bluuebunny/crossref_metadata_2025 huggingface dataset:
MODELING AND VERIFICATION OF HEAT AND MOISTURE TRANSFER IN AN ENTHALPY EXCHANGER MADE OF PAPER MEMBRANE
Authors: LEE EUL-JONG , LEE JUNG-PYO , SIM HYUN-MIN , KIM NAE-HYUN
Published: August 2012

In this study, heat and moisture transfer model of an enthalpy exchanger is proposed. With separately measured sorption constant and diffusion coefficient, the model predicts the heat and moisture transfer effectiveness of an enthalpy exchanger. Two sample enthalpy exchangers were tested at a KS condition to verify the model. The model predicts the heat transfer effectiveness within 4%, and the moisture transfer effectiveness within 10%. Pressure drop is predicted within 6%. The spacer fin efficiency for heat transfer was 0.11 to 0.13. The fin efficiency for moisture transfer, however, was negligibly small. For heat transfer, the conduction resistance to total thermal resistance was less than 1%. For moisture transfer, however, membrane resistance was dominant to convective moisture transfer resistance.
EIGENVALUE VARIANCE BOUNDS FOR WIGNER AND COVARIANCE RANDOM MATRICES
Authors: DALLAPORTA S.
Published: August 2012

This work is concerned with finite range bounds on the variance of individual eigenvalues of Wigner random matrices, in the bulk and at the edge of the spectrum, as well as for some intermediate eigenvalues. Relying on the GUE example, which needs to be investigated first, the main bounds are extended to families of Hermitian Wigner matrices by means of the Tao and Vu Four Moment Theorem and recent localization results by Erdös, Yau and Yin. The case of real Wigner matrices is obtained from interlacing formulas. As an application, bounds on the expected 2-Wasserstein distance between the empirical spectral measure and the semicircle law are derived. Similar results are available for random covariance matrices.
Diamond Field-Effect Transistors with 1.3 A/mm Drain Current Density by Al2O3 Passivation Layer
Authors: Hirama Kazuyuki , Sato Hisashi , Harada Yuichi , Yamamoto Hideki , Kasu Makoto
Published: August 2012

Using nitrogen-dioxide (NO2) adsorption treatment and Al2O3 passivation technique, we improved drain current (I
DS) of hydrogen-terminated (H-terminated) diamond field-effect transistors (FETs). The Al2O3 passivation layer also serves as a gate-insulator in a gate region. Maximum I
DS (I
DSmax) of -1.35 A/mm was obtained for the diamond FETs with NO2 adsorption and the Al2O3 passivation layer. This I
DSmax is the highest ever reported for diamond FETs and indicates that the Al2O3 passivation layer can stabilize adsorbed NO2, which increases the hole carrier concentration on the H-terminated diamond surface. In RF small-signal characteristics, the diamond FETs with NO2 adsorption and the Al2O3 passivation layer showed high cutoff-frequency (f
T) and maximum frequency of oscillation (f
max) in a wide gate–source voltage (V
GS) range (>10 V). This is because the Al2O3 gate insulator with a high potential barrier against hole carriers can confine and control the high concentration of hole carriers and then high forward-bias voltage can be applied without noticeable gate leakage current.
High-Voltage Vacuum Switch with a Diamond p–i–n Diode Using Negative Electron Affinity
Authors: Takeuchi Daisuke , Makino Toshiharu , Kato Hiromitsu , Ogura Masahiko , Okushi Hideyo , Ohashi Hiromichi , Yamasaki Satoshi
Published: August 2012

We demonstrated high-voltage on/off switching with a vacuum switch by electron emission from a diamond p–i–n diode using negative electron affinity. An equivalent electrical circuit was modeled to evaluate and discuss the performance and potential of switches such as a high-voltage switch for high-voltage dc power grids.
Device Design of Diamond Schottky-pn Diode for Low-Loss Power Electronics
Authors: Makino Toshiharu , Kato Hiromitsu , Takeuchi Daisuke , Ogura Masahiko , Okushi Hideyo , Yamasaki Satoshi
Published: August 2012

The device parameters of a novel diamond diode, namely, a Schottky-pn diode (SPND), are analyzed to realize a fast switching time, a low on-resistance, and a high blocking voltage simultaneously. The SPND is composed of an n-type active layer sandwiched between a highly doped p+-type layer and a Schottky metal. The key structure is the fully depleted n-type layer. From the simulations of the energy band diagram based on the key structure of the SPND using Poisson's equations, it is concluded that the low donor density in the n-type layer and the high acceptor density in the p+-type layer are key points for the high-performance SPND.
Polyoxometalate-Modified Boron-Doped Diamond Electrodes
Authors: Kondo Takeshi , Taniguchi Yuichi , Yuasa Makoto , Kawai Takeshi
Published: August 2012

Polyoxometalates were immobilized on a boron-doped diamond (BDD) surface modified by a photochemical modification method. The BDD surface was first modified with allyltriethylammonium bromide (ATAB) to form surface quaternary ammonium groups. The ATAB–BDD was then immersed in a phosphomolybdic acid (H3PMo12O40, denoted as PMo12) solution to fabricate PMo12-adsorbed ATAB–BDD (PMo12–ATAB–BDD). The electrostatic interaction between PMo12 and the quaternary ammonium group on ATAB–BDD is considered to be critical to the stable immobilization. Polyoxometalate-modified BDD was also fabricated from phosphonic-acid-terminated BDD. BDD was first modified with vinylphosphonic acid (VPA), followed by the reaction of the surface phosphonic acid groups with ammonium molybdate to generate a lacunary phosphomolybdic acid (PMo
x
) group. Although the coverage of the PMo
x
group on PMo
x
–BDD was less than that of PMo12–ATAB–BDD, PMo
x
–BDD was found to be more stable to potential cycling than PMo12–ATAB–BDD, indicating that covalent modification methods are effective for creating stable functional groups on diamond.
Electron Cyclotron Resonance-Sputtered Nanocarbon Film Electrode Compared with Diamond-Like Carbon and Glassy Carbon Electrodes as Regards Electrochemical Properties and Biomolecule Adsorption
Authors: Xue Qiang , Kato Dai , Kamata Tomoyuki , Umemura Shigeru , Hirono Shigeru , Niwa Osamu
Published: August 2012

