bluuebunny/crossref_metadata_2025 huggingface dataset:
Small Multidrug Resistance Protein EmrE Reduces Host pH and Osmotic Tolerance to Metabolic Quaternary Cation Osmoprotectants
Authors: Bay Denice C. , Turner Raymond J.
Published: September 2012

The small multidrug resistance (SMR) transporter protein EmrE in
Escherichia coli
is known to confer resistance to toxic antiseptics classified as quaternary cation compounds (QCCs). Naturally derived QCCs synthesized during metabolic activities often act as osmoprotectants, such as betaine and choline, and participate in osmotic homoestasis. The goal of this study was to determine if EmrE proteins transport biological QCC-based osmoprotectants. Plasmid-encoded copies of
E. coli
emrE
and the inactive variant
emrE
-E14C (
emrE
with the E→C change at position 14) were expressed in various
E. coli
strains grown in either rich or minimal media at various pHs (5 to 9) and under hypersaline (0.5 to 1.0 M NaCl and KCl) conditions to identify changes in growth phenotypes induced by osmoprotectant transport. The results demonstrated that
emrE
expression reduced pH tolerance of
E. coli
strains at or above neutral pH and when grown in hypersaline media at or above NaCl or KCl concentrations of 0.75 M. Hypersaline growth conditions were used to screen QCC osmoprotectants betaine, choline,
l
-carnitine,
l
-lysine,
l
-proline, and
l
-arginine. The study identified that betaine and choline are natural QCC substrates of EmrE.
Noncoding RNAs Binding to the Nucleoid Protein HU in Escherichia coli
Authors: Macvanin Mirjana , Edgar Rotem , Cui Feng , Trostel Andrei , Zhurkin Victor , Adhya Sankar
Published: September 2012

Some unidentified RNA molecules, together with the nucleoid protein HU, were suggested to be involved in the nucleoid structure of
Escherichia coli
. HU is a conserved protein known for its role in binding to DNA and maintaining negative supercoils in the latter. HU also binds to a few RNAs, but the full spectrum of its binding targets in the cell is not known. To understand any interaction of HU with RNA in the nucleoid structure, we immunoprecipitated potential HU-RNA complexes from cells and examined bound RNAs by hybridization to whole-genome tiling arrays. We identified associations between HU and 10 new intragenic and intergenic noncoding RNAs (ncRNAs), 2 of which are homologous to the annotated bacterial interspersed mosaic elements (BIMEs) and
boxC
DNA repeat elements. We confirmed direct binding of HU to BIME RNA
in vitro
. We also studied the nucleoid shape of HU and two of the ncRNA mutants (nc1 and nc5) by transmission electron microscopy and showed that both HU and the two ncRNAs play a role in nucleoid morphology. We propose that at least two of the ncRNA species complex with HU and help the formation or maintenance of the architecture of the
E. coli
chromosome. We also observed binding of HU with rRNA and tRNA segments, a few small RNAs, and a distinct small set of mRNAs, although the significance, if any, of these associations is not known.
Injury in elite New Zealand cricketers 2002–2008: descriptive epidemiology
Authors: Frost Warren Leonard , Chalmers David John
Published: September 2012

Objective

To describe the incidence, prevalence, nature and severity of injury to elite New Zealand cricketers for the 2002/2003 to 2007/2008 seasons.

Design

Prospective cohort.

Setting

Elite cricket in New Zealand.

Participants

248 elite male cricketers.

Main outcome measures

Incidence and prevalence rates.

Results

The overall match injury incidence rate for the international competition (51.6 injuries per 10 000 player-hours; 95% CI 40.1 to 65.3) was almost twice that of the domestic competition (27.2; 23.5 to 31.4). The prevalence rate for the international competition (12%; 11.3% to 12.8%) was significantly higher than that for the domestic competition (9.7%; 9.4% to 10.1%). Overall, 79.5% of injuries occurred in matches and 48.7% of all injuries were sustained while bowling. The lower limb was the body region most commonly injured (43.5%), the most common specific diagnosis was hamstring strains/tears (11.1%) and the injuries contributing the highest proportion of match days lost were stress fractures to the low back (22%).

Conclusions

The findings of this study support ongoing injury surveillance in New Zealand and other test cricket playing nations for the purpose of describing injury and monitoring the effect of interventions over time.
What happens to clinical training fellows? A retrospective study of the 20 years outcome of a Medical Research Council UK cohort
Authors: Stewart Paul M , Bryan Simone , Dukes Peter , van Oudheusden Hannah Lesley , Walker Rhoswyn , Maxwell Patrick H
Published: August 2012

Objectives

The Clinical Research Training Fellowship (CRTF) allows up to 3 years support for clinically qualified candidates to undertake specialised or further research training in biomedical sciences. CRTFs are perceived as a crucial step in the career development and progression of Clinical Academics but there are no published data to support this notion. We conducted an electronic survey of a large cohort of Medical Research Council (MRC) CRTFs followed for up to 20 years.

Design

Retrospective analysis of CRTF outcome data held with the MRC, UK.

Participants

Two cohorts comprising 40 CRFTs awarded by the MRC in the year 1991 and 299 MRC CRTFs who were awarded a fellowship between 1993 and 2003.

Results

The MRC CRTF scheme built capacity in clinical academia across the UK with 40% of CRTFs progressing to a University professorship. Importantly, the CRTF scheme is also providing NHS consultants who remain research active.

