bluuebunny/crossref_metadata_2025 huggingface dataset:
Managing diabetes in dialysis patients
Authors: O'Toole Sam M , Fan Stanley L , Yaqoob M Magdi , Chowdhury Tahseen A
Published: January 2012

Burgeoning levels of diabetes are a major concern for dialysis services, as diabetes is now the most common cause of end-stage renal disease in most developed nations. With the rapid rise in diabetes prevalence in developing countries, the burden of end stage renal failure due to diabetes is also expected to rise in such countries. Diabetic patients on dialysis have a high burden of morbidity and mortality, particularly from cardiovascular disease, and a higher societal and economic cost compared to non-diabetic subjects on dialysis. Tight glycaemic and blood pressure control in diabetic patients has an important impact in reducing risk of progression to end stage renal disease. The evidence for improving glycaemic control in patients on dialysis having an impact on mortality or morbidity is sparse. Indeed, many factors make improving glycaemic control in patients on dialysis very challenging, including therapeutic difficulties with hypoglycaemic agents, monitoring difficulties, dialysis strategies that exacerbate hyperglycaemia or hypoglycaemia, and possibly a degree of therapeutic nihilism or inertia on the part of clinical diabetologists and nephrologists. Standard drug therapy for hyperglycaemia (eg, metformin) is clearly not possible in patients on dialysis. Thus, sulphonylureas and insulin have been the mainstay of treatment. Newer therapies for hyperglycaemia, such as gliptins and glucagon-like peptide-1 analogues have become available, but until recently, renal failure has precluded their use. Newer gliptins, however, are now licensed for use in ‘severe renal failure’, although they have yet to be trialled in dialysis patients. Diabetic patients on dialysis have special needs, as they have a much greater burden of complications (cardiac, retinal and foot). They may be best managed in a multidisciplinary diabetic–renal clinic setting, using the skills of diabetologists, nephrologists, clinical nurse specialists in nephrology and diabetes, along with dietitians and podiatrists.
ON THE CLASSIFICATION OF EVEN UNIMODULAR LATTICES WITH A COMPLEX STRUCTURE
Authors: HENTSCHEL MICHAEL , KRIEG ALOYS , NEBE GABRIELE
Published: January 2012

This paper classifies the even unimodular lattices that have a structure as a Hermitian [Formula: see text]-lattice of rank r ≤ 12 for rings of integers in imaginary quadratic number fields K of class number 1. The Hermitian theta series of such a lattice is a Hermitian modular form of weight r for the full modular group, therefore we call them theta lattices. For arbitrary imaginary quadratic fields we derive a mass formula for the principal genus of theta lattices which is applied to show completeness of the classifications.
INTEGER OPERATORS IN FINITE VON NEUMANN ALGEBRAS
Authors: THOM ANDREAS
Published: January 2012

Motivated by the study of spectral properties of self-adjoint operators in the integral group ring of a sofic group, we define and study integer operators. We establish a relation with classical potential theory and in particular the circle of results obtained by Fekete and Szegö, see [3, 4, 13]. More concretely, we use results by Rumely, see [12], on equidistribution of algebraic integers to obtain a description of those integer operator which have spectrum of logarithmic capacity less than or equal to one.

Finally, we relate the study of integer operators to a recent construction by Petracovici and Zaharescu, see [10].
VEECH GROUPS FOR HOLONOMY-FREE TORUS COVERS
Authors: SCHMOLL MARTIN
Published: January 2012

For fixed coprime k, l ∈ ℕ and each pair (w, z) ∈ ℂ2we define an infinite cyclic cover Σk,l(w, z) → 𝕋, called a k-l-surface or k-l-cover. We show that [Formula: see text] classifies k-l-covers up to isomorphism away from a rather small set. The diagonal action of SL2(ℤ) on ℂ2descends to [Formula: see text], reflecting the SL2(ℤ)-action on the family of k-l-surfaces equipped with a translation structure. The moduli space of holonomy free k-l-surfaces is a compact SL2(ℤ) invariant subspace [Formula: see text] containing all k-l-surfaces with a lattice stabilizer with respect to the SL2(ℤ) action. We calculate the stabilizer, the Veech group, explicitly and represent k-l-covers branched over two points by a generalized class of staircase surfaces. Finally we study SL2(ℤ)-equivariant translation maps from the Hurwitz space of k-(d - k)-covers to Hurwitz spaces of ℤ/d-covers branched over two points.
THE WEINSTEIN CONJECTURE IN THE PRESENCE OF SUBMANIFOLDS HAVING A LEGENDRIAN FOLIATION
Authors: NIEDERKRÜGER KLAUS , RECHTMAN ANA
Published: January 2012

Helmut Hofer introduced in 1993 a novel technique based on holomorphic curves to prove the Weinstein conjecture. Among the cases where these methods apply are all contact 3-manifolds (M, ξ) with π2(M) ≠ 0. We modify Hofer's argument to prove the Weinstein conjecture for some examples of higher-dimensional contact manifolds. In particular, we are able to show that the connected sum with a real projective space always has a closed contractible Reeb orbit.
Emissive Liquid-Crystal Display Panels Consisting of Red–Green–Blue Patterned Phosphor Layers and Near-Ultraviolet Light-Emitting-Diode Backlight
Authors: Yata Tatsuya , Miyamoto Yoshinobu , Ohmi Koutoku
Published: January 2012

