bluuebunny/crossref_metadata_2025 huggingface dataset:
Research Activities in the Field of Electromagnetic Energy Harvesting Micro Systems
Authors: Wurz Marc Christopher
Published: May 2015

The use of energy from the ambient shows a great possibility to reduce energy consumption. One point is energy harvesting, which means to obtain electrical energy from available sources like solar, thermal or vibrational energy [1]. Therefore the development of new forms for converting energy is in the focus of researchers. For macroscopic systems solar cells and wind turbines are the most common used energy transformation systems. In the field of microsystems the use of vibrational energy seems to be the best convertible energy form. At this moment there are many activities to develop self-sufficient systems for sensor and also for actuator applications [2]. One vision in this context is a self-sufficient sensor network. This paper gives a review about the state of the art in the field of electromagnetic energy harvesting systems and especially the research activities at the IMPT
Kinetic and Thermodynamic Study of Mercury (II) Adsorption on Ca-Bentonite
Authors: Robles Irma , Godínez L , Bustos Erika
Published: May 2015

The adsorption of Hg (II) from aqueous solution into Ca-bentonite was studied using a batch technique under controlled condition of temperature and constant pressure. Adsorption percentage was determined as a function of shaking time and temperature to study the adsorption thermodynamics and kinetics of Hg (II) on Ca-bentonite. The results showed that the adsorption behavior of Hg (II) on Ca-bentonite was strongly dependent on time and temperature. The adsorption isotherms were simulated by the Langmuir, Freundlich, Temkin, Dubinin-Radushkevich and Flory-Huggins models. The results of kinetics studies show that the adsorption reaction is second order with respect to the metal cation solution concentration. The thermodynamic parameters (ΔHº, ΔSº and ΔGº) were determined at four different temperatures. The results of thermodynamic investigation indicates the adsorption reaction ΔG° (Hgads < Hgsol), with a bond energy ΔH° of -40.57 KJ·mol-1 and a low energy ΔS° minor of cero.
Effect of SAM Chain Length on Mediated Amperometric Detection of Glucose
Authors: Suroviec Alice H
Published: May 2015

Alkanethiol self-assembled monolayers of three different chain lengths were used to immobilize glucose oxidase onto gold disk electrodes and the effect of the length on the kinetics of the electron-transfer reaction were investigated. 6 – mercaptohexanoic acid and 9 – mercaptononanoic acid was synthesized to provide a chain length shorter then the commercially available 11 – mercaptoundecanoic acid. The surface coverage of these SAMs, the detection sensitivity, and enzyme kinetics were investigated using cyclic voltammetry. Results showed that SAM of the 6-mercaptohexanoic acid had a higher degree of surface coverage as well as more efficient enzyme kinetics than expected.
Finite Elements Analysis of an Electrochemical Coating Process of an Irregularly Shaped Cathode with COMSOL Multiphysics®
Authors: Giaccherini A , Caporali S , Berretti E , Marcantelli P , Sanzari I , Perissi I , Innocenti Massimo
Published: May 2015

The overall goal of this work is the use of COMSOL Multiphysics® in the modelling of the current density distributions for the electrodeposition of Aluminium coatings from Ionic Liquids baths. The local current distribution is strongly dependant on the conductivity, on the distribution of concentrations and on the geometry of the galvanic cell, such a calculation can only be performed by the numerical solution of the PDE’s governing the system. This work approach is to exploit computational techniques based on the well-known FEA (Finite Elements Analysis) to obtain stationary and dynamical solutions of such problem. The ability to predict the local current density on an electrode is crucial to eventually evidence portions where the deposition may be invalidated.
Alternative to H3PO4 for Si3N4 Removal by Using Chemical Downstream Etching
Authors: de Buttet Côme , Gourhant Olivier , Bouyssou Régis , Zoll Stephane
Published: May 2015

Silicon Nitride is with SiO2, one of the most used material in the VLSI. Most of the time it is deposited as a sacrificial layer: etch stop and CMP buffer layers, temporary or permanent spacers, hard masks for epitaxies, etc… In the present work we have been able to remove Si3N4 without the use of conventional H3PO4 chemistry. We managed to integrate a chemical downstream etching (CDE) process to 28nm and 14nm FDSOI wafers. Aspects of uniformity, selectivity and defectivity will be discussed in this paper.
A Study on the Decomposition of SPS and Its Effects on Via Filling Performance
Authors: Kimizuka Ryoichi , Toda Hisayuki , Eda Tetsuro , Kishimoto Kazuki , Takaya Yasuko , Oh Reisei , Takai Osamu
Published: May 2015