Conclusions

This is the first analysis of outcome of CRTFs in the UK and provides robust evidence of the importance of this capacity building mode of funding to underpin research excellence at the University–NHS interface.
Stenting of the vertebral artery origin with ostium dilation: technical note
Authors: Dumont Travis M , Kan Peter , Snyder Kenneth V , Hopkins L Nelson , Levy Elad I , Siddiqui Adnan H
Published: August 2012

Endovascular treatment of vertebral artery (VA) origin stenosis typically requires placement of the proximal end of the stent within the lumen of the subclavian artery or aorta to provide complete coverage of the ostial lesion. This configuration may complicate subsequent endovascular access into the stented VA. We describe a technique modification of VA origin stenting and angioplasty with a monorail angioplasty balloon system designed specifically for dilation of the ostial origin which may be helpful in conforming the proximal portion of the stent to the VA origin. Simplified endovascular access to the VA origin after angioplasty is demonstrated.
Venous sinus manometry and intervention using the PrimeWire Prestige pressure guidewire: technique and initial experience
Authors: Lopes Demetrius Klee , Johnson Andrew Kelly , Tan Lee A
Published: September 2012

Background

Cerebral venography and manometry are used for the diagnosis of hemodynamically significant venous sinus stenosis in patients with the syndrome of idiopathic intracranial hypertension. Intravenous pressure measurements using the traditional microcatheter technique can be cumbersome, time consuming and potentially unreliable. The PrimeWire Prestige pressure guidewire conducts pressure electrically and can be used as a guidewire for intervention. It has been validated in interventional cardiology procedures.

Objective

We describe our initial clinical experience with the PrimeWire Prestige pressure guidewire system for cerebral venous manometry and intervention.

Method

Cerebral venous pressure gradient was directly measured by advancing the pressure wire across a region of stenosis. The pressure wire was also used as a guidewire for intravascular ultrasound, angioplasty and stenting.

Results

The PrimeWire Prestige pressure guidewire successfully navigated the intracranial venous sinus anatomy. Transfer of devices over the guidewire in a monorail fashion was uncomplicated, and measurement of sinus pressure between the steps of the intervention was efficiently performed.

Conclusion

The PrimeWire Prestige pressure guidewire system provided a safe, fast and effective method for intracranial venous sinus manometry and intervention. It has several potential advantages over the traditional microcatheter method, including efficiency, accuracy and cost.
Endovascular management of spinal arteriovenous malformations
Authors: Ducruet Andrew F , Crowley R Webster , McDougall Cameron G , Albuquerque Felipe C
Published: August 2012

Spinal arteriovenous malformations (sAVMs) are rare vascular lesions whose natural history remains incompletely defined. Several classification schemes for sAVMs have evolved based on an improved understanding of the anatomic characteristics as well as pathophysiologic behavior of these arteriovenous shunts. Advances in endovascular technology have inspired the adoption of interventional techniques both as stand-alone treatment and as part of a multi-modality management paradigm for sAVMs. Further refinements in liquid embolic agents as well as improved microcatheter navigability will contribute to an ever-expanding role for endovascular intervention in the management of these lesions.
NOVEL CONSENSUS APPROACHES TO THE RELIABLE RANKING OF FEATURES FOR SEABED IMAGERY CLASSIFICATION
Authors: HARRISON RICHARD , BIRCHALL ROGER , MANN DAVE , WANG WENJIA
Published: August 2012

Feature saliency estimation and feature selection are important tasks in machine learning applications. Filters, such as distance measures are commonly used as an efficient means of estimating the saliency of individual features. However, feature rankings derived from different distance measures are frequently inconsistent. This can present reliability issues when the rankings are used for feature selection. Two novel consensus approaches to creating a more robust ranking are presented in this paper. Our experimental results show that the consensus approaches can improve reliability over a range of feature parameterizations and various seabed texture classification tasks in sidescan sonar mosaic imagery.
OPTIMAL BROADCASTING IN TORI WITH DYNAMIC FAULTS
Authors: DOBREV S. , VRTO I.
Published: September 2012

We consider a broadcasting problem in the n-dimensional k-ary even torus in the shouting communication mode, i.e. any node of a network can inform all its neighbours in one time step. In addition, during any time step a number of links of the network can be faulty. Moreover the faults are dynamic. The problem is to determine the minimum broadcasting time if at most 2n - 1 faults are allowed in any step. In [4], it was shown that the broadcasting time is at most diameter+O(1), provided that k is limited by a polynomial of n. In our paper we drop this additional assumption and prove that the broadcasting can be always done in time diameter +2. The bound is the best possible.
PERMUTATION COMMUNICATION IN ALL-OPTICAL RINGS
Authors: PATERSON M. S. , SCHRÖDER H. , SÝKORA O. , VRTO I.
Published: September 2012

We study the wavelength problem and arc (edge) congestion problem for communicating permutation instances on a ring. We prove the best possible upper bounds on the number of wavelengths and arc (edge) congestion in both directed and undirected cases.
COMPACT MULTICAST ALGORITHMS ON GRIDS AND TORI WITHOUT INTERMEDIATE BUFFERING
Authors: BARTH DOMINIQUE , FRAGOPOULOU PARASKEVI
Published: September 2012

We consider a communication model in which the intermediate nodes cannot store in-transit messages. Under this communication model we study the all-node multicast operation on multidimensional grids and tori. We derive optimal algorithms that are compactly described using a short sequence of node identities. This characteristic contributes to the simplicity of the router, the unit that resides at each processor and is dedicated to handle communication.
COENDOMORPHISM LEFT BIALGEBROIDS
Authors: ARDIZZONI A. , EL KAOUTIT L. , MENINI C.
Published: September 2012

The main purpose of this paper is to give a rigorous proof of the construction of coendomorphism left bialgebroids as well as an explicit description of their structure maps. We also compute some concrete examples of these objects by means of their generators and relations.
A REMARK ON GENERIC TAMENESS PRESERVATION UNDER BASE FIELD EXTENSION
Authors: MÉNDEZ GILBERTO , PÉREZ EFRÉN
Published: September 2012