Emissive liquid crystal display (e-LCD) panels consisting of 405 nm near-UV light-emitting-diode (LED) backlight and patterned red–green–blue phosphor layers have been proposed. Improvements in luminous efficiency and lifetime have been systematically attempted. From the results of the accelerated aging test under near-UV irradiation under high temperature and humidity conditions, it has been confirmed that the e-LCD panel has a sufficiently long lifetime for practical use. The light conversion efficiency of the phosphor layer has been significantly improved by using optical filters. Commission Internationale de l'Eclairage (CIE) color coordinates are (0.69, 0.31) for red, (0.27, 0.68) for green and (0.15, 0.04) for blue sub-pixels. The corresponding color gamut is over 100% compared with that of the National Television System Committee. The e-LCD panel also has a considerable wide-viewing-angle property, and its overall luminous efficiency is more than twice higher than those of conventional LCD panels consisting of white-LED and color filters.
Variation in Absorber Layer Defect Density in Amorphous and Microcrystalline Silicon Thin Film Solar Cells with 2 MeV Electron Bombardment
Authors: Smirnov Vladimir , Astakhov Oleksandr , Carius Reinhard , Petrusenko Yuri , Borysenko Valeriy , Finger Friedhelm
Published: January 2012

The effect of the defect density in hydrogenated amorphous and microcrystalline silicon (a-Si:H and µc-Si:H) absorber layers on the performance of thin film solar cells was investigated. The defect density was varied reproducibly over more than two orders of magnitude by 2 MeV electron bombardment and subsequent thermal annealing. Considerable quantitative and qualitative differences were observed for the dependences of the cells parameters on the defect densities of a-Si:H and µc-Si:H. The experimental data suggest further possible improvement of µc-Si:H based solar cells with further reduced defect densities, while for a-Si:H based solar cells, a saturation of performance is observed below a defect density of about 1016cm-3. Moreover, the experimental data provide an excellent database for numerical simulation over a range unavailable so far particularly in µc-Si:H based solar cells.
Performance Test and Evaluation of Multilevel Fresnel Zone Plate with Three-Step Profile Fabricated with Electron-Beam Lithography
Authors: Takeuchi Akihisa , Suzuki Yoshio , Uesugi Kentaro , Okada Ikuo , Iriguchi Hiroki
Published: January 2012

A multilevel Fresnel zone plate (FZP) designed as an approximation of a kinoform profile has been developed. The FZP is made by electron-beam lithography and reactive ion etching. The zone structure consists of three levels made from tantalum with a total thickness of 4 µm. The half pitch of the outermost zone structure is 0.6 µm. The theoretical efficiency of the 1st-order diffraction is 0.49 at an X-ray energy of 9.85 keV. A performance test is carried out at the beamline 20XU of SPring-8. The focused beam width is measured to be 0.6 µm. The measured efficiency of the 1st-order diffraction is 0.39 at 9.85 keV. Although the measured efficiency is less than the theoretical value, it is superior to the efficiency of an optimized tantalum binary FZP. The diffraction efficiencies of the 0th, -1st, and ±2nd orders are also measured. Using the measured data, the structure of the fabricated zone is evaluated.
Characterization of Magnetic Markers for Liquid-Phase Immunoassays Using Brownian Relaxation
Authors: Enpuku Keiji , Watanabe Hideki , Higuchi Yuichi , Yoshida Takashi , Kuma Hiroyuki , Hamasaki Naotaka , Mitsunaga Masakazu , Kanzaki Hisao , Kandori Akihiko
Published: January 2012

We characterized the magnetic markers used in biological immunoassays based on Brownian relaxation. Because the markers are composed of aggregated nanoparticles, i.e., magnetic nanoclusters, we first clarified their magnetic properties using AC susceptibility measurements, magnetization (M–H) curves, and magnetic relaxation properties. Analyzing the experimental results, we obtained the key parameters for the immunoassay, i.e., hydrodynamic diameter d
h, magnetic moment m
B, and anisotropy energy E
B of the markers. Because these parameters were distributed in practical samples, we took their distribution into account in the analysis. Next, we showed the relationship between these parameters obtained from different samples. It was shown that m
B increased approximately in proportion to d
h. On the other hand, no clear correlation between m
B and E
B was obtained. These results were very different from those expected from single-domain nanoparticles and must be taken into account when magnetic markers are used in immunoassays based on Brownian relaxation.
Understanding of Thermal Engineering for Vertical Nanowire Phase-Change Random Access Memory Partially Wrapped by Low-Conductivity Layer
Authors: Zhang Jiayong , Wang Xiaofeng , Wang Xiaodong , Ma Huili , Fu Yingchun , Ji An , Song Zhitang , Feng Songlin , Yang Fuhua
Published: January 2012

A phase-change random access memory (PCRAM) geometric model is proposed to improve the thermal efficiency. A low-κ layer with very low thermal conductivity is inserted into the insulation layer. Then, the effective programming area and the programming current are greatly reduced. In addition, the selection conditions for the low-κ layer are carefully studied to help us find a suitable material that can be used as a low-κ layer. It is believed that this simple geometric model is a useful tool for increasing the thermal efficiency of PCRAM devices and for selecting the appropriate conditions for a low-κ layer allowing low-current operation.
Preparation of Low Resistivity Transparent Conductive Nb-Doped TiO2 Films by the Co-sputtering Method
Authors: Li Meng-Chi , Kuo Chien-Cheng , Peng Ssu-Hsiang , Chen Sheng-Hui , Lee Cheng-Chung
Published: January 2012

Low resistivity Nb-doped TiO2 transparent conducting oxide (TNO) thin films have been achieved by a pulsed dc magnetron co-sputtering at room temperature and the annealing treatment. Pulsed dc power provides the stabilization of reactive sputtering. The dc power of Nb target is controlled to find the optimum Nb content in TNO films. The carrier concentration is linearly proportional to Nb content in TNO films. The lowest resistivity was measured as 4.55×10-4 Ω cm at 24 W dc power of Nb and the average absorbance in the visible light region was smaller than 8% for different dc powers. The results of contact angle revealed that TNO films still keep the surface hydrophilicity and have the characteristic of photo-catalyst.
Silicon Epitaxial Growth Rate and Transport Phenomena in a Vertical Stacked-Type Multi-Wafer Reactor
Authors: Habuka Hitoshi , Tsuji Masaki
Published: January 2012