The electrochemical properties and biocompatible characteristics at an electron cyclotron resonance (ECR)-sputtered nanocarbon film electrode, a diamond-like carbon (DLC) electrode and a glassy carbon (GC) electrode have been studied. The three carbon electrodes show significant current reductions with increased peak separations as a result of protein fouling before oxygen plasma treatment, but the current reductions of the ECR-sputtered nanocarbon and DLC film electrodes are smaller than that of the GC electrode due to their superior surface flatness. The oxygen plasma pretreated ECR-sputtered nanocarbon film electrode exhibits a significant improvement in anti-fouling performance with an improved electron transfer. This is because the pretreated ECR-sputtered nanocarbon film enabled the surface to introduce surface oxygen functionalities that not only improve the interaction between the analytes and the electrode surface but also make the film surface more hydrophilic, which is important for the suppression of biomolecule adsorption. At the same time, the pretreated ECR-sputtered nanocarbon film also retained an ultraflat surface even after pretreatment as a result of the low background current. This excellent performance can only be achieved with our ECR-sputtered nanocarbon film, indicating that our film is promising for application to electrochemical detectors for various biomolecular analytes.
Characteristics of Diamond-Like Carbon Films Deposited on Polymer Dental Materials
Authors: Ohtake Naoto , Uchi Tomio , Yasuhara Toshiyuki , Takashima Mai
Published: August 2012

Characterizations of diamond-like carbon (DLC) deposited on a polymer artificial tooth were performed. DLC films were deposited on dental parts made of poly(methyl methacrylate) (PMMA) resin by dc-pulse plasma chemical vapor deposition (CVD) from methane. Wear resistance test results revealed that a DLC-coated resin tooth has a very high wear resistance against tooth brushing, and endures 24 h brushing without a marked weight decrease. Cell cultivation test results show that DLC plays an important role in preventing cell death. Moreover, a biocompatibility test using a rabbit revealed that a connective tissue in the vicinity of DLC-coated PMMA is significantly thinner than that of noncoated PMMA. The numbers of inflammatory cells in the vicinity of DLC-coated and noncoated surfaces are 0 and 508 cells/mm2, respectively. These results led us to conclude that DLC films are an excellent material for use as the coating of a polymer artificial tooth in terms of not only high wear resistance but also biocompatibility.
Human Umbilical Vein Endothelial Cell Interaction with Fluorine-Incorporated Amorphous Carbon Films
Authors: Yoshimoto Yukihiro , Hasebe Terumitsu , Nagashima So , Kamijo Aki , Nakatani Tatsuyuki , Yamagami Takuji , Kitamura Noriko , Kitagawa Tomoya , Hotta Atsushi , Takahashi Koki , Suzuki Tetsuya
Published: August 2012

A major clinical concern in coronary intervention for cardiovascular disease is late stent thrombosis after the implantation of drug eluting stents (DES). DES widely used in clinical settings currently utilize polymer coatings, which can induce persistent arterial wall inflammation and delayed vascular healing, resulting in impaired endothelialization. We examined the viability of human umbilical vein endothelial cells (HUVECs) for fluorine-incorporated amorphous carbon (a-C:H:F) coatings, which are known to be anti-thrombogenic. a-C:H:F and a-C:H were synthesized on the tissue culture dishes using radio frequency plasma enhanced chemical vapor deposition by varying the ratio of hexafluoroethane and acetylene. HUVECs were seeded on coated dishes for 6 days. The results indicate that the a-C:H:F surface does not disturb HUVEC proliferation in 6 days of culture and is promising for stent materials that allows the preservation of endothelialization, even if the fluorine concentration of a-C:H surface affects the early adhesion of endothelial cells.
Analysis of Gain-Switching Characteristics Including Strong Gain Saturation Effects in Low-Dimensional Semiconductor Lasers
Authors: Chen Shaoqiang , Yoshita Masahiro , Ito Takashi , Mochizuki Toshimitsu , Akiyama Hidefumi , Yokoyama Hiroyuki , Kamide Kenji , Ogawa Tetsuo
Published: August 2012

The effects of gain nonlinearities on gain-switched short-pulse-generation characteristics are analyzed via rate equations assuming a nonlinear-gain model including a gain saturation parameter g
s to quantitatively describe the strong gain-saturation nonlinearity in low-dimensional semiconductor lasers at high carrier densities. It was found that the minimum pulse width and the delay time are mainly determined by g
s rather than a differential gain coefficient g
0 and a gain compression factor ε. By tracing the temporal evolution of carrier density, photon density, and material gain during gain switching, distinctly different effects of g
s, ε, and cavity lifetime τp on pulse generation were clarified.
Searching for Solutions in Aquaculture: Charting a Sustainable Course
Authors: Klinger Dane , Naylor Rosamond
Published: August 2012

Aquaculture is currently the fastest growing animal food production sector and will soon supply more than half of the world's seafood for human consumption. Continued growth in aquaculture production is likely to come from intensification of fish, shellfish, and algae production. Intensification is often accompanied by a range of resource and environmental problems. We review several potential solutions to these problems, including novel culture systems, alternative feed strategies, and species choices. We examine the problems addressed; the stage of adoption; and the benefits, costs, and constraints of each solution. Policies that provide incentives for innovation and environmental improvement are also explored. We end the review by identifying easily adoptable solutions and promising technologies worth further investment.
Environmental Informatics
Authors: Frew James E. , Dozier Jeff
Published: August 2012

Environmental informatics uses large multidimensional, complex datasets to study environmental problems, which can be both discrete and continuous in space or time. These datasets and their requisite metadata can be managed by queryable databases. Geospatial Web application programming interfaces (APIs) provide remote access to dynamic subsets of environmental information. Persistent identifiers make data citable. The storage-computing trade-off is now heavily skewed in favor of moving calculations to the data. Provenance metadata help determine a data object's reliability and trustworthiness.