Let k be a perfect field, K its algebraic closure and let Λ be a finite-dimensional k-algebra. A result of Kasjan asserts that if k is infinite and Λ is generically tame then Λ ⊗k K is generically tame. We show that the infiniteness requirement can be removed.
DECODING OF MATRIX-PRODUCT CODES
Authors: HERNANDO FERNANDO , RUANO DIEGO
Published: September 2012

We propose a decoding algorithm for the (u | u + v)-construction that decodes up to half of the minimum distance of the linear code. We extend this algorithm for a class of matrix-product codes in two different ways. In some cases, one can decode beyond the error-correction capability of the code.
AUTOMATED IDENTIFICATION OF EPILEPTIC AND ALCOHOLIC EEG SIGNALS USING RECURRENCE QUANTIFICATION ANALYSIS
Authors: NG EE PING , LIM TEIK-CHENG , CHATTOPADHYAY SUBHAGATA , BAIRY MURALIDHAR
Published: August 2012

Epilepsy is a common neurological disorder characterized by recurrence seizures. Alcoholism causes organic changes in the brain, resulting in seizure attacks similar to epileptic fits. Hence, it is challenging to differentiate the cause of fits as epileptic or alcoholism, which is important for deciding on the treatment in the neurology ward. The focus of this paper is to automatically differentiate epileptic, normal, and alcoholic electroencephalogram (EEG) signals. As the EEG signals are non-linear and dynamic in nature, it is difficult to tell the subtle changes in these signals with the help of linear techniques or by the naked eye. Therefore, to analyze the normal (control), epileptic, and alcoholic EEG signals, two non-linear methods, such as recurrence plots (RPs) and then recurrence quantification analysis (RQA) are adopted. Approximately 10 RQA parameters have been used to classify the EEG signals into three distinct classes, i.e., normal, epileptic, and alcoholic. Six classifiers, such as support vector machine (SVM), radial basis probabilistic neural network (RBPNN), decision tree (DT), Gaussian mixture model (GMM), k-nearest neighbor (kNN), and fuzzy Sugeno classifiers have been developed to accomplish this task. Results show that the GMM classifier outperformed the other classifiers with a classification sensitivity of 99.6%, specificity of 98.3%, and accuracy of 98.6%.
INTERACTIVE DYNAMIC SIMULATOR FOR MULTIBODY SYSTEMS
Authors: CHARDONNET JEAN-RÉMY
Published: August 2012

We propose an interactive dynamic simulator for humanoid robots using constraint-based methods for computing interaction forces with friction. This simulator is a part of a general framework for prototyping called AMELIF and is a successful integration of physical models. We focus on optimizing the computation of the dynamics to obtain real-time simulations allowing multimodal interactivity. Our simulator has been validated in two ways: first by comparing real sensors' measures and simulated values, then through different scenarios of complex manipulation tasks on the HRP-2 humanoid robot, bringing new insights to interactive robotics.
ON THE CMD PROJECTION METHOD AND THE ASSOCIATED STATISTICAL TESTS IN CLIMATE DATA ANALYSIS
Authors: ZHOU JIANSONG , TUNG KA-KIT
Published: August 2012

The composite mean difference (CMD) projection method is similar to the empirical orthogonal function (EOF) expansion commonly used in climate data analysis except that its first mode is empirically defined to be phenomenon-specific instead of being the mode that explains the most variance in the data as in the latter. The EOF, being a mathematically defined statistical quantity, may contain contributions from several phenomena, making its physical interpretation difficult. Furthermore, because the modes in the EOF expansion are ordered according to the magnitudes of their variances, the first few modes are often made up of internal variability, with smaller forced responses relegated to the higher modes, which are seldom studied. In CMD, a known (forcing) index of a quasi-periodic phenomenon under consideration is used to define two groups (e.g., high and low index years) by CMD of the data segregated in time into these two groups, yielding a spatial pattern of the "response" to this forcing. An associated time series that represents the temporal behavior of this "response" is then obtained by projecting the original spatial-time data onto the spatial CMD pattern. Bootstrap Monte Carlo statistical tests have been devised to test if the association of the "response" with the "forcing" index is distinguishable from that obtained by random chance. In this paper, synthetic data that simulate the real temperature observations will be used to empirically examine how trustworthy the conclusion from such statistical tests is. The results confirm the conclusions from bootstrap tests previously proposed, even in the presence of deterministic variability in the "noise."
ENSEMBLE EMPIRICAL MODE DECOMPOSITION FOR HYPERSPECTRAL IMAGE CLASSIFICATION
Authors: ZHANG MIN , SHEN YI
Published: August 2012

Ensemble empirical mode decomposition (EEMD) is a novel adaptive time-frequency analysis method, which is particularly suitable for extracting useful information from noisy nonlinear or nonstationary data. This paper presents the utilization of EEMD for hyperspectral images to extract signals from them, generated in noisy nonlinear and nonstationary processes. First, EEMD is applied to each hyperspectral image band and defines the true intrinsic mode function (IMF) components as the mean of an ensemble of trials, each consisting of the signal plus a white noise of finite amplitude. After EEMD is performed to each band, new bands are reconstructed as the sum of IMFs and the trend, and classification is executed over these new bands. Finally, the hyperspectral image with new bands was classified with support vector machine (SVM) to show the classification performance of the proposed approach. Experimental results show that the utilization of the EEMD significantly increases the classification accuracy compared to the dataset processed by empirical mode decomposition (EMD) and the original dataset.
EMPIRICAL MODE DECOMPOSITION DETECTS A PHASE-SHIFT OF SEASONAL OSCILLATION
Authors: CAPPARELLI V. , VECCHIO A. , CARBONE V.
Published: August 2012