The silicon epitaxial growth rate in a trichlorosilane–hydrogen system using a vertical stacked-type multi-wafer reactor, having more than 100 substrate pieces, together with two horizontal gas inlet nozzles for each substrate, was studied by means of numerical calculations. In this study, the authors developed a compact model that consisted of the minimal set of reactor parts, by taking into account the gas flow condition around the stacked susceptors. Because the direction of the gases horizontally injected to the substrate is bent by the gas flowing downward along the stacked susceptors, a part of the horizontally injected gas in the downstream positions is forced to directly go to the exhaust, and not to the substrate. The wafer-to-wafer uniformity of epitaxial thickness is expected to be improved by means of finely adjusting the susceptor position, particularly at the downstream positions.
Breast cancer cell-derived matrix supports vascular morphogenesis
Authors: Hielscher Abigail C. , Qiu Connie , Gerecht Sharon
Published: January 2012

The extracellular matrix (ECM), important for maintaining tissue homeostasis, is abnormally expressed in mammary tumors and additionally plays a crucial role in angiogenesis. We hypothesize that breast cancer cells (BCCs) deposit ECM that supports unique patterns of vascular morphogenesis of endothelial cells (ECs). Evaluation of ECM expression revealed that a nontumorigenic cell line (MCF10A), a tumorigenic cell line (MCF7), and a metastatic cell line (MDA-MB-231) express collagens I and IV, fibronectin, and laminin, with tenascin-C limited to MCF10A and MCF7. The amount of ECM deposited by BCCs was found to be higher in MCF10A compared with MCF7 and MDA231, with all ECM differing in their gross structure but similar in mean fiber diameter. Nonetheless, deposition of ECM from BCC lines was overall difficult to detect and insufficient to support capillary-like structure (CLS) formation of ECs. Therefore, a coculture approach was undertaken in which individual BCC lines were cocultured with fibroblasts. Variation in abundance of deposited ECM, deposition of ECM proteins, such as absent collagen I deposition from MDA231-fibroblast cocultures, and fibril organization was found. Deposited ECM from fibroblasts and each coculture supported rapid CLS formation of ECs. Evaluation of capillary properties revealed that CLS grown on ECM deposited from MDA231-fibroblast cocultures possessed significantly larger lumen diameters, occupied the greatest percentage of area, expressed the highest levels of von Willebrand factor, and expressed the greatest amount of E-selectin, which was upregulated independent of exposure to TNF-α. To our knowledge, this is the first study to report tumor cell ECM-mediated differences in vascular capillary features, and thus offers the framework for future investigations interrogating the role of the tumor ECM in supporting vascular morphogenesis.
Endothelial Ca2+ wavelets and the induction of myoendothelial feedback
Authors: Tran Cam Ha T. , Taylor Mark S. , Plane Frances , Nagaraja Sridevi , Tsoukias Nikolaos M. , Solodushko Viktoryiya , Vigmond Edward J. , Furstenhaupt Tobias , Brigdan Mathew , Welsh Donald G.
Published: January 2012

When arteries constrict to agonists, the endothelium inversely responds, attenuating the initial vasomotor response. The basis of this feedback mechanism remains uncertain, although past studies suggest a key role for myoendothelial communication in the signaling process. The present study examined whether second messenger flux through myoendothelial gap junctions initiates a negative-feedback response in hamster retractor muscle feed arteries. We specifically hypothesized that when agonists elicit depolarization and a rise in second messenger concentration, inositol trisphosphate (IP3) flux activates a discrete pool of IP3 receptors (IP3Rs), elicits localized endothelial Ca2+ transients, and activates downstream effectors to moderate constriction. With use of integrated experimental techniques, this study provided three sets of supporting observations. Beginning at the functional level, we showed that blocking intermediate-conductance Ca2+-activated K+ channels (IK) and Ca2+ mobilization from the endoplasmic reticulum (ER) enhanced the contractile/electrical responsiveness of feed arteries to phenylephrine. Next, structural analysis confirmed that endothelial projections make contact with the overlying smooth muscle. These projections retained membranous ER networks, and IP3Rs and IK channels localized in or near this structure. Finally, Ca2+ imaging revealed that phenylephrine induced discrete endothelial Ca2+ events through IP3R activation. These events were termed recruitable Ca2+ wavelets on the basis of their spatiotemporal characteristics. From these findings, we conclude that IP3 flux across myoendothelial gap junctions is sufficient to induce focal Ca2+ release from IP3Rs and activate a discrete pool of IK channels within or near endothelial projections. The resulting hyperpolarization feeds back on smooth muscle to moderate agonist-induced depolarization and constriction.
Altered sinoatrial node function and intra-atrial conduction in murine gain-of-function Scn5a+/ΔKPQ hearts suggest an overlap syndrome
Authors: Wu Jingjing , Zhang Yanmin , Zhang Xinzhao , Cheng Longxian , Lammers Wim J. , Grace Andrew A. , Fraser James A. , Zhang Henggui , Huang Christopher L. -H. , Lei Ming
Published: January 2012

