bluuebunny/crossref_metadata_2025 huggingface dataset:
High Mobility P-Channel Thin-Film Transistors with Ultralarge-Grain Polycrystalline Silicon Formed Using Nickel-Induced Crystallization
Authors: Jang Kyungsoo , Lee Wonbaek , Choi Woojin , Yi Junsin
Published: September 2012

In this study, p-channel polycrystalline silicon (poly-Si) thin-film transistors (TFTs) using an active layer of ultralarge-grain (ULG) silicon and multistack gate insulators of SiN
x
/SiO2 were fabricated and investigated. The ULG silicon thin films were formed by nickel (Ni)-induced crystallization and the average grain area of ULG silicon is 118 µm2. The field-effect mobility of p-channel ULG poly-Si TFTs was 111 cm2/(V·s), which can be sufficiently applied to high driving parts of display systems. The p-channel ULG poly-Si TFT has a low threshold voltage of -1.06 V, a high ON/OFF current ratio of 9.2×107, and a subthreshold swing of 0.27 V/decade. Moreover, the fabricated TFTs have stable characteristics under temperature and gate bias stress owing to the large grains and smooth surface. These results show that the ULG poly-Si TFTs are remarkably suitable for the application to a low power and high speed pixel-driving device in flat panel displays.
Effects of Photoirradiation on Electrical Characteristics of Chemical Vapor Deposited Diamond Schottkey Barrier Diode
Authors: Paosawatyanyong Boonchoat , Bhanthumnavin Worawan
Published: September 2012

Diamond Schottky barrier diodes (SBDs) are fabricated on thin polycrystalline diamond films deposited by the microwave plasma-enhanced chemical vapor deposition (CVD) process. The diodes are photoirradiated with white light of different intensities while the changes in their electrical response to DC and time-varying signals were recorded. For time-varying signals, large signal sinusoidal waveforms, which drive the diodes between reverse bias and forward bias, have been utilized. The experimental results of the large switching signal test are compared with those of computer simulations. The results indicate that deep-lying and/or interface states of the CVD diamond SBDs, rather than the minority carrier storage effect in the CVD films, are responsible for the photoirradiation-dependent properties of diamond SBDs.
A Study of Stacked Buffer Layers for the Epitaxial Growth of Zn0.58Mg0.42O Films on c-Sapphire by Pulsed Laser Deposition
Authors: Kim Chang Hoi , Kim Hong Seung , Lee Jong Hoon , Pin Min Wook , Park Mi Seon , Lee Won Jae , Jang Nak Won , Yun Young
Published: September 2012

We report the growth of hexagonal Zn0.58Mg0.42O thin films on a c-plane sapphire substrate via pulsed laser deposition using Zn0.7Mg0.3O/Zn0.9Mg0.1O/ZnO stacked buffer layers of various thicknesses. The effects of the stacked buffer layer thickness on the structural and optical properties were investigated by X-ray diffraction (XRD), atomic force microscopy (AFM), energy dispersive X-ray (EDX), and UV–visible spectroscopy. The XRD results showed that whereas the cubic and hexagonal phases formed without a stacked buffer layer, only the hexagonal Zn0.58Mg0.42O phase grew in the stacked buffer layer configuration. The stacked buffer layer could accommodate structural inconsistencies and prevent phase separation in high-Mg films. As the thickness of each stacked buffer layer decreased, the crystalline quality of the hexagonal Zn0.5Mg0.5O film was enhanced.
Electrical Instabilities in Amorphous InGaZnO Thin Film Transistors with Si3N4 and Si3N4/Al2O3 Gate Dielectrics
Authors: Kim Yu-Mi , Jeong Kwang-Seok , Yun Ho-Jin , Yang Seung-Dong , Lee Sang-Youl , Lee Hi-Deok , Lee Ga-Won
Published: September 2012

Bottom-gate staggered amorphous indium–gallium zinc oxide (a-IGZO) thin-film transistors (TFTs) with Si3N4 and Si3N4/Al2O3 gate dielectrics were fabricated on glass substrates to investigate the electrical instabilities. An anomalous hump was observed only in the Si3N4 device under the positive bias stress. To analyze the anomalous hump, the transmission electron microscope (TEM) images and the two-dimensional (2D) device simulation were investigated, and results showed that insulator thinning and electric field enforcement at the gate edge are not the causes of the hump. In the time dependence of ΔV
TH under stress, Si3N4/Al2O3 and Si3N4 devices follow the stretched-exponential and logarithmic time dependences, respectively. That is, in the Si3N4/Al2O3 device, the trapped electrons are spatially redistributed easily in dielectrics or near the interface, which seems to suppress the hump.
Modeling of Electromagnetic Wave Propagation with Tapered Transmission Line
Authors: Lee Kun-A , Ko Kwang-Cheol
Published: September 2012

Tapered transmission line was used for impedance matching, for high voltage pulse, and atmospheric medium is applied to characteristic equation of tapered transmission line and reflection coefficient so that nonlinear load and circuit modeling of atmospheric medium was simulated by electromagnetic transient program (EMTP). A characteristic of atmospheric medium and Time delay are decided by inductance and capacitance of tapered transmission line. For electromagnetic wave propagation modeling, in this paper, tapered transmission line is implemented. It is difficult to model tapered transmission line directly. Other transmission line that can be expressed by the circuit is used. So object of this paper is efficient modeling of tapered transmission line.
Improved Device Performances in Phosphorescent Organic Light-Emitting Diodes by Microcavity Effects
Authors: Joo Chul Woong , Moon Jaehyun , Hwang Joohyun , Han Jun-Han , Shin Jin-Wook , Cho Doo-Hee , Huh Jin Woo , Chu Hye Yong , Lee Jeong-Ik
Published: September 2012