Through the empirical mode decomposition (EMD), we extrapolated the seasonal component of monthly temperature oscillation of N = 1167 distributed on whole USA covering a period of 111 years from 1898 to 2008. We found an occasional destabilization of the phase of the seasonal component; moreover, the time distribution of these anomaly events is strongly correlated in time with a dominant periodicity remarkably close to the 18.6-year period of the Earth's nutation that represents the stronger modulation to the Earth's precession. Probably, phase-shift effect of seasonal oscillation is due to an orbit-climate relationship related to nutational forcing.
FUZZY INTRINSIC MODE ENTROPY FOR DATA FEATURE EXTRACTION
Authors: TSOLIS GEORGE S. , XENOS THOMAS D.
Published: August 2012

The notion of fuzzy entropy (FuzzyEn) is extended to the multiscale case by combining FuzzyEn and empirical mode decomposition (EMD). The proposed technique, fuzzy intrinsic entropy (FIMEn) performs better than its predecessor intrinsic monde entropy (IMEn) and it is less dependent on the algorithmic parameters. In a pattern recognition context, FIMEn provides more separable clusters than IMEn when used for feature extraction, thus allowing for less classification error. The above results suggest that the proposed multiscale entropy metric is a very promising technique for evaluating data regularity and can be used effectively for feature extraction in pattern recognition problems.
USING EMPIRICAL MODE DECOMPOSITION WEIGHTING FUNCTIONALS AS TIME SERIES FILTERING COEFFICIENTS FOR PHYSIOLOGICAL RECORDINGS
Authors: AVEN JOHN L. , MANDELL ARNOLD J. , COPPOLA RICHARD
Published: August 2012

We present a method for enhancing signals possessing nonlinear and nonstationary characteristics, which we call weighting functional-empirical mode decomposition (WF-EMD). The filtering method is based upon the empirical mode decomposition (EMD) and utilizes an energy-based weighting scheme to recombine the decomposed modes into a single cleansed version of the signal. The filter has been developed in such a way that no restrictive assumptions about the data are required. Furthermore, the temporal resolution of the data is left unaltered, as it would occur in many common data-smoothing methods. The design of this filter has been influenced by improving the calculation accuracy of dynamical measures, such as fractal dimensions and Lyapunov exponents, of neurodynamical recordings such as those obtained through electroencephalography (EEG) or magnetoencephalography (MEG).
China's Expanding Outward Investment in Singapore
Authors: WANG Luyao
Published: September 2012

Despite China's comparatively small investment in Singapore, it has experienced continued expansion in recent years. The main driving forces include good bilateral relations and government policies, sound urban environment, well organised social system, mature financial market and preferential tax rate. Overall, these two countries so far have not fully reaped the expected benefits in terms of capital inflows and outflows. There remains great space for further development and cooperation.
SEMICONDUCTING GRAPHENE
Authors: SHINDE PRASHANT P. , KUMAR VIJAY
Published: September 2012

This article reviews the fundamental aspects of the electronic structure of two-dimensional graphene and modification of the electronic structure at the Dirac point in order to create a band gap. We discuss how the states near the Dirac point are affected by confinement, adsorption and interaction with a substrate. The physical mechanism for controlling the electronic properties of graphene by BN doping is discussed in detail and this looks like a promising way for making semiconducting graphene for applications.
Vascular insulin resistance related to endoplasmic reticulum stress in aortas from a rat model of chronic kidney disease
Authors: Zhou Qiu Gen , Fu Xiao Jing , Xu Guo Yu , Cao Wei , Liu Hong Fa , Nie Jing , Liang Min , Hou Fan Fan
Published: September 2012

Metabolic insulin resistance has been demonstrated in patients with nondiabetic chronic kidney disease (CKD), yet their vascular insulin signaling remains poorly understood. Here we tested the hypothesis that vascular insulin signaling was impaired and related with endoplasmic reticulum (ER) stress in aortas from the reduced renal mass (RRM) model of CKD. The activity of insulin signaling and markers of ER were determined in aortas from rats with RRM and cultured human umbilical vein endothelial cells. Tyrosine phosphorylation of insulin receptor-β and insulin receptor substrate (IRS)-1 and phosphorylation of protein kinase B and endothelial nitric oxide synthase were all decreased in aorta from RRM rats, whereas serine phosphorylation of IRS-1, a marker of insulin resistance, was increased. In addition, nitric oxide generation and insulin-mediated vasorelaxation were decreased in aortas from RRM rats. Insulin signaling in cultured vascular endothelial cells was impaired by induction of ER stress and was restored in aortas of RRM rats by inhibition of ER stress. Taken together, rats with RRM had vascular insulin resistance that was linked to ER stress. This identified vascular insulin resistance and ER stress as a potential therapeutic target for cardiovascular complications in patients with CKD.
Synergistic stimulation of myogenesis by glucocorticoid and IGF-I signaling
Authors: Pansters N. A. , Langen R. C. , Wouters E. F. , Schols A. M.
Published: August 2012

