bluuebunny/crossref_metadata_2025 huggingface dataset:
Woman with chest pain and shortness of breath since age 18
Authors: Lobo Ronstan , Lim Ren Yik , Meany Brendan , Kiernan Thomas John
Published: August 2013

We present an interesting case of a 38-year-old woman who presented with a history of left-sided chest pain, dyspnoea and palpitations. The symptoms have been occurring since age 18, and were previously diagnosed as costochondritis. Because of the suspicious history, the patient underwent further cardiac investigations. The echocardiogram demonstrated an abnormal structure adjacent to the aortic valve. A diagnostic coronary angiogram revealed a large left circumflex artery fistulating into the right atrium. Surgery was performed to ligate the fistula. The patient recovered well and has been asymptomatic since.
A generalised model for individualising a treatment recommendation based on group-level evidence from randomised clinical trials
Authors: Marcucci Maura , Sinclair John C
Published: August 2013

Objectives

Randomised controlled trials report group-level treatment effects. However, an individual patient confronting a treatment decision needs to know whether that person's expected treatment benefit will exceed the expected treatment harm. We describe a flexible model for individualising a treatment decision. It individualises group-level results from randomised trials using clinical prediction guides.

Methods

We constructed models that estimate the size of individualised absolute risk reduction (ARR) for the target outcome that is required to offset individualised absolute risk increase (ARI) for the treatment harm. Inputs to the model include estimates for the individualised predicted absolute treatment benefit and harm, and the relative value assigned by the patient to harm/benefit. A decision rule recommends treatment when the predicted benefit exceeds the predicted harm, value-adjusted. We also derived expressions for the maximum treatment harm, or the maximum relative value for harm/benefit, above which treatment would not be recommended.

Results

For the simpler model, including one kind of benefit and one kind of harm, the individualised ARR required to justify treatment was expressed as required ARRtarget(i)=ARIharm(i) × RVharm/target(i). A complex model was also developed, applicable to treatments causing multiple kinds of benefits and/or harms. We demonstrated the applicability of the models to treatments tested in superiority trials (either placebo or active control, either fixed harm or variable harm) and non-inferiority trials.

Conclusions

Individualised treatment recommendations can be derived using a model that applies clinical prediction guides to the results of randomised trials in order to identify which individual patients are likely to derive a clinically important benefit from the treatment. The resulting individualised prediction-based recommendations require validation by comparison with strategies of treat all or treat none.
Entrapment of a micro-guidewire during stenting of basilar stenosis
Authors: Ma Ning , Liu Lian , Wang Tie-Jun , Xu Xiao-Tong , Miao Zhong-Rong
Published: August 2013

Entrapment of a microwire related to intracranial endovascular therapy is an uncommon complication. A 64-year-old man with symptomatic basilar artery stenosis was treated with stenting. A 300 cm Synchro microwire became trapped in the P1 segment of the left posterior cerebral artery during the procedure. The decision was made to leave the microwire in place, considering that aggressive retrieval procedures could cause injury to the cerebral vasculature. The entrapped microwire was later inadvertently dislocated and removed while pulling the microwire back into the femoral artery with a looped catheter from the left femoral access. This demonstrates that, although entrapment of a microwire during endovascular therapy is a rare event, an optimal salvage technique needs to be explored further.
A prospective, multicenter pilot study investigating the utility of flat detector derived parenchymal blood volume maps to estimate cerebral blood volume in stroke patients
Authors: Fiorella David , Turk Aquilla , Chaudry Imran , Turner Raymond , Dunkin Jared , Roque Clemente , Sarmiento Marily , Deuerling-Zheng Yu , Denice Christine M , Baumeister Marlene , Parker Adrian T , Woo Henry H
Published: August 2013

Purpose

Newer flat panel angiographic detector (FD) systems have the capability to generate parenchymal blood volume (PBV) maps. The ability to generate these maps in the angiographic suite has the potential to markedly expedite the triage and treatment of patients with acute ischemic stroke. The present study compares FP-PBV maps with cerebral blood volume (CBV) maps derived using standard dynamic CT perfusion (CTP) in a population of patients with stroke.

Methods

56 patients with cerebrovascular ischemic disease at two participating institutions prospectively underwent both standard dynamic CTP imaging followed by FD-PBV imaging (syngo Neuro PBV IR; Siemens, Erlangen, Germany) under a protocol approved by both institutional review boards. The feasibility of the FD system to generate PBV maps was assessed. The radiation doses for both studies were compared. The sensitivity and specificity of the PBV technique to detect (1) any blood volume deficit and (2) a blood volume deficit greater than one-third of a vascular territory, were defined using standard dynamic CTP CBV maps as the gold standard.

Results

Of the 56 patients imaged, PBV maps were technically adequate in 42 (75%). The 14 inadequate studies were not interpretable secondary to patient motion/positioning (n=4), an injection issue (n=2), or another reason (n=8). The average dose for FD-PBV was 219 mGy (median 208) versus 204 mGy (median 201) for CT-CBV. On CT-CBV maps 26 of 42 had a CBV deficit (61.9%) and 15 (35.7%) had a deficit that accounted for greater than one-third of a vascular territory. FD-PBV maps were 100% sensitive and 81.3% specific to detect any CBV deficit and 100% sensitive and 62.9% specific to detect any CBV deficit of greater than one-third of a territory.