Mutations in SCN5A, the gene encoding the pore-forming subunit of cardiac Na+ channels, cause a spectrum of arrhythmic syndromes. Of these, sinoatrial node (SAN) dysfunction occurs in patients with both loss- and gain-of-function SCN5A mutations . We explored for corresponding alterations in SAN function and intracardiac conduction and clarified possible mechanisms underlying these in an established mouse long QT syndrome type 3 model carrying a mutation equivalent to human SCN5A-ΔKPQ. Electrophysiological characterizations of SAN function in living animals and in vitro sinoatrial preparations were compared with cellular SAN and two-dimensional tissue models exploring the consequences of Scn5a+/ΔKPQ mutations. Scn5a+/ΔKPQ mice showed prolonged electrocardiographic QT and corrected QT intervals confirming long QT phenotypes. They showed frequent episodes of sinus bradycardia, sinus pause/arrest, and significantly longer sinus node recovery times, suggesting compromised pacemaker activity compared with wild-type mice. Electrocardiographic waveforms suggested depressed intra-atrial, atrioventricular node, and intraventricular conduction in Scn5a+/ΔKPQ mice . Isolated Scn5a+/ΔKPQ sinoatrial preparations similarly showed lower mean intrinsic heart rates and overall slower conduction through the SAN to the surrounding atrium than did wild-type preparations. Computer simulations of both single SAN cells as well as two-dimensional SAN-atrial models could reproduce the experimental observations of impaired pacemaker and sinoatrial conduction in terms of changes produced by both augmented tail and reduced total Na+ currents, respectively. In conclusion, the gain-of-function long QT syndrome type 3 murine Scn5a+/ΔKPQ cardiac system, in overlap with corresponding features reported in loss-of-function Na+ channel mutations, shows compromised SAN pacemaker and conduction function explicable in modeling studies through a combination of augmented tail and reduced peak Na+ currents.
CaMKII inhibition in heart failure, beneficial, harmful, or both
Authors: Cheng Jun , Xu Lin , Lai Dongwu , Guilbert Arnaud , Lim Hyun Joung , Keskanokwong Thitima , Wang Yanggan
Published: January 2012

Calmodulin-dependent protein kinase II (CaMKII) has been proposed to be a therapeutic target for heart failure (HF). However, the cardiac effect of chronic CaMKII inhibition in HF has not been well understood. We have tested alterations of Ca2+ handling, excitation-contraction coupling, and in vivo β-adrenergic regulation in pressure-overload HF mice with CaMKIIδ knockout (KO). HF was produced in wild-type (WT) and KO mice 1 wk after severe thoracic aortic banding (sTAB) with a continuous left ventricle (LV) dilation and reduction of ejection fraction for up to 3 wk postbanding. Cardiac hypertrophy was similar between WT HF and KO HF mice. However, KO HF mice manifested exacerbation of diastolic function and reduction in cardiac reserve to β-adrenergic stimulation. Compared with WT HF, L-type calcium channel current ( ICa) density in KO HF LV was decreased without changes in ICa activation and inactivation kinetics, whereas ICa recovery from inactivation was accelerated and Ca2+-dependent ICa facilitation, a positive staircase blunted in WT HF, was recovered. However, ICa response to isoproterenol was reduced. KO HF myocytes manifested dramatic decrease in sarcoplasmic reticulum (SR) Ca2+ leak and slowed cytostolic Ca2+ concentration decline. Sarcomere shortening was increased, but relaxation was slowed. In addition, an increase in myofilament sensitivity to Ca2+ and the slow skeletal muscle troponin I-to-cardiac troponin I ratio and interstitial fibrosis and a decrease in Na/Ca exchange function and myocyte apoptosis were observed in KO HF LV. CaMKIIδ KO cannot suppress severe pressure-overload-induced HF. Although cellular contractility is improved, it reduces in vivo cardiac reserve to β-adrenergic regulation and deteriorates diastolic function. Our findings challenge the strategy of CaMKII inhibition in HF.
A biomechanical model for encoding joint dynamics: applications to transfemoral prosthesis control
Authors: McGibbon Chris A.
Published: January 2012

This paper presents and tests a framework for encoding joint dynamics into energy states using kinematic and kinetic knee joint sensor data and demonstrates how to use this information to predict the future energy state (torque and velocity requirements) of the joint without a priori knowledge of the activity sequence. The intended application is for enhancing micro-controlled prosthetics by making use of the embedded sensory potential of artificial limbs and classical mechanical principles of a prosthetic joint to report instantaneous energy state and most probable next energy state. When applied to the knee during preferred and fast speed walking in 8 human subjects (66 preferred-speed trials and 50 fast-speed trials), it was found that joint energy states could be consistently sequenced (75% consensus) according to mechanical energy transference conditions and subsequences appeared to reflect the stability and energy dissipation requirements of the knee during gait. When simple constraints were applied to the energy transfer input conditions (their signs), simulations indicated that it was possible to predict the future energy state with an accuracy of >80% when 2% cycle in advance (∼20 ms) of the switch and >60% for 4% (∼40 ms) in advance. This study justifies future research to explore whether this encoding algorithm can be used to identify submodes of other human activity that are relevant to TFP control, such as chair and stair activities and their transitions from walking, as well as unexpected perturbations.
Contribution of the Infection-Associated Complement Regulator-Acquiring Surface Protein 4 (ErpC) to Complement Resistance ofBorrelia burgdorferi
Authors: Hammerschmidt Claudia , Hallström Teresia , Skerka Christine , Wallich Reinhard , Stevenson Brian , Zipfel Peter F. , Kraiczy Peter
Published: January 2012

Borrelia burgdorferievades complement-mediated killing by interacting with complement regulators through distinct complement regulator-acquiring surface proteins (CRASPs). Here, we extend our analyses to the contribution of CRASP-4 in mediating complement resistance ofB. burgdorferiand its interaction with human complement regulators. CRASP-4 (also known as ErpC) was immobilized onto magnetic beads and used to capture proteins from human serum. Following Western blotting, factor H (CFH), CFH-related protein 1 (CFHR1), CFHR2, and CFHR5 were identified as ligands of CRASP-4. To analyze the impact of native CRASP-4 on mediating survival of serum-sensitive cells in human serum, aB. gariniistrain was generated that ectopically expresses CRASP-4. CRASP-4-producing bacteria bound CFHR1, CFHR2, and CFHR5 but not CFH. In addition, transformed spirochetes deposited significant amounts of lethal complement components on their surface and were susceptible to human serum, thus indicating that CRASP-4 plays a subordinate role in complement resistance ofB. burgdorferi.
Periodic Boundary Value Problems for Semilinear Fractional Differential Equations
Authors: Mu Jia , Li Yongxiang
Published: January 2012