Muscle wasting is associated with poor prognosis in chronic obstructive pulmonary disease (COPD). Exercise stimulates muscle recovery, but its efficacy is variable, depending on the clinical condition and medical treatment. Systemic glucocorticoids, commonly administered in high doses during acute disease exacerbations or as maintenance treatment in end-stage disease, are known to contribute to muscle wasting. As muscle mass recovery involves insulin-like growth factor (IGF)-I signaling, which can be stimulated by anabolic steroids, the impact of glucocorticoids and the effect of simultaneous IGF-I stimulation by anabolic steroids on muscle recovery and growth were investigated. The effects of, and interactions between, glucocorticoid and IGF-I signaling on skeletal muscle growth were assessed in differentiating C2C12 myocytes. As proof of principle, we performed a post hoc analysis stratifying patients by glucocorticoid use of a clinical trial investigating the efficacy of anabolic steroid supplementation on muscle recovery in muscle-wasted patients with COPD. Glucocorticoids strongly impaired protein synthesis signaling, myotube formation, and muscle-specific protein expression. In contrast, in the presence of glucocorticoids, IGF-I synergistically stimulated myotube fusion and myofibrillar protein expression, which corresponded with restored protein synthesis signaling by IGF-I and increased transcriptional activation of muscle-specific genes by glucocorticoids. In COPD patients on maintenance glucocorticoid treatment, the clinical trial also revealed an enhanced effect of anabolic steroids on muscle mass and respiratory muscle strength. In conclusion, synergistic effects of anabolic steroids and glucocorticoids on muscle recovery may be caused by relief of the glucocorticoid-imposed blockade on protein synthesis signaling, allowing effective translation of glucocorticoid-induced accumulation of muscle-specific gene transcripts.
Effects of the Nanostructured Fe‐V‐Nb Modificators on the Microstructure and Mechanical Properties of Si‐Mn Steel
Authors: Wang Tiebao , Cui Chunxiang , Jia Kuo , Zhao Lichen
Published: September 2012

The nanostructured Fe‐V‐Nb master alloy was prepared in vacuum rapid quenching furnace and then was added in the steel melts as modificators before casting. Next, the effects of the nanostructured Fe‐V‐Nb modificators on the microstructure and mechanical properties of the steel were studied. The results show that the grain size of the steel has been effectively refined, which is mainly because the dispersed nanoscale particles can produce more nucleation sites during the solidification of the liquid steel. Tensile properties and fracture morphology reveal that the yield strength and toughness of the steel modified by nanostructured Fe‐V‐Nb modificators are better than that of the microalloyed steel. TEM analysis shows that vanadium and niobium in the modificators exist in the form of (V, Nb) C which effectively increases the nucleation rate and leads to better mechanical properties of the steel.
ROCK1 and ROCK2 Are Required for Non-Small Cell Lung Cancer Anchorage-Independent Growth and Invasion
Authors: Vigil Dominico , Kim Tai Young , Plachco Ana , Garton Andrew J. , Castaldo Linda , Pachter Jonathan A. , Dong Hanqing , Chen Xin , Tokar Brianna , Campbell Sharon L. , Der Channing J.
Published: September 2012

Evidence is emerging that the closely related ROCK1 and ROCK2 serine/threonine kinases support the invasive and metastatic growth of a spectrum of human cancer types. Therefore, inhibitors of ROCK are under preclinical development. However, a key step in their development involves the identification of genetic biomarkers that will predict ROCK inhibitor antitumor activity. One identified mechanism for ROCK activation in cancer involves the loss of function of the DLC1 tumor suppressor gene, which encodes a GTPase activating protein (RhoGAP) for the RhoA and RhoC small GTPases. DLC-1 loss may lead to hyperactivation of RhoA/C and its downstream effectors, the ROCK kinases. We therefore determined whether loss of DLC-1 protein expression identifies non-small cell lung carcinoma (NSCLC) cell lines whose growth and invasion phenotypes are sensitive to ROCK inhibition. We identified and characterized a novel small molecule pharmacologic inhibitor of ROCK and additionally applied genetic approaches to impair ROCK1 and/or ROCK2 activity, and we determined that although NSCLC anchorage-dependent growth was ROCK-independent, both anchorage-independent growth and Matrigel invasion were ROCK-dependent. However, loss of DLC-1 expression did not correlate with ROCK activation or with OXA-06 sensitivity. Unexpectedly, suppression of ROCK1 or ROCK2 expression alone was sufficient to impair anchorage-independent growth, supporting their nonoverlapping roles in oncogenesis. Mechanistically, the block in anchorage-independent growth was associated with accumulation of cells in the G0–G1 phase of the cell cycle, but not increased anoikis. We conclude that ROCK may be a useful therapeutic target for NSCLC. Cancer Res; 72(20); 5338–47. ©2012 AACR.
IKK-ϵ Coordinates Invasion and Metastasis of Ovarian Cancer
Authors: Hsu Sarah , Kim Marianne , Hernandez Lidia , Grajales Valentina , Noonan Anne , Anver Miriam , Davidson Ben , Annunziata Christina M.
Published: September 2012

Inhibitor of IκB kinases (IKK) are key regulators of NF-κB signaling. Three IKK isoforms—α, β, and ϵ—have been linked to oncogenesis, yet the precise components of NF-κB signaling in ovarian cancer have not yet been dissected. We surveyed 120 ovarian cancer specimens for IKK-ϵ expression. Notably, cytoplasmic expression was elevated in metastatic lesions relative to primary tumors (P = 0.03). Therefore, we hypothesized that IKK-ϵ drives ovarian cancer metastasis. IKK-ϵ was identified previously as a breast cancer oncogene and was associated with poor clinical outcome in ovarian cancer. We now define an ovarian cancer–specific IKK-ϵ–regulated gene expression signature using stably expressed short hairpin RNA targeting IKK-ϵ. Pathway analysis of the signature indicated that IKK-ϵ regulates expression of genes involved in cell motility and inflammation. We further showed that IKK-ϵ depletion in metastatic ovarian cancer cell lines decreased growth, adhesion, and invasion. Consistently, human xenografts depleted of IKK-ϵ in mice showed decreased aggressiveness, whereas overexpression of IKK-ϵ in a less invasive ovarian cancer cell line increased metastasis in vivo. Taken together, these data provide evidence that IKK-ϵ is a key coordinator of invasion and metastasis programs in ovarian cancer. Inhibition of IKK-ϵ signaling thus emerges as a viable therapeutic strategy in women whose ovarian cancer shows aberrant activation of this pathway. Cancer Res; 72(21); 5494–504. ©2012 AACR.
Autophagy Induced by Conventional Chemotherapy Mediates Tumor Cell Sensitivity to Immunotherapy
Authors: Ramakrishnan Rupal , Huang Chun , Cho Hyun-Il , Lloyd Mark , Johnson Joseph , Ren Xiubao , Altiok Soner , Sullivan Daniel , Weber Jeffrey , Celis Esteban , Gabrilovich Dmitry I.
Published: September 2012