Rising atmospheric CO2, the Antarctic ozone hole, and Gulf Stream warm-core rings were all discovered by analyzing long-term datasets. Similar work continues on mapping evapotranspiration and snow water equivalent. In these “fourth paradigm” problems, data (especially data collected operationally) drive hypothesis formation. Making data available requires new discovery mechanisms and policies favoring data sharing. Cloud computing and array-friendly databases will help bring processing to the data. Ubiquitous location sensing and geotagging will help turn citizen scientists into environmental information collectors.
Toward Principles for Enhancing the Resilience of Ecosystem Services
Authors: Biggs Reinette , Schlüter Maja , Biggs Duan , Bohensky Erin L. , BurnSilver Shauna , Cundill Georgina , Dakos Vasilis , Daw Tim M. , Evans Louisa S. , Kotschy Karen , Leitch Anne M. , Meek Chanda , Quinlan Allyson , Raudsepp-Hearne Ciara , Robards Martin D. , Schoon Michael L. , Schultz Lisen , West Paul C.
Published: August 2012

Enhancing the resilience of ecosystem services (ES) that underpin human well-being is critical for meeting current and future societal needs, and requires specific governance and management policies. Using the literature, we identify seven generic policy-relevant principles for enhancing the resilience of desired ES in the face of disturbance and ongoing change in social-ecological systems (SES). These principles are (P1) maintain diversity and redundancy, (P2) manage connectivity, (P3) manage slow variables and feedbacks, (P4) foster an understanding of SES as complex adaptive systems (CAS), (P5) encourage learning and experimentation, (P6) broaden participation, and (P7) promote polycentric governance systems. We briefly define each principle, review how and when it enhances the resilience of ES, and conclude with major research gaps. In practice, the principles often co-occur and are highly interdependent. Key future needs are to better understand these interdependencies and to operationalize and apply the principles in different policy and management contexts.
Social Influence, Consumer Behavior, and Low-Carbon Energy Transitions
Authors: Axsen Jonn , Kurani Kenneth S.
Published: August 2012

Realizing a low-carbon energy future requires pervasive changes in consumer behavior. Here, we examine the role of social influence in transitioning toward new low-carbon products and practices. We review and critique five research perspectives of how social interactions affect the spread of new behaviors through social networks: diffusion of functional information across social groups; conformity to others' behaviors; dissemination by organized, resourceful social groups motivated to promote societal goods; translation of consumers' perceptions between social groups; and reflexivity of individuals' continual search for self-development and expression through lifestyle practices, including their social context and consumption. Each perspective observes different social processes and holds different implications for policies and strategies to achieve low-carbon energy transitions. No single perspective seems adequate to characterize social influence. We conclude with a set of priorities to develop an integrative framework to guide strategy and policy.
Functional TRPV6 channels are crucial for transepithelial Ca2+absorption
Authors: Woudenberg-Vrenken Titia E. , Lameris Anke L. , Weißgerber Petra , Olausson Jenny , Flockerzi Veit , Bindels René J. M. , Freichel Marc , Hoenderop Joost G. J.
Published: August 2012

TRPV6 is considered the primary protein responsible for transcellular Ca2+absorption. In vitro studies demonstrate that a negatively charged amino acid (D) within the putative pore region of mouse TRPV6 (position 541) is critical for Ca2+permeation of the channel. To elucidate the role of TRPV6 in transepithelial Ca2+transport in vivo, we functionally analyzed a TRPV6D541A/D541Aknockin mouse model. After weaning, mice were fed a regular (1% wt/wt) or Ca2+-deficient (0.02% wt/wt) diet and housed in metabolic cages. Blood was sampled for Ca2+measurements, and the expression of Ca2+transport proteins was analyzed in kidney and duodenum. Intestinal45Ca2+uptake was measured in vivo by an absorption assay. Challenging the mice with the Ca2+-deficient diet resulted in hypocalcemia in wild-type and TRPV6D541A/D541Amice. On a low-Ca2+diet both mouse strains displayed increased expression of intestinal TRPV6, calbindin-D9K, and renal TRPV5. TRPV6D541A/D541Amice showed significantly impaired intestinal Ca2+uptake compared with wild-type mice, and duodenal TRPV5 expression was increased in TRPV6D541A/D541Amice. On a normal diet, serum Ca2+concentrations normalized in both mouse strains. Under these conditions, intestinal Ca2+uptake was similar, and the expression levels of renal and intestinal Ca2+transport proteins were not affected. We demonstrate that TRPV6D541A/D541Amice exhibit impaired transcellular Ca2+absorption. Duodenal TRPV5 expression was increased in TRPV6D541A/D541Amice, albeit insufficient to correct for the diminished Ca2+absorption. Under normal conditions, when passive Ca2+transport is predominant, no differences between wild-type and TRPV6D541A/D541Amice were observed. Our results demonstrate a specific role for TRPV6 in transepithelial Ca2+absorption.
Heliox increases quadriceps muscle oxygen delivery during exercise in COPD patients with and without dynamic hyperinflation
Authors: Louvaris Zafeiris , Zakynthinos Spyros , Aliverti Andrea , Habazettl Helmut , Vasilopoulou Maroula , Andrianopoulos Vasileios , Wagner Harrieth , Wagner Peter , Vogiatzis Ioannis
Published: August 2012