We study the periodic boundary value problem for semilinear fractional differential equations in an ordered Banach space. The method of upper and lower solutions is then extended. The results on the existence of minimal and maximal mild solutions are obtained by using the characteristics of positive operators semigroup and the monotone iterative scheme. The results are illustrated by means of a fractional parabolic partial differential equations.
On the Line Graph of the Zero Divisor Graph for the Ring of Gaussian Integers Modulo n
Authors: Nazzal Khalida , Ghanem Manal
Published: January 2012

Let Γ(ℤn[i]) be the zero divisor graph for the ring of the Gaussian integers modulo n. Several properties of the line graph of Γ(ℤn[i]), L(Γ(ℤn[i])) are studied. It is determined when L(Γ(ℤn[i])) is Eulerian, Hamiltonian, or planer. The girth, the diameter, the radius, and the chromatic and clique numbers of this graph are found. In addition, the domination number of L(Γ(ℤn[i])) is given when n is a power of a prime. On the other hand, several graph invariants for Γ(ℤn[i]) are also determined.
PTP1B Is an Androgen Receptor–Regulated Phosphatase That Promotes the Progression of Prostate Cancer
Authors: Lessard Laurent , Labbé David P. , Deblois Geneviève , Bégin Louis R. , Hardy Serge , Mes-Masson Anne-Marie , Saad Fred , Trotman Lloyd C. , Giguère Vincent , Tremblay Michel L.
Published: January 2012

The androgen receptor (AR) signaling axis plays a key role in the pathogenesis of prostate cancer. In this study, we found that the protein tyrosine phosphatase PTP1B, a well-established regulator of metabolic signaling, was induced after androgen stimulation of AR-expressing prostate cancer cells. PTP1B induction by androgen occurred at the mRNA and protein levels to increase PTP1B activity. High-resolution chromosome mapping revealed AR recruitment to two response elements within the first intron of the PTP1B encoding gene PTPN1, correlating with an AR-mediated increase in RNA polymerase II recruitment to the PTPN1 transcriptional start site. We found that PTPN1 and AR genes were coamplified in metastatic tumors and that PTPN1 amplification was associated with a subset of high-risk primary tumors. Functionally, PTP1B depletion delayed the growth of androgen-dependent human prostate tumors and impaired androgen-induced cell migration and invasion in vitro. However, PTP1B was also required for optimal cell migration of androgen-independent cells. Collectively, our results established the AR as a transcriptional regulator of PTPN1 transcription and implicated PTP1B in a tumor-promoting role in prostate cancer. Our findings support the preclinical testing of PTP1B inhibitors for prostate cancer treatment. Cancer Res; 72(6); 1529–37. ©2012 AACR.
Myeloid Progenitor Cells in the Premetastatic Lung Promote Metastases by Inducing Mesenchymal to Epithelial Transition
Authors: Gao Dingcheng , Joshi Natasha , Choi Hyejin , Ryu Seongho , Hahn Mary , Catena Raul , Sadik Helen , Argani Pedram , Wagner Patrick , Vahdat Linda T. , Port Jeffrey L. , Stiles Brendon , Sukumar Saraswati , Altorki Nasser K. , Rafii Shahin , Mittal Vivek
Published: January 2012

Tumors systemically initiate metastatic niches in distant target metastatic organs. These niches, composed of bone marrow–derived hematopoietic cells, provide permissive conditions for future metastases. However, the mechanisms by which these cells mediate outgrowth of metastatic tumor cells are not completely known. Using mouse models of spontaneous breast cancer, we show enhanced recruitment of bone marrow–derived CD11b+Gr1+ myeloid progenitor cells in the premetastatic lungs. Gene expression profiling revealed that the myeloid cells from metastatic lungs express versican, an extracellular matrix proteoglycan. Notably, versican in metastatic lungs was mainly contributed by the CD11b+Ly6Chigh monocytic fraction of the myeloid cells and not the tumor cells or other stromal cells. Versican knockdown in the bone marrow significantly impaired lung metastases in vivo, without impacting their recruitment to the lungs or altering the immune microenvironment. Versican stimulated mesenchymal to epithelial transition of metastatic tumor cells by attenuating phospho-Smad2 levels, which resulted in elevated cell proliferation and accelerated metastases. Analysis of clinical specimens showed elevated versican expression within the metastatic lung of patients with breast cancer. Together, our findings suggest that selectively targeting tumor-elicited myeloid cells or versican represents a potential therapeutic strategy for combating metastatic disease. Cancer Res; 72(6); 1384–94. ©2012 AACR.
Effective Treatment of Metastatic Forms of Epstein-Barr Virus–Associated Nasopharyngeal Carcinoma with a Novel Adenovirus-Based Adoptive Immunotherapy
Authors: Smith Corey , Tsang Janice , Beagley Leone , Chua Daniel , Lee Victor , Li Vivian , Moss Denis J. , Coman William , Chan Kwok H. , Nicholls John , Kwong Dora , Khanna Rajiv
Published: January 2012