Electrolytic copper via filling based on three additive component copper sulfate bath chemistry has been and currently is widely used in electronic packaging. Progression in copper sulfate plating chemistry is vital to development of smart phones among other devices. In order to further elucidate bath chemistry and possible methods to improve performance, degradation of the disodium 3,3'-dithiobis(1-propanesulfonate) (SPS) additive, which is employed as brightener, during copper via filling by electrodeposition and the influence of a byproduct on plating was investigated. Oxidative decomposition of SPS and formation of disodium 1,3-propanedisulfonate (PDS) at an IrO2 coated Ti insoluble anode during electrolysis was confirmed by NMR analysis. By addition to a fresh bath, PDS was then shown to compromise via filling performance. This study clarified the anodic oxidation of SPS to PDS under electrolytic filling conditions and that the PDS concentration correlated to the filling ability of the copper plating bath.
Development of Glyoxylic Acid Based Electroless Copper Deposition on Ruthenium
Authors: Inoue Fumihiro , Philipsen Harold , van der Veen Marleen , Van Huylenbroeck Stefaan , Armini Silvia , Struyf Herbert , Shingubara Shoso , Tanaka Tetsu
Published: May 2015

Glyoxylic acid is seen as a promising candidate to replace formaldehyde as reducing agent in electroless Cu baths. For deposition on ruthenium, the anodic reaction of glyoxylic acid has been evaluated and compared to formaldehyde using linear sweep voltammetry. Significant differences were observed for the deposition of copper on ruthenium. First of all, a faster nucleation to shorten the total process time, was inferred from open-circuit potential measurements. Secondary, we found 2,2’ bipyridyl worked as stabilizer, brightener, and suppressor in this glyoxylic acid-based electroless bath. Thirdly, the purity of the copper films improved when 2,2’ bipyridyl was present in the solution. Using the optimized composition for the electroless bath, we demonstrate a conformal Cu seed layer deposition (~100 nm) inside high aspect ratio (16.7) through Si vias. This work shows the potential for electroless Cu seeding for a through Si via metallization.
Cu Displacement Plating on Electroless Plated CoWB Layer on SiO2 and Its Adhesion Property
Authors: Ohta Kohei , Inoue Fumihiro , Shimizu Tomohiro , Shingubara Shoso
Published: May 2015

For realizing high aspect ratio TSV with a low cost, the all-wet process utilizing electroless barrier and Cu-seed layers prior to Cu electroplated fill is one of the most promising methods. However, improvement of adhesion property of electroless plated barrier and seed layers on SiO2 has been intensively required. In this study, we studied displacement plating of Cu on electroless CoWB layer formed on SiO2 in an acidic bath. It turned out that displacement-plated Cu film grew with sacrifice of the partial CoWB layer, and showed a high adhesion strength that was enough to pass CMP process.
Stability Evaluation of Non-Agglomerated Pd Nanoparticle Catalyst Dispersion for Electroless Deposition
Authors: Nakamura Noriaki , Taniuchi Junichi , Sone Takayuki , Sasaki Kotoe , Inoue Fumihiro , Shimizu Tomohiro , Shingubara Shoso
Published: May 2015

We investigated the stability and adsorption properties of a Pd nanoparticles which are used for catalyst of electroless plating on dielectrics substrate. Some additives for Pd nanoparticle dispersion significantly improved the stability of the dispersion without deteriorating the adsorption of the Pd nanoparticles. Furthermore, the additives redispersed agglomerated Pd nanoparticles. These results suggest a method for applying Pd nanoparticles in manufacturing processes.
Barrier Metal Slurry for Low Defect Copper Damascene Chemical Mechanical Polishing
Authors: Kim Hojoong , Seo Kyewon , Moon Jinok , Kim Hyunsoo , Hwang Hasub
Published: May 2015

To make a superior flat surface in Cu damascene process, chemical mechanical planarization or polishing (CMP) is inevitably utilized. CMP process uses slurry reacts with various materials on wafer surface such as Cu line, barrier metal, and oxide dielectric. Thus, slurry should have balanced reaction between mechanical and chemical effect to achieve flatness. Not only flatness but also defect occurrence on the surface is another important parameter in mass semiconductor fabrication. In present study, we developed slurry having lower defect occurrence than conventional one. Optimizations are applied to components in the slurry such as abrasive morphology, abrasive surface treatment and organics acids in slurry chemical
Methods of Patterned Mist Deposition of Nano-Crystalline Quantum Dot Films
Authors: Sabeeh Ala , Thakur Yash , Chao Ju-Hung , Kshirsagar Aditya , Ruzyllo Jerzy
Published: May 2015

This paper is concerned with patterning of ultra-thin films formed by means of mist deposition technique using colloidal solutions of nanocrystalline quantum dots (NQDs). It discusses patterns created using mechanical masks as well as area selective bottom-up growth of quantum dot films which follows patterns created by means of pre-mist deposition surface functionalization. A new method of nanocrystalline quantum dot film patterning by means of a lift-off process is proposed and investigated. The results obtained show effectiveness of both gas-phase (oxygen plasma) and liquid-phase (acetone) based lift-off steps in forming NQD patterns with the resolution defined by the resolution of the photolithographic process used to pattern photoresist.
Emission of White Light from Doped and Undoped Oxide Nanopowders
Authors: Bilir Gokhan , Ozen Gonul , Collins John , Di Bartolo Baldassare
Published: May 2015