Autophagy attenuates the efficacy of conventional chemotherapy but its effects on immunotherapy have been little studied. Here, we report that chemotherapy renders tumor cells more susceptible to lysis by CTL in vivo. Moreover, bystander tumor cells that did not express antigen were killed by CTL. This effect was mediated by transient but dramatic upregulation of the mannose-6-phosphate receptor (MPR) on the tumor cell surface. Antitumor effects of combined treatment related to the kinetics of MPR upregulation and abrogation of this event abolished the combined effect of immunotherapy and chemotherapy. MPR accumulation on the tumor cell surface during chemotherapy was observed in different mouse tumor models and in patients with multiple myeloma. Notably, this effect was the result of redistribution of the receptor caused by chemotherapy-inducible autophagy. Together, our findings reveal one molecular mechanism through which the antitumor effects of conventional cancer chemotherapy and immunotherapy are realized. Cancer Res; 72(21); 5483–93. ©2012 AACR.
Breakdown of the FLT3-ITD/STAT5 Axis and Synergistic Apoptosis Induction by the Histone Deacetylase Inhibitor Panobinostat and FLT3-Specific Inhibitors
Authors: Pietschmann Kristin , Bolck Hella Anna , Buchwald Marc , Spielberg Steffi , Polzer Harald , Spiekermann Karsten , Bug Gesine , Heinzel Thorsten , Böhmer Frank-Dietmar , Krämer Oliver H.
Published: September 2012

Activating mutations of the class III receptor tyrosine kinase FLT3 are the most frequent molecular aberration in acute myeloid leukemia (AML). Mutant FLT3 accelerates proliferation, suppresses apoptosis, and correlates with poor prognosis. Therefore, it is a promising therapeutic target. Here, we show that RNA interference against FLT3 with an internal tandem duplication (FLT3-ITD) potentiates the efficacy of the histone deacetylase inhibitor (HDACi) panobinostat (LBH589) against AML cells expressing FLT3-ITD. Similar to RNA interference, tyrosine kinase inhibitors (TKI; AC220/cpd.102/PKC412) in combination with LBH589 exhibit superior activity against AML cells. Median dose–effect analyses of drug-induced apoptosis rates of AML cells (MV4-11 and MOLM-13) revealed combination index (CI) values indicating strong synergism. AC220, the most potent and FLT3-specific TKI, shows highest synergism with LBH589 in the low nanomolar range. A 4-hour exposure to LBH589 + AC220 already generates more than 50% apoptosis after 24 hours. Different cell lines lacking FLT3-ITD as well as normal peripheral blood mononuclear cells are not significantly affected by LBH589 + TKI, showing the specificity of this treatment regimen. Immunoblot analyses show that LBH589 + TKI induce apoptosis via degradation of FLT3-ITD and its prosurvival target STAT5. Previously, we showed the LBH589-induced proteasomal degradation of FLT3-ITD. Here, we show that activated caspase-3 also contributes to the degradation of FLT3-ITD and that STAT5 is a direct target of this protease. Our data strongly emphasize HDACi/TKI drug combinations as promising modality for the treatment of FLT3-ITD–positive AMLs. Mol Cancer Ther; 11(11); 2373–83. ©2012 AACR.
Platypnea-Orthodeoxia Syndrome in Review: Defining a New Disease?
Authors: Rodrigues Patrícia , Palma Paulo , Sousa-Pereira Luís
Published: August 2012

Platypnea-orthodeoxia syndrome is an intriguing condition that comprehends multiple pathologic phenomena. It requires a high clinical suspicion and is probably underdiagnosed. Its identification has therapeutic implications and can have a huge impact on the patient’s everyday life. We made a review of the literature and analyzed 188 cases described thus far, trying to identify the underlying mechanisms and risk factors. We propose that a separate entity is created within the spectrum of platypnea-orthodeoxia syndrome that is responsible for the majority of cases, namely platypnea-orthodeoxia disease, which would be defined as the existence of an interatrial communication, with a right-to-left shunt, normal pressure in the right atrium and, of course, platypnea and orthodeoxia. Most patients with this disease were submitted to percutaneous closure of the patent foramen ovale or atrial septal defect, with favorable results, making it the first-line therapeutic approach nowadays.
Plasmacytoid Dendritic Cells Play a Key Role in Promoting Atherosclerosis in Apolipoprotein E–Deficient Mice
Authors: MacRitchie Neil , Grassia Gianluca , Sabir Suleman R. , Maddaluno Marcella , Welsh Paul , Sattar Naveed , Ialenti Armando , Kurowska-Stolarska Mariola , McInnes Iain B. , Brewer James M. , Garside Paul , Maffia Pasquale
Published: August 2012

Objective—

Clinical studies have identified that reduced numbers of circulating plasmacytoid dendritic cells (pDCs) act as a predictor of cardiovascular events in coronary artery disease and that pDCs are detectable in the shoulder region of human atherosclerotic plaques, where rupture is most likely to occur. Results from animal models are controversial, with pDCs seen to inhibit or promote lesion development depending on the experimental settings. Here, we investigated the role of pDCs in atherosclerosis in apolipoprotein E−deficient mice.