Nasopharyngeal carcinoma (NPC) is endemic in China and Southeast Asia where it is tightly associated with infections by Epstein-Barr virus (EBV). The role of tumor-associated viral antigens in NPC renders it an appealing candidate for cellular immunotherapy. In earlier preclinical studies, a novel adenoviral vector–based vaccine termed AdE1-LMPpoly has been generated that encodes EBV nuclear antigen-1 (EBNA1) fused to multiple CD8+ T-cell epitopes from the EBV latent membrane proteins, LMP1 and LMP2. Here, we report the findings of a formal clinical assessment of AdE1-LMPpoly as an immunotherapeutic tool for EBV-associated recurrent and metastatic NPC. From a total of 24 patients with NPC, EBV-specific T cells were successfully expanded from 16 patients with NPC (72.7%), whereas six patients with NPC (27.3%) showed minimal or no expansion of virus-specific T cells. Transient increase in the frequencies of LMP1&2- and EBNA1-specific T-cell responses was observed after adoptive transfer to be associated with grade I flu-like symptoms and malaise. The time to progression in these patients ranged from 38 to 420 days with a mean time to progression of 136 days. Compared with patients who did not receive T cells, the median overall survival increased from 220 to 523 days. Taken together, our findings show that adoptive immunotherapy with AdE1-LMPpoly vaccine is safe and well tolerated and may offer clinical benefit to patients with NPC. Cancer Res; 72(5); 1116–25. ©2012 AACR.
Akt/PKB-Mediated Phosphorylation of Twist1 Promotes Tumor Metastasis via Mediating Cross-Talk between PI3K/Akt and TGF-β Signaling Axes
Authors: Xue Gongda , Restuccia David F. , Lan Qiang , Hynx Debby , Dirnhofer Stephan , Hess Daniel , Rüegg Curzio , Hemmings Brian A.
Published: January 2012

Metastatic breast tumor cells display an epithelial–mesenchymal transition (EMT) that increases cell motility, invasion, and dissemination. Although the transcription factor Twist1 has been shown to contribute to EMT and cancer metastasis, the signaling pathways regulating Twist1 activity are poorly understood. Here, we show that Twist1 is ubiquitously phosphorylated in 90% of 1,532 invasive human breast tumors. Akt/protein kinase B (PKB)–mediated Twist1 phosphorylation promotes EMT and breast cancer metastasis by modulating its transcriptional target TGF-β2, leading to enhanced TGF-β receptor signaling, which in turn maintains hyperactive phosphoinositide 3-kinase (PI3K)/Akt signaling. Preventing phosphorylation of Twist1, as well as depletion of TGF-β2, significantly impaired the metastatic potential of cancer cells in vivo, indicating a key role of phosphorylated Twist1 (phospho-Twist1) in mediating cross-talk between the PI3K/Akt and TGF-β/Smad signaling axes that supports metastatic tumor development. Our results describe a novel signaling event linking PI3K/Akt hyperactivation in tumor cells to direct regulation of Twist1 activation and tumor metastasis.

Significance: We identified the first phospho-Twist1 transcriptional target TGF-β2, which mediates cross-talk between PI3K/Akt and TGF-β signaling and promotes tumor metastasis. Our results thus illustrate a direct role of PI3K/Akt signaling in metastatic cancer development and suggest that Twist1 phosphorylation could be a potential therapeutic target in clinical cancer treatment. Cancer Discovery; 2(3); 248–59. ©2012 AACR.

This article is highlighted in the In This Issue feature, p. 193
Acute Cardiac Tamponade: An Unusual Cause of Acute Renal Failure
Authors: Phadke Gautam , Whaley-Connell Adam , Dalal Pranavkumar , Markley John , Rich Andrew
Published: January 2012

We are reporting a case of acute renal failure after cardiac surgery due to acute pericardial effusion. The patient had normal baseline renal function but developed acute oliguric renal failure with a significant increase in serum creatinine postoperatively. Pericardiotomy led to an improvement in blood pressure, immediate diuresis and quick recovery of renal function back to baseline. Pericardial tamponade should be included in the consideration of causes of the cardiorenal syndrome.
Selective Class I Histone Deacetylase Inhibition Suppresses Hypoxia-Induced Cardiopulmonary Remodeling Through an Antiproliferative Mechanism
Authors: Cavasin Maria A. , Demos-Davies Kim , Horn Todd R. , Walker Lori A. , Lemon Douglas D. , Birdsey Nicholas , Weiser-Evans Mary C.M. , Harral Julie , Irwin David C. , Anwar Adil , Yeager Michael E. , Li Min , Watson Peter A. , Nemenoff Raphael A. , Buttrick Peter M. , Stenmark Kurt R. , McKinsey Timothy A.
Published: January 2012

Rationale:

Histone deacetylase (HDAC) inhibitors are efficacious in models of hypertension-induced left ventricular heart failure. The consequences of HDAC inhibition in the context of pulmonary hypertension with associated right ventricular cardiac remodeling are poorly understood.

Objective:

This study was performed to assess the utility of selective small-molecule inhibitors of class I HDACs in a preclinical model of pulmonary hypertension.

Methods and Results:

Rats were exposed to hypobaric hypoxia for 3 weeks in the absence or presence of a benzamide HDAC inhibitor, MGCD0103, which selectively inhibits class I HDACs 1, 2, and 3. The compound reduced pulmonary arterial pressure more dramatically than tadalafil, a standard-of-care therapy for human pulmonary hypertension that functions as a vasodilator. MGCD0103 improved pulmonary artery acceleration time and reduced systolic notching of the pulmonary artery flow envelope, which suggests a positive impact of the HDAC inhibitor on pulmonary vascular remodeling and stiffening. Similar results were obtained with an independent class I HDAC-selective inhibitor, MS-275. Reduced pulmonary arterial pressure in MGCD0103-treated animals was associated with blunted pulmonary arterial wall thickening because of suppression of smooth muscle cell proliferation. Right ventricular function was maintained in MGCD0103-treated animals. Although the class I HDAC inhibitor only modestly reduced right ventricular hypertrophy, it had multiple beneficial effects on the right ventricle, which included suppression of pathological gene expression, inhibition of proapoptotic caspase activity, and repression of proinflammatory protein expression.