We have obtained white light (WL) with high efficiency and color rendering index (CRI) approaching the theoretical limit. We report the production of a broad band (ranging from 400 to 900 nm) WL following the monochromatic infrared light (803.5 and 975 nm) excitation of both nominally un-doped and rare earth and transition metal ions-doped oxide nano-powders. Experimental results indicate that such an emission feature is a nano-scale phenomenon, cannot be ascribed to an overlap of sharp emission bands in the un-doped case and, even if assisted by the dopant presence, is a host matrix-related process. The spectral distribution of the detected WL resembles very closely that of an incandescent lamp, which in turn is the most comfortable light to human eyes. Our experimental results make our WL emission very interesting at both the fundamental and the applicative level and may open the way to an alternative route with respect to incandescent lamps.
The Study of Dissolved Oxygen Control in TSV Electroplating Deposition Process
Authors: Kim Dae-Gil , Lee Dosun , Kim Young-Wan , Kim Sang-Yun , Seo Jung-Suk , Hong Jin-suk
Published: May 2015

The effects of various parameters in copper electroplating electrolyte on the filling characteristics of through silicon via(TSVs). Among the various parameters, the concentration of dissolved oxygen was found to be susceptible to bottom-up filling rate. The concentration of dissolved oxygen was effectively lowered by installing the hardware named 'degasser' at the circulation line. The installation of 'degasser' enabled the maintenance of stable bottom-up filling rates for the defect-free filling of TSVs.
Electrochemical Deposition of ZnO Nanotubes with Small Dimples on the External Surface
Authors: Osamura Keisuke , Matsunaga Mariko
Published: May 2015

To improve the photoelectric conversion efficiency of dye-sensitized solar cells, various semiconductor oxides, including zinc oxide (ZnO) and titanium oxide (TiO2), have been studied as photo electrodes. ZnO generally possesses better electron conductivity than TiO2, although TiO2 is one of the best substrate for the stable loading of dye molecules due to the strength of the dye-TiO2 chemical interaction. Therefore, it is important to improve the ZnO loading performance without diminishing its electron conductivity. ZnO nanotubes are known to exhibit high surface area and high conductivity. Recently, we focused our research on the high density ZnO nanotubes prepared by one-step electrodeposition at moderate temperature (<100 °C). Since the surface of the oxide semiconductor plays a significant role for loading the dye molecules, we report how the deposition conditions influence the surface morphology of the one-step electrodeposited ZnO.
Assessment of Cytocompatibility and Magnetic Properties of Nanostructured Silicon Loaded with Superparamagnetic Iron Oxide Nanoparticles
Authors: Granitzer Petra , Rumpf Klemens , Tian Yuan , Coffer Jeffery , Akkaraju Giri , Poelt Peter , Reissner Michael
Published: May 2015

The aim of this work is to create a biocompatible superparamagnetic nanocomposite applicable as vehicle for magnetically guided drug delivery. Both materials, the nanostructured silicon as well as the iron oxide nanoparticles offer low toxicity. Therefore Fe3O4-nanoparticles have been incorporated within nanostructured silicon. On the one hand the iron oxide nanoparticles have been synthesized in solution and then infiltrated and on the other hand they have been chemically grown within the pores. The magnetic properties of the system have been optimized concerning the blocking temperature TB and the magnetic moment M, which are conflicting parameters. A particle-size/distance and template dependent assessment of the magnetic properties of the nanocomposite will be presented. Although the growth of iron oxide particles within the porous template is not easy to control the blocking temperature of the composite could be achieved far below room temperature.
Right ventricular nitric oxide signaling in an ovine model of congenital heart disease: a preserved fetal phenotype
Authors: Kameny Rebecca Johnson , He Youping , Morris Catherine , Sun Christine , Johengen Michael , Gong Wenhui , Raff Gary W. , Datar Sanjeev A. , Oishi Peter E. , Fineman Jeffrey R.
Published: May 2015

We recently reported superior right ventricle (RV) performance in response to acute afterload challenge in lambs with a model of congenital heart disease with chronic left-to-right cardiac shunts. Compared with control animals, shunt lambs demonstrated increased contractility because of an enhanced Anrep effect (the slow increase in contractility following myocyte stretch). This advantageous physiological response may reflect preservation of a fetal phenotype, since the RV of shunt lambs remains exposed to increased pressure postnatally. Nitric oxide (NO) production by NO synthase (NOS) is activated by myocyte stretch and is a necessary intermediary of the Anrep response. The purpose of this study was to test the hypothesis that NO signaling is increased in the RV of fetal lambs compared with controls and shunt lambs have persistence of this fetal pattern. An 8-mm graft was placed between the pulmonary artery and aorta in fetal lambs (shunt). NOS isoform expression, activity, and association with activating cofactors were determined in fetal tissue obtained during late-gestation and in 4-wk-old juvenile shunt and control lambs. We demonstrated increased RNA and protein expression of NOS isoforms and increased total NOS activity in the RV of both shunt and fetal lambs compared with control. We also found increased NOS activation and association with cofactors in shunt and fetal RV compared with control. These data demonstrate preserved fetal NOS phenotype and NO signaling in shunt RV, which may partially explain the mechanism underlying the adaptive response to increased afterload seen in the RV of shunt lambs.
Females have a blunted cardiovascular response to one year of intensive supervised endurance training
Authors: Howden Erin J. , Perhonen Merja , Peshock Ronald M. , Zhang Rong , Arbab-Zadeh Armin , Adams-Huet Beverley , Levine Benjamin D.
Published: May 2015