In order to improve the external quantum efficiency of organic light-emitting diodes (OLEDs), we purpose an anode which has a structure of indium tin oxide (ITO)/Ag/ITO, in which the Ag layer has a function of micro-cavity inducing reflector. In order to maximize the microcavity effect the thicknesses of the hole transport layers of blue and red phosphorescent OLEDs (PhOLEDs) were deduced using simulations. By the use of our optically designed anode, it was possible to achieve approximately 50% improvements in the external quantum efficiency.
An Experimental Study of the Effects of Source/Drain to Gate Overlap in Pentacene Thin-Film Transistors
Authors: Park Jaehoon , Do Lee-Mi , Pearson Christopher , Petty Michael , Kim Dong Wook , Choi Jong Sun
Published: September 2012

The effects of the source/drain (S/D) to gate overlap on the electrical characteristics of pentacene organic thin-film transistors (OTFTs) are reported. The S/D to gate overlap dimension was varied by adjusting the gate width, while the channel length and width were fixed. The threshold voltage was found to decrease on increasing the overlap dimension; in contrast, the field-effect mobility increased. These characteristic variations are explained on aspects of charge injection and transport properties in pentacene OTFTs, due to the presence of S/D to gate overlaps. The results demonstrate the significant effect of the overlap on the OTFT performance.
Fabrication of Organic Thin-Film Transistors Based on Cross-Linked Hybrid Dielectric Materials
Authors: Wang Yuedan , Kim Yeonok , Lee Eunju , Kim Hongdoo
Published: September 2012

We report here the synthesis and dielectric properties of cross-linked hybrid dielectrics for organic field-effect transistor application. Hybrid thin films were first fabricated by hydrolysis of methacrylate-modified titanium and zirconium alkoxides and were further cross-linked via polymerization under UV. The dielectrics exhibit high dielectric constants (5.2–9) and good insulating properties with low leakage current densities (10-6–10-7 A/cm2) even though the dielectric film thickness was about 25–150 nm. Furthermore, the hybrid thin films had smooth and hydrophobic surfaces. The fabricated pentacene field-effect transistors using these dielectrics show good electric performance, including a carrier mobility as large as 0.29 cm2 V-1 s-1, a subthreshold swing as low as 0.13 V/decade, an on/off current ratio of ∼105, and a low threshold voltage of 0.3 V with TiO2 hybrid dielectrics. Organic thin-film transistors (OTFTs) fabricated with ZrO2 hybrid insulators exhibit a carrier mobility of 0.21 cm2 V-1 s-1 with an I
on/I
off ratio of ∼104, a threshold voltage of -0.83 V, and a subthreshold swing of 0.39 V/decade.
Capillary-Driven Dynamics of Water in Hydrophilic Microscope Coverslip Nanochannels
Authors: Kuo Ju-Nan , Lin Yi-Kai
Published: September 2012

The capillary-driven filling speed of water in hydrophilic microscope coverslip planar nanofluidic channels is investigated. Nanochannels with depths ranging from 40 to 575 nm and widths ranging from 30 to 200 µm are fabricated on a coverslip substrate of borosilicate glass with a thickness of 160 µm using buffered oxide wet etching and glass–glass fusion bonding techniques. Capillary filling speed is measured experimentally and compared with the theoretical and numerical predictions. It is found that the obtained experimental capillary filling speed is consistent with that predicted by the numerical model, but is significantly lower than that predicted by the classical Washburn equation. The failure of the theoretical model to correctly predict the filling speed is attributed to the erroneous assumption of a constant contact angle irrespective of flow rate and other flow obstructions. The experimental results show that capillary filling speed reduces with a reducing channel depth and an increasing filling length, but is insensitive to channel width.
Bidirectional Two-Terminal Switching Device Using Schottky Barrier for Spin-Transfer-Torque Magnetic Random Access Memory
Authors: Park Yong-Sik , Kil Gyu-Hyun , Song Yun-Heub
Published: September 2012

We present a bidirectional two-terminal switching device using a Schottky barrier for spin-transfer-torque magnetic random access memory (STT-MRAM), which is composed of a Schottky barrier contact with a metal/semiconductor/metal (M/S/M) structure. The proposed M/S/M switching device provides a bidirectional current flow sufficient to write STT-MRAM using a punch through with an extended depletion region at a junction under a reverse bias of M/S or S/M. In addition, a high on–off ratio of 105 is confirmed under the read condition, which is acceptable for the operation of STT-MRAM. From this work, it is expected that an M/S/M structure with bilateral Schottky junctions will be a promising switch device for STT MRAM beyond 20 nm.
Rock magnetic characterization of early and late diagenesis in a stratigraphic well from the Llanos foreland basin (Eastern Colombia)
Authors: Costanzo-Álvarez Vincenzo , Aldana Milagrosa , Bayona Germán , López-Rodríguez Diego , Blanco Joan Marie
Published: September 2012

