bluuebunny/crossref_metadata_2025 huggingface dataset:
(Invited) Atomic Layer Deposition of Multicomponent Metal Sulfides Applied to Thin Film Photovoltaics
Authors: Thimsen Elijah
Published: October 2013

This paper is a perspective on the applicability of atomic layer deposition (ALD) to the synthesis of photovoltaic absorber layers. ALD offers digital control over composition with excellent uniformity and conformal morphology. Two types of thin film photovoltaic (PV) device architectures where ALD is viable to deposit the absorber layer are extremely thin absorber (ETA) cells and plasmon-enhanced cells. Metal sulfides are an attractive class of compounds for the absorber material. Successful absorber layers are engineered materials, optimized to meet the application specifications of performance and stability. Historical precedence in engineered materials contains many prominent multicomponent examples. Fortunately, atomic mixing is facile in multicomponent metal sulfide thin films synthesized by ALD, and so the synthetic approach is up to the task. Cu2ZnSnS4 is used as an example.
(Invited) Spatial Atomic Layer Deposition of Transparent Conductive Oxides
Authors: Illiberi A. , Scherpenborg R. , Poodt P. , Roozeboom F.
Published: October 2013

Undoped and indium doped ZnO films have been grown by Spatial Atomic Layer Deposition at atmospheric pressure. The electrical properties of ZnO films are controlled by varying the indium content in the range from 0 to 15 %. A minimum resistivity value of 3 mΩ·cm is measured in 180 nm thick films for In/(In+Zn) ratio equal to 6 %, corresponding to a majority carrier density of 6·1020 cm-3 and a mobility of 3 cm2/Vs. All the films are highly transparent (> 80 %) in the visible range.
(Invited) Conformal Deposition for 3D Thin-Film Batteries
Authors: Vereecken Philippe M. , Huyghebaert Cedric
Published: October 2013

For the application of durable micro-storage for autonomous systems and implants, 3D thin-film batteries are leading candidates. Lithium ion batteries have the highest energy density of all known systems and are thus the best choice also for these rechargeable micro-batteries. Since liquid electrolyte based batteries present safety issues and limitations in size and design, pure solid state devices are considered particularly for miniaturization. Planar thinfilm lithium and lithium ion batteries are at present commercially available but have limited capacity (<1mAh/cm2). The capacity can be increased by coating the thin-film stacks on micro-or nanostructured surfaces (3D thin-film batteries). The main advantage of thin-film (TF) batteries is that its power can be increased by scaling down the film thickness. The main technological challenges in the introduction 3D TF batteries are pinhole-free and chemically uniform conformal coating of the cathode, electrolyte and anode thin-film stack.
High Surface Capacity Li-Ion All Solid State 3D Microbattery Based on Anatase TiO2 Deposited by ALD on Silicon Microstructures
Authors: Eustache Etienne , Tilmant Pascal , Morgenroth Laurence , Roussel Pascal , Rolland Nathalie , Brousse Thierry , Lethien Christophe
Published: October 2013

The proposed study deals with the design, the fabrication and the characterization of 3D silicon microstructures decorated with step conformal and pin hole free anatase TiO2 negative electrode deposited by atomic layer deposition. A high aspect ratio and dense array of 3D silicon micropillars or microtubes are fabricated on silicon wafer. The obtained surface capacity of the TiO2 layer (150nm) deposited on 3D microtubes (area enlargement factor =25) reaches 0.15 mAh/cm2 at C/4. The reported 3D topologies enhance the capacity of standard TiO2 2D thin film electrode.
(Invited) Advanced Dielectrics Targeting 2X DRAM MIM Capacitors
Authors: Popovici Mihaela , Swerts Johan , Aoulaiche Marc , Redolfi Augusto , Kaczer Ben , Kim Min-Soo , Douhard Bastien , Delabie Annelies , Clima Sergiu , Jurczak Malgorzata , Van Elshocht S.
Published: October 2013

Reducing the equivalent oxide thickness below 0.45 nm at low leakage current density of 10-7A/cm2 at ± 1V is required for DRAM MIM capacitors for the 2X node. This can be achieved using a bi-layer stack TiO2/Sr rich STO (62%), which is converted into a STO layer having 54% Sr content after crystallization anneal. The impact of TiO2 content in the initial bi-layer on the grain morphology and electrical properties of the final stack was studied. An optimal TiO2 thickness range was identified, correlated with the grain size. Ti richer STO results in a larger amount of nano-cracks and higher leakage current. The electrode/STO interface is critical in reducing the leakage current. In this regard, Ru has shown improved properties as compared to TiN. Moreover, Sr diffusion into Ru identified by SIMS measurements seems to have a beneficial effect on improving the interface and electrical properties.
Atomic Layer Deposition of Thin Oxide Films for Resistive Switching
Authors: Fröhlich Karol , Jančovič Peter , Hudec Boris , Dérer Jan , Paskaleva Albena , Bertaud Thomas , Schroeder Thomas
Published: October 2013

Atomic layer deposition was used for preparation of TiO2 and HfO2 thin films for resistive switching in metal-insulator-metal structures with Pt and TiN top and bottom electrodes, respectively. To obtain stable bipolar resistive switching loops in TiO2-based structures Al2O3 barrier with the thickness of 3 - 5 nm was necessary. HfO2-based structures with the insulator thickness less than 10 nm exhibited stable bipolar resistive switching. Ratio between high resistivity and low resistivity state varied between 20 and 100 depending on structure preparation and composition as well as on parameters of DC current – voltage measurement. Resistive switching effect was demonstrated in metal-insulator-metal structures with HfO2 layers thickness below 3 nm.
Conductivity Improvements of Atomic Layer Deposited Ta3N5
Authors: Dekkers Hendrik F.W. , Lima Lucas Petersen Barbosa , Van Elshocht S.
Published: October 2013