Cross-sectional studies in athletes suggest that endurance training augments cardiovascular structure and function with apparently different phenotypes in athletic males and females. It is unclear whether the longitudinal response to endurance training leads to similar cardiovascular adaptations between sexes. We sought to determine whether males and females demonstrate similar cardiovascular adaptations to 1 yr of endurance training, matched for training volume and intensity. Twelve previously sedentary males (26 ± 7, n = 7) and females (31 ± 6, n = 5) completed 1 yr of progressive endurance training. All participants underwent a battery of tests every 3 mo to determine maximal oxygen uptake (V̇o2max) and left ventricle (LV) function and morphology (cardiac magnetic resonance imaging). Pulmonary artery catheterization was performed before and after 1 yr of training, and pressure-volume and Starling curves were constructed during decreases (lower-body negative pressure) and increases (saline infusion) in cardiac volume. Males progressively increased V̇o2max, LV mass, and mean wall thickness, before reaching a plateau from month 9 to 12 of training. In contrast, despite exactly the same training, the response in females was markedly blunted, with V̇o2max, LV mass, and mean wall thickness plateauing after only 3 mo of training. The response of LV end-diastolic volume was not influenced by sex (males +20% and females +18%). After training Starling curves were shifted upward and left, but the effect was greatest in males (interaction P = 0.06). We demonstrate for the first time clear sex differences in response to 1 yr of matched endurance training, such that the development of ventricular hypertrophy and increase in V̇o2maxin females is markedly blunted compared with males.
Molecular Pathways and Therapies in Autosomal-Dominant Polycystic Kidney Disease
Authors: Saigusa Takamitsu , Bell P. Darwin
Published: May 2015

Autosomal-dominant polycystic kidney disease (ADPKD) is the most prevalent inherited renal disease, characterized by multiple cysts that can eventually lead to kidney failure. Studies investigating the role of primary cilia and polycystins have significantly advanced our understanding of the pathogenesis of PKD. This review will present clinical and basic aspects of ADPKD, review current concepts of PKD pathogenesis, evaluate potential therapeutic targets, and highlight challenges for future clinical studies.
Mitochondria, Muscle Health, and Exercise with Advancing Age
Authors: Carter Heather N. , Chen Chris C. W. , Hood David A.
Published: May 2015

Skeletal muscle health is dependent on the optimal function of its mitochondria. With advancing age, decrements in numerous mitochondrial variables are evident in muscle. Part of this decline is due to reduced physical activity, whereas the remainder appears to be attributed to age-related alterations in mitochondrial synthesis and degradation. Exercise is an important strategy to stimulate mitochondrial adaptations in older individuals to foster improvements in muscle function and quality of life.
Increase in Short-Interval Intracortical Facilitation of the Motor Cortex after Low-Frequency Repetitive Magnetic Stimulation of the Unaffected Hemisphere in the Subacute Phase after Stroke
Authors: Mello Eduardo Arruda , Cohen Leonardo G. , Monteiro dos Anjos Sarah , Conti Juliana , Andrade Karina Nocelo F. , Tovar Moll Fernanda , Marins Theo , Fernandes Corina A. , Rodrigues Waldyr , Conforto Adriana Bastos
Published: April 2015

Low-frequency repetitive transcranial magnetic stimulation of the unaffected hemisphere (UH-LF-rTMS) in patients with stroke can decrease interhemispheric inhibition from the unaffected to the affected hemisphere and improve hand dexterity and strength of the paretic hand. The objective of this proof-of-principle study was to explore, for the first time, effects of UH-LF-rTMS as add-on therapy to motor rehabilitation on short-term intracortical inhibition (SICI) and intracortical facilitation (ICF) of the motor cortex of the unaffected hemisphere (M1UH) in patients with ischemic stroke. Eighteen patients were randomized to receive, immediately before rehabilitation treatment, either active or sham UH-LF-rTMS, during two weeks. Resting motor threshold (rMT), SICI, and ICF were measured inM1UHbefore the first session and after the last session of treatment. There was a significant increase in ICF in the active group compared to the sham group after treatment, and there was no significant differences in changes in rMT or SICI. ICF is a measure of intracortical synaptic excitability, with a relative contribution of spinal mechanisms. ICF is typically upregulated by glutamatergic agonists and downregulated by gabaergic antagonists. The observed increase in ICF in the active group, in this hypothesis-generating study, may be related toM1UHreorganization induced by UH-LF-rTMS.
On the Equivalence of Differential Equations in the Sense of Coincidence Reflecting Functions
Authors: Zhou Zhengxin
Published: April 2015