We have carried out rock magnetic characterizations of different lithofacies along the stratigraphic well Saltarín 1A, in order to learn about the various diagenetic events that could have affected the Miocene sequence of the Llanos foreland basin (Colombia). Thermomagnetic and low-temperature susceptibility measurements performed on some selected samples were complemented with analyses of Scanning Electron Microscopy (SEM), Energy Dispersive X-ray (EDX) and isothermal remanent magnetization (IRM) acquisition curves. The identification of the magnetic mineral assemblages at each depth level analysed, as well as their relative concentrations, were determined from a direct signal analysis (DSA) of the IRM curves. Samples from the top of the Guayabo formation reveal the presence of hydrocarbons-related microscopic framboids of pyrite with partial replacement of magnetite. The bottom of the Guayabo formation shows hematite and goethite and appears to record a thoroughly documented Middle Miocene global regression. In samples from the León formation, pyrrhotite could have resulted from an early diagenesis that took place in a lacustrine environment via sulphate reduction. Traces of crude oil in samples from the Carbonera formation, and the additional occurrence of hematite and magnetite, suggest that a hydrocarbons-mediated late diagenesis could also have affected the lowermost levels of Saltarín 1A.
Heterogeneity in histone 2B-green fluorescent protein-retaining putative small intestinal stem cells at cell position 4 and their absence in the colon
Authors: Hughes Kevin R. , Gândara Ricardo M. C. , Javkar Tanvi , Sablitzky Fred , Hock Hanno , Potten Christopher S. , Mahida Yashwant R.
Published: September 2012

Stem cells have been identified in two locations in small intestinal crypts; those intercalated between Paneth cells and another population (which retains DNA label) are located above the Paneth cell zone, at cell position 4. Because of disadvantages associated with the use of DNA label, doxycycline-induced transient transgenic expression of histone 2B (H2B)-green fluorescent protein (GFP) was investigated. H2B-GFP-retaining putative stem cells were consistently seen, with a peak at cell position 4, over chase periods of up to 112 days. After a 28-day chase, a subpopulation of the H2B-GFP-retaining cells was cycling, but the slow cycling status of the majority was illustrated by lack of expression of pHistone H3 and Ki67. Although some H2B-GFP-retaining cells were sensitive to low-dose radiation, the majority was resistant to low- and high-dose radiation-induced cell death, and a proportion of the surviving cells proliferated during subsequent epithelial regeneration. Long-term retention of H2B-GFP in a subpopulation of small intestinal Paneth cells was also seen, implying that they are long lived. In contrast to the small intestine, H2B-GFP-retaining epithelial cells were not seen in the colon from 28-day chase onward. This implies important differences in stem cell function between these two regions of the gastrointestinal tract, which may have implications for region-specific susceptibility to diseases (such as cancer and ulcerative colitis), in which epithelial stem cells and their progeny are involved.
Colitis is associated with a loss of intestinofugal neurons
Authors: Linden David R.
Published: September 2012

Intestinofugal neurons sense and receive information regarding mechanical distension of the bowel and transmit this information to postganglionic sympathetic neurons in the prevertebral ganglia. Previous studies have demonstrated that trinitrobenzene sulfonic acid (TNBS)-induced colitis is associated with a loss of myenteric neurons that occurs within the first 12 h following the inflammatory insult. The purpose of this study was to test the hypothesis that intestinofugal neurons are among the myenteric neurons lost during TNBS-induced colitis. The retrograde tracing dye Fast Blue was used to label intestinofugal neurons, and immunohistochemical staining for the RNA-binding proteins HuC/D was used to count all myenteric neurons. Ongoing synaptic input to neurons in the guinea pig inferior mesenteric ganglion (IMG) was recorded via conventional intracellular electrophysiology. In control preparations, intestinofugal neurons account for 0.25% of myenteric neurons. In the distal colon of TNBS-treated animals, the proportion of intestinofugal neurons was reduced to 0.05% (an 80% reduction) within the region of inflammation where 20–25% of myenteric neurons were lost. Neither intestinofugal neurons specifically nor myenteric neurons were reduced in more proximal uninflamed regions. There is a reduction in the frequency of ongoing synaptic potentials in visceromotor neurons of the IMG at 12 and 24 h and 6 and 56 days after TNBS. Collectively, the results of this study suggest that intestinofugal neurons are among the myenteric neurons lost during inflammation and may be selectively targeted. Because intestinofugal neurons are a major driver of sympathetic output to the gut, the loss of intestinofugal neurons may have a profound pathophysiological significance.
Blocking β-adrenergic signaling attenuates reductions in circulating leptin, cancellous bone mass, and marrow adiposity seen with dietary energy restriction
Authors: Baek Kyunghwa , Bloomfield Susan A.
Published: September 2012

We tested whether β-adrenergic blockade attenuates bone loss and increased marrow adiposity during energy restriction (ER) and whether such an effect is associated with changes in serum leptin and leptin expression in bone and marrow tissues. Female 4-mo-old Sprague-Dawley rats were assigned into four groups ( n = 10 each): two groups of 40% ER treated with vehicle (ERVEH; saline) or β-blocker (ERBB; DL-propranolol; 250 μg·kg−1·h−1) during 12 wk, and two groups of ad libitum-fed controls treated with the same two agents (CONVEH, CONBB, respectively). Over 84 days, CONVEH and CONBB rats gained but ERVEH and ERBB rats lost body fat mass; lean mass did not change in any group. Reduction in serum leptin in ERVEH rats was mitigated in ERBB rats (−5.32 vs. −1.15 ng/ml, respectively). The decline in proximal tibia cancellous vBMD observed in ERVEH rats was attenuated in ERBB rats (−85.24 vs. −53.94 mg/cm3, respectively). Adipocyte number in ERVEH rats was dramatically higher vs. CON rats at week 12, but this increment was abolished by β-blockade in ERBB animals. The number of osteoblastic cells and marrow adipocytes staining positively for leptin in ERVEH rats tended to be lower vs. that of both CON groups, but β-blockade appears to reverse this effect in ERBB rats. In summary, β-adrenergic blockade mitigated metaphyseal bone loss and bone marrow adiposity during energy restriction and attenuated reductions in serum leptin. These data suggest an important role for β-adrenoreceptor signaling pathway in the cancellous bone and marrow fat response to energy restriction.
Halofuginone Inhibits the Establishment and Progression of Melanoma Bone Metastases
Authors: Juárez Patricia , Mohammad Khalid S. , Yin Juan Juan , Fournier Pierrick G. J. , McKenna Ryan C. , Davis Holly W. , Peng Xiang H. , Niewolna Maria , Javelaud Delphine , Chirgwin John M. , Mauviel Alain , Guise Theresa A.
Published: September 2012