Conclusions

PBV maps can be generated using FP systems. The average radiation dose is similar to a standard CTP examination. PBV maps have a high sensitivity for detecting CBV deficits defined by conventional CTP. PBV maps often overestimate the size of CBV deficits. We hypothesize that the FP protocol initiates PBV imaging prior to complete saturation of the blood volume in areas perfused via indirect pathways (ie, leptomeningeal collaterals), resulting in an overestimation of CBV deficits, particularly in the setting of large vessel occlusion.
GAUSS QUADRATURES – THE KEYSTONE OF LATTICE BOLTZMANN MODELS
Authors: PIAUD BENJAMIN , BLANCO STÉPHANE , FOURNIER RICHARD , AMBRUŞ VICTOR EUGEN , SOFONEA VICTOR
Published: August 2013

In this paper, we compare two families of Lattice Boltzmann (LB) models derived by means of Gauss quadratures in the momentum space. The first one is the HLB (N;Qx,Qy,Qz) family, derived by using the Cartesian coordinate system and the Gauss–Hermite quadrature. The second one is the SLB (N;K,L,M) family, derived by using the spherical coordinate system and the Gauss–Laguerre, as well as the Gauss–Legendre quadratures. These models order themselves according to the maximum order N of the moments of the equilibrium distribution function that are exactly recovered. Microfluidics effects (slip velocity, temperature jump, as well as the longitudinal heat flux that is not driven by a temperature gradient) are accurately captured during the simulation of Couette flow for Knudsen number (kn) up to 0.25.
AN IMPROVED LATTICE KINETIC SCHEME FOR INCOMPRESSIBLE VISCOUS FLUID FLOWS
Authors: SUZUKI KOSUKE , INAMURO TAKAJI
Published: August 2013

The lattice Boltzmann method (LBM) is an explicit numerical scheme for the incompressible Navier–Stokes equations (INSE) without integrating the Poisson equation for the pressure. In spite of its merit, the LBM has some drawbacks in accuracy. First, we review drawbacks for three numerical methods based on the LBM. The three methods are the LBM with the Bhatnagar–Gross–Krook model (LBGK), the lattice kinetic scheme (LKS) and the link-wise artificial compressibility method (LWACM). Second, in order to remedy the drawbacks, we propose an improved LKS. The present method incorporates (i) the scheme used in the LWACM for determining the kinematic viscosity, (ii) an iterative calculation of the pressure and (iii) a semi-implicit algorithm, while preserving the simplicity of the algorithm of the original LKS. Finally, in simulations of test problems, we find that the improved LKS eliminates the drawbacks and gives more accurate and stable results than LBGK, LKS and LWACM.
DIRECT SIMULATION MONTE CARLO FOR DENSE HARD SPHERES
Authors: CHAO LIU , KWAK SANG KYU , ANSUMALI SANTOSH
Published: August 2013

We propose a modified direct simulation Monte Carlo (DSMC) method, which extends the validity of DSMC from rarefied to dense system of hard spheres (HSs). To assess this adapted method, transport properties of hard-sphere (HS) systems have been predicted both at dense states as well as dilute, and we observed the excellent accuracy over existing DSMC-based algorithms including the Enskog theory. The present approach provides an intuitive and systematic way to accelerate molecular dynamics (MD) via mesoscale approach.
ADAPTIVE SYNCHRONIZATION OF TWO CHAOTIC CHEN SYSTEMS WITH UNKNOWN PARAMETERS
Authors: KHORDAD R. , DEHGHANI M. A. , DEHGHANI A.
Published: August 2013

Many methods have been proposed to synchronize chaotic systems. One of these methods is adaptive synchronization. Our purpose is the synchronization of two identical Chen systems using adaptive method and simulation of the results. The presented results show that these systems can synchronize with this method perfectly.
THE CO-HOPFIAN PROPERTY OF SURFACE BRAID GROUPS
Authors: KIDA YOSHIKATA , YAMAGATA SAEKO
Published: August 2013

Let g and n be integers at least 2, and let G be the pure braid group with n strands on a closed orientable surface of genus g. We describe any injective homomorphism from a finite index subgroup of G into G. As a consequence, we show that any finite index subgroup of G is co-Hopfian.
EFFECT OF SILICON DOPING IN CVD DIAMOND FILMS FROM MICROCRYSTALLINE TO NANOCRYSTALLINE ON WC-Co SUBSTRATES
Authors: ZHANG JIANGUO , CUI YUXIAO , SHEN BIN , SUN FANGHONG
Published: August 2013

Si -doped diamond films with various Si concentrations are deposited on WC- Co substrates using HFCVD method, with the mixture of acetone, tetraethoxysilane (TEOS) and hydrogen as the reactant source. A variety of characterizations, including FE-SEM, AFM, Raman, XRD, surface profilometer and Rockwell indentation, are conducted to systematically investigate the influence of Si incorporation on diamond films. As the Si / C ratio from 0% to 5%, the grain size of as-deposited films decreases from 4 μm to about 50 nm, and the surface roughness reduces from Ra ~ 290 nm to Ra ~ 180 nm. Besides, the intensity ratio of I (111)/ I (220) varies from 0.57 to 0, indicating the 〈110〉 preferred orientation of the nanocrystalline structure in the 5% doped diamond films. The silicon doping is beneficial for the formation of non-diamond carbide phases in the films, according to the Raman spectra. Moreover, the film adhesion is also improved with the increase of Si / C ratio.
SUSCEPTIBILITY OF COMMERCIAL NEURAMINIDASE INHIBITORS AGAINST 2013 A/H7N9 INFLUENZA VIRUS: A DOCKING AND MOLECULAR DYNAMICS STUDY
Authors: YANG ZHIWEI , WU FEI , LIU JUNXING , WANG SHUQIU , YUAN XIAOHUI
Published: August 2013

The latest influenza A ( H 7 N 9) virus attracted a worldwide attention due to the first report of human infections and the continuing reported cases in China. In this work, homology modeling, docking and molecular dynamics simulations were combined to study the interactions between neuraminidase ( N 9_2013, from novel A/ H 7 N 9 virus) and agents zanamivir, oseltamivir, peramivir. It was found that N 9_2013 protein is structurally close to the template (PDB code: 1F8B), especially the active site. The binding properties of N 9_2013 protein were nearly identical to those of template. As a result, the three available drugs should be still efficacious for the new emerging A ( H 7 N 9) virus. However, the stabilities of docked complexes and binding affinities (Eint) were slightly reduced, in contrast to the corresponding inhibitor-template complexes, with the values of -82.27 (-84.30), -78.84 (-80.28) and -77.52 (-81.94) kcal mol-1, respectively. Besides, R292K mutation might induce the resistance of the novel virus to the commercial inhibitors. Thus, it arouses the need for continuous monitoring of antiviral drug susceptibilities.
IDENTIFICATION OF HYBRID DYNAMICAL SYSTEM IN GLYCEROL FERMENTATION: ESTIMATING THE INHIBITION RANGE OF 3-HPA ONTO TWO KEY ENZYMES BASED ON BIOLOGICAL ROBUSTNESS
Authors: WANG HONGLI , WANG LEI , DAI DANDAN , FENG ENMIN , XIU ZHILONG
Published: August 2013

As an important intermediate substance in the process of producing 1,3-propanediol (1,3-PD) by bio-dissimilation of glycerol, the concentration of 3-hydroxypropionaldehyde (3-HPA) has inhibitory action on glycerol dehydratase (GDHt) and 1,3-propanediol oxidoreductase (PDOR). Considering the transmission of glycerol and 1,3-PD across cell membrane by both passive diffusion and active transmission as well as the inhibitory action of 3-HPA on the specific rate of growth, this paper aims to establish and discuss a nonlinear hybrid dynamical system model to ascertain the concentration range of 3-HPA where it does exhibit an inhibitory action on GDHt and PDOR. A quantitative definition of biological robustness is presented and an identification model is established based on biological robustness. An algorithm procedure is constructed to solve the identification problem. Numerical results show that only within a proper concentration range 3-HPA can have inhibitory action on the two enzymes mentioned above.
FACILE SYNTHESIS AND UNUSUAL ELECTROCHEMICAL CAPACITANCE OF Ni-DOPED TITANATE NANOTUBES
Authors: YUAN CHANGZHOU , ZHANG LONGHAI , HOU LINRUI , PANG GANG , ZHANG XIAOGANG
Published: August 2013

In this paper, we developed an intriguing ion-exchange reaction to synthesize Ni -doped titanate nanotubes ( Ni - Ti -NTs), and utilized the sample as an appealing pseudocapacitive electrode for electrochemical capacitors (ECs). The energy storage mechanism of the resulting Ni - Ti -NTs electrode in alkaline KOH aqueous electrolyte was further tentatively proposed. Compared with the pristine titanate nanotubes ( Ti -NTs), Ni - Ti -NTs with rich porous channels possessed much better electronic conductivity and larger specific surface area, rendering the electrons and OH − ions easily contact the Ni species uniformly distributed on their surfaces for efficient energy storage at high rates. Remarkably, the SC of the Ni - Ti -NTs electrode increased with further cycling, and even reached a SC of 278 F g−1 at a current density of 2 A g−1 after 7500 charge–discharge cycles without relaxation. The prominent electrochemical performance demonstrated that the Ni - Ti -NTs would be a promising candidate and/or even excellent support for other electroactive materials for advanced ECs application.
Caveolin-1/PTRF upregulation constitutes a mechanism for mediating p53-induced cellular senescence: implications for evidence-based therapy of delayed wound healing in diabetes
Authors: Bitar Milad S. , Abdel-Halim Samy M. , Al-Mulla Fahd
Published: August 2013

A heightened state of oxidative stress and senescence of fibroblasts constitute potential therapeutic targets in nonhealing diabetic wounds. Here, we studied the underlying mechanism mediating diabetes-induced cellular senescence using in vitro cultured dermal fibroblasts and in vivo circular wounds. Our results demonstrated that the total antioxidant capacity and mRNA levels of thioredoxinreductase and glucose-6-phosphate dehydrogenase as well as the ratio of NADPH/NADP were decreased markedly in fibroblasts from patients with type 2 diabetes (DFs). Consistent with this shift in favor of excessive reactive oxygen species, DFs also displayed a significant increase in senescence-associated β-galactosidase activity and phospho-γ-histone H2AX (pH2AX) level. Moreover, the ability of PDGF to promote cell proliferation/migration and regulate the phosphorylation-dependent activation of Akt and ERK1/2 appears to be attenuated as a function of diabetes. Mechanistically, we found that diabetes-induced oxidative stress upregulated caveolin-1 (Cav-1) and PTRF expression, which in turn sequestered Mdm2 away from p53. This process resulted in the activation of a p53/p21-dependent pathway and the induction of premature senescence in DFs. Most of the aforementioned oxidative stress and senescence-based features observed in DFs were recapitulated in a 10-day-old diabetic wound. Intriguingly, we confirmed that the targeted depletion of Cav-1 or PTRF using siRNA- or Vivo-Morpholino antisense-based gene therapy markedly inhibited diabetes/oxidative stress-induced premature senescence and also accelerated tissue repair in this disease state. Overall, our data illuminate Cav-1/PTRF-1 as a key player of a novel signaling pathway that may link a heightened state of oxidative stress to cellular senescence and impaired wound healing in diabetes.
Direct and indirect effects of growth hormone receptor ablation on liver expression of xenobiotic metabolizing genes
Authors: Li Xinna , Bartke Andrzej , Berryman Darlene E. , Funk Kevin , Kopchick John J. , List Edward O. , Sun Liou , Miller Richard A.
Published: August 2013

Detoxification of ingested xenobiotic chemicals, and of potentially toxic endogenous metabolites, is carried out largely through a series of enzymes synthesized in the liver, sometimes called “xenobiotic metabolizing enzymes” (XME). Expression of these XME is sexually dimorphic in rodents and humans, with many of the XME expressed at higher levels in females. This expression pattern is thought to be regulated, in part, by the sex differences in circadian growth hormone (GH) pulsatility. We have evaluated mRNA, in the liver, for 52 XME genes in male and female mice of four mutant stocks, with diminished levels of GH receptor (GHR) either globally (GKO), or in liver (LKO), fat (FKO), or muscle (MKO) tissue specifically. The data show complex, sex-specific changes. For some XME, the expression pattern is consistent with direct control of hepatic mRNA by GHR in the liver. In contrast, other XME show evidence for indirect pathways in which hepatic XME expression is altered by GH signals in fat or skeletal muscle. The effects of GHR-null mutations on glucose control, responses to dietary interventions, steroid metabolism, detoxification pathways, and lifespan may depend on a mixture of direct hepatic effects and cross talk between different GH-responsive tissues.
Human angiotensinogen +11525 C/A polymorphism modulates its gene expression through microRNA binding
Authors: Mopidevi Brahmaraju , Ponnala Madhusudhan , Kumar Ashok
Published: August 2013

Hypertension is a serious risk factor for cardiovascular disease. Like other complex disease, hypertension is caused by a combination of genetic and environmental factors. The renin-angiotensin system plays an important role in the regulation of blood pressure. Angiotensinogen (AGT) gene is associated with essential hypertension in Caucasians, Japanese, and Asian-Indian subjects. AGT gene may also be associated with cardiac hypertrophy, coronary atherosclerosis, and microangiopathy related cerebral damage. Human AGT gene has a C/A polymorphism at nucleoside 11525 (rs7079) that is located in the 3′-untranslated region (3′-UTR) and is modestly associated with increased blood pressure. We show here that miR-31 and miR-584 bind strongly to the hAGT 3′-UTR containing 11525C allele compared with 11525A allele. We also show that transfection of miR-31 and miR-584 downregulates the hAGT mRNA and protein levels in human liver cells. These studies may provide new therapeutic approach to reduce hypertension.
An Efficient Ensemble Learning Method for Gene Microarray Classification
Authors: Osareh Alireza , Shadgar Bita
Published: August 2013

The gene microarray analysis and classification have demonstrated an effective way for the effective diagnosis of diseases and cancers. However, it has been also revealed that the basic classification techniques have intrinsic drawbacks in achieving accurate gene classification and cancer diagnosis. On the other hand, classifier ensembles have received increasing attention in various applications. Here, we address the gene classification issue using RotBoost ensemble methodology. This method is a combination of Rotation Forest and AdaBoost techniques which in turn preserve both desirable features of an ensemble architecture, that is, accuracy and diversity. To select a concise subset of informative genes, 5 different feature selection algorithms are considered. To assess the efficiency of the RotBoost, other nonensemble/ensemble techniques including Decision Trees, Support Vector Machines, Rotation Forest, AdaBoost, and Bagging are also deployed. Experimental results have revealed that the combination of the fast correlation-based feature selection method with ICA-based RotBoost ensemble is highly effective for gene classification. In fact, the proposed method can create ensemble classifiers which outperform not only the classifiers produced by the conventional machine learning but also the classifiers generated by two widely used conventional ensemble learning methods, that is, Bagging and AdaBoost.
Epithelial–Mesenchymal Transition and Tumor Suppression Are Controlled by a Reciprocal Feedback Loop between ZEB1 and Grainyhead-like-2
Authors: Cieply Benjamin , Farris Joshua , Denvir James , Ford Heide L. , Frisch Steven M.
Published: August 2013

Epithelial–mesenchymal transition (EMT) in carcinoma cells enhances malignant progression by promoting invasion and survival. EMT is induced by microenvironmental factors, including TGF-β and Wnt agonists, and by the E–box-binding transcription factors Twist, Snail, and ZEB. Grainyhead-like-2 (GRHL2), a member of the mammalian Grainyhead family of wound-healing regulatory transcription factors, suppresses EMT and restores sensitivity to anoikis by repressing ZEB1 expression and inhibiting TGF-β signaling. In this study, we elucidate the functional relationship between GRHL2 and ZEB1 in EMT/MET and tumor biology. At least three homeodomain proteins, Six1, LBX1, and HoxA5, transactivated the ZEB1 promoter, in the case of Six1, through direct protein–promoter interaction. GRHL2 altered the Six1–DNA complex, inhibiting this transactivation. Correspondingly, GRHL2 expression prevented tumor initiation in xenograft assays, sensitized breast cancer cells to paclitaxel, and suppressed the emergence of CD44highCD24low cells (defining the cancer stem cell phenotype in the cell type studied). GRHL2 was downregulated in recurrent mouse tumors that had evolved to an oncogene-independent, EMT-like state, supporting a role for GRHL2 downregulation in this phenotypic transition, modeling disease recurrence. The combination of TGF-β and Wnt activation repressed GRHL2 expression by direct interaction of ZEB1 with the GRHL2 promoter, inducing EMT. Together, our observations indicate that a reciprocal feedback loop between GRHL2 and ZEB1 controls epithelial versus mesenchymal phenotypes and EMT-driven tumor progression. Cancer Res; 73(20); 6299–309. ©2013 AACR.
Histone Acetyltransferase PCAF Is Required for Hedgehog–Gli-Dependent Transcription and Cancer Cell Proliferation
Authors: Malatesta Martina , Steinhauer Cornelia , Mohammad Faizaan , Pandey Deo P. , Squatrito Massimo , Helin Kristian
Published: August 2013