Some reports suggest that heliox breathing during exercise may improve peripheral muscle oxygen availability in patients with chronic obstructive pulmonary disease (COPD). Besides COPD patients who dynamically hyperinflate during exercise (hyperinflators), there are patients who do not hyperinflate (non-hyperinflators). As heliox breathing may differently affect cardiac output in hyperinflators (by increasing preload and decreasing afterload of both ventricles) and non-hyperinflators (by increasing venous return) during exercise, it was reasoned that heliox administration would improve peripheral muscle oxygen delivery possibly by different mechanisms in those two COPD categories. Chest wall volume and respiratory muscle activity were determined during constant-load exercise at 75% peak capacity to exhaustion, while breathing room air or normoxic heliox in 17 COPD patients: 9 hyperinflators (forced expiratory volume in 1 s = 39 ± 5% predicted), and 8 non-hyperinflators (forced expiratory volume in 1 s = 48 ± 5% predicted). Quadriceps muscle blood flow was measured by near-infrared spectroscopy using indocyanine green dye. Hyperinflators and non-hyperinflators demonstrated comparable improvements in endurance time during heliox (231 ± 23 and 257 ± 28 s, respectively). At exhaustion in room air, expiratory muscle activity (expressed by peak-expiratory gastric pressure) was lower in hyperinflators than in non-hyperinflators. In hyperinflators, heliox reduced end-expiratory chest wall volume and diaphragmatic activity, and increased arterial oxygen content (by 17.8 ± 2.5 ml/l), whereas, in non-hyperinflators, heliox reduced peak-expiratory gastric pressure and increased systemic vascular conductance (by 11.0 ± 2.8 ml·min−1·mmHg−1). Quadriceps muscle blood flow and oxygen delivery significantly improved during heliox compared with room air by a comparable magnitude (in hyperinflators by 6.1 ± 1.3 ml·min−1·100 g−1 and 1.3 ± 0.3 ml O2·min−1·100 g−1, and in non-hyperinflators by 7.2 ± 1.6 ml·min−1·100 g−1 and 1.6 ± 0.3 ml O2·min−1·100 g−1, respectively). Despite similar increase in locomotor muscle oxygen delivery with heliox in both groups, the mechanisms of such improvements were different: 1) in hyperinflators, heliox increased arterial oxygen content and quadriceps blood flow at similar cardiac output, whereas 2) in non-hyperinflators, heliox improved central hemodynamics and increased systemic vascular conductance and quadriceps blood flow at similar arterial oxygen content.
Muscle Invasive Bladder Cancer: From Diagnosis to Survivorship
Authors: Mohamed N. E. , Diefenbach M. A. , Goltz H. H. , Lee C. T. , Latini D. , Kowalkowski M. , Philips C. , Hassan W. , Hall S. J.
Published: August 2012

Bladder cancer is the fifth most commonly diagnosed cancer and the most expensive adult cancer in average healthcare costs incurred per patient in the USA. However, little is known about factors influencing patients' treatment decisions, quality of life, and responses to treatment impairments. The main focus of this paper is to better understand the impact of muscle invasive bladder cancer on patient quality of life and its added implications for primary caregivers and healthcare providers. In this paper, we discuss treatment options, side effects, and challenges that patients and family caregivers face in different phases along the disease trajectory and further identify crucial areas of needed research.
Well‐Posedness by Perturbations for Variational‐Hemivariational Inequalities
Authors: Lv Shu , Xiao Yi-bin , Liu Zhi-bin , Li Xue-song
Published: August 2012

We generalize the concept of well‐posedness by perturbations for optimization problem to a class of variational‐hemivariational inequalities. We establish some metric characterizations of the well‐posedness by perturbations for the variational‐hemivariational inequality and prove their equivalence between the well‐posedness by perturbations for the variational‐hemivariational inequality and the well‐posedness by perturbations for the corresponding inclusion problem.
S-Nitrosylation of EGFR and Src Activates an Oncogenic Signaling Network in Human Basal-Like Breast Cancer
Authors: Switzer Christopher H. , Glynn Sharon A. , Cheng Robert Y.-S. , Ridnour Lisa A. , Green Jeffrey E. , Ambs Stefan , Wink David A.
Published: August 2012

Increased inducible nitric oxide synthase (NOS2) expression in breast tumors is associated with decreased survival of estrogen receptor negative (ER−) breast cancer patients. We recently communicated the preliminary observation that nitric oxide (NO) signaling results in epidermal growth factor receptor (EGFR) tyrosine phosphorylation. To further define the role of NO in the pathogenesis of ER− breast cancer, we examined the mechanism of NO-induced EGFR activation in human ER− breast cancer. NO was found to activate EGFR and Src by a mechanism that includes S-nitrosylation. NO, at physiologically relevant concentrations, induced an EGFR/Src-mediated activation of oncogenic signal transduction pathways (including c-Myc, Akt, and β-catenin) and the loss of PP2A tumor suppressor activity. In addition, NO signaling increased cellular EMT, expression and activity of COX-2, and chemoresistance to adriamycin and paclitaxel. When connected into a network, these concerted events link NO to the development of a stem cell–like phenotype, resulting in the upregulation of CD44 and STAT3 phosphorylation. Our observations are also consistent with the finding that NOS2 is associated with a basal-like transcription pattern in human breast tumors. These results indicate that the inhibition of NOS2 activity or NO signaling networks may have beneficial effects in treating basal-like breast cancer patients. Mol Cancer Res; 10(9); 1203–15. ©2012 AACR.
Biological Responses to TGF-β in the Mammary Epithelium Show a Complex Dependency on Smad3 Gene Dosage with Important Implications for Tumor Progression
Authors: Kohn Ethan A. , Yang Yu-an , Du Zhijun , Nagano Yoshiko , Van Schyndle Catherine M.H. , Herrmann Michelle A. , Heldman Madeleine , Chen Jin-Qiu , Stuelten Christina H. , Flanders Kathleen C. , Wakefield Lalage M.
Published: August 2012

TGF-β plays a dual role in epithelial carcinogenesis with the potential to either suppress or promote tumor progression. We found that levels of Smad3 mRNA, a critical mediator of TGF-β signaling, are reduced by approximately 60% in human breast cancer. We therefore used conditionally immortalized mammary epithelial cells (IMEC) of differing Smad3 genotypes to quantitatively address the Smad3 requirement for different biologic responses to TGF-β. We found that a two-fold reduction in Smad3 gene dosage led to complex effects on TGF-β responses; the growth-inhibitory response was retained, the pro-apoptotic response was lost, the migratory response was reduced, and the invasion response was enhanced. Loss of the pro-apoptotic response in the Smad3+/− IMECs correlated with loss of Smad3 binding to the Bcl-2 locus, whereas retention of the growth-inhibitory response in Smad3 IMECs correlated with retention of Smad3 binding to the c-Myc locus. Addressing the integrated outcome of these changes in vivo, we showed that reduced Smad3 levels enhanced metastasis in two independent models of metastatic breast cancer. Our results suggest that different biologic responses to TGF-β in the mammary epithelium are differentially affected by Smad3 dosage and that a mere two-fold reduction in Smad3 is sufficient to promote metastasis. Mol Cancer Res; 10(10); 1389–99. ©2012 AACR.
Comparative Genomic Analysis of Esophageal Adenocarcinoma and Squamous Cell Carcinoma
Authors: Agrawal Nishant , Jiao Yuchen , Bettegowda Chetan , Hutfless Susan M. , Wang Yuxuan , David Stefan , Cheng Yulan , Twaddell William S. , Latt Nyan L. , Shin Eun J. , Wang Li-Dong , Wang Liang , Yang Wancai , Velculescu Victor E. , Vogelstein Bert , Papadopoulos Nickolas , Kinzler Kenneth W. , Meltzer Stephen J.
Published: August 2012

Esophageal cancer ranks sixth in cancer death. To explore its genetic origins, we conducted exomic sequencing on 11 esophageal adenocarcinomas (EAC) and 12 esophageal squamous cell carcinomas (ESCC) from the United States. Interestingly, inactivating mutations of NOTCH1 were identified in 21% of ESCCs but not in EACs. There was a substantial disparity in the spectrum of mutations, with more indels in ESCCs, A:T>C:G transversions in EACs, and C:G>G:C transversions in ESCCs (P < 0.0001). Notably, NOTCH1 mutations were more frequent in North American ESCCs (11 of 53 cases) than in ESCCs from China (1 of 48 cases). A parallel analysis found that most mutations in EACs were already present in matched Barrett esophagus. These discoveries highlight key genetic differences between EACs and ESCCs and between American and Chinese ESCCs, and suggest that NOTCH1 is a tumor suppressor gene in the esophagus. Finally, we provide a genetic basis for the evolution of EACs from Barrett esophagus.

Significance: This is the first genome-wide study of mutations in esophageal cancer. It identifies key genetic differences between EACs and ESCCs including general mutation spectra and NOTCH1 loss-of-function mutations specific to ESCCs, shows geographic disparities between North American and Chinese ESCCs, and shows that most mutations in EACs are already present in matched Barrett esophagus. Cancer Discov; 2(10); 899–905. ©2012 AACR.

Read the Commentary on this article by Collisson and Cho, p. 870.

This article is highlighted in the In This Issue feature, p. 857.
RAF/MEK Dependence of KRAS-Mutant Pancreatic Ductal Adenocarcinomas
Authors: Hanrahan Aphrothiti J. , Solit David B.
Published: August 2012

Summary: Studies using genetically engineered mouse models indicate that RAF activation is sufficient to induce pancreatic intraepithelial neoplasms, suggesting that mitogen-activated protein kinase (MAPK)/extracellular signal–regulated kinase (ERK) kinase (MEK) inhibitor–based combination approaches may have clinical use in patients with pancreatic ductal adenocarcinomas. Cancer Discov; 2(8); 666–9. ©2012 AACR.

Commentary on Collisson et al., p. 685.
Discovery in Context: Leveraging Multidimensional Glioblastoma Datasets to Identify Targetable Regulatory Networks
Authors: Babic Ivan , Mischel Paul S.
Published: August 2012

Summary: The Cancer Genome Atlas (TCGA) promises to transform the treatment of patients with cancer by identifying new drug targets. However, extracting mechanistically insightful, therapeutically actionable information from complex multidimensional datasets remains a significant challenge. In this issue of Cancer Discovery, Genovese and colleagues apply a context-dependent modeling algorithm to the glioblastoma TCGA datasets and couple it with functional genetic screens and experimental validation to identify a novel, and potentially targetable, microRNA-mediated regulatory pathway. Cancer Discov; 2(8); 676–8. ©2012 AACR.

Commentary on Genovese et al., p. 736.
STATe-of-the-Art Approach: Using Oligonucleotide Decoys to Target the “Undruggable”
Authors: Koppikar Priya , Bromberg Jacqueline
Published: August 2012

Summary: Sen and colleagues have shown for the first time the clinical application of an oligonucleotide decoy targeting the oncogenic transcription factor STAT3 for the treatment of head and neck tumors. Intratumoral injection of decoy effectively reduced the activity of STAT3 as evidenced by a decrease in several of its transcriptional targets. However, its low bioavailability makes them unacceptable for systemic therapy. Cyclization of the STAT3 decoy markedly increased its half-life while preserving specificity and showed significant antitumor activity upon systemic delivery in preclinical models of head and neck cancer. These findings have broad therapeutic implications for the treatment of many malignancies. Cancer Discov; 2(8); 670–2. ©2012 AACR.

Commentary on Sen et al., p. 694.
Impact of Coronary Bifurcation Angle on Clinical Outcomes after Percutaneous Coronary Intervention in Real-World Practice: Results from the COBIS Registry
Authors: Yang Jeong Hoon , Song Young Bin , Song Pil Sang , Hahn Joo-Yong , Choi Seung-Hyuk , Choi Jin-Ho , Lee Sang Hoon , Kim Hyo-Soo , Jang Yangsoo , Tahk Seung-Jea , Seung Ki Bae , Park Seung-Jung , Gwon Hyeon-Cheol
Published: August 2012

Objectives: Bifurcation angle has emerged as a predictor of outcome after percutaneous coronary intervention (PCI) for bifurcation lesions. We investigated the impact of bifurcation angle on clinical outcomes in patients undergoing bifurcation lesion PCI. Methods: Consecutive patients who received PCI for bifurcation lesions were enrolled from 16 centers in Korea between January 2004 and June 2006. Patients were divided into low-angle and high-angle groups using the median bifurcation angle (50°). We compared major adverse cardiac events, including cardiac death, myocardial infarction and target lesion revascularization as well as periprocedural outcomes between the 2 groups. Results: We evaluated 1,432 patients with bifurcation lesions with a median follow-up duration of 21 months. The rates of interventional side branch procedures such as guide-wiring of side branches, side-branch ballooning, final kissing ballooning and side-branch stenting were higher in the low-angle group. However, the incidences of major adverse cardiac events and target lesion revascularization were not significantly different between the 2 groups (6.6 vs. 6.9%, p = 0.856 and 4.6 vs. 5.7%, p = 0.375, respectively). Conclusions: Bifurcation angle may not influence long-term clinical outcome in patients with non-left main bifurcation lesion undergoing PCI despite its association with more interventional side-branch procedures.
Giant Abdominopelvic Haematoma Arising from Ovulation in a Glanzmann’s Thrombasthenia Patient with Platelet Refractoriness: Treatment with Surgery and Intra-Abdominal Tranexamic Acid
Authors: Buyukasik Yahya , Boyraz Gokhan , Selcuk Ilker , Bektas Ozlen , Selcuk Tuncer Z.
Published: August 2012

Glanzmann’s thrombasthenia (GT) is a very rare autosomal recessive genetic bleeding disorder. Women with coagulation abnormalities are at increased risk of corpus luteum rupture and haemoperitoneum. Here we present a severe case of GT resulting in a haematoma extending from the pelvis to the liver that could only be controlled by surgery and intra-abdominal tranexamic acid.
Ustekinumab Treatment of TNF Antagonist-Induced Paradoxical Psoriasis Flare in a Patient with Psoriatic Arthritis: Case Report and Review
Authors: Puig Lluís , Morales-Múnera Caridad E. , López-Ferrer Anna , Geli Carme
Published: August 2012

Background: Therapy with tumour necrosis factor α (TNF) inhibitors can be associated with paradoxical reactions, namely the de novo development or flaring of conditions that usually respond to these therapeutic agents, such as arthritis, inflammatory bowel disease, sarcoidosis or psoriasis. They are considered a class effect of these drugs, and their incidence ranges from 1 to 5%, with paradoxical psoriasis (psoriasis vulgaris, palmoplantar pustulosis, scalp psoriasis and their combinations) being most frequently reported. Treatment of paradoxical psoriasis often requires withdrawal of the inducing drug and switching to another anti-TNF agent, but often this cannot avoid recurrence or persistence of the rash and/or loss of the therapeutic effect on the underlying condition. Case Report: We report on a 47-year-old woman who developed incapacitating palmoplantar pustulosis and psoriasis vulgaris flare with severe scalp and nail involvement after 5 months of treatment with adalimumab for psoriatic arthritis. Several treatments, including topical corticosteroids, photochemotherapy, ciclosporin, acitretin and etanercept 50 mg twice a day for 1 month, were ineffective or not tolerated. Treatment with ustekinumab 45 mg provided complete resolution of skin lesions with acceptable therapeutic control of the arthritis, with a follow-up duration of 16 months. Conclusion: A review of the reported cases suggests that this may be a therapeutic option in patients who develop paradoxical psoriasis while under treatment for arthritis or Crohn’s disease.
Evidence for Ape and Human Specializations in Geniculostriate Projections from VGLUT2 Immunohistochemistry
Authors: Bryant Katherine L. , Suwyn Carolyn , Reding Katherine M. , Smiley John F. , Hackett Troy A. , Preuss Todd M.
Published: August 2012

Vesicular glutamate transporters (VGLUTs) reuptake glutamate into synaptic vesicles at excitatory synapses. VGLUT2 is localized in the cortical terminals of neuronal somas located in the main sensory nuclei of the thalamus. Thus, immunolabeling of cortex with antibodies to VGLUT2 can reveal geniculostriate terminal distributions in species in which connectivity cannot be studied with tract-tracing techniques, permitting broader comparative studies of cortical specializations. Here, we used VGLUT2 immunohistochemistry to compare the organization of geniculostriate afferents in primary visual cortex in hominid primates (humans, chimpanzees, and an orangutan), Old World monkeys (rhesus macaques and vervets), and New World monkeys (squirrel monkeys). The New and Old World monkeys had a broad, dense band of terminal-like labeling in cortical layer 4C, a narrow band of labeling in layer 4A, and additional labeling in layers 2/3 and 6, consistent with results from conventional tract-tracing studies in these species. By contrast, although the hominid primates had a prominent layer 4C band, labeling of layer 4A was sparse or absent. Labeling was also present in layers 2/3 and 6, although labeling of layer 6 was weaker in hominids and possibly more individually variable than in Old and New World monkeys. These findings are consistent with previous observations from cytochrome oxidase histochemistry and a very small number of connectivity studies, suggesting that the projections from the parvocellular layers of the lateral geniculate nucleus to layer 4A were strongly reduced or eliminated in humans and apes following their evolutionary divergence from the other anthropoid primates.
Xylitol Carryover Effects on Salivary Mutans Streptococci after 13 Months of Chewing Xylitol Gum
Authors: Shinga-Ishihara C. , Nakai Y. , Milgrom P. , Söderling E. , Tolvanen M. , Murakami K.
Published: August 2012

To assess mutans streptococci (MS) during xylitol gum chewing (mean 3.8 g/day, 2.9 times/day) for 13 months and then for 15 months after the intervention, Japanese mothers with high salivary MS were randomized into two groups: xylitol gum (n = 56) and no gum (n = 51). The proportion of low MS levels was highest at 3 months of consumption (48.8%), but was significantly lower compared to baseline at the end of the intervention (p < 0.001). MS levels did not change during the postintervention period. The data suggest that in the xylitol group 23.3% showed persistent carryover effects by xylitol gum chewing in the postintervention period.
Nanoparticle-Mediated Delivery of Pioglitazone Enhances Therapeutic Neovascularization in a Murine Model of Hindlimb Ischemia
Authors: Nagahama Ryoji , Matoba Tetsuya , Nakano Kaku , Kim-Mitsuyama Shokei , Sunagawa Kenji , Egashira Kensuke
Published: August 2012

Objective—

Critical limb ischemia is a severe form of peripheral artery disease (PAD) for which neither surgical revascularization nor endovascular therapy nor current medicinal therapy has sufficient therapeutic effects. Peroxisome proliferator activated receptor-γ agonists present angiogenic activity in vitro; however, systemic administration of peroxisome proliferator−activated receptor-γ agonists is hampered by its side effects, including heart failure. Here, we demonstrate that the nanoparticle (NP)-mediated delivery of the peroxisome proliferator activated receptor-γ agonist pioglitazone enhances its therapeutic efficacy on ischemia-induced neovascularization in a murine model.

Methods and Results—

In a nondiabetic murine model of hindlimb ischemia, a single intramuscular injection of pioglitazone-incorporated NP (1 µg/kg) into ischemic muscles significantly improved the blood flow recovery in the ischemic limbs, significantly increasing the number of CD31-positive capillaries and α-smooth muscle actin–positive arterioles. The therapeutic effects of pioglitazone-incorporated NP were diminished by the peroxisome proliferator activated receptor-γ antagonist GW9662 and were not observed in endothelial NO synthase–deficient mice. Pioglitazone-incorporated NP induced endothelial NO synthase phosphorylation, as demonstrated by Western blot analysis, as well as expression of multiple angiogenic growth factors in vivo, including vascular endothelial growth factor-A, vascular endothelial growth factor-B, and fibroblast growth factor-1, as demonstrated by real-time polymerase chain reaction. Intramuscular injection of pioglitazone (1 µg/kg) was ineffective, and oral administration necessitated a >500 μg/kg per day dose to produce therapeutic effects equivalent to those of pioglitazone-incorporated NP.

Conclusion—

NP-mediated drug delivery is a novel modality that may enhance the effectiveness of therapeutic neovascularization, surpassing the effectiveness of current treatments for peripheral artery disease with critical limb ischemia.
Elevated Protein Kinase C-δ Contributes to Aneurysm Pathogenesis Through Stimulation of Apoptosis and Inflammatory Signaling
Authors: Morgan Stephanie , Yamanouchi Dai , Harberg Calvin , Wang Qiwei , Keller Melissa , Si Yi , Burlingham William , Seedial Stephen , Lengfeld Justin , Liu Bo
Published: August 2012

Objective—

Apoptosis of smooth muscle cells (SMCs) is a prominent pathological characteristic of abdominal aortic aneurysm (AAA). We have previously shown that SMC apoptosis stimulates proinflammatory signaling in a mouse model of AAA. Here, we test whether protein kinase C-δ (PKCδ), an apoptotic mediator, participates in the pathogenesis of AAA by regulating apoptosis and proinflammatory signals.

Methods and Results—

Mouse experimental AAA is induced by perivascular administration of CaCl
2
. Mice deficient in PKCδ exhibit a profound reduction in aneurysmal expansion, SMC apoptosis, and transmural inflammation as compared with wild-type littermates. Delivery of PKCδ to the aortic wall of PKCδ
–/–
mice restores aneurysm, whereas overexpression of a dominant negative PKCδ mutant in the aorta of wild-type mice attenuates aneurysm. In vitro, PKCδ
–/–
aortic SMCs exhibit significantly impaired monocyte chemoattractant protein-1 production. Ectopic administration of recombinant monocyte chemoattractant protein-1 to the arterial wall of PKCδ
–/–
mice restores inflammatory response and aneurysm development.

Conclusion—

PKCδ is an important signaling mediator for SMC apoptosis and inflammation in a mouse model of AAA. By stimulating monocyte chemoattractant protein-1 expression in aortic SMCs, upregulated PKCδ exacerbates the inflammatory process, in turn perpetuating elastin degradation and aneurysmal dilatation. Inhibition of PKCδ may serve as a potential therapeutic strategy for AAA.
Increased Epidermal Growth Factor–Like Ligands Are Associated With Elevated Vascular Nicotinamide Adenine Dinucleotide Phosphate Oxidase in a Primate Model of Atherosclerosis
Authors: Stanic Bojana , Pandey Deepesh , Fulton David J. , Miller Francis J.
Published: August 2012

Objective—

To characterize the relationship between the expression of epidermal growth factor (EGF)-like ligands and vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression and activity in a primate model of atherosclerosis.

Methods and Results—

Adult male Cynomolgus monkeys were fed a normal or atherogenic (AS) diet for 45 months, after which animals from the AS group were placed on a normal diet for 8 months (regression). The expression of membrane-associated EGF-like ligands was increased in arteries from animals on the AS diet and normalized in the regression group. EGF-like ligands were distributed throughout atherosclerotic vessels but predominantly colocalized with macrophages. Consistent with ligand shedding, circulating heparin-bound EGF was elevated in the plasma of AS monkeys but not in those on regression diet. Atherosclerosis was associated with the activation of EGF receptor signaling. Expression of NADPH oxidase subunits Nox1 and Nox2 but not Nox4 or Nox5 was increased in arteries from monkeys on the AS diet and returned to normal with regression. Levels of Nox1 and Nox2 positively correlated with EGF-like ligands. In cultured monkey smooth muscle cells, treatment with EGF-like ligands increased Nox1 expression and activity.

Conclusion—

These data identify EGF-like ligands as potential modulators of atherogenesis, resulting in part from increased vascular NADPH oxidase activity.
Arterial Stiffness and Cerebral Small Vessel Disease
Authors: Poels Mariëlle M.F. , Zaccai Kèren , Verwoert Germaine C. , Vernooij Meike W. , Hofman Albert , van der Lugt Aad , Witteman Jacqueline C.M. , Breteler Monique M.B. , Mattace-Raso Francesco U.S. , Ikram M. Arfan
Published: August 2012

Background and Purpose—

Aging and vascular risk factors contribute to arterial stiffening. Increased arterial stiffness exposes the small vessels in the brain to abnormal flow pulsations and, as such, may contribute to the pathogenesis of cerebral small vessel disease. In a population-based study, we investigated the association between arterial stiffness, as measured by aortic pulse wave velocity (aPWV), and small vessel disease.

Methods—

Overall, 1460 participants (mean age, 58.2 years) underwent aPWV measurement and brain MRI scanning. We calculated aPWV by measuring time differences and distances between pulse waves in the carotid and femoral arteries. Using automated MRI analysis, we obtained white matter lesion volumes. Infarcts and microbleeds were rated visually. We used linear and logistic regression models to associate aPWV with small vessel disease, adjusting for age, sex, mean arterial pressure, and heart rate and additionally for cardiovascular risk factors. Subsequently, we explored associations in strata of hypertension.

Results—

In the study group, higher aPWV was associated with larger white matter lesion volume (difference in volume per SD increase in aPWV 0.07; 95% CI, 0.02–0.12) but not with lacunar infarcts or microbleeds. In persons with uncontrolled hypertension, higher aPWV was significantly associated with larger white matter lesion volume (difference in volume per SD increase in aPWV 0.09; 95% CI, 0.00–0.18), deep or infratentorial microbleeds (OR, 2.13; 95% CI, 1.16–3.91), and to a lesser extent also with lacunar infarcts (OR, 1.63; 95% CI, 0.98–2.70). No such associations were present in persons with controlled hypertension or without hypertension.

Conclusions—

In our study, increased arterial stiffness is associated with a larger volume of white matter lesions.
Higher Prehospital Priority Level of Stroke Improves Thrombolysis Frequency and Time to Stroke Unit
Authors: Berglund Annika , Svensson Leif , Sjöstrand Christina , von Arbin Magnus , von Euler Mia , Wahlgren Nils , Engerström Lars , Höjeberg Bo , Käll Tor-Björn , Mjörnheim Susanna , Engqvist Ann
Published: August 2012

Background and Purpose—

Early initiated treatment of stroke increases the chances of a good recovery. This randomized controlled study evaluates how an increased priority level for patients with stroke, from level 2 to 1, from the Emergency Medical Communication Center influences thrombolysis frequency, time to stroke unit, and whether other medical emergencies reported negative consequences.

Methods—

Patients aged 18 to 85 years in Stockholm, Sweden, with symptoms of stroke within 6 hours were randomized from the Emergency Medical Communication Center or emergency medical services to an intervention group, priority level 1, immediate call of an ambulance, or to a control group with standard priority level, that is, priority level 2 (within 30 minutes). Before study start, an educational program on identification of stroke and importance of early initiated treatment was directed to all medical dispatchers and ambulance and emergency department personnel.

Results—

During 2008, 942 patients were randomized of which 53% (n=496) had a final stroke/transient ischemic attack diagnosis. Patients in the Emergency Medical Communication Center randomized intervention group reached the stroke unit 26 minutes earlier than the control group (
P
<0.001) after the emergency call. Thrombolysis was given to 24% of the patients in the intervention group compared with 10% of the control subjects (
P
<0.001). The higher priority level showed no negative effect on other critical ill patients requiring priority level 1 prehospital attention.

Conclusion—

This randomized study shows negligible harm to other medical emergencies, a significant increase in thrombolysis frequency, and a shorter time to the stroke unit for patients with stroke upgraded to priority level 1 from the Emergency Medical Communication Center and through the acute chain of stroke care.