Using TaCl5 as a precursor for thermal ALD of TaN results in an orthorhombic phase of Ta3N5 which is considered as a dielectric material. Conductivity of this film is found to depend on deposition and annealing temperature, which also modifies the X-ray diffraction spectrum. Both changes are induced by lowering the N:Ta ratio which adds new diffraction peaks. This modification is stronger when annealing is performed with TaN films covered by Al. This treatment makes Ta3N5 as attractive as metallic phase, δ-TaN to be used in work function metal stacks with Al contacts.
Tetragonal Zirconia Stabilization by Metal Addition for Metal-Insulator-Metal Capacitor Applications
Authors: Ferrand Julien , Beugin Virginie , Crisci Alexandre , Coindeau Stéphane , Jeannot Simon , Gros-Jean Mickael , Blanquet Elisabeth
Published: October 2013

Zirconium dioxide is a good candidate to reach the capacitance density of 40fF/μm² required for decoupling applications. Indeed zirconia has a promising dielectric constant of 47 in the tetragonal phase. However, pure tetragonal zirconia layers deposited by PEALD do not fulfill the reliability criteria. We thus stabilize zirconia by addition of different metals. Tantalum is alloyed with zirconia. Since Ta solubility in ZrO2 is low, an orthorhombic ternary compounds appears and reduce the global dielectric constant of the layer. We also alloy zirconium dioxide with germanium. At high Ge concentration ZrO2 layers remain amorphous even after post deposition annealing, with a reduced dielectric constant. However at lower germanium concentration zirconia layers crystallize in tetragonal phase with better electrical properties than pure ZrO2.
(Invited) Synthesis, Characterization, and Application of Tunable Resistance Coatings Prepared by Atomic Layer Deposition
Authors: Elam Jeffrey W. , Mane Anil U , Libera Joseph A. , Hryn John N. , Siegmund Oswald HW , McPhate Jason , Wetstein Matthew J , Elagin Andrey , Minot Michael J , O'Mahony Aileen , Wagner Robert G , Tong William M , Brodie Alan D. , McCord Mark A. , Bevis Christopher F.
Published: October 2013

We describe the synthesis, characterization, and application of nanocomposite, tunable resistance coatings consisting of conducting, metallic nanoparticles embedded in an amorphous dielectric matrix. These films are comprised of M:Al2O3 with M=Mo or W, and are prepared by atomic layer deposition (ALD) using alternating exposures to trimethyl aluminum and H2O for the Al2O3 ALD and alternating MF6/Si2H6 exposures for the metal ALD. By varying the ratio of ALD cycles for the metal and the Al2O3 components in the film, we can tune precisely the resistance of these coatings over a very broad range from 105-1012 Ohm.cm. These films exhibit ohmic behavior and resist breakdown even at high electric fields of 107 V/m. Moreover, the self-limiting nature of ALD allows us to grow these films inside of porous substrates and on complex 3D surfaces. As a result of these qualities, our nanocomposite films have proved exceptional as resistive coatings in microchannel plate electron multipliers and as charge drain coatings in electron-optical devices.
(Invited) Molecular Layer Deposition
Authors: Cameron David C , Ivanova Tatyana V
Published: October 2013

Molecular Layer Deposition (MLD) is analogous to Atomic Layer Deposition (ALD) but using organic precursors and forming completely organic thin films. It has many of the advantages of ALD in terms of uniformity and controllability but also some disadvantages due to the nature of the precursors and film material. This paper gives a review of the limited amount of work which has been carried out to date on MLD since its initiation in the 1990s. It covers the polymeric materials which have been deposited and describes the various processes and precursors which have been used. Some of the difficulties peculiar to MLD are considered and also some of the process developments which have been made to try to overcome these.
(Invited) Plasma-Enhanced Atomic Layer Deposition of III-Nitride Thin Films
Authors: Ozgit-Akgun Cagla , Donmez Inci , Biyikli Necmi
Published: October 2013

AlN and GaN thin films were deposited by plasma-enhanced atomic layer deposition using trimethylmetal precursors. The films were found to have high oxygen incorporation, which was attributed to oxygen contamination related to the plasma system. The choice of nitrogen containing plasma gas (N2, N2/H2 or NH3) determined the severity of oxygen incorporation into deposited films. Lowest oxygen concentrations were attained for AlN and GaN thin films using NH3 and N2 plasma, respectively. Initial experiments have shown that GaN thin films with low impurity concentrations can be deposited when plasma-related oxygen contamination is avoided by the use of an alternative plasma source.
A Comprehensive Study of Thermal Stability on Microstructure and Residual Stress for ALD HfZrO2 Films at 28nm HKMG CMOS Applications
Authors: Chiang Chen-Kuo , Chang J. C. , Chien C. C. , Yang C. L. , Wu J. Y.
Published: October 2013

The influence of thermal stability on microstructure, surface morphology and residual stress for gate stack structure of HfZrO2 dielectrics grown by atomic layer deposition (ALD) were investigated. The difference of spectra, residual stress, and structures for HfZrO2 films are obtained by the changed thermal energy. A tetragonal to monoclinic phase transformation is observed during high temperature annealing for HfZrO2 films. The variations of spectra can be attributed to the different residual stress of ALD HfZrO2 films induced by the annealing temperature. The tensile residual stress of HfZrO2 films were increased when increasing annealing temperature either for N2 or O2 annealing. This work provides an extensive study for the interface characteristics of high-k/metal (HKMG) stacks at 28nm advanced CMOS technology node.
Ultrathin SiO2 Films Grown by Atomic Layer Deposition Using Tris(dimethylamino)silane (TDMAS) and Ozone
Authors: Han Lei , Chen Zhi David
Published: October 2013

Atomic layer deposition of SiO2 using tris(dimethylamino)silane and ozone were studied comprehensively. It was found that SiO2 grew linearly at different temperatures while the growth rate increased at higher temperatures. For thickness <3.5 nm, the direct tunneling current of the ALD SiO2 is comparable to that of thermally grown SiO2 when considering its equivalent oxide thickness (EOT). ALD could grow high-quality conformal SiO2 films on non-silicon substrates and on high aspect-ratio pores and nanostructures. The ALD SiO2 can be used as high-quality gate insulators for thin-film MOS transistors, and insulators for sensor structures and nanostructures on non-silicon substrates.
Application of Atomic Layer Deposition Tungsten (ALD W) as Gate Filling Metal for 22 nm and Beyond Nodes CMOS Technology
Authors: Wang Guilei , Xu Qiang , Yang Tao , Luo Jun , Xiang Jinjuan , Xu Jing , Xu Gaobo , Li Chunlong , Li Junfeng , Yan Jiang , Zhao Chao , Chen Dapeng , Ye Tianchun
Published: October 2013

By using two different precursors i.e. SiH4 and B2H6, atomic layer deposition (ALD) Tungsten (W) as gate filling metal for 22 nm and beyond nodes CMOS technology were investigated in this work. In order to evaluate the potential for applications of two kinds of ALD W in CMOS devices, their properties were extensively characterized by means of X-ray Reflectivity (XRR), scanning electron microscopy (SEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) and electrical capacitance-voltage (C-V) and current-voltage (I-V) methods. It is revealed that the amorphous ALD W using B2H6 and WF6 shows lower growth rate, lower resistivity and better gap filling capability in high aspect ratio gate trenches, in contrast to the polycrystalline ALD W using SiH4 and WF6. It is further evidenced that the doping of boron (B) in ALD W does not affect the C-V and I-V characteristics of as-prepared capacitors, demonstrating that the ALD W using B2H6 and WF6 is a good gate filling metal which can be widely used in advanced devices.
Self-Cleaning and Electrical Characteristics of ZrO2 (HfO2)/GaAs MOS Capacitor Fabricated by Atomic Layer Deposition
Authors: White Curtis , Donovan Thomas , Cashwell Irving , Konda R. B. , Sahu D. R. , Xiao Bo , Bahoura M. , Pradhan Aswini K
Published: October 2013

The reduction of native oxides on GaAs substrates is studied by short time pulsing of the metal precursor for self-cleaning mechanism using atomic layer deposition (ALD) of Trimethyl aluminum (TMA). The short time pulsing of the TMA is effective for self-cleaning mechanism to reduce the GaAs native oxides. X-ray photoelectron studies demonstrated that the pulsed deposition of TMA in the range of 2 to 4s is the most effective way of cleaning the GaAs native oxides. Microscopic studies clearly demonstrate the sharp interface between dielectric/GaAs. GaAs based metal oxide semiconductor (MOS) capacitors were fabricated with ZrO2 and HfO2 gate dielectrics using ALD. The effect of growth temperature of dielectric films on GaAs was studied. The as deposited samples have a significant amount of fixed charge in the bulk of the gate dielectric and at dielectric/semiconductor (ZrO2 or HfO2/GaAs) interface, which causes the flat band shift and frequency dispersion.
Bulk-Heterojunction Solar Cells Based on Mixed Donorsof P3HT and Phenylene–Thiophene Oligomer Derivative
Authors: Okukawa Takanori , Fujii Shunjiro , Duan Zongfan , Ohori Yurina , Kaneko Yuta , Yanagi Yuichiro , Yoshida Akira , Ohzeki Masaya , Yanagidate Tatsuki , Arai Yuki , Zhao Gaoyang , Kataura Hiromichi , Nishioka Yasushiro
Published: October 2013

Two donors with different spectral sensitivities and an accepter were used to fabricate bulk hetero-junction (BHJ) solar cells with a wider absorption range. In this research, ultraviolet and visible spectra of two donors: poly(3-hexylthiophene) (P3HT) and 3,7-bis [5-(4-n -hexylphenyl)-2-thienyl] dibenzothiophene -5, 5-dioxide (37HPTDBTSO) and accepter: [6,6]-phenyl C61 butyric acid methyl ester (PCBM) in the forms of solutions or films were investigated. Based on these results, BHJ solar cells were fabricated using a ternary mixed solution of P3HT, 37HPTDBTSO, and PCBM. The measured incident photon to charge carrier efficiency spectra indicated that the solar cell based on the two donors showed a wider spectral sensitivity range. The open circuit voltage Voc
was also improved to be 0.63 V, and a short circuit current density Jsc
was 3.65 mA/cm2, and a power conversion efficiency was 0.81%.
Flexible PTB7:PC70BM Bulk-Heterojunction Solar Cells with Lif Cathode Buffer Layer
Authors: Yanagidate Tatsuki , Fujii Shunjiro , Ohzeki Masaya , Yanagi Yuichiro , Arai Yuki , Okukawa Takanori , Yoshida Akira , Kataura Hiromichi , Nishioka Yasushiro
Published: October 2013

Bulk heterojunction solar cells were fabricated using [poly[[4,8-bis[(2-ethylhexyl)oxy]benzo [1,2-b:4,5-b']dithiophene-2,6-diyl][3-fluoro-2-[(2-ethylhexyl)carbonyl]thieno[3,4-b]-thiophenediyl] (PTB7) and [6,6]-phenyl C71 butyric acid methyl ester (PC71BM) after a layer of poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) on a flexible indium tin oxide (ITO)-coated polyethylene terephthalate substrate. The fabricated structures were Al/LiF/PTB7:PC71BM/PEDOT:PSS/ITO with or without a lithium fluoride (LiF) buffer layer, and the influence of the LiF buffer layer on the performance of the solar cells was investigated. The LiF layer significantly enhanced the open-circuit voltages and fill factors of the solar cells presumably because of the work function shift of the aluminum cathode. As a result, the conversion efficiency increased from 2.31% to 4.02% owing to the presence of the LiF layer.
Rapid Thermal Processing in CdS/CdTe Thin Film Solar Cells by Intense Pulsed Light Sintering
Authors: Dharmadasa Ruvini , Echendu Obi Kingsley , Dharmadasa I.M. , Druffel Thad
Published: October 2013

Rapid thermal sintering under atmospheric conditions can drastically cut down processing times from tens of minutes to 1-2 minutes. Intense Pulse Light (IPL) sintering is one such technique that has the potential to combat this target. Unlike traditional heat treatment methods, heating is initiated through the absorption of light from the UV to IR region, resulting in localized heating. Little work exists on the employment of IPL to process semiconductor materials and solar cells. In this study a low-cost deposition technique has been coupled with IPL. CdS and CdTe thin films were grown by electrochemical deposition (ED). ED CdS/CdTe thin film solar cells require the heat treatment of both the CdS and the CdTe layers. Improvements to the optical, morphological and crystalline properties were observed after IPL treatment.
Electrochemical Deposition of Compact and Nanostructured Doped ZnO Films
Authors: Ramírez Daniel Luis , Álvarez Katherine Nicole , Riveros Gonzalo , Tejos Marisol , Lobos María Gabriela
Published: October 2013

This study reviews the electrodeposition of compact films and ZnO nanostructures doped with aluminum, gallium and indium. Electrodeposition in an aqueous perchlorate media favored the formation of relatively compact films with highly preferred orientation along the c-axis. By means of impedance measurements it was able to determine the doping level of each sample. Changing the aqueous perchlorate media to a sulfate one favored the formation of lamellar nanostructures, which did not affect the incorporation of aluminum and gallium impurities. Morphology, optical and crystallographic properties of these films for possible application in fields such as photovoltaics and photocatalysis are analyzed.
Enterotoxigenic Escherichia coli infection and intestinal thiamin uptake: studies with intestinal epithelial Caco-2 monolayers
Authors: Ghosal Abhisek , Chatterjee Nabendu S. , Chou Tristan , Said Hamid M.
Published: October 2013

Infections with enteric pathogens like enterotoxigenic Escherichia coli ( ETEC) is a major health issue worldwide and while diarrhea is the major problem, prolonged, severe, and dual infections with multiple pathogens may also compromise the nutritional status of the infected individuals. There is almost nothing currently known about the effect of ETEC infection on intestinal absorptions of water-soluble vitamins including thiamin. We examined the effect of ETEC infection on intestinal uptake of the thiamin using as a model the human-derived intestinal epithelial Caco-2 cells. The results showed that infecting confluent Caco-2 monolayers with live ETEC (but not with boiled/killed ETEC or nonpathogenic E. coli) or treatment with bacterial culture supernatant led to a significant inhibition in thiamin uptake. This inhibition appears to be caused by a heat-labile and -secreted ETEC component and is mediated via activation of the epithelial adenylate cyclase system. The inhibition in thiamin uptake by ETEC was associated with a significant reduction in expression of human thiamin transporter-1 and -2 (hTHTR1 and hTHTR2) at the protein and mRNA levels as well as in the activity of the SLC19A2 and SLC19A3 promoters. Dual infection of Caco-2 cells with ETEC and EPEC (enteropathogenic E. coli) led to compounded inhibition in intestinal thiamin uptake. These results show for the first time that infection of human intestinal epithelial cells with ETEC causes a significant inhibition in intestinal thiamin uptake. This inhibition is mediated by a secreted heat-labile toxin and is associated with a decrease in the expression of intestinal thiamin transporters.
Modulation of NF-κB and Nrf2 control of inflammatory responses in FHs 74 Int cell line is tocopherol isoform-specific
Authors: Elisia Ingrid , Kitts David D.
Published: October 2013

The present study investigates the relative ability of α-, γ-, and δ-tocopherol (Toc) to modulate cell signaling events that are associated with inflammatory responses in fetal-derived intestinal (FHs 74 Int) cells. Secretion of the proinflammatory cytokine IL-8 in FHs 74 Int cells was stimulated in the following order: α-Toc < γ-Toc < δ-Toc. A similar proinflammatory response was observed when inflammation was induced in FHs 74 Int cells. Modulation of IL-8 expression by Toc corresponded to an isoform-specific modulation of NF-κB and nuclear factor-erythroid 2-related factor 2 (Nrf2) cell signaling pathways involved in expression of proinflammatory cytokines and antioxidant enzymes, respectively. δ-Toc and, to a lesser extent, γ-Toc activated NF-κB and Nrf2 signaling, as indicated by the greater nuclear translocation of transcription factors. Activation of NF-κB signaling by γ- and δ-Toc was accompanied by upregulation of NF-κB target genes, such as IL-8 and prostaglandin-endoperoxide synthase 2, with and without a prior IFNγ-PMA challenge. Nevertheless, γ- and δ-Toc, particularly δ-Toc, concurrently downregulated glutamate-cysteine ligase, a Nrf2 target gene that encodes for glutathione biosynthesis. This observation was substantiated by confirmation that γ- and δ-Toc were effective at decreasing glutamate-cysteine ligase protein expression and cellular glutathione content. Downregulation of glutathione content in fetal intestinal cells corresponded to induction of apoptosis-mediated cytotoxicity. In conclusion, γ- and δ-Toc are biologically active isoforms of vitamin E and show superior bioactivity to α-Toc in modulating cell signaling events that contribute to a proinflammatory response in fetal-derived intestinal cells.
Tibialis anterior muscle fascicle dynamics adequately represent postural sway during standing balance
Authors: Day James T. , Lichtwark Glen A. , Cresswell Andrew G.
Published: October 2013

To maintain a stable, upright posture, the central nervous system (CNS) must integrate sensory information from multiple sources and subsequently generate corrective torque about the ankle joint. Although proprioceptive information from the muscles that cross this joint has been shown to be vital in this process, the specific source of this information remains questionable. Recent research has been focused on the potential role of tibialis anterior (TA) muscle during standing, largely due to the lack of modulation of its activity throughout the sway cycle. Ten young, healthy subjects were asked to stand normally under varying conditions, for periods of 60 s. During these trials, intramuscular electromyographic (EMG) activity and the fascicle length of three distinct anatomical regions of TA were sampled synchronously with kinematic data regarding sway position. In the quiet standing conditions, TA muscle activity was unmodulated and fascicle length changes in each region were tightly coupled with changes in sway position. In the active sway condition, more EMG activity was observed in TA and the fascicle length changes were decoupled from sway position. No regional specific differences in correlation values were observed, contrasting previous observations. The ability of the fascicles to follow sway position builds upon the suggestion that TA is well placed to provide accurate, straightforward sensory information to the CNS. As previously suggested, through reciprocal inhibition, afferent information from TA could help to regulate plantar flexor torque at relevant phases of the sway cycle. The proprioceptive role of TA appears to become complicated during more challenging conditions.
Genes–Environment Interactions in Obesity- and Diabetes-Associated Pancreatic Cancer: A GWAS Data Analysis
Authors: Tang Hongwei , Wei Peng , Duell Eric J. , Risch Harvey A. , Olson Sara H. , Bueno-de-Mesquita H. Bas , Gallinger Steven , Holly Elizabeth A. , Petersen Gloria M. , Bracci Paige M. , McWilliams Robert R. , Jenab Mazda , Riboli Elio , Tjønneland Anne , Boutron-Ruault Marie Christine , Kaaks Rudolf , Trichopoulos Dimitrios , Panico Salvatore , Sund Malin , Peeters Petra H.M. , Khaw Kay-Tee , Amos Christopher I. , Li Donghui
Published: October 2013

Background: Obesity and diabetes are potentially alterable risk factors for pancreatic cancer. Genetic factors that modify the associations of obesity and diabetes with pancreatic cancer have previously not been examined at the genome-wide level.

Methods: Using genome-wide association studies (GWAS) genotype and risk factor data from the Pancreatic Cancer Case Control Consortium, we conducted a discovery study of 2,028 cases and 2,109 controls to examine gene–obesity and gene–diabetes interactions in relation to pancreatic cancer risk by using the likelihood-ratio test nested in logistic regression models and Ingenuity Pathway Analysis (IPA).

Results: After adjusting for multiple comparisons, a significant interaction of the chemokine signaling pathway with obesity (P = 3.29 × 10−6) and a near significant interaction of calcium signaling pathway with diabetes (P = 1.57 × 10−4) in modifying the risk of pancreatic cancer were observed. These findings were supported by results from IPA analysis of the top genes with nominal interactions. The major contributing genes to the two top pathways include GNGT2, RELA, TIAM1, and GNAS. None of the individual genes or single-nucleotide polymorphism (SNP) except one SNP remained significant after adjusting for multiple testing. Notably, SNP rs10818684 of the PTGS1 gene showed an interaction with diabetes (P = 7.91 × 10−7) at a false discovery rate of 6%.

Conclusions: Genetic variations in inflammatory response and insulin resistance may affect the risk of obesity- and diabetes-related pancreatic cancer. These observations should be replicated in additional large datasets.

Impact: A gene–environment interaction analysis may provide new insights into the genetic susceptibility and molecular mechanisms of obesity- and diabetes-related pancreatic cancer. Cancer Epidemiol Biomarkers Prev; 23(1); 98–106. ©2013 AACR.
Trastuzumab Emtansine: A Novel Antibody–Drug Conjugate for HER2-Positive Breast Cancer
Authors: Krop Ian , Winer Eric P.
Published: October 2013

Trastuzumab emtansine (T-DM1) is a novel HER2-directed antibody–drug conjugate. T-DM1 consists of the potent antimicrotubule agent DM1, linked via a noncleavable linker to the HER2-specific monoclonal antibody trastuzumab. Preclinical studies demonstrate that T-DM1 has dual mechanisms of action: selective delivery of DM1 to the HER2-positive (HER2+) tumor cell combined with trastuzumab's activation of antibody-dependent cell-mediated cytotoxicity and inhibition of HER2-mediated signal transduction. In phase II studies, T-DM1 was active in patients with trastuzumab- and lapatinib-refractory metastatic breast cancer and led to improved progression-free survival compared with the combination of trastuzumab and docetaxel in the first-line setting. In a recent phase III trial in patients with metastatic breast cancer who previously received trastuzumab and a taxane, T-DM1 resulted in improved progression-free and overall survival compared with capecitabine and lapatinib. T-DM1 is associated with a favorable toxicity profile; reversible thrombocytopenia and hepatic transaminase elevations are the only grade ≥3 adverse event present in 5% or more of patients. Alopecia, peripheral neuropathy, and neutropenia are distinctly uncommon. On the basis of its improved efficacy and toxicity compared with capecitabine/lapatinib, T-DM1 should be considered the standard for patients with HER2+ metastatic breast cancer who have previously progressed on trastuzumab and a taxane. Results from additional randomized studies in metastatic breast cancer are pending, and trials in the (neo)adjuvant setting are being initiated. Clin Cancer Res; 20(1); 15–20. ©2013 AACR.
ATP Citrate Lyase Mediates Resistance of Colorectal Cancer Cells to SN38
Authors: Zhou Yunfei , Bollu Lakshmi Reddy , Tozzi Federico , Ye Xiangcang , Bhattacharya Rajat , Gao Guang , Dupre Elizabeth , Xia Ling , Lu Jia , Fan Fan , Bellister Seth , Ellis Lee M. , Weihua Zhang
Published: October 2013

Combination chemotherapy is standard for metastatic colorectal cancer; however, nearly all patients develop drug resistance. Understanding the mechanisms that lead to resistance to individual chemotherapeutic agents may enable identification of novel targets and more effective therapy. Irinotecan is commonly used in first- and second-line therapy for patients with metastatic colorectal cancer, with the active metabolite being SN38. Emerging evidence suggests that altered metabolism in cancer cells is fundamentally involved in the development of drug resistance. Using Oncomine and unbiased proteomic profiling, we found that ATP citrate lyase (ACLy), the first-step rate-limiting enzyme for de novo lipogenesis, was upregulated in colorectal cancer compared with its levels in normal mucosa and in chemoresistant colorectal cancer cells compared with isogenic chemo-naïve colorectal cancer cells. Overexpression of exogenous ACLy by lentivirus transduction in chemo-naïve colorectal cancer cells led to significant chemoresistance to SN38 but not to 5-fluorouracil or oxaliplatin. Knockdown of ACLy by siRNA or inhibition of its activity by a small-molecule inhibitor sensitized chemo-naïve colorectal cancer cells to SN38. Furthermore, ACLy was significantly increased in cancer cells that had acquired resistance to SN38. In contrast to chemo-naïve cells, targeting ACLy alone was not effective in resensitizing resistant cells to SN38, due to a compensatory activation of the AKT pathway triggered by ACLy suppression. Combined inhibition of AKT signaling and ACLy successfully resensitized SN38-resistant cells to SN38. We conclude that targeting ACLy may improve the therapeutic effects of irinotecan and that simultaneous targeting of ACLy and AKT may be warranted to overcome SN38 resistance. Mol Cancer Ther; 12(12); 2782–91. ©2013 AACR.
The Molecular Balancing Act of p16INK4a in Cancer and Aging
Authors: LaPak Kyle M. , Burd Christin E.
Published: October 2013

p16INK4a, located on chromosome 9p21.3, is lost among a cluster of neighboring tumor suppressor genes. Although it is classically known for its capacity to inhibit cyclin-dependent kinase (CDK) activity, p16INK4a is not just a one-trick pony. Long-term p16INK4a expression pushes cells to enter senescence, an irreversible cell-cycle arrest that precludes the growth of would-be cancer cells but also contributes to cellular aging. Importantly, loss of p16INK4a is one of the most frequent events in human tumors and allows precancerous lesions to bypass senescence. Therefore, precise regulation of p16INK4a is essential to tissue homeostasis, maintaining a coordinated balance between tumor suppression and aging. This review outlines the molecular pathways critical for proper p16INK4a regulation and emphasizes the indispensable functions of p16INK4a in cancer, aging, and human physiology that make this gene special. Mol Cancer Res; 12(2); 167–83. ©2013 AACR.
Mechanisms of Cholesterol-Lowering Effects of Lactobacilli and Bifidobacteria Strains as Potential Probiotics with Their bsh Gene Analysis
Authors: Öner Özer , Aslim Belma , Aydaş Selcen Babaoğlu
Published: October 2013

The bile salt hydrolase (BSH) enzyme activities of human-derived lactic acid bacteria and bifidobacteria were evaluated. The highest enzyme activity was identified as 1.76 ± 0.23 U/mg protein for Bifidobacterium breve A26 and 1.42 ± 0.11 U/mg protein for Lactobacillus plantarum LA3. The bile salt deconjugation ability of the 6 isolates representing the highest BSH enzyme activity was calculated as the release of cholic acid and was between the range of 2.03 ± 0.22 and 1.05 ± 0.25 mM. The strains with high BSH enzyme activity also showed high deconjugation ability (p < 0.01). The effect of increasing bile concentrations on the growth of bacteria and their cholesterol removal abilities based on cholesterol precipitation were determined. Cholesterol removal in control medium was between 22.6 ± 0.4 and 26.5 ± 0.4%. The highest value was recorded at a 0.2% bile concentration. As the biliary concentration increased, a decrease in cholesterol removal and viability of the bacteria was noted in all strains. The percent of similarity of the bsh gene region between different genes was specified. The results may throw some light on proving the ability of these probiotics either as a novel alternative or as adjuvants to chemical drugs in treating hypercholesterolemia.
Celastrol Inhibits Lipopolysaccharide-Induced Angiogenesis by Suppressing TLR4-Triggered Nuclear Factor-Kappa B Activation
Authors: Ni Haiwen , Zhao Wanzhou , Kong Xiangtu , Li Haitao , Ouyang Jian
Published: October 2013

Celastrol is an active compound extracted from the root bark of the traditional Chinese medicine Tripterygium wilfordii Hook F. In this study, we investigated the effect of celastrol on lipopolysaccharide (LPS)-activated LP-1 human multiple myeloma cell-induced angiogenesis, and identified its molecular mechanism of action. Migration of human umbilical vein endothelial cells (HUVECs) was tested using a wound-healing assay. HUVEC invasion was assayed using a Transwell chamber. Cell surface expression of Toll-like receptor 4 (TLR4) was analyzed by flow cytometry. Angiogenic factor vascular endothelial growth factor (VEGF) level was quantified by LUMINEX and protein expression was analyzed by Western blot. Translocation of nuclear factor-kappa B (NF-κB) was observed by fluorescence microscopy. Celastrol inhibited LPS-stimulated LP-1 human multiple myeloma-induced HUVEC migration and invasion in a concentration-dependent manner. Wound diameters increased by 72.9, 165.4 and 246.2% at 0.025, 0.05 and 0.1 µM, respectively, compared to LPS alone. A 45-74% inhibition of LPS-dependent cell invasion was achieved in the presence of 0.025-0.1 µM celastrol. Celastrol significantly downregulated LPS-induced TLR4 expression and inhibited LPS-induced VEGF secretion in LP-1 cells. VEGF levels decreased by 64.8, 84.4 and 92.9% after coexposure to celastrol at 0.025, 0.05 and 0.1 µM, respectively, compared to LPS alone. Celastrol also inhibited the IκB kinase (IKK)/NF-κB pathway induced by LPS. Protein levels of NF-κB p65, IKKa and IκB-a decreased in a dose-dependent manner after coexposure to celastrol. Celastrol also blocked nuclear translocation of the p65 subunit. These results suggest that celastrol inhibits LPS-induced angiogenesis by suppressing TLR4-triggered NF-κB activation.
Inactivation of Pyruvate Kinase or the Phosphoenolpyruvate: Sugar Phosphotransferase System Increases Shikimic and Dehydroshikimic Acid Yields from Glucose in Bacillus subtilis
Authors: Licona-Cassani Cuauhtemoc , Lara Alvaro R. , Cabrera-Valladares Natividad , Escalante Adelfo , Hernández-Chávez Georgina , Martinez Alfredo , Bolívar Francisco , Gosset Guillermo
Published: October 2013

The glycolytic intermediate phosphoenolpyruvate (PEP) is a precursor of several cellular components, including various aromatic compounds. Modifications to the PEP node such as PEP:sugar phosphotransferase system (PTS) or pyruvate kinase inactivation have been shown to have a positive effect on aromatics production capacity in Escherichia coli and Bacillus subtilis. In this study, pyruvate kinase and PTS-deficient B. subtilis strains were employed for the construction of derivatives lacking shikimate kinase activity that accumulate two industrially valuable chemicals, the intermediates of the common aromatic pathway, shikimic and dehydroshikimic acids. The pyruvate kinase-deficient strain (CLC6-PYKA) showed the best production parameters under resting-cell conditions. Compared to the PTS-deficient strain, the shikimic and dehydroshikimic acids specific production rates for CLC6-PYKA were 1.8- and 1.7-fold higher, respectively. A batch fermentor culture using complex media supplemented with 83 g/l of glucose was developed with strain CLC6-PYKA, where final titers of 4.67 g/l (shikimic acid) and 6.2 g/l (dehydroshikimic acid) were produced after 42 h.
Crucial Role of ROCK2 in Vascular Smooth Muscle Cells for Hypoxia-Induced Pulmonary Hypertension in Mice
Authors: Shimizu Toru , Fukumoto Yoshihiro , Tanaka Shin-ichi , Satoh Kimio , Ikeda Shohei , Shimokawa Hiroaki
Published: October 2013

Objective—

Rho/Rho-kinase (ROCK) pathway in vascular smooth muscle cells (VSMCs) plays an important role in the pathogenesis of cardiovascular diseases, including pulmonary arterial hypertension (PAH). Rho-kinase has 2 isoforms, ROCK1 and ROCK2, with different functions in different cells; ROCK1 for circulating inflammatory cells and ROCK2 for the vasculature. In the present study, we aimed to examine whether ROCK2 in VSMC is involved in the pathogenesis of PAH.

Approach and Results—

In patients with PAH, the expression of ROCK2 was increased in pulmonary arterial media and primary pulmonary arterial smooth muscle cells when compared with controls. To investigate the role of ROCK2 in VSMC, we generated VSMC-specific heterozygous ROCK2-deficient (ROCK2
+/−
) mice and VSMC-specific ROCK2-overexpressing transgenic (ROCK2-Tg) mice. The extent of hypoxia-induced pulmonary hypertension was reduced in ROCK2
+/−
mice and was enhanced in ROCK2-Tg mice compared with respective littermates. The protein expression of ROCK activity and phosphorylated extracellular signal–regulated kinase and the number of Ki67-positive proliferating cells in the lung were reduced in ROCK2
+/−
mice and were increased in ROCK2-Tg mice compared with respective littermates. In cultured mouse aortic VSMC, migration and proliferation activities were reduced in ROCK2
+/−
mice, and migration activity was increased in ROCK2-Tg mice compared with respective littermates. In addition, in primary pulmonary arterial smooth muscle cells from a patient with PAH, ROCK2 was required for migration and proliferation through ROCK and extracellular signal–regulated kinase activation.

Conclusions—

ROCK2 in VSMC contributes to the pathogenesis of PAH.
Pericyte Regulation of Vascular Remodeling Through the CXC Receptor 3
Authors: Bodnar Richard J. , Rodgers Margaret E. , Chen William C.W. , Wells Alan
Published: October 2013

Objective—

To understand the role, if any, played by pericytes in the regulation of newly formed vessels during angiogenesis. In this study, we investigate whether pericytes regulate the number of nascent endothelial tubes.

Approach and Results—

Using an in vitro angiogenesis assay (Matrigel assay), we demonstrate that pericytes can inhibit vessel formation and induce vessel dissociation via CXCR3-induced involution of the endothelial cells. In a coculture Matrigel assay for cord formation, pericytes prevented endothelial cord formation of human dermal microvascular endothelial cells but not umbilical vein endothelial cells. Blockade of endothelial CXCR3 function or expression inhibited the repressing effect of the pericytes. We further show that pericytes are also able to induce regression of newly formed microvascular cords through CXCR3 activation of calpain. When CXCR3 function was inhibited by a neutralizing antibody or downregulated by siRNA, cord regression mediated by pericytes was abolished.

Conclusions—

We show for the first time that pericytes regulate angiogenic vessel formation, and that this is mediated through CXCR3 expressed on endothelial cells. This suggests a role for pericytes in the pruning of immature vessels overproduced during wound repair.
Assessment of Mitral Valve Area During Percutaneous Mitral Valve Repair Using the MitraClip System
Authors: Biaggi Patric , Felix Christian , Gruner Christiane , Herzog Bernhard A. , Hohlfeld Sabine , Gaemperli Oliver , Stähli Barbara E. , Paul Michaela , Held Leonhard , Tanner Felix C. , Grünenfelder Jürg , Corti Roberto , Bettex Dominique
Published: October 2013

Background—

Quantification of the mitral valve area (MVA) is important to guide percutaneous mitral valve repair using the MitraClip system. However, little is known about how to best assess MVA in this specific situation.