We use a new method for constructing some differential equations which are equivalent to a given equation in the sense of having the same reflecting function. We completely solve the problem: when is a polynomial differential equation equivalent to a given polynomial differential equation? Many sufficient conditions have been established for one differential equation to be equivalent to a given differential equation. We apply the obtained results to study the boundary value problem of two equivalent differential equations.
Vitamin D Potentiates the Inhibitory Effect of MicroRNA‐130a in Hepatitis C Virus Replication Independent of Type I Interferon Signaling Pathway
Authors: Duan Xiaoqiong , Guan Yujuan , Li Yujia , Chen Shan , Li Shilin , Chen Limin
Published: April 2015

Calcitriol, the bioactive metabolite of vitamin D, was reported to inhibit HCV production in a synergistic fashion with interferon, a treatment in vitro. Our previous study established that miR‐130a inhibits HCV replication by restoring the host innate immune response. We aimed to determine whether there is additive inhibitory effect of calcitriol and miR‐130a on HCV replication. Here we showed that calcitriol potentiates the anti‐HCV effect of miR‐130a in both Con1b replicon and J6/JFH1 culture systems. Intriguingly, this potentiating effect of calcitriol on miR‐130a was not through upregulating the expression of cellular miR‐130a or through increasing the miR‐130a‐mediated IFNα/β production. All these findings may contribute to the development of novel anti‐HCV therapeutic strategies although the antiviral mechanism needs to be further investigated.
The Sparsity of Underdetermined Linear System vialpMinimization for0
0such that the following conclusions hold whenp<γ(A,b):(1)the problem(Pp)generates sparser solution as the value ofpdecreases;(2)the sparsest optimal solution to the problem(Pp)is unique under the sense of absolute value permutation;(3)letX1andX2be the sparsest optimal solution to the problems(Pp1)and(Pp2)  (p1<p2), respectively, and letX1not be the absolute value permutation ofX2. Then there existt1,t2∈[p1,p2]such thatX1is the sparsest optimal solution to the problem(Pt)  (∀t∈[p1,t1])andX2is the sparsest optimal solution to the problem(Pt)  (∀t∈(t2,p2]).
The Role of Inspiratory Muscle Training in Sickle Cell Anemia Related Pulmonary Damage due to Recurrent Acute Chest Syndrome Attacks
Authors: Camcıoğlu Burcu , Boşnak-Güçlü Meral , Karadallı Müşerrefe Nur , Akı Şahika Zeynep , Türköz-Sucak Gülsan
Published: April 2015

Background. The sickling of red blood cells causes a constellation of musculoskeletal, cardiovascular, and pulmonary manifestations. A 32-year-old gentleman with sickle cell anemia (SCA) had been suffering from recurrent acute chest syndrome (ACS).Aim. To examine the effects of inspiratory muscle training (IMT) on pulmonary functions, respiratory and peripheral muscle strength, functional exercise capacity, and quality of life in this patient with SCA.Methods. Functional exercise capacity was evaluated using six-minute walk test, respiratory muscle strength using mouth pressure device, hand grip strength using hand-held dynamometer, pain using Visual Analogue Scale, fatigue using Fatigue Severity Scale, dyspnea using Modified Medical Research Council Scale, and health related quality of life using European Organization for Research and Treatment of Cancer QOL measurement.Results. A significant improvement has been demonstrated in respiratory muscle strength, functional exercise capacity, pain, fatigue, dyspnea, and quality of life. There was no admission to emergency department due to acute chest syndrome in the following 12 months after commencing regular erythrocytapheresis.Conclusion. This is the first report demonstrating the beneficial effects of inspiratory muscle training on functional exercise capacity, respiratory muscle strength, pain, fatigue, dyspnea, and quality of life in a patient with recurrent ACS.
Isolation, Structural Characterization, and Valorization of Pectic Substances from Algerian Argan Tree Leaves (Argania spinosa(L.) Skeels)
Authors: Hachem Kadda , Labani Abderrahmane , Kaid-Harche Meriem
Published: April 2015

Pectic polysaccharides were solubilized from Algerian argan tree leaves by sequential extraction with water at 100°C (water-soluble pectin; AL-WSP) and EDTA solution at 80°C (chelating-soluble pectin; AL-CSP). Both AL-WSP and AL-CSP were rich in arabinose (28% and 74.5%, resp.) and had a high content of uronic acid (38.5% and 21.5%, resp.). Pectic substances were deesterified and fractionated by anion exchange chromatography, giving five fractions for each extract. Most of the fractions were characterized by methylation analysis and then analyzed by13C nuclear magnetic resonance spectroscopy. The results showed that AL-WSP consisted of rhamnogalacturonan type I, with arabinan and galactan branching at the O-4 position of the main rhamnose chain, while AL-CSP consisted of rhamnogalacturonan type I and a block of homogalacturonan. Antioxidant activities of AL-WSP and AL-CSP were evaluated by electronic spin resonance. The results showed that the antioxidant potential of AL-WSP (8.1%) and AL-CSP (−1.2%) was significantly lower than that of vitamin E.
High-Frequency Targetable EGFR Mutations in Sinonasal Squamous Cell Carcinomas Arising from Inverted Sinonasal Papilloma
Authors: Udager Aaron M. , Rolland Delphine C.M. , McHugh Jonathan B. , Betz Bryan L. , Murga-Zamalloa Carlos , Carey Thomas E. , Marentette Lawrence J. , Hermsen Mario A. , DuRoss Kathleen E. , Lim Megan S. , Elenitoba-Johnson Kojo S.J. , Brown Noah A.
Published: May 2015

Inverted sinonasal papilloma (ISP) is a locally aggressive neoplasm associated with sinonasal squamous cell carcinoma (SNSCC) in 10% to 25% of cases. To date, no recurrent mutations have been identified in ISP or SNSCC. Using targeted next-generation sequencing and Sanger sequencing, we identified activating EGFR mutations in 88% of ISP and 77% of ISP-associated SNSCC. Identical EGFR genotypes were found in matched pairs of ISP and associated SNSCC, providing the first genetic evidence of a biologic link between these tumors. EGFR mutations were not identified in exophytic or oncocytic papillomas or non–ISP-associated SNSCC, suggesting that the ISP/SNSCC spectrum is biologically distinct among sinonasal squamous tumors. Patients with ISP harboring EGFR mutations also exhibited an increased progression-free survival compared with those with wild-type EGFR. Finally, treatment of ISP-associated carcinoma cells with irreversible EGFR inhibitors resulted in inactivation of EGFR signaling and growth inhibition. These findings implicate a prominent role for activating EGFR mutations in the pathogenesis of ISP and associated SNSCC and rationalize consideration of irreversible EGFR inhibitors in the therapy of these tumors. Cancer Res; 75(13); 2600–6. ©2015 AACR.
Building a Funded Research Program in Cancer Health Disparities: Considerations for Young Investigators
Authors: Ochs-Balcom Heather M. , Phillips Lynette S. , Nichols Hazel B. , Martinez Elena , Thompson Beti , Ojeifo John , Rebbeck Timothy R.
Published: May 2015

A workshop entitled “Building a funded research program in cancer health disparities” was held at the 38th Annual American Society of Preventive Oncology (ASPO) Meeting. Organized by the Junior Members Interest Group, the session addressed topics relevant to career development for cancer disparities investigators. Such considerations include the development of research programs on a backdrop of existing multi- and transdisciplinary teams, recognizing opportunities for advancing their research, given the growth of consortia-related research, and development of effective community-based partnerships. Key strategies for developing a sustainable career in cancer health disparities in the current environment include the need to effectively engage with communities, appreciate the value of team science and develop cross-discipline collaborations, and navigate the use and utility of consortia for disparities research. Academic considerations related to earning tenure and promotion that may be faced by the junior investigator in cancer health disparities were also discussed. This report may serve to both educate and provide lessons for early-stage investigators who wish to tackle complex scientific questions while developing their careers in cancer health disparities. Cancer Epidemiol Biomarkers Prev; 24(5); 882–5. ©2015 AACR.
IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma
Authors: Carson Craig C. , Moschos Stergios J. , Edmiston Sharon N. , Darr David B. , Nikolaishvili-Feinberg Nana , Groben Pamela A. , Zhou Xin , Kuan Pei Fen , Pandey Shaily , Chan Keefe T. , Jordan Jamie L. , Hao Honglin , Frank Jill S. , Hopkinson Dennis A. , Gibbs David C. , Alldredge Virginia D. , Parrish Eloise , Hanna Sara C. , Berkowitz Paula , Rubenstein David S. , Miller C. Ryan , Bear James E. , Ollila David W. , Sharpless Norman E. , Conway Kathleen , Thomas Nancy E.
Published: May 2015

Purpose: IL2 inducible T-cell kinase (ITK) promoter CpG sites are hypomethylated in melanomas compared with nevi. The expression of ITK in melanomas, however, has not been established and requires elucidation.

Experimental Design: An ITK-specific monoclonal antibody was used to probe sections from deidentified, formalin-fixed paraffin-embedded tumor blocks or cell line arrays and ITK was visualized by IHC. Levels of ITK protein differed among melanoma cell lines and representative lines were transduced with four different lentiviral constructs that each contained an shRNA designed to knockdown ITK mRNA levels. The effects of the selective ITK inhibitor BI 10N on cell lines and mouse models were also determined.

Results: ITK protein expression increased with nevus to metastatic melanoma progression. In melanoma cell lines, genetic or pharmacologic inhibition of ITK decreased proliferation and migration and increased the percentage of cells in the G0–G1 phase. Treatment of melanoma-bearing mice with BI 10N reduced growth of ITK-expressing xenografts or established autochthonous (Tyr-Cre/Ptennull/BrafV600E) melanomas.

Conclusions: We conclude that ITK, formerly considered an immune cell–specific protein, is aberrantly expressed in melanoma and promotes tumor development and progression. Our finding that ITK is aberrantly expressed in most metastatic melanomas suggests that inhibitors of ITK may be efficacious for melanoma treatment. The efficacy of a small-molecule ITK inhibitor in the Tyr-Cre/Ptennull/BrafV600E mouse melanoma model supports this possibility. Clin Cancer Res; 21(9); 2167–76. ©2015 AACR.
Synergistic Leukemia Eradication by Combined Treatment with Retinoic Acid and HIF Inhibition by EZN-2208 (PEG-SN38) in Preclinical Models of PML-RARα and PLZF-RARα–Driven Leukemia
Authors: Coltella Nadia , Valsecchi Roberta , Ponente Manfredi , Ponzoni Maurilio , Bernardi Rosa
Published: May 2015

Purpose: Retinoic acid-arsenic trioxide (ATRA-ATO) combination therapy is the current standard of care for patients with acute promyelocytic leukemia (APL) carrying the oncogenic fusion protein PML-RARα. Despite the high cure rates obtained with this drug combination, resistance to arsenic is recently emerging. Moreover, patients with APL carrying the PLZF-RARα fusion protein are partially resistant to ATRA treatment. Hypoxia-inducible factor-1α (HIF-1α) activation has been recently reported in APL, and EZN-2208 (PEG-SN38) is a compound with HIF-1α inhibitory function currently tested in clinical trials. This study investigates the effect of EZN-2208 in different preclinical APL models, either alone or in combination with ATRA.

Experimental Design: Efficacy of EZN-2208 in APL was measured in vitro by assessing expression of HIF-1α target genes, cell migration, clonogenicity, and differentiation, vis a vis the cytotoxic and cytostatic effects of this compound. In vivo, EZN-2208 was used in mouse models of APL driven by PML-RARα or PLZF-RARα, either alone or in combination with ATRA.

Results: Treatment of APL cell lines with noncytotoxic doses of EZN-2208 causes dose-dependent downregulation of HIF-1α bona fide target genes and affects cell migration and clonogenicity in methylcellulose. In vivo, EZN-2208 impairs leukemia progression and prolongs mice survival in APL mouse models. More importantly, when used in combination with ATRA, EZN-2208 synergizes in debulking leukemia and eradicating leukemia-initiating cells.

Conclusions: Our preclinical data suggest that the combination ATRA-EZN-2208 may be tested to treat patients with APL who develop resistance to ATO or patients carrying the PLZF-RARα fusion protein. Clin Cancer Res; 21(16); 3685–94. ©2015 AACR.
AMG 595, an Anti-EGFRvIII Antibody–Drug Conjugate, Induces Potent Antitumor Activity against EGFRvIII-Expressing Glioblastoma
Authors: Hamblett Kevin J. , Kozlosky Carl J. , Siu Sophia , Chang Wesley S. , Liu Hua , Foltz Ian N. , Trueblood Esther S. , Meininger David , Arora Taruna , Twomey Brian , Vonderfecht Steven L. , Chen Qing , Hill John S. , Fanslow William C.
Published: May 2015

Epidermal growth factor receptor variant III (EGFRvIII) is a cancer-specific deletion mutant observed in approximately 25% to 50% of glioblastoma multiforme (GBM) patients. An antibody drug conjugate, AMG 595, composed of the maytansinoid DM1 attached to a highly selective anti-EGFRvIII antibody via a noncleavable linker, was developed to treat EGFRvIII-positive GBM patients. AMG 595 binds to the cell surface and internalizes into the endo-lysosomal pathway of EGFRvIII-expressing cells. Incubation of AMG 595 with U251 cells expressing EGFRvIII led to potent growth inhibition. AMG 595 treatment induced significant tumor mitotic arrest, as measured by phospho-histone H3, in GBM subcutaneous xenografts expressing EGFRvIII. A single intravenous injection of AMG 595 at 17 mg/kg (250 μg DM1/kg) generated complete tumor regression in the U251vIII subcutaneous xenograft model. AMG 595 mediated tumor regression in the D317 subcutaneous xenograft model that endogenously expresses EGFRvIII. Finally, AMG 595 treatment inhibited the growth of D317 xenografts orthotopically implanted into the brain as determined by magnetic resonance imaging. These results demonstrate that AMG 595 is a promising candidate to evaluate in EGFRvIII-expressing GBM patients. Mol Cancer Ther; 14(7); 1614–24. ©2015 AACR.
Combined Inhibition of Cyclin-Dependent Kinases (Dinaciclib) and AKT (MK-2206) Blocks Pancreatic Tumor Growth and Metastases in Patient-Derived Xenograft Models
Authors: Hu Chaoxin , Dadon Tikva , Chenna Venugopal , Yabuuchi Shinichi , Bannerji Rajat , Booher Robert , Strack Peter , Azad Nilofer , Nelkin Barry D. , Maitra Anirban
Published: May 2015

KRAS is activated by mutation in the vast majority of cases of pancreatic cancer; unfortunately, therapeutic attempts to inhibit KRAS directly have been unsuccessful. Our previous studies showed that inhibition of cyclin-dependent kinase 5 (CDK5) reduces pancreatic cancer growth and progression, through blockage of the centrally important RAL effector pathway, downstream of KRAS. In the current study, the therapeutic effects of combining the CDK inhibitor dinaciclib (SCH727965; MK-7965) with the pan-AKT inhibitor MK-2206 were evaluated using orthotopic and subcutaneous patient-derived human pancreatic cancer xenograft models. The combination of dinaciclib (20 mg/kg, i.p., three times a week) and MK-2206 (60 mg/kg, orally, three times a week) dramatically blocked tumor growth and metastasis in all eight pancreatic cancer models examined. Remarkably, several complete responses were induced by the combination treatment of dinaciclib and MK-2206. The striking results obtained in these models demonstrate that the combination of dinaciclib with the pan-AKT inhibitor MK-2206 is promising for therapeutic evaluation in pancreatic cancer, and strongly suggest that blocking RAL in combination with other effector pathways downstream from KRAS may provide increased efficacy in pancreatic cancer. Based on these data, an NCI–CTEP-approved multicenter phase I clinical trial for pancreatic cancer of the combination of dinaciclib and MK-2206 (NCT01783171) has now been opened. Mol Cancer Ther; 14(7); 1532–9. ©2015 AACR.
Abstract 1108: B-cell lymphoma-derived exosomes are reservoirs of inhibitors of apoptosis
Authors: Bennit Heather R. Ferguson , Valenzuela Malyn M. Asuncion , Jutzy Jessica S. , Wall Nathan R.
Published: May 2015

B-cells, along with other normal and cancerous cells, secrete 50-150 nm vesicles called exosomes. Exosomes carry proteins, mRNA, and miRNA that can be functional upon cellular uptake and are often specific to cell of origin, offering potential as disease biomarkers. Our lab has identified within exosomes from solid tumor cells a cancer-specific protein, Survivin, which is a member of the Inhibitors of Apoptosis (IAP) family. Whether Survivin and other IAP family members such as XIAP, cIAP1 or cIAP2 are also expressed in exosomes from hematopoietic malignancies is yet to be determined. In this study, we aim to investigate the exosomes released from B-cell lymphoma cells and determine the IAP content under basal and sublethal stress conditions. Three human non EBV-transformed B-cell lymphoma lines developed at Wayne State University were used. WSU-FSCCL (follicular small cleaved cell), WSU-DLCL-2 (diffuse large cell), and WSU-WM (Waldenstrom Macroglobulinemia) represent different levels of aggressiveness. Cells were cultured for 24 or 48 hours before exosome isolation from the conditioned media using either ultracentrifugation on a sucrose cushion or ExoQuick (System Biosciences). Sublethal levels of UV irradiation were determined for each cell line by analyzing DNA content by propidium iodide staining with a FACSCalibur. Protein quantity of exosomes was measured using a BCA assay, and protein content was studied using Western blotting. Corresponding gene expression was identified using RT-PCR. Here we report IAP protein and mRNA (except XIAP) within exosomes from basal cells. We are currently probing exosomes from stressed cells for comparison. We hypothesize that the IAP exosomal profile may change under stressed conditions. The specificity and variability in exosomal content offers capabilities not only as disease biomarkers, but also in the immunomodulating activity of exosomes which have shown roles in both stimulating and inhibiting the immune system, We have found evidence that exosomal Survivin plays an immune role in skewing Th1/Th2 populations and decreasing cytotoxic function. Changes in exosome content between basal and stressed cells may have roles in the immunomodulation of the tumor microenvironment which facilitates the evasion of lymphoma cells to immune destruction, as well as possible prognostic benefit as to whether treatments are being effective or detrimental.

Citation Format: Heather R. Ferguson Bennit, Malyn M. Asuncion Valenzuela, Jessica S. Jutzy, Nathan R. Wall. B-cell lymphoma-derived exosomes are reservoirs of inhibitors of apoptosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1108. doi:10.1158/1538-7445.AM2014-1108
Abstract 1151: SIRT6 induces EMT and promotes cancer cell invasion and migration in prostate cancer
Authors: Xie Qian , Wong Alice S. , Xia Weiliang
Published: May 2015

Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer related death in males in the developed countries. One of the major clinical challenges is the propensity for advanced PCa to metastasize to bone or other organs, which is primarily responsible for its effect on patient mortality. SIRT6, one of Sirtuins family members, is an important histone modifying protein that regulates diverse physiological functions such as aging and metