It was the aim of this study to assess the impact of the total variant allele count of CYP2C9 and VKORC1 genes on bleeding related to warfarin treatment. Methods: In a retrospective cohort-design study, patients were genotyped for polymorphisms in genes CYP2C9 (*1, *2, *3) and VKORC1 (haplotype A, B). Extensive clinical data were obtained. Adjusted hazard ratios (HR) for the occurrence of major bleeding events (MBE) were counted separately for the induction and maintenance phases of warfarin therapy. Results: Out of the 329 patients in our clinical database, 194 patients were eligible and included in the analysis. MBE occurred in 51 patients (26.3%) during a mean follow-up of 26 months: 6 patients (11.8%) experienced early MBE during warfarin initiation, and 45 MBE occurred during the maintenance phase. The adjusted HR for MBE risk for patients with any CYP2C9 variant allele was 1.962 [95% confidence interval (CI) 1.08-3.56, p = 0.027]; for the VKORC1 AA haplotype, HR was 1.841 (95% CI 0.97-3.48, p = 0.06), while for 3 variant allele carriers of both genes, HR was 4.34 (95% CI 1.95-9.65, p < 0.001). Despite the insignificant association of the VKORC1 genotype with bleeding in our study, we have noted a warfarin dose-dependent effect with risk significance ascending: CYP2C9 *1/*1 + VKORC1 B/B < CYP2C9 *1/*1 + VKORC1 A/B < CYP2C9 *1/*2 + VKORC1 B/B. Conclusion: Patients who are carriers of 3 variant alleles of the genes CYP2C9 and VKORC1 exhibited a significantly higher risk of MBE during the initiation and maintenance phases of warfarin therapy. Vigilant and careful management of patients with a higher variant allele count, including switching to newer anticoagulants, could be considered in this high-risk cohort.
Discharge after Primary Angioplasty at 24 h: Feasible and Safe or a Step Too Far?
Authors: Khavandi Ali , Freeman Phillip , Meier Pascal
Published: June 2013

Current clinical practice regarding surveillance period and length of hospital stay after an ST elevation myocardial infarction is very variable among different countries and hospitals. In general, there has been a significant reduction in length of stay overall, which is mainly due to the increasing use of primary percutaneous coronary intervention. Length of stay after a ST elevation myocardial infaction, which is a rather common event, has a major impact on health care costs and patients' quality of life. We try to evaluate how far we could push the limits.
Relationship between Glutathione S-Transferase P1 (GSTP1), X-Ray Repair Cross Complementing Group 1 (XRCC1) and 5,10-Methylenetetrahydrofolate Reductase (5,10-MTHFR) Gene Polymorphisms and Response to Chemotherapy in Advanced Gastric Cancer
Authors: Ji Mei , Xu Bin , Jiang Jing-Ting , Wu Jun , Li Xiao-Dong , Zhao Wei-Qing , Zhang Hong-Yu , Zhou Wen-Jie , Wu Chang-Ping
Published: June 2013

Background: Our study aimed to investigate the relationship between glutathione S-transferase P1 (GSTP1), 5,10-methylenetetrahydrofolate reductase (5,10-MTHFR) and X-ray repair cross complementing group 1 (XRCC1) gene polymorphisms and the response to chemotherapy in advanced gastric cancer. Patients and Methods: 59 cases of advanced gastric cancer were enrolled. All patients were treated with the DCF regimen comprising docetaxel, cisplatin, and 5-fluorouracil. All patients' genotypes regarding GSTP1, XRCC1, and 5,10-MTHFR were analyzed by polymerase chain reaction/ligase detection reaction (PCR-LDR). Results: There were 15 (25.42%) cases of G/G genotype, 21 (35.59%) of G/A genotype, and 23 (38.98%) of A/A genotype for GSTP1, 16 (27.12%) cases of A/A genotype, 18 (30.51%) of G/A genotype, and 25 (42.37%) of G/G genotype for XRCC1, and 21 (35.59%) cases of C/C genotype, 22 (37.29%) of C/T genotype, and 16 (27.12%) of T/T genotype for 5,10-MTHFR. After 2 cycles of chemotherapy, there were 4 cases of complete remission, 14 of partial remission, 19 of stable disease, and 22 of advanced disease, with a total effective rate of 30.51%. Better survival was shown for GSTP1 G/G genotype, XRCC1 A/A genotype, and 5,10-MTHFR T/T genotype (p < 0.05). Conclusion: The gene polymorphisms of GSTP1 G/G, XRCC1 A/A, and 5,10-MTHFR T/T have clinical value for predicting the response to the DCF regimen for advanced gastric cancer.
Intraocular Surgery in Kyphosis: An Easier Approach
Authors: Kooner Karanjit S. , Barte Felise M.
Published: June 2013

We describe a 49-year-old man with advanced kyphosis and dense cataract, who could only recline to about 40° from the vertical axis despite a maximal reverse Trendelenburg position and pillows under the head, neck, shoulders and knees. With a single corneal retraction suture at 6 o'clock, the eye could be rotated horizontally, which enabled the surgeon to perform a complex cataract surgery despite prior glaucoma shunt, posterior synechiae, a small pupil and the need to stain the capsule. As the eye can be brought into any desired position with a retraction suture, patients with kyphosis or other conditions that prevent them from assuming a supine position can still have safe intraocular procedures. This maneuver reduces the need to tilt patients to an uncomfortable position that may cause pain, increased breathing difficulty and elevated posterior vitreous pressure.
Validation and Prognosis of Coronary Artery Calcium Scoring in Nontriggered Thoracic Computed Tomography
Authors: Xie Xueqian , Zhao Yingru , de Bock Geertruida H. , de Jong Pim A. , Mali Willem P. , Oudkerk Matthijs , Vliegenthart Rozemarijn
Published: June 2013

Background—

Coronary calcium score (CS), traditionally based on electrocardiography-triggered computed tomography (CT), predicts cardiovascular risk. Currently, nontriggered thoracic CT is extensively used, such as in lung cancer screening. The purpose of the study was to determine the correlation in CS between nontriggered and electrocardiography-triggered CT, and to evaluate the prognostic performance of the CS derived from nontriggered CT.

Methods and Results—

PubMed, Embase, and Web of Knowledge were searched until November 2012. Two reviewers independently screened 2120 records to identify studies reporting the CS in nontriggered CT and extracted information. Study quality was evaluated by standardized assessment tools. Cohen κ was extracted for agreement of CS categories between nontriggered and electrocardiography-triggered CT (validation). Hazard ratio (HR) was extracted for prognostic performance. Five studies about validation comprising 1316 individuals were included. Five studies about prognosis comprising 34 028 cardiac asymptomatic individuals, mainly from lung cancer screening trials, were included. All studies were of high quality. Meta-analysis could only be performed for validation studies because studies on prognostic performance were highly heterogeneous. Pooled Cohen κ for agreement between the 2 techniques was 0.89 (95% confidence interval, 0.83–0.95) for increasing CS categories. Increasing CS categories were associated with increasing risk of cardiovascular death or events. Nontriggered CT yielded false-negative CS in 8.8% of individuals and underestimated high CS in 19.1% of individuals.

Conclusions—

Our analysis shows the prognostic value and potential role of nontriggered assessment of coronary calcium, but it does not suggest that electrocardiography-triggered CT should be replaced by nontriggered examinations.
Vasodilatory Capacity of the Coronary Microcirculation is Preserved in Selected Patients With Non–ST-Segment–Elevation Myocardial Infarction
Authors: Layland Jamie , Carrick David , McEntegart Margaret , Ahmed Nadeem , Payne Alex , McClure John , Sood Arvind , McGeoch Ross , MacIsaac Andrew , Whitbourn Robert , Wilson Andrew , Oldroyd Keith , Berry Colin
Published: June 2013

Background—

The use of fractional flow reserve in patients with non–ST-segment–elevation myocardial infarction (NSTEMI) is a controversial issue. We undertook a study to assess the vasodilatory capacity of the coronary microcirculation in patients with NSTEMI when compared with a model of preserved microcirculation (stable angina [SA] cohort: culprit and nonculprit vessel) and acute microcirculatory dysfunction (ST-segment–elevation myocardial infarction [STEMI] cohort). We hypothesized that the vasodilatory response of the microcirculation would be preserved in NSTEMI.

Methods and Results—

A total of 140 patients undergoing single vessel percutaneous coronary intervention were included: 50 stable angina, 50 NSTEMI, and 40 STEMI. The index of microvascular resistance (IMR), fractional flow reserve, and coronary flow reserve were measured before stenting in the culprit vessel and in an angiographically normal nonculprit vessel in patients with SA. The resistive reserve ratio, a measure of the vasodilatory capacity of the microcirculation and calculated using the equation: baseline resistance index (
Tmn
Base
×
Pa
Base
[
Pd
Base
–
Pw
/
Pa
Base
–
Pw
])–IMR/IMR, where
Tmn
Base
referred to nonhyperemic transit time;
Pa
Base
and
Pd
Base
, the nonhyperemic aortic and distal coronary pressures, respectively; and
Pw
referred to the coronary wedge pressure, was also measured. Troponin was also measured ≤24 hours after percutaneous coronary intervention. The resistive reserve ratio was significantly lower in the STEMI patients compared with the stable angina patients both culprit and nonculprit vessel (STEMI, 1.7 versus SA culprit, 2.8;
P
≤0.001 and SA nonculprit, 2.9;
P
<0.0001) and compared with NSTEMI patients (NSTEMI, 2.46;
P
≤0.001). The resistive reserve ratio was similar in stable angina and NSTEMI patients (
P
=0.6). IMR was significantly higher pre-PCI in STEMI compared with SA and NSTEMI (IMR STEMI, 36.51 versus IMR NSTEMI, 22.73 [
P
=0.01] versus IMR SA, 18.26 [
P
<0.0001]). However, there was no significant difference in IMR pre-PCI between NSTEMI and SA (IMR NSTEMI, 22.73; IMR SA, 18.26 [
P
=0.1]).

Conclusions—

The vasodilatory capacity of the microcirculation is preserved in selected patients with NSTEMI. The clinical use of fractional flow reserve in the culprit vessel may be preserved in selected patents with NSTEMI.
Bloodstream Infections Occurring in Patients With Percutaneously Implanted Bioprosthetic Pulmonary Valve
Authors: Buber Jonathan , Bergersen Lisa , Lock James E. , Gauvreau Kimberlee , Esch Jesse J. , Landzberg Michael J. , Valente Anne Marie , Sandora Thomas J. , Marshall Audrey C.
Published: June 2013

Background—

Percutaneous pulmonary valve implantation using a stent-based bioprosthetic valve provides an alternative to surgery in select patients. Systemic infections in Melody valve–implanted patients with and without identified valve involvement have been reported, yet the incidence is unknown, and risk factors remain unidentified.

Methods and Results—

Between 2007 and 2012, a total of 147 consecutive patients with congenital heart disease underwent Melody percutaneous pulmonary valve implantation at our institution. Demographic and clinical variables were collected at baseline and at follow-up and analyzed as predictors. The occurrence of bloodstream infection (BSI), defined as a bacterial infection treated with ≥4 weeks of antibiotics, served as our primary outcome. The mean age at implantation for the study population was 21.5±11 years, and tetralogy of Fallot was the cardiac condition in 59%. During a median follow-up of 19 months, 14 patients experienced BSI (9.5%; 95% confidence interval, 5.3%–15%). Of these, 4 (2.7%) patients had Melody valve endocarditis. Two patients died during the event, neither of whom had known valve involvement. The median procedure to infection time was 15 months (range, 1–56). In univariate analysis, male sex, previous endocarditis, in situ stents in the right ventricular outflow tract, and presence of outflow tract irregularities at the implant site were associated with BSI occurrence.

Conclusions—

In this cohort, 9.5% of patients who underwent Melody percutaneous pulmonary valve implantation experienced subsequent BSI, occurring 1 to 56 months after implant, and 2.7% of patients had prosthetic endocarditis. Our findings suggest that patient and nonvalve anatomic factors may be associated with BSI after percutaneous pulmonary valve implantation.
End of Study Transition From Study Drug to Open-Label Vitamin K Antagonist Therapy
Authors: Mahaffey Kenneth W. , Hellkamp Anne S. , Patel Manesh R. , Hannan Karen L. , Schwabe Kimberly , Nessel Christopher C. , Berkowitz Scott D. , Halperin Jonathan L. , Hankey Graeme J. , Becker Richard C. , Piccini Jonathan P. , Breithardt Günter , Hacke Werner , Singer Daniel E. , Califf Robert M. , Fox Keith A.A.
Published: June 2013

Background—

To evaluate the previously reported excess of thromboembolic events during the 30 days after the end of study (EOS) visit when participants transitioned from blinded therapy to open-label vitamin K antagonist.

Methods and Results—

At the EOS visit, open-label vitamin K antagonist was recommended, and the international normalized ratio (INR) was not to be measured until 3 days later to preserve blinding. We analyzed transition strategies, clinical outcomes, and INR values. Event rates are per 100 patient-years. A total of 9248 (65%) participants were taking study drug at EOS, and, between days 3 and 30, an excess of stroke and systemic embolic events were observed in participants assigned to rivaroxaban (rivaroxaban 22 events, event rate 6.42; warfarin 6 events, event rate 1.73; hazard ratio, 3.72; 95% confidence interval, 1.51–9.16;
P
=0.0044). No INR values were reported for ≈5% of participants transitioned to warfarin. By 30 days after EOS, 83% of the warfarin group and 52% of the rivaroxaban group had ≥1 therapeutic INR value. Median time to first therapeutic INR was 3 days in the warfarin group and 13 days in the rivaroxaban group.

Conclusions—

The excess of events at EOS was likely because of a period of inadequate anticoagulation in rivaroxaban participants switched to vitamin K antagonist therapy. If transition from rivaroxaban to vitamin K antagonist is needed, timely monitoring and careful dosing should be used to ensure consistent and adequate anticoagulation.