Methods and Results—

We demonstrated that the aorta and spleen of both apolipoprotein E−deficient and C57BL/6 mice displayed similar numbers of pDCs, with similar activation status. In contrast, assessment of antigen uptake/presentation using the Eα/Y-Ae system revealed that aortic pDCs in apolipoprotein E−deficient
-
mice were capable of presenting in vivo systemically administered antigen. Continuous treatment of apolipoprotein E−deficient mice with anti−mouse plasmacytoid dendritic cell antigen 1 (mPDCA-1) antibody caused specific depletion of pDCs in the aorta and spleen and significantly reduced atherosclerosis formation in the aortic sinus (by 46%;
P
<0.001). Depletion of pDCs also reduced macrophages (by 34%;
P
<0.05) and increased collagen content (by 41%;
P
<0.05) in aortic plaques, implying a more stable plaque phenotype. Additionally, pDC depletion reduced splenic T-cell activation and inhibited interleukin-12, chemokine (C-X-C motif) ligand 1, monokine induced by interferon-γ, interferon γ−induced protein 10, and vascular endothelium growth factor serum levels.

Conclusion—

These results identify a critical role for pDCs in atherosclerosis and suggest a potential role for pDC targeting in the control of the pathology.
Hepatocyte Growth Factor Inhibits Lipopolysaccharide-Induced Oxidative Stress via Epithelial Growth Factor Receptor Degradation
Authors: Shimizu Kazutaka , Taniyama Yoshiaki , Sanada Fumihiro , Azuma Junya , Iwabayashi Masaaki , Iekushi Kazuma , Rakugi Hiromi , Morishita Ryuichi
Published: August 2012

Objective—

Lipopolysaccharide (LPS) triggers sepsis and systemic inflammatory response syndrome, which results in multiple organ failure. Our recent reports demonstrated that hepatocyte growth factor (HGF) attenuated angiotensin II–induced oxidative stress via epithelial growth factor receptor (EGFR) degradation in vascular smooth muscle cells. Here, we examined whether HGF can protect against systemic inflammatory response syndrome induced by LPS and investigated the mechanism.

Methods and Results—

HGF inhibited the increase in the expression of vascular cell adhesion molecule-1 and EGFR by LPS in vitro. HGF inhibited colocalization of EGFR and Src homology domain 2–containing inositol 5′-phosphatase 2. Furthermore, HGF inhibited reactive oxygen species production. We also injected LPS into HGF transgenic mice with increased HGF serum concentration and their littermates. HGF transgenic mice reduced LPS-induced vascular cell adhesion molecule-1 and reactive oxygen species compared with control, accompanied by significant EGFR degradation. Furthermore, HGF transgenic mice significantly improved survival in the LPS injection model.

Conclusion—

The present study revealed inhibition of LPS-induced vascular cell adhesion molecule-1 expression by HGF via the degradation of EGFR. We demonstrated that HGF regulated Src homology domain 2–containing inositol 5′-phosphatase 2 recruitment to EGFR and inhibited LPS-induced inflammation via EGFR degradation. This effect of HGF may be useful for the treatment of inflammatory disease.
Elevated Levels of the Mediator of Catabolic Bone Remodeling RANKL in the Bone Marrow Environment Link Chronic Heart Failure with Osteoporosis
Authors: Leistner David M. , Seeger Florian H. , Fischer Ariane , Röxe Tino , Klotsche Jens , Iekushi Kazuma , Seeger Timon , Assmus Birgit , Honold Jörg , Karakas Mahir , Badenhoop Klaus , Frantz Stefan , Dimmeler Stefanie , Zeiher Andreas M.
Published: September 2012

Background—

Chronic heart failure (CHF) is associated with a 4-fold increased risk for osteoporotic fractures. Therefore, we sought to identify the pathophysiological link between chronic heart failure and catabolic bone remodeling.

Methods and Results—

In a total cohort of 153 subjects (123 patients with CHF, 30 patients with coronary artery disease and preserved cardiac function) as well as mice with heart failure, bone marrow (BM) plasma levels of the catabolic receptor activator of NF-κB ligand (RANKL), and its antagonist, osteoprotegerin were measured. The osteoclast inducing activity of BM plasma was tested in cell culture. BM plasma levels of RANKL and of the ratio RANKL/osteoprotegerin were significantly elevated in patients with CHF. On multivariate regression analysis, parameters of severity and duration of heart failure were independent determinants of elevated BM plasma RANKL levels. BM plasma levels of RANKL were directly correlated with the systemic marker of bone turnover C-telopeptide of type 1 collagen (
r
=0.6;
P
<0.001). Alterations in BM plasma levels of RANKL/osteoprotegerin were confirmed in a mouse model of postinfarction heart failure. Stimulation of human mesenchymal cells with BM plasma obtained from CHF patients increased the formation of osteoclasts, and this effect was blocked by the RANKL inhibition.

Conclusions—

CHF is associated with a profound and selective elevation of the bone resorption stimulating RANKL within the BM microenvironment. These data for the first time disclose a direct pathophysiological pathway linking CHF with catabolic bone remodeling associated with an increased osteoporotic fracture risk.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifiers: NCT 00289822, NCT 00284713, NCT 00326989, NCT 00962364.
Short Sleep Duration Is Associated With Carotid Intima-Media Thickness Among Men in the Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: Sands Megan R. , Lauderdale Diane S. , Liu Kiang , Knutson Kristen L. , Matthews Karen A. , Eaton Charles B. , Linkletter Crystal D. , Loucks Eric B.
Published: August 2012

Background and Purpose—

Carotid intima-media thickness (CIMT) is a subclinical marker of cardiovascular disease. Recent studies suggest that shorter sleep duration is a risk factor for cardiovascular disease, but there is limited evidence regarding this association using high-quality, objective assessments of sleep. The aim of this study is to determine whether sleep duration is associated with CIMT.