Conclusions:

By targeting distinct pathogenic mechanisms, isoform-selective HDAC inhibitors have potential as novel therapeutics for pulmonary hypertension that will complement vasodilator standards of care.
Percutaneous Coronary Intervention in Patients With Severe Aortic Stenosis
Authors: Goel Sachin S. , Agarwal Shikhar , Tuzcu E. Murat , Ellis Stephen G. , Svensson Lars G. , Zaman Tarique , Bajaj Navkaranbir , Joseph Lee , Patel Neil S. , Aksoy Olcay , Stewart William J. , Griffin Brian P. , Kapadia Samir R.
Published: January 2012

Background—

With the availability of transcatheter aortic valve replacement, management of coronary artery disease in patients with severe aortic stenosis (AS) is posing challenges. Outcomes of percutaneous coronary intervention (PCI) in patients with severe AS and coronary artery disease remain unknown. We sought to compare the short-term outcomes of PCI in patients with and without AS.

Methods and Results—

From our PCI database, we identified 254 patients with severe AS who underwent PCI between 1998 and 2008. Using propensity matching, we found 508 patients without AS who underwent PCI in the same period. The primary end point of 30-day mortality after PCI was similar in patients with and without severe AS (4.3% [11 of 254] versus 4.7% [24 of 508]; hazard ratio, 0.93; 95% confidence interval, 0.51–1.69;
P
=0.2). Patients with low ejection fraction (≤30%) and severe AS had a higher 30-day post-PCI mortality compared with those with an ejection fraction >30% (5.4% [7 of 45] versus 1.2% [4 of 209];
P
<0.001). In addition, AS patients with high Society of Thoracic Surgeons score (≥10) had a higher 30-day post-PCI mortality than those with a Society of Thoracic Surgeons score <10 (10.4% [10 of 96] versus 0%;
P
<0.001).

Conclusions—

PCI can be performed in patients with severe symptomatic AS and coronary artery disease without an increased risk of short-term mortality compared with propensity-matched patients without AS. Patients with ejection fraction ≤30% and Society of Thoracic Surgeons score ≥10% are at a highest risk of 30-day mortality after PCI. This finding has significant implications in the management of severe coronary artery disease in high-risk severe symptomatic AS patients being considered for transcatheter aortic valve replacement.
Is Aortic Atherothrombotic Disease Detected Using Multidetector-Row CT Associated With an Increased Risk of Early Ischemic Lesion Recurrence After Acute Ischemic Stroke?
Authors: Ko Youngchai , Kim Wook-Joo , Jang Myung Suk , Yang Mi Hwa , Park Jung Hyun , Choi Sang Il , Chun Eun Ju , Lee Soo Joo , Han Moon-Ku , Bae Hee-Joon
Published: January 2012

Background and Purpose—

Multidetector-row CT (MDCT) is emerging as a new tool for diagnosing aortic atherothrombotic disease (AAD). We elucidated whether MDCT-detected AAD is associated with an increased risk of early ischemic lesion recurrence on diffusion-weighted MRI after ischemic stroke.

Methods—

A consecutive series of patients with acute ischemic stroke confirmed using diffusion-weighted MRI who were hospitalized within 48 hours after symptom onset and underwent MDCT were identified in a prospective stroke registry database. AAD on MDCT was defined as the presence of plaque formation that was noncalcified and ≥4 mm thick, ulcerative, or soft and thrombosed (vulnerable) in the proximal aortic arch. Ischemic lesion recurrence on diffusion-weighted MRI was defined as the occurrence of any new lesion separate from the index lesion on follow-up diffusion-weighted MRI performed within 14 days after symptom onset.

Results—

A total of 138 patients was selected. MDCT detected AAD in 24 of 138 (17.4%); ≥4 mm thickness in 17 of 138 (12.3%); ulcerated plaque in 20 of 138 (14.5%); and vulnerable plaque in 16 of 138 (11.6%). With respect to diffusion-weighted MRI lesion recurrence, the crude ORs (95% CIs) were as follows: AAD, 3.56 (1.43–8.89); vulnerable plaque, 3.21 (1.11–9.30); ulcerated plaque, 3.37 (1.27–8.95); and ≥4 mm thickness of the noncalcified plaque, 4.23 (1.11–16.19). These results remained significant after adjustments for potential confounders were made.

Conclusions—

This study shows that AAD detected by MDCT increases the risk of early ischemic lesion recurrence after acute ischemic stroke, thus supporting the role of MDCT in diagnosing AAD and assessing its contribution to recurrence.
Ambulatory Systolic–Diastolic Pressure Regression Index as a Predictor of Clinical Events
Authors: Aznaouridis Konstantinos , Vlachopoulos Charalambos , Protogerou Athanase , Stefanadis Christodoulos
Published: January 2012

Background and Purpose—

Blood pressure variables derived by ambulatory monitoring are important prognostic markers in hypertensive patients. Recent studies showed that ambulatory systolic–diastolic pressure regression index (ASDPRI), also known as ambulatory arterial stiffness index, may correlate with cardiovascular (CV) outcomes.

Methods—

We explored the predictive value of ASDPRI for future CV events, stroke, and all-cause mortality by meta-analyses of 7 longitudinal studies that had evaluated ASDPRI and had followed 20 505 subjects for a mean follow-up of 7.8 years.

Results—

The pooled relative risk of total CV events (including CV mortality), stroke, and all-cause mortality was 1.51 (95% CI, 1.18–1.93;
P
=0.001; 5 studies), 2.01 (95% CI, 1.60–2.52;
P
<0.001; 4 studies), and 1.25 (95% CI, 1.10–1.41;
P
=0.001; 4 studies), respectively, for high ASDPRI versus low ASDPRI subjects. An increase of ASDPRI by 1 standard deviation was associated with an age-adjusted, sex-adjusted, and risk factor-adjusted relative risk increase of total CV events and stroke by 15% and 30%, respectively. ASDPRI predicted stroke better than total CV events, predicted stroke better in normotensive subjects than in hypertensive patients, and also predicted total CV events better in females than in males. There was not significant publication bias.

Conclusions—

ASDPRI is an ambulatory blood pressure-derived biomarker that strongly predicts future CV events, stroke, and all-cause mortality. These findings suggest that this index may be useful for risk stratification purposes.
Overlap between the Neural Correlates of Cued Recall and Source Memory: Evidence for a Generic Recollection Network?
Authors: Hayama Hiroki R. , Vilberg Kaia L. , Rugg Michael D.
Published: January 2012

Recall of a studied item and retrieval of its encoding context (source memory) both depend on recollection of qualitative information about the study episode. This study investigated whether recall and source memory engage overlapping neural regions. Participants (n = 18) studied a series of words, which were presented either to the left or right of fixation. fMRI data were collected during a subsequent test phase in which three-letter word-stems were presented, two thirds of which could be completed by a study item. Instructions were to use each stem as a cue to recall a studied word and, when recall was successful, to indicate the word's study location. When recall failed, the stem was to be completed with the first word to come to mind. Relative to stems for which recall failed, word-stems eliciting successful recall were associated with enhanced activity in a variety of cortical regions, including bilateral parietal, posterior midline, and parahippocampal cortex. Activity in these regions was enhanced when recall was accompanied by successful rather than unsuccessful source retrieval. It is proposed that the regions form part of a “recollection network” in which activity is graded according to the amount of information retrieved about a study episode.
The Southern Annular Mode Seen through Weather Regimes
Authors: Pohl Benjamin , Fauchereau Nicolas
Published: January 2012

This article investigates the prominent features of the Southern Hemisphere (south of 20°S) atmospheric circulation when extracted using EOF analysis and a k-means clustering algorithm. The focus is on the southern annular mode (SAM), the nature of its recent trend, and the zonal symmetry of associated spatial patterns. The study uses the NCEP–Department of Energy Atmospheric Model Intercomparison Project II Reanalysis (NCEP-2) (period 1979–2009) to obtain robust patterns over the recent years and the Twentieth Century Reanalysis Project (period 1871–2008) to document decadal changes. Also presented is a comparison of these signals against a station-based reconstruction of the SAM index and a gridded interpolated dataset [Hadley Centre Sea Level Pressure dataset version 2 (HadSLP2)].

Over their common period, both reanalyses are in fair agreement, both in terms of spatial patterns and temporal variability. In particular, both datasets show weather regimes that can be interpreted as the opposite phases of the SAM. At the decadal time scale, the study shows that the trend toward the positive SAM phase (as inferred from the usual EOF-based index) is related more to an increase in the frequency of clusters corresponding to the positive phase, with little changes in the frequency of the negative SAM events. Similarly, the long-term tropospheric warming trend already discussed in the literature is shown to be related more to a decrease in the number of abnormally cold days, with little changes in the number of abnormally warm days. The cluster analysis therefore allows for complement descriptions based on simple indexes or EOF decompositions, highlighting the nonlinear nature of the decadal changes in the Southern Hemisphere atmospheric circulation and temperature.
Parameterization of Tropical Instability Waves and Examination of Their Impact on ENSO Characteristics
Authors: Imada Yukiko , Kimoto Masahide
Published: January 2012

The impact of tropical instability waves (TIWs) on El Niño–Southern Oscillation (ENSO) characteristics is investigated by introducing a new parameterization of TIWs into an atmosphere–ocean general circulation model (AOGCM), the Model for Interdisciplinary Research on Climate (MIROC), with a medium-resolution (~1.4°) ocean model (known as MIROCmedres). Because this resolution is not sufficient to reproduce eddies at the spatial scale of TIWs, this approach isolates TIW effects from other factors that can affect ENSO characteristics. The parameterization scheme represents the effect of baroclinic eddy heat transport by TIWs. A 100-yr integration reveals a significant role of TIWs in observed ENSO asymmetry. Asymmetric heat transport associated with TIWs that are active (inactive) during La Niña (El Niño) generates a significant asymmetric negative feedback to ENSO and explains the observed asymmetric feature of a stronger-amplitude El Niño and weaker-amplitude La Niña. Furthermore, the parameterized eddy heat flux also affects the mean subsurface heat balance via the shallowing and steepening thermocline. This change in subsurface stratification induces a stronger thermocline feedback and a longer ENSO period.
Impact of the Vertical Resolution of Analysis Data on the Estimates of Large-Scale Inertio-Gravity Energy
Authors: Žagar Nedjeljka , Terasaki Koji , Tanaka Hiroshi L.
Published: January 2012

This paper deals with the large-scale inertio-gravity (IG) wave energy in the operational ECMWF analyses in July 2007. Energy percentages of the IG waves obtained from the standard-pressure-level data are compared to those derived from various discretizations of the model-level data. The results show a small albeit systematic increase of the IG energy percentage as the vertical level density increases from the standard-pressure levels toward the model-level density; the small relative change is explained by the sufficient vertical resolution to resolve the large-scale IG waves in the tropics that make the majority of the global IG energy on large scales. A relatively larger increase of the IG energy is obtained when the mesospheric model levels are included; however, the analyses at these levels in July 2007 are less reliable. Furthermore, two numerical methods for the normal-mode function (NMF) decomposition are shown to provide similar results. The decomposition of atmospheric analyses into the NMF series is proposed as a tool to analyze the spatial and temporal variations of the large-scale equatorial waves and their role in global energetics.