TGF-β derived from bone fuels melanoma bone metastases by inducing tumor secretion of prometastatic factors that act on bone cells to change the skeletal microenvironment. Halofuginone is a plant alkaloid derivative that blocks TGF-β signaling with antiangiogenic and antiproliferative properties. Here, we show for the first time that halofuginone therapy decreases development and progression of bone metastasis caused by melanoma cells through the inhibition of TGF-β signaling. Halofuginone treatment of human melanoma cells inhibited cell proliferation, phosphorylation of SMAD proteins in response to TGF-β, and TGF-β–induced SMAD-driven transcription. In addition, halofuginone reduced expression of TGF-β target genes that enhance bone metastases, including PTHrP, CTGF, CXCR4, and IL11. Also, cell apoptosis was increased in response to halofuginone. In nude mice inoculated with 1205Lu melanoma cells, a preventive protocol with halofuginone inhibited bone metastasis. The beneficial effects of halofuginone treatment were comparable with those observed with other anti–TGF-β strategies, including systemic administration of SD208, a small-molecule inhibitor of TGF-β receptor I kinase, or forced overexpression of Smad7, a negative regulator of TGF-β signaling. Furthermore, mice with established bone metastases treated with halofuginone had significantly less osteolysis than mice receiving placebo assessed by radiography. Thus, halofuginone is also effective in reducing the progression of melanoma bone metastases. Moreover, halofuginone treatment reduced melanoma metastasis to the brain, showing the potential of this novel treatment against cancer metastasis. Cancer Res; 72(23); 6247–56. ©2012 AACR.
Adenylate Kinase-4 Is a Marker of Poor Clinical Outcomes That Promotes Metastasis of Lung Cancer by Downregulating the Transcription Factor ATF3
Authors: Jan Yi-Hua , Tsai Hong-Yuan , Yang Chih-Jen , Huang Ming-Shyan , Yang Yi-Fang , Lai Tsung-Ching , Lee Chien-Hsin , Jeng Yung-Ming , Huang Chi-Ying , Su Jen-Liang , Chuang Yung-Jen , Hsiao Michael
Published: September 2012

Biomarkers predicting metastatic capacity might assist the development of better therapeutic strategies for aggressive cancers such as lung cancer. In this study, we show that adenylate kinase-4 (AK4) is a progression-associated gene in human lung cancer that promotes metastasis. Analysis of published microarray data showed that AK4 was upregulated in lung adenocarcinoma compared with normal cells. High AK4 expression was associated with advanced stage, disease recurrence and poor prognosis. Loss of AK4 expression suppressed the invasive potential of lung cancer cell lines, whereas AK4 overexpression promoted invasion in vitro and in vivo. Mechanistically, the transcription factor ATF3 was identified as a pivotal regulatory target of AK4. Simultaneous reduction in AK4 and ATF3 expression abolished the inhibitory effects of ATF3 on invasion. ATF3 overexpression in AK4-overexpressing cells limits invasion activity. Furthermore, patients with high AK4 and low ATF3 expression showed unfavorable outcomes compared with patients with low AK4 and high ATF3 expression. Taken together, our findings indicated that AK4 promotes malignant progression and recurrence by promoting metastasis in an ATF3-dependent manner. Cancer Res; 72(19); 5119–29. ©2012 AACR.
Intratumor Heterogeneity: Evolution through Space and Time
Authors: Swanton Charles
Published: September 2012

Recent technologic advances have permitted higher resolution and more rapid analysis of individual cancer genomes at the single-nucleotide level. Such advances have shown bewildering intertumor heterogeneity with limited somatic alterations shared between tumors of the same histopathologic subtype. Exacerbating such complexity, increasing evidence of intratumor genetic heterogeneity (ITH) is emerging, both within individual tumor biopsies and spatially separated between biopsies of the same tumor. Sequential analysis of tumors has also revealed evidence that ITH temporally evolves during the disease course. ITH has implications for predictive or prognostic biomarker strategies, where the tumor subclone that may ultimately influence therapeutic outcome may evade detection because of its absence or presence at low frequency at diagnosis or because of its regional separation from the tumor biopsy site. In this review, the implications of “trunk and branch” tumor evolution for drug discovery approaches and emerging evidence that low-frequency somatic events may drive tumor growth through paracrine signaling fostering a tumor ecologic niche are discussed. The concept of an “actionable mutation” is considered within a model of clonal dominance and heterogeneous tumor cell dependencies. Evidence that cancer therapeutics may augment ITH and the need to track the tumor subclonal architecture through treatment are defined as key research areas. Finally, if combination therapeutic approaches to limit the consequences of ITH prove challenging, identification of drivers or suppressors of ITH may provide attractive therapeutic targets to limit tumor evolutionary rates and adaptation. Cancer Res; 72(19); 4875–82. ©2012 AACR.
Targeting Olfactomedin-like 3 Inhibits Tumor Growth by Impairing Angiogenesis and Pericyte Coverage
Authors: Miljkovic-Licina Marijana , Hammel Philippe , Garrido-Urbani Sarah , Lee Boris P.-L. , Meguenani Mehdi , Chaabane Chiraz , Bochaton-Piallat Marie-Luce , Imhof Beat A.
Published: September 2012