The Hedgehog (Hh) signaling pathway plays an important role in embryonic patterning and development of many tissues and organs as well as in maintaining and repairing mature tissues in adults. Uncontrolled activation of the Hh–Gli pathway has been implicated in developmental abnormalities as well as in several cancers, including brain tumors like medulloblastoma and glioblastoma. Inhibition of aberrant Hh–Gli signaling has, thus, emerged as an attractive approach for anticancer therapy; however, the mechanisms that mediate Hh–Gli signaling in vertebrates remain poorly understood. Here, we show that the histone acetyltransferase PCAF/KAT2B is an important factor of the Hh pathway. Specifically, we show that PCAF depletion impairs Hh activity and reduces expression of Hh target genes. Consequently, PCAF downregulation in medulloblastoma and glioblastoma cells leads to decreased proliferation and increased apoptosis. In addition, we found that PCAF interacts with GLI1, the downstream effector in the Hh–Gli pathway, and that PCAF or GLI1 loss reduces the levels of H3K9 acetylation on Hh target gene promoters. Finally, we observed that PCAF silencing reduces the tumor-forming potential of neural stem cells in vivo. In summary, our study identified the acetyltransferase PCAF as a positive cofactor of the Hh–Gli signaling pathway, leading us to propose PCAF as a candidate therapeutic target for the treatment of patients with medulloblastoma and glioblastoma. Cancer Res; 73(20); 6323–33. ©2013 AACR.
FGFR4 Promotes Stroma-Induced Epithelial-to-Mesenchymal Transition in Colorectal Cancer
Authors: Liu Rui , Li Jingyi , Xie Ke , Zhang Tao , Lei Yunlong , Chen Yi , Zhang Lu , Huang Kai , Wang Kui , Wu Hong , Wu Min , Nice Edouard C. , Huang Canhua , Wei Yuquan
Published: August 2013

Tumor cells evolve by interacting with the local microenvironment; however, the tumor–stroma interactions that govern tumor metastasis are poorly understood. In this study, proteomic analyses reveal that coculture with tumor-associated fibroblasts (TAF) induces significant overexpression of FGFR4, but not other FGFRs, in colorectal cancer cell lines. Mechanistic study shows that FGFR4 plays crucial roles in TAF-induced epithelial-to-mesenchymal transition (EMT) in colorectal cancer cell lines. Accumulated FGFR4 in cell membrane phosphorylates β-catenin, leading to translocation of β-catenin into the nucleus. Further, TAF-derived CCL2 and its downstream transcription factor, Ets-1, are prerequisites for TAF-induced FGFR4 upregulation. Furthermore, FGFR4-associated pathways are shown to be preferentially activated in colorectal tumor samples, and direct tumor metastasis in a mouse metastasis model. Our study shows a pivotal role of FGFR4 in tumor–stroma interactions during colorectal cancer metastasis, and suggests novel therapeutic opportunities for the treatment of colorectal cancer. Cancer Res; 73(19); 5926–35. ©2013 AACR.
Prognostic Significance of AMPK Activation and Therapeutic Effects of Metformin in Hepatocellular Carcinoma
Authors: Zheng Longyi , Yang Wen , Wu Fuquan , Wang Chao , Yu Lexing , Tang Liang , Qiu Bijun , Li Yuqiong , Guo Linna , Wu Mengchao , Feng Gensheng , Zou Dajin , Wang Hongyang
Published: August 2013

Purpose: The AMP-activated protein kinase (AMPK) serves as an energy sensor in eukaryotic cells and occupies a central role in linking metabolism and cancer development. However, the phosphorylation status of AMPK and its therapeutic value in human hepatocellular carcinoma (HCC) remain unclear.

Experimental Design: The phosphorylation status of AMPK (Thr172) was determined by immunoblotting and immunostaining in specimens from 273 patients with HCC (including 253 patients with hepatitis B virus -related HCC). Kaplan–Meier survival analysis was used to determine the correlation with prognosis. The effects of therapeutic metformin/AMPK activation were assessed in cultured human HCC cell lines and primary HCC cells in vitro and in xenograft tumors model in vivo. To define the mechanisms of anticancer effects of metformin, we examined its influence on AMPK activation and NF-κB pathway.

Results: AMPK is dysfunctional in patients with HCC, and low p-AMPK staining is correlated with aggressive clinicopathologic features and poor prognosis. Activation of AMPK by metformin not only inhibited HCC cells growth in vitro and in vivo, but also augmented cisplatin-induced growth inhibition in HCC cells. Knockdown of AMPKα expression can greatly decrease the inhibitory effect of metformin, indicating that AMPK activation is required for the anticancer action of metformin. Mechanistically, metformin/AMPK activation inhibited NF-κB signaling through upregulation of IκBα. Activation of NF-κB signaling by ectopic expression of P65 or overexpression of an undegradable mutant form of IκBα attenuated the anticancer effects of metformin.

Conclusions: These results present novel insight into a critical role of AMPK in HCC progression. Anticancer effects of therapeutic metformin/AMPK activation unravel metformin's potential in treatment of HCC. Clin Cancer Res; 19(19); 5372–80. ©2013 AACR.
Histone Deacetylase Inhibition Overcomes Drug Resistance through a miRNA-Dependent Mechanism
Authors: Murray-Stewart Tracy , Hanigan Christin L. , Woster Patrick M. , Marton Laurence J. , Casero Robert A.
Published: August 2013

The treatment of specific tumor cell lines with poly- and oligoamine analogs results in a superinduction of polyamine catabolism that is associated with cytotoxicity; however, other tumor cells show resistance to analog treatment. Recent data indicate that some of these analogs also have direct epigenetic effects. We, therefore, sought to determine the effects of combining specific analogs with an epigenetic targeting agent in phenotypically resistant human lung cancer cell lines. We show that the histone deacetylase inhibitor MS-275, when combined with (N1, N11)-bisethylnorspermine (BENSpm) or (N1, N12)-bis(ethyl)-cis-6,7-dehydrospermine tetrahydrochloride (PG-11047), synergistically induces the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase (SSAT), a major determinant of sensitivity to the antitumor analogs. Evidence indicates that the mechanism of this synergy includes reactivation of miR-200a, which targets and destabilizes kelch-like ECH-associated protein 1 (KEAP1) mRNA, resulting in the translocation and binding of nuclear factor (erythroid-derived 2)-like 2 (NRF2) to the polyamine-responsive element of the SSAT promoter. This transcriptional stimulation, combined with positive regulation of SSAT mRNA and protein by the analogs, results in decreased intracellular concentrations of natural polyamines and growth inhibition. The finding that an epigenetic targeting agent is capable of inducing a rate-limiting step in polyamine catabolism to overcome resistance to the antitumor analogs represents a completely novel chemotherapeutic approach. In addition, this is the first demonstration of miRNA-mediated regulation of the polyamine catabolic pathway. Furthermore, the individual agents used in this study have been investigated clinically; therefore, translation of these combinations into the clinical setting holds promise. Mol Cancer Ther; 12(10); 2088–99. ©2013 AACR.
Malnutrition in an Elderly Population without Cognitive Impairment Living in Nursing Homes in Spain: Study of Prevalence Using the Mini Nutritional Assessment Test
Authors: Serrano-Urrea R. , Garcia-Meseguer M.J.
Published: August 2013

Background: The prevalence of malnutrition in institutionalized elderly people is generally high. A good nutritional status is related to a decrease in mortality and costs of morbidity treatments. Therefore, it is essential to know the nutritional status in order to establish action policies. However, there are not enough studies about malnutrition in institutionalized elderly in Spain. Objectives: The objectives of this survey were to assess the prevalence of malnutrition and risk of malnutrition in elderly people living in nursing homes in the province of Albacete (Spain) using the Mini Nutritional Assessment (MNA®) test, to analyze their distribution according to age, gender and different nursing home features, and to identify the MNA items that best predict the MNA total score. Methods: A cross-sectional study was conducted with data collected from 895 elders living in 34 nursing homes all over the province of Albacete, including facilities located in the main city, towns and villages. Prevalence of malnutrition and risk of malnutrition were assessed using the MNA full form test. Groups of malnutrition were compared by using mean MNA scores. Stepwise linear regression analyses were used to identify the items in the MNA which best predicted the MNA total scores. Results: According to the MNA, the prevalence of malnutrition among elderly people staying in Albacete province nursing homes was 2.8%, and the prevalence of being at risk of malnutrition was 37.3%. MNA total score was significantly higher in men (24.3 ± 2.9) than in women (23.7 ± 3.3) and significantly higher in residents living in nursing homes located in towns and villages (24.2 ± 2.8) than in those who were living in institutions placed in the main city (23.7 ± 3.4). The MNA score was found to decrease with increasing age, except for individuals aged 90 years or older. Conclusions: The prevalence of malnutrition and risk of malnutrition was 40.1%. Female gender and living in institutions located in the main city were identified as malnutrition risk factors. In general, an increase in malnutrition with age was detected, except for people in the last years of their lives. The MNA questions that best predicted the nutritional status were the ones relating to the anthropometrical and self-assessments.
Disease Flare after Discontinuation of Crizotinib in Anaplastic Lymphoma Kinase-Positive Lung Cancer
Authors: Kuriyama Yuka , Kim Young Hak , Nagai Hiroki , Ozasa Hiroaki , Sakamori Yuichi , Mishima Michiaki
Published: August 2013

We report the case of a 50-year-old male former smoker. He was diagnosed as having lung adenocarcinoma and treated with induction chemoradiation therapy followed by surgery and adjuvant chemotherapy. Molecular testing revealed that his tumor had an echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangement. Therefore, he was treated with crizotinib when his disease recurred. He achieved a partial response, which persisted for 10 months until progressive disease was confirmed. Crizotinib was continued for 1 month and the tumor size increased slightly. At that time, crizotinib was discontinued and he participated in a clinical trial of erlotinib ± Met inhibitor; however, his disease progressed rapidly after discontinuation of crizotinib, and the diagnosis of disease flare was made. Readministration of crizotinib was started immediately; however, his disease progressed rapidly, and he died 2 days after starting crizotinib retreatment. Currently, the incidence of disease flare is unknown and it is impossible to predict who will experience it. Therefore, continuing crizotinib after disease progression may be a reasonable option to avoid disease flare.
Thrombolysis for Ischemic Stroke Associated With Infective Endocarditis
Authors: Asaithambi Ganesh , Adil Malik M. , Qureshi Adnan I.
Published: August 2013

Background and Purpose—

Cerebral ischemic events are highly prevalent and associated with high rates of death and disability in patients with infective endocarditis (IE). However, the role of thrombolysis in these patients remains unclear. We sought to determine the rates and outcomes of acute ischemic stroke patients with IE treated with intravenous thrombolysis (IVT).

Methods—

We determined the rates of post-thrombolytic intracerebral hemorrhage and favorable outcome among acute ischemic stroke patients with IE treated with IVT. Patients were identified using Nationwide Inpatient Sample data from 2002 to 2010. We compared the rates of various outcomes with ischemic stroke patients without IE treated with IVT.

Results—

There were 222 patients (mean age 59±18 years; 46% women) who were treated with IVT for acute ischemic stroke associated with IE and 134 048 patients (mean age 69±15 years; 49% women) who were treated for stroke without IE. The rate of post-thrombolytic intracerebral hemorrhage was significantly higher in patients with IE compared with those without IE (20% versus 6.5%;
P
=0.006). There was a significantly lower rate of favorable outcome in the IE group (10% versus 37%;
P
=0.01).

Conclusions—

High rates of post-thrombolytic intracerebral hemorrhage and low rates of favorable outcome mandate caution in using IVT in acute ischemic stroke patients with IE.
Dynamic Cerebral Autoregulation in Acute Intracerebral Hemorrhage
Authors: Oeinck Maximilian , Neunhoeffer Florian , Buttler Klaus-Juergen , Meckel Stephan , Schmidt Bernhard , Czosnyka Marek , Weiller Cornelius , Reinhard Matthias
Published: August 2013

Background and Purpose—

Cerebral autoregulation (CA) is not universally impaired in acute intracerebral hemorrhage (ICH); however, the dynamic components of CA are probably more vulnerable. This study, therefore, evaluates the time course of dynamic CA in acute ICH and its relationship to clinical outcome.

Methods—

Twenty-six patients with ICH were studied on days 1, 3, and 5 after ictus. Dynamic CA was measured from spontaneous fluctuations in blood pressure and middle cerebral artery flow velocity by transfer function phase (reflecting rapidity of CA) and gain (reflecting damping characteristics of CA) in the low frequency range. Results were compared with those from 55 controls and related with clinical factors and 90-day outcome (modified Rankin scale).

Results—

Phase did not fluctuate significantly over time, nor did it differ between sides or differ from controls. Gain was always higher in patients than in controls but showed no significant association with outcome or other clinical factors. At day 1, poorer ipsilateral phase was associated with lower blood pressure and higher ICH volume. Poorer phase always coincided with lower Glasgow Coma Scale values. Poorer ipsilateral phase on day 5 was related with poorer clinical outcome according to multivariate analysis (
P
=0.013).

Conclusions—

Dynamic temporal characteristics of CA (phase) are not generally altered in acute ICH. Poorer individual phase values are, however, associated with larger ICH volume, lower blood pressure, and worsened outcome. Dampening characteristics of CA (gain) are generally impaired in acute ICH but not related to clinical factors or outcome.
Cost-Effectiveness of Surgical Decompression for Space-Occupying Hemispheric Infarction
Authors: Hofmeijer Jeannette , van der Worp H. Bart , Kappelle L. Jaap , Eshuis Sara , Algra Ale , Greving Jacoba P.
Published: August 2013

Background and Purpose—

Surgical decompression reduces mortality and increases the probability of a favorable functional outcome after space-occupying hemispheric infarction. Its cost-effectiveness is uncertain.

Methods—

We assessed clinical outcomes, costs, and cost-effectiveness for the first 3 years in patients who were randomized to surgical decompression or best medical treatment within 48 hours after symptom onset in the Hemicraniectomy After Middle Cerebral Artery Infarction With Life-Threatening Edema Trial (HAMLET). Data on medical consumption were derived from case record files, hospital charts, and general practitioners. We calculated costs per quality-adjusted life year (QALY). Uncertainty was assessed with bootstrapping. A Markov model was constructed to estimate costs and health outcomes after 3 years.

Results—

Of 39 patients enrolled within 48 hours, 21 were randomized to surgical decompression. After 3 years, 5 surgical (24%) and 14 medical patients (78%) had died. In the first 3 years after enrollment, operated patients had more QALYs than medically treated patients (mean difference, 1.0 QALY [95% confidence interval, 0.6–1.4]), but at higher costs (mean difference, €127 000 [95% confidence interval, 73 100–181 000]), indicating incremental costs of €127 000 per QALY gained. Ninety-eight percent of incremental cost-effectiveness ratios replicated by bootstrapping were >€80 000 per QALY gained. Markov modeling suggested costs of ≈€60 000 per QALY gained for a patient’s lifetime.

Conclusions—

Surgical decompression for space-occupying infarction results in an increase in QALYs, but at very high costs.

Clinical Trial Registration—

URL:
http://www.controlled-trials.com
. Unique identifier: ISRCTN94237756.
From Sensation to Oblivion: Boven Digoel in Sino-Malay Novels
Authors: Chandra Elizabeth
Published: August 2013

Abstract

The so-called ‘Sino-Malay literature’ has often been characterized as literary publications that were commercial and very rarely political. This essay however draws attention to three novels written by prominent Indies Chinese authors on the colonial internment camp for communist activists, Boven Digoel. Written in three different decades, Kwee Tek Hoay’s Drama di Boven Digoel (Drama in Boven Digoel, 1928-1932), Liem Khing Hoo’s Merah (Red, 1937), and Njoo Cheong Seng’s Taufan gila (Mad typhoon, 1950) reflect not only individual journeys of Digoel-bound activists, but also the political landscapes in which they were written.
Displaced Archives, Displaced History: Recovering the Seized Archives of Indonesia
Authors: Karabinos Michael Joseph
Published: August 2013

Abstract

This article examines the post-war conflict of colonial retention that the Netherlands engaged in with Indonesia, and the invasion of Yogyakarta on 19 December 1948. While arresting high-ranking members of the Republican government, Dutch troops seized papers that were left behind. These documents were not returned to Indonesia until nearly 50 years later. By studying the archival collection, fluctuations in the relationship between Indonesia and the Netherlands are revealed. The seized archives relate directly to the building of a new nation; their history reflects the history of Indonesia.
Vigilante Citizenship: Sovereign Practices and the Politics of Insult in Indonesia
Authors: Telle Kari
Published: August 2013

Abstract

This article examines the informal authority wielded by civilian security groups (pamswakarsa) on the island of Lombok. Taking as its point of departure the Balinese minority’s plan to build a large Hindu temple in northern Lombok, the article shows how the project was thwarted by a combination of rumours, pamphlets, violence as well as legal obstacles from district and provincial authorities. Outlining how the campaign against the temple gained momentum, I suggest that rumours and documents issued by a security force claiming to represent the island’s Muslim majority played an important role in preventing the realization of the temple. Discussing the ‘conviviality’ between non-state security groups and state officials in post-Suharto Lombok, I argue that civilian security groups exercise a form of vigilante citizenship.
Projected Changes in Late-Twenty-First-Century Tropical Cyclone Frequency in 13 Coupled Climate Models from Phase 5 of the Coupled Model Intercomparison Project
Authors: Tory K. J. , Chand S. S. , McBride J. L. , Ye H. , Dare R. A.
Published: August 2013

Changes in tropical cyclone (TC) frequency under anthropogenic climate change are examined for 13 global models from phase 5 of the Coupled Model Intercomparison Project (CMIP5), using the Okubo–Weiss–Zeta parameter (OWZP) TC-detection method developed by the authors in earlier papers. The method detects large-scale conditions within which TCs form. It was developed and tuned in atmospheric reanalysis data and then applied without change to the climate models to ensure model and detector independence. Changes in TC frequency are determined by comparing TC detections in the CMIP5 historical runs (1970–2000) with high emission scenario (representative concentration pathway 8.5) future runs (2070–2100). A number of the models project increases in frequency of higher-latitude tropical cyclones in the late twenty-first century. Inspection reveals that these high-latitude systems were subtropical in origin and are thus eliminated from the analysis using an objective classification technique. TC detections in 8 of the 13 models reproduce observed TC formation numbers and geographic distributions reasonably well, with annual numbers within ±50% of observations. TC detections in the remaining five models are particularly low in number (10%–28% of observed). The eight models with a reasonable TC climatology all project decreases in global TC frequency varying between 7% and 28%. Large intermodel and interbasin variations in magnitude and sign are present, with the greatest variations in the Northern Hemisphere basins. These results are consistent with results from earlier-generation climate models and thus confirm the robustness of coupled model projections of globally reduced TC frequency.
The analytical study of terrorism
Authors: Sandler Todd
Published: August 2013

This article presents an eclectic review of the analytical study of terrorism that views all agents as rational decisionmakers. This analytical literature began in earnest with the seminal study of US skyjackings by William Landes in 1978. After 11 September 2001, the analytical literature on terrorism grew rapidly. Based on policy relevance, my survey article identifies five key areas of intense research interests. These include analyses of terrorist attack trends, the economic consequences of terrorism, the study of counterterrorism effectiveness, the causes of terrorism, and the relationship of terrorism and liberal democracies. New developments in the field focused on distinguishing key differences between domestic and transnational terrorism. Additionally, recent game-theoretic advances permitted more active agents and stages to the games. Other major developments involved the study of networked terrorists and the role of counterterrorism foreign aid. Fruitful future directions include using advanced econometric methods to discern the true impact of terrorism on growth, applying spatial econometrics to the study of terrorism, ascertaining the determinants of terrorist groups’ longevity, and learning how to foster international counterterrorism cooperation.
Are Commuters in the EU Better Educated than Non-commuters but Worse than Migrants?
Authors: Huber Peter
Published: August 2013

This paper analyses the skill and age structure of commuters in 14 EU countries. Theory implies that commuters can be either more or less able than stayers, but are always less able and older than migrants. Empirically, all types of commuters are younger and have higher education than region stayers, but older and less educated than migrants. Internal commuters are better educated and younger than cross-border commuters, education decreases while age increases with distance commuted and recent migrants are younger but also more highly educated than commuters.
A gradient-based iterative algorithm for generalized coupled Sylvester matrix equations over generalized centro-symmetric matrices
Authors: Hajarian Masoud
Published: August 2013

An [Formula: see text] real matrix [Formula: see text] is said to be a symmetric orthogonal matrix if [Formula: see text]. An [Formula: see text] real matrix [Formula: see text] is called a generalized centro-symmetric matrix with respect to [Formula: see text], if [Formula: see text]. It is obvious that every [Formula: see text] matrix is also a generalized centro-symmetric matrix with respect to [Formula: see text] (identity matrix). In the present paper, we propose a gradient-based iterative algorithm to solve the generalized coupled Sylvester matrix equations

[Formula: see text]

over the generalized centro-symmetric matrix pair [Formula: see text]. It is proved that the iterative method is always convergent for any initial generalized centro-symmetric matrix pair [Formula: see text] Finally, a numerical example is discussed to illustrate the results.