Methods and Results—

Immediately before and after MitraClip implantation, comprehensive 3-dimensional (3D) transesophageal echocardiography data were acquired for MVA assessment by the pressure half-time method and by two 3D quantification methods (mitral valve quantification software and 3D quantification software). In addition, transmitral gradients by continuous-wave Doppler (dPmean
CW
) were measured to indirectly assess MVA. Data are given as median (interquartile range). Thirty-three patients (39% women) with a median age of 77.1 years (12.4 years) were studied. Before intervention, the median MVAs by the pressure half-time method, mitral valve quantification software, and 3D quantification software were 4.4 cm
2
(2.0 cm
2
), 4.7 cm
2
(2.4 cm
2
), and 6.2 cm
2
(2.4 cm
2
), respectively (
P
<0.001). After intervention, MVA was reduced to 1.9 cm
2
(0.7 cm
2
), 2.1 cm
2
(1.1 cm
2
), and 2.8 cm
2
(1.1 cm
2
), respectively (
P
=0.001). The median values for dPmean
CW
before and after intervention were 1.0 mm Hg (1.0 mm Hg) and 3.0 mm Hg (3.0 mm Hg;
P
<0.001), respectively. At discharge, the median dPmean
CW
was 4.0 mm Hg (3.0 mm Hg). In multivariate regression analyses including body surface area, the 3 different MVA methods, and dPmean
CW
, a post-dPmean
CW
≥5 mm Hg was the best independent predictor of an elevated transmitral gradient at discharge.

Conclusions—

Transmitral gradients by continuous-wave Doppler are quick, feasible in all patients, and superior to direct peri-interventional assessment of MVA. A postinterventional transmitral gradient by continuous-wave Doppler of ≥5 mm Hg best predicted elevated transmitral gradients at discharge.
Placental Vascular Dysfunction, Fetal and Childhood Growth, and Cardiovascular Development
Authors: Gaillard Romy , Steegers Eric A.P. , Tiemeier Henning , Hofman Albert , Jaddoe Vincent W.V.
Published: October 2013

Background—

Suboptimal fetal nutrition may influence early growth and cardiovascular development. We examined whether umbilical and uterine artery resistance indices, as measures of feto-placental and utero-placental vascular function, respectively, are associated with fetal and childhood growth and cardiovascular development.

Methods and Results—

This study was embedded in a population-based prospective cohort study among 6716 mothers and their children. Umbilical artery pulsatility index and uterine artery resistance index and fetal growth were measured in third trimester. Childhood growth was repeatedly assessed from birth to the age of 6 years. We measured body fat distribution, left ventricular mass, and blood pressure at the age of 6 years. Higher third trimester umbilical and uterine artery vascular resistance were associated with lower fetal length and weight growth in third trimester resulting in a smaller size at birth among boys and girls (
P
values < 0.05). These differences in length and weight growth became smaller from the age of 6 months onwards, but were still present at the age of 6 years. Higher third trimester umbilical artery vascular resistance, but not uterine artery vascular resistance, was associated with higher childhood body mass index, total fat mass, android/gynoid fat mass ratio, and systolic blood pressure, and with a lower left ventricular mass (
P
values<0.05). These associations were not explained by birth weight. Stronger associations tended to be present among girls as compared with boys.

Conclusions—

Higher third trimester feto-placental vascular resistance, but not utero-placental vascular resistance, was associated with slower fetal growth rates and cardiovascular adaptations in childhood.
MnSOD
tg
Mice Control Myocardial Inflammatory and Oxidative Stress and Remodeling Responses Elicited in Chronic Chagas Disease
Authors: Dhiman Monisha , Wan Xianxiu , Popov Vsevolod L. , Vargas Gracie , Garg Nisha Jain
Published: October 2013

Background

We utilized genetically modified mice equipped with a variable capacity to scavenge mitochondrial and cellular reactive oxygen species to investigate the pathological significance of oxidative stress in
C
hagas disease.

Methods and Results

C57
BL
/6 mice (wild type, Mn
SOD
tg
, Mn
SOD
+/−
,
GP
x1
−/−
) were infected with
Trypanosoma cruzi
and harvested during the chronic disease phase. Chronically infected mice exhibited a substantial increase in plasma levels of inflammatory markers (nitric oxide, myeloperoxidase), lactate dehydrogenase, and myocardial levels of inflammatory infiltrate and oxidative adducts (malondialdehyde, carbonyls, 3‐nitrotyrosine) in the order of wild type=Mn
SOD
+/−
>
GP
x1
−/−
>Mn
SOD
tg
. Myocardial mitochondrial damage was pronounced and associated with a >50% decline in mitochondrial
DNA
content in chronically infected wild‐type and
GP
x1
−/−
mice. Imaging of intact heart for cardiomyocytes and collagen by the nonlinear optical microscopy techniques of multiphoton fluorescence/second harmonic generation showed a significant increase in collagen (>10‐fold) in chronically infected wild‐type mice, whereas
GP
x1
−/−
mice exhibited a basal increase in collagen that did not change during the chronic phase. Chronically infected Mn
SOD
tg
mice exhibited a marginal decline in mitochondrial
DNA
content and no changes in collagen signal in the myocardium. P47
phox−/−
mice lacking phagocyte‐generated reactive oxygen species sustained a low level of myocardial oxidative stress and mitochondrial
DNA
damage in response to
Trypanosoma cruzi
infection. Yet chronically infected p47
phox−/−
mice exhibited increase in myocardial inflammatory and remodeling responses, similar to that noted in chronically infected wild‐type mice.

Conclusions

Inhibition of oxidative burst of phagocytes was not sufficient to prevent pathological cardiac remodeling in Chagas disease. Instead, enhancing the mitochondrial reactive oxygen species scavenging capacity was beneficial in controlling the inflammatory and oxidative pathology and the cardiac remodeling responses that are hallmarks of chronic Chagas disease.