Antiangiogenic drugs have been used as anticancer agents to target tumor endothelial cells or pericytes. Because of limited efficacy of the current monotherapies, there is a strong demand for the dual targeting of endothelial cells and pericytes. Here, we identify Olfactomedin-like 3 (Olfml3) as a novel proangiogenic cue within the tumor microenvironment. Tumor-derived Olfml3 is produced by both tumor endothelial cells and accompanying pericytes and deposited in the perivascular compartment. Blockade of Olfml3 by anti-Olfml3 antibodies is highly effective in reducing tumor vascularization, pericyte coverage, and tumor growth. In vitro, Olfml3 targeting is sufficient to inhibit endothelioma cell migration and sprouting. Olfml3 alone or through binding to BMP4 enhances the canonical SMAD1/5/8 signaling pathway required for BMP4-induced angiogenesis. Therefore, Olfml3 blockade provides a novel strategy to control tumor growth by targeting two distinct cell types within the tumor microenvironment using a single molecule. Mol Cancer Ther; 11(12); 2588–99. ©2012 AACR.
FGFR Genetic Alterations Predict for Sensitivity to NVP-BGJ398, a Selective Pan-FGFR Inhibitor
Authors: Guagnano Vito , Kauffmann Audrey , Wöhrle Simon , Stamm Christelle , Ito Moriko , Barys Louise , Pornon Astrid , Yao Yao , Li Fang , Zhang Yun , Chen Zhi , Wilson Christopher J. , Bordas Vincent , Le Douget Mickaël , Gaither L. Alex , Borawski Jason , Monahan John E. , Venkatesan Kavitha , Brümmendorf Thomas , Thomas David M. , Garcia-Echeverria Carlos , Hofmann Francesco , Sellers William R. , Graus-Porta Diana
Published: September 2012

Patient stratification biomarkers that enable the translation of cancer genetic knowledge into clinical use are essential for the successful and rapid development of emerging targeted anticancer therapeutics. Here, we describe the identification of patient stratification biomarkers for NVP-BGJ398, a novel and selective fibroblast growth factor receptor (FGFR) inhibitor. By intersecting genome-wide gene expression and genomic alteration data with cell line–sensitivity data across an annotated collection of cancer cell lines called the Cancer Cell Line Encyclopedia, we show that genetic alterations for FGFR family members predict for sensitivity to NVP-BGJ398. For the first time, we report oncogenic FGFR1 amplification in osteosarcoma as a potential patient selection biomarker. Furthermore, we show that cancer cell lines harboring FGF19 copy number gain at the 11q13 amplicon are sensitive to NVP-BGJ398 only when concomitant expression of β-klotho occurs. Thus, our findings provide the rationale for the clinical development of FGFR inhibitors in selected patients with cancer harboring tumors with the identified predictors of sensitivity.

Significance: The success of a personalized medicine approach using targeted therapies ultimately depends on being able to identify the patients who will benefit the most from any given drug. To this end, we have integrated the molecular profiles for more than 500 cancer cell lines with sensitivity data for the novel anticancer drug NVP-BGJ398 and showed that FGFR genetic alterations are the most significant predictors for sensitivity. This work has ultimately endorsed the incorporation of specific patient selection biomakers in the clinical trials for NVP-BGJ398. Cancer Discov; 2(12); 1118–33. ©2012 AACR.

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Influence of Spatial Neglect, Hemianopia and Hemispace on the Subjective Vertical
Authors: Saj Arnaud , Honoré Jacques , Bernati Thérèse , Rousseaux Marc
Published: September 2012

The perception of the vertical is frequently shifted to the contralesional side in patients with hemispheric lesions, and this is amplified by spatial neglect. However, we do not know the specific influence of hemianopia and space of perception on this phenomenon. Here, we analyzed the respective influences of spatial neglect, hemianopia and hemispace on the subjective vertical in patients with right hemispheric stroke. Twelve neglect patients with and 5 without hemianopia were compared to 3 non-neglect patients with and 13 without hemianopia. They had to match a luminous rod to the vertical, either in the mid-sagittal plane or in the right or the left hemispace. Patients showed a counter-clockwise deviation, and this was exaggerated by both neglect and hemianopia. In patients with neglect, the error was greater in the left hemispace. In conclusion, neglect and hemianopia had additive effects on the contralesional bias of the subjective vertical.
Blood Concentrations of Homocysteine and Methylmalonic Acid among Demented and Non-Demented Swedish Elderly with and without Home Care Services and Vitamin B12 Prescriptions
Authors: Hagnelius Nils-Olof , Wahlund Lars-Olof , Schneede Jörn , Nilsson Torbjörn K.
Published: September 2012

Background and Aims: Total plasma homocysteine (tHcy) has been suggested as a risk factor of dementia. Our aim was to investigate potential differences in tHcy status in relation to the prescription of vitamin B12 and dementia diagnosis. We examined whether vitamin B12 prescriptions, a family history of dementia, or the need for home care service might be associated with tHcy values. Methods: A cross-sectional monocenter study comprising 926 consecutive subjects attending our Memory Care Unit was conducted. Results: Demented subjects being prescribed vitamin B12 had higher serum vitamin B12 (p = 0.025) but also higher tHcy (p < 0.001) and serum methylmalonate (p = 0.032), and lower serum folate (p < 0.001) than those who did not receive vitamin B12 prescriptions. tHcy levels were significantly higher in non-demented subjects receiving home care service (p = 0.007). This group also had lower serum albumin (dementia: p < 0.001; non-dementia: p = 0.004). There was no difference in renal function (estimated glomerular filtration rate) in demented or non-demented subjects with or without vitamin B12 prescriptions (dementia with/without vitamin B12 prescription: p = 0.561; non-dementia with/without vitamin B12 prescription: p = 0.710). Conclusion: Despite vitamin B12 prescriptions, demented subjects had higher tHcy and methylmalonate values. The elevated metabolite values could not be explained by differences in renal function. Thus, elderly subjects on vitamin B12 prescription appear to have unmet nutritional needs.
Hyaluronan, a Ready Choice to Fuel Regeneration: A Mini-Review
Authors: Reitinger Stephan , Lepperdinger Günter
Published: September 2012

Background: Hyaluronan (HA) is present in extracellular spaces and interstitia of many tissue types. As it is capable of binding high amounts of water, HA provides ideal conditions for cell migration and proliferation. Under conditions of cellular crowding, it also permits lineage-specific differentiation and thus promotes many aspects of healing and tissue remodeling. Methods: The simplicity of its structure makes it amenable to chemical modifications and/or combined formulations with other bioactive substances. Thus a wide variety of clinical applications have been proposed, several of which are currently being implemented in advanced therapies. Results: Known features of HA biology, in particular regarding synthesis and processes related to signaling and control, have been adopted to elaborate specific products in order to support progress in regenerative medicine. Purified HA, HA-based hydrogels or special HA composites have been formulated together with other well-characterized biomaterials and bioactive factors. HA is currently employed in a variety of therapeutic applications both in its pure form and in a biofunctionalized form. Conclusions: HA plays an essential role in regenerative processes. Owing to the growing scientific knowledge in this field, medicinal products based on HA have been devised and are being routinely applied in ophthalmology or in trauma and transplantation surgery. Further areas of application are contemplated, such as the use of HA composite scaffold material in tissue engineering, or refined HA hydrogels enabling controlled release of medication.
Treatment of Epidermal Growth Factor Receptor Inhibitor-Induced Acneiform Eruption with Topical Recombinant Human Epidermal Growth Factor
Authors: Shin J.U. , Park J.H. , Cho B.-C. , Lee J.H.
Published: September 2012

Background: Epidermal growth factor receptor (EGFR) inhibitors have been used as anticancer agents for the treatment of a variety of solid tumors. Related skin toxicities are the most common adverse effects and occur with all EGFR inhibitors. Several treatment approaches, such as antiseptic soaps, topical and oral antibiotics, and topical and oral corticosteroids, have been reported; however, the responses have been varied. Acneiform eruption induced by EGFR inhibitor treatment results from disturbed normal keratinocyte and hair follicle biology and may therefore benefit from local restoration of EGF pathway. Observations: We treated HaCaT cells with EGFR inhibitor and evaluated the expression of EGFR. After treatment of cells with EGFR inhibitor, EGFR expression was increased in a dose-dependent manner. We hypothesized that newly synthesized EGFR, not inhibited by EGFR inhibitors, may perform their biological action in keratinocytes in the presence of additional EGF. In this study, we therefore treated acneiform eruption patients with topical recombinant human EGF (rhEGF) with institutional review board approval. Here, we report three cases of such eruptions who responded to topical rhEGF. Conclusion: Topical rhEGF may be an effective treatment option for EGFR inhibitor-induced acneiform eruption.
Predictors of Renal Replacement Therapy in Acute Kidney Injury
Authors: Koziolek Michael J. , Datta Rabi R. , Mattes Harry , Jung Klaus , Heise Daniel , Streich Jan H. , Mühlhausen Johannes , Mueller Gerhard A. , Dihazi Hassan
Published: September 2012

Backgrounds: Criteria that may guide early renal replacement therapy (RRT) initiation in patients with acute kidney injury (AKI) currently do not exist. Methods: In 120 consecutive patients with AKI, clinical and laboratory data were analyzed on admittance. The prognostic power of those parameters which were significantly different between the two groups was analyzed by receiver operator characteristic curves and by leave-1-out cross validation. Results: Six parameters (urine albumin, plasma creatinine, blood urea nitrogen, daily urine output, fluid balance and plasma sodium) were combined in a logistic regression model that estimates the probability that a particular patient will need RRT. Additionally, a second model without daily urine output was established. Both models yielded a higher accuracy (89 and 88% correct classification rate, respectively) than the best single parameter, cystatin C (correct classification rate 74%). Conclusions: The combined models may help to better predict the necessity of RRT using clinical and routine laboratory data in patients with AKI.
Serum Uric Acid Independently Predicts Cardiovascular Events in Advanced Nephropathy
Authors: Kanbay Mehmet , Yilmaz Mahmut Ilker , Sonmez Alper , Solak Yalcin , Saglam Mutlu , Cakir Erdinc , Unal Hilmi Umut , Arslan Erol , Verim Samet , Madero Magdalena , Caglar Kayser , Oguz Yusuf , McFann Kim , Johnson Richard J.
Published: September 2012

Background: Chronic kidney disease (CKD) is associated with increased risk for cardiovascular (CV) disease and is also associated with elevated uric acid, which is emerging as a nontraditional CV risk factor. We therefore evaluated uric acid as a risk factor for CV disease in subjects presenting to nephrologists with CKD who were not on medications known to alter endothelial function. Methods: 303 subjects with stage 3–5 CKD were followed for a mean of 39 months (range 6–46) and assessed for fatal and nonfatal CV events. Hyperuricemia was defined as uric acid >6.0 mg/dl for women and >7.0 mg/dl for men. In addition to other CV risk factors, endothelial function (flow-mediated dilatation), inflammatory markers (hsCRP), and insulin resistance (HOMA index and fasting insulin levels) were included in the analysis. We evaluated the association between uric acid and flow-mediated dilatation with linear regression. The impact of uric acid on composite CV events was assessed with Cox regression analysis. Results: Of a total of 303 patients, 89 had normouricemia and 214 had hyperuricemia. Both fatal (32 of 214 vs. 1 of 89 subjects) and combined fatal and nonfatal (100 of 214 vs. 13 of 89 subjects) CV events were more common in subjects with hyperuricemia compared with normal uric acid levels, and this was independent of estimated glomerular filtration rate, traditional CV risk factors including diabetes, hypertension and BMI, and nontraditional risk factors (hsCRP and endothelial function). The 46-month survival rate was 98.7% in the group with low uric acid compared to 85.8% in patients with high uric acid (p = 0.002). Conclusions: Hyperuricemia is an independent risk factor for CV events in subjects presenting with CKD who are not on medications known to alter endothelial function.
A Systematic Approach to the Differential Diagnosis and Management of the Complications of Monochorionic Twin Pregnancies
Authors: Gratacós E. , Ortiz J.U. , Martinez J.M.
Published: September 2012

Monochorionic (MC) twins represent a significant proportion of perinatal morbidity and mortality. Overall, 1 of 3 MC twin pregnancies will develop complications in relation to the MC placenta and the presence of interfetal placental anastomoses. From a clinical standpoint, these complications can be grouped into four main types of clinical problems: chronic transfusion, acute transfusion, growth discordance, and discordant malformation. Differential diagnosis of MC twin complications is still challenging due to frequent overlap of their clinical signs and the complex relationships between them. Clinical experience demonstrates that most instances of wrong management derive from failure to comply with a basic set of rules for diagnosis and management. In this review, we propose a simplified approach to the understanding of MC twin pregnancy, its potential complications, and the key concepts allowing adequate differential diagnosis and targeted management.
The Effects of Insertion Speed on Inner Ear Function during Cochlear Implantation: A Comparison Study
Authors: Rajan Gunesh P. , Kontorinis Georgios , Kuthubutheen Jafri
Published: September 2012

Objective: To investigate the insertion speed and its impact on electrode insertion characteristics, hearing preservation and clinical vestibular function in a prospective cohort study with a retrospective control group at a tertiary otology/neurotology centre. Interventions: Hearing-preserving cochlear implantation using systemic and topical steroids in conjunction with a round-window approach, a complete cochlear coverage electrode and two different electrode insertion speeds [60 mm/min (n = 18) vs. 15 mm/min (n = 22)] was performed. Results: The insertion speed had a significant impact on various insertion characteristics as well as hearing preservation and vestibular function. In conclusion, a slow electrode insertion speed appears to facilitate full electrode insertion, reduce the occurrence of insertion resistance as well as promote preservation of residual hearing and vestibular function after cochlear implantation.
Remitting Seronegative Symmetrical Synovitis with Pitting Edema Syndrome Caused by Crystal-Induced Arthritis of the Wrist: A Case Report
Authors: Hakozaki Michiyuki , Fukuda Hironari , Tajino Takahiro , Kikuchi Shinichi , Abe Satoshi , Konno Shinichi
Published: September 2012

Objective: To describe a rare case of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome caused by gouty arthritis. Clinical Presentation and Intervention: A 76-year-old man presented with swelling and pain in the dorsum of feet and hands bilaterally. From the laboratory and radiologic findings, the diagnosis of gout-induced RS3PE syndrome was made. Conservative therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular corticosteroid injection in the wrist joint completely and rapidly resolved all symptoms. The patient was successfully treated with oral administration of NSAIDs and a one-time intra-articular corticosteroid injection in the left wrist joint. Conclusion: This case demonstrated the importance of considering the possibility of crystal-induced arthritis such as gout and pseudogout, as well as malignant disease, when diagnosing the primary disease responsible for RS3PE syndrome.
The Role of Rac1 in Glycoprotein Ib-IX–Mediated Signal Transduction and Integrin Activation
Authors: Delaney M. Keegan , Liu Junling , Zheng Yi , Berndt Michael C. , Du Xiaoping
Published: September 2012

Objective—

The platelet receptor for von Willebrand factor, the glycoprotein Ib-IX (GPIb-IX) complex, mediates platelet adhesion at sites of vascular injury and transmits signals leading to platelet activation. von Willebrand factor/GPIb-IX interaction sequentially activates the Src family kinase Lyn (SFK), phosphoinositide 3-kinase (PI3K), and Akt, leading to activation of integrin α
IIb
β
3
and integrin-dependent stable platelet adhesion and aggregation. It remains unclear how Lyn activates the PI3K/Akt pathway after ligand binding to GPIb-IX.

Methods and Results—

Using platelet-specific Rac1
−/−
mice and the Rac1 inhibitor NSC23766, we examined the role of Rac1 in GPIb-IX–dependent platelet activation. Rac1
−/−
mouse platelets and NSC23766-treated human platelets were defective in GPIb-dependent stable adhesion to von Willebrand factor under shear stress, integrin activation, thromboxane A
2
synthesis, and platelet aggregation. Interestingly, GPIb-induced activation of Rac1 and the guanine nucleotide exchange factor for Rac1, Vav, was abolished in both Lyn
−/−
and SFK inhibitor-treated platelets but was unaffected by the PI3K inhibitor LY294002, indicating that Lyn mediates activation of Vav and Rac1 independently of PI3K. Furthermore, GPIb-induced activation of Akt was abolished in Rac1-deficient platelets, suggesting that Rac1 is upstream of the PI3K/Akt pathway.

Conclusion—

A Lyn-Vav-Rac1-PI3K-Akt pathway mediates von Willebrand factor–induced activation of integrin α
IIb
β
3
to promote GPIb-IX–dependent platelet activation.
White Adipose Tissue Apolipoprotein C-I Secretion in Relation to Delayed Plasma Clearance of Dietary Fat in Humans
Authors: Wassef Hanny , Salem Huda , Bissonnette Simon , Baass Alexis , Dufour Robert , Davignon Jean , Faraj May
Published: September 2012

Objective—

White adipose tissue (WAT) dysfunction is characterized by delayed clearance of dietary triglyceride-rich lipoproteins (TRL). We reported that apolipoprotein (apo) C-I, a transferable apolipoprotein that inhibits lipoprotein lipase activity when bound to TRL, was produced by a human adipocyte model. Thus, we aimed to determine whether increased WAT apoC-I secretion is related to delayed dietary fat clearance in humans.

Methods and Results—

After the ingestion of a
13
C-triolein–labeled high-fat meal, postmenopausal obese women with high-fasting WAT apoC-I secretion (median >0.81 μmol/L per g/4 hours, n=9) had delayed postprandial plasma clearance of
13
C-triglyceride and
13
C-nonesterified fatty acids over 6 hours compared with controls. WAT apoC-I secretion over 4 hours correlated with fasting total and non–high-density lipoprotein apoC-I but not with high-density lipoprotein apoC-I and was the primary predictor of 4-hour postprandial increases in TRL apoC-I. Correction for TRL apoC-I eliminated the association of WAT apoC-I with 6-hour area under the curve of plasma
13
C-triglyceride; correction for insulin sensitivity or inflammation did not. Finally, in addition to apoC-I, WAT secreted considerable amount of apoC-II, apoC-III, and apoE over 24 hours; however, only WAT apoC-I secretion was associated with 6-hour area under the curve of plasma
13
C-triglyceride.

Conclusion—

Increased WAT apoC-I secretion in obese women is associated with delayed postprandial dietary fat clearance mediated by increased TRL apoC-I. Thus, we hypothesize that reducing WAT apoC-I secretion ameliorates WAT dysfunction and associated cardiometabolic risks in humans.
Apelin/APJ Signaling Is a Critical Regulator of Statin Effects in Vascular Endothelial Cells—Brief Report
Authors: McLean Danielle L. , Kim Jongmin , Kang Yujung , Shi Hong , Atkins G. Brandon , Jain Mukesh K. , Chun Hyung J.
Published: September 2012

Objective—

The endothelial response elicited by the G-protein−coupled receptor pathway involving apelin and APJ predicts an overall vasoprotective effect. As a number of downstream endothelial targets of apelin/APJ signaling are also known to be targeted by statins (3-hydroxy-3-methyl-glutaryl [HMG]-CoA reductase inhibitors) as potential mediators of their known pleiotropic effects, we evaluated for the involvement of apelin/APJ signaling in statin endothelial effects.

Methods and Results—

We found that disruption of apelin/APJ signaling in endothelial cells leads to significantly decreased expression of Krűppel-like factor 2, endothelial nitric oxide synthase, and thrombomodulin. We found that statin-mediated induction of Krűppel-like factor 2, endothelial nitric oxide synthase, and thrombomodulin expression, as well as inhibition of monocyte-endothelial adhesion, was abrogated by concurrent apelin knockdown. Moreover, we found that statins can transcriptionally regulate APJ in a Krűppel-like factor 2−dependent manner, demonstrating the presence of a positive-feedback loop.

Conclusion—

Our findings provide a novel mechanism by which the apelin/APJ pathway serves as a critical intermediary that links statin to its pleiotropic effects in regulating endothelial gene targets and function.
Addition of Inflammatory Biomarkers Did Not Improve Diabetes Prediction in the Community: The Framingham Heart Study
Authors: Dallmeier Dhayana , Larson Martin G. , Wang Na , Fontes João D. , Benjamin Emelia J. , Fox Caroline S.
Published: September 2012

Background

Prior studies have reported conflicting findings with regard to the association of biomarkers in the prediction of incident type 2 diabetes. We evaluated 12 biomarkers as possible diabetes predictors in the
F
ramingham
H
eart
S
tudy.

Methods and Results

Biomarkers representing inflammation (
C
‐reactive protein, interleukin‐6, monocyte chemoattractant protein‐1, tumor necrosis factor receptor 2, osteoprotegerin, and fibrinogen), endothelial dysfunction (intercellular adhesion molecule‐1), vascular damage (
CD
40‐ligand,
P
‐selectin, and lipoprotein‐associated phospholipase A2 mass and activity), and oxidative stress (urinary isoprostanes) were measured in participants without diabetes attending the Offspring seventh (n=2499) or multiethnic Omni second (n=189) examination (1998–2001). Biomarkers were log
e
transformed and standardized. Multivariable logistic regression tested each biomarker in association with incident diabetes at a follow‐up examination (the Offspring eighth and Omni third examination; mean 6.6 years later), with adjustment for age, sex, cohort, body mass index, fasting glucose, systolic blood pressure, high‐density lipoprotein cholesterol, triglycerides, and smoking.

C

statistics were evaluated with and without inflammatory markers. In 2638 participants (56% women, mean age 59 years), 162 (6.1%) developed type 2 diabetes. All biomarkers, excluding osteoprotegerin, were associated with the outcome with adjustment for age, sex, and cohort; however, none remained significant after multivariable adjustment (all
P
>0.05). The
c
statistic from the model including only clinical covariates (0.89) did not statistically significantly improve after addition of biomarkers (all
P
>0.10).

Conclusions

Biomarkers representing different inflammatory pathways are associated with incident diabetes but do not remain statistically significant after adjustment for established clinical covariates. Inflammatory biomarkers might not be an effective resource to predict type 2 diabetes in community‐based samples.