Methods—

The study used an observational cohort consisting of 617 black and white middle-aged healthy participants (37–52 years; 58% female) in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Multivariable-adjusted linear regression analyses were performed. Sleep duration was measured using wrist actigraphy monitors. CIMT was calculated using the average of 20 measurements of the mean common carotid, bulb, and internal CIMT, which was assessed using ultrasound images.

Results—

After adjusting for covariates, 1 hour of longer sleep duration was associated with 0.026 mm less CIMT among men (
P
=0.02; 95% CI, −0.047 to −0.005) and 0.001 mm less CIMT among women (
P
=0.91; 95% CI, −0.020 to 0.022). Segment-specific analyses indicated that the carotid bulb was a key driver of the observed association.

Conclusions—

Shorter objectively assessed sleep duration was associated with greater CIMT among men but not women.
Long-Term Rate of Change in Memory Functioning Before and After Stroke Onset
Authors: Wang Qianyi , Capistrant Beatrix D. , Ehntholt Amy , Glymour M. Maria
Published: August 2012

Background and Purpose—

Memory impairment is a predictor and a consequence of stroke, but memory decline is common even in healthy elderly individuals. We compared the long-term trajectory of memory functioning before and after stroke with memory change in stroke-free elderly individuals.

Methods—

Health and Retirement Study participants aged 50 years and older (n=17 340) with no stroke history at baseline were interviewed biennially up to 10 years for first self-reported or proxy-reported stroke (n=1574). Age-, sex-, and race-adjusted segmented linear regression models were used to compare annual rates of change in a composite memory score before and after stroke among 3 groups: 1189 stroke survivors; 385 stroke decedents; and 15 766 cohort members who remained stroke-free.

Results—

Before stroke onset, individuals who later survived stroke had significantly (
P
<0.001) faster average annual rates of memory decline (−0.143 points per year) than those who remained stroke-free throughout follow-up (−0.101 points per year). Stroke decedents had even faster prestroke memory decline (−0.212 points per year). At stroke onset, memory declined an average of −0.369 points among stroke survivors, comparable with 3.7 years of age-related decline in stroke-free cohort members. After stroke, memory in stroke survivors continued to decline at −0.142 points per year, similar to their prestroke rates (
P
=0.93). Approximately 50% of the memory difference between stroke survivors soon after stroke and age-matched stroke-free individuals was attributable to prestroke memory.

Conclusions—

Although stroke onset induced large decrements in memory, memory differences were apparent years before stroke. Memory declines before stroke, especially among those who did not survive the stroke, were faster than declines among stroke-free adults.
30-Day Risk-Standardized Mortality and Readmission Rates After Ischemic Stroke in Critical Access Hospitals
Authors: Lichtman Judith H. , Leifheit-Limson Erica C. , Jones Sara B. , Wang Yun , Goldstein Larry B.
Published: August 2012

Background and Purpose—

The critical access hospital (CAH) designation was established to provide rural residents with local access to emergency and inpatient care. CAHs, however, have poorer short-term outcomes for pneumonia, heart failure, and myocardial infarction compared with other hospitals. We assessed whether 30-day risk-standardized mortality rates (RSMRs) and risk-standardized readmission rates (RSRRs) after ischemic stroke differ between CAHs and non-CAHs.

Methods—

The study included all fee-for-service Medicare beneficiaries 65 years of age or older with a primary discharge diagnosis of ischemic stroke (
International Classification of Diseases,
9th revision codes 433, 434, 436) in 2006. Hierarchical generalized linear models calculated hospital-level RSMRs and RSRRs, adjusting for patient demographics, medical history, and comorbid conditions. Non-CAHs were categorized by hospital volume quartiles and the RSMR and RSRR posterior probabilities in comparison with CAHs were determined using linear regression with Markov chain Monte Carlo simulation.

Results—

There were 10 267 ischemic stroke discharges from 1165 CAHs and 300 114 discharges from 3381 non-CAHs. The RSMRs of CAHs were higher than non-CAHs (11.9%±1.4% vs 10.9%±1.7%;
P
<0.001), but the RSRRs were comparable (13.7%±0.6% vs 13.7%±1.4%;
P
=0.3). The RSMRs for the 2 higher volume quartiles of non-CAHs were lower than CAHs (posterior probability of RSMRs higher than CAHs=0.007 for quartile 3;
P
<0.001 for quartile 4), but there were no differences for lower volume hospitals; RSRRs did not vary by annual hospital volume.

Conclusions—

CAHs had higher RSMRs compared with non-CAHs, but readmission rates were similar. The observed differences may be partly explained by patient characteristics and annual hospital volume.
Evolution and Analysis of Genetic Networks for Stable Cellular Growth and Regeneration
Authors: Schramm Lisa , Jin Yaochu , Sendhoff Bernhard
Published: September 2012

A computational model is presented that simulates stable growth of cellular structures that are in some cases capable of regeneration. In the model, cellular growth is governed by a gene regulatory network. By evolving the parameters and structure of the genetic network using a modified evolution strategy, a dynamically stable state can be achieved in the developmental process, where cell proliferation and cell apoptosis reach an equilibrium. The results of evolution with different setups in fitness evaluation during the development are compared with respect to their regeneration capability as well as their gene regulatory network structure. Network motifs responsible for stable growth and regeneration that emerged from the evolution are also analyzed. We expect that our findings can help to gain a better understanding of the process of growth and regeneration inspired by biological systems, in order to solve complex engineering problems, such as the design of self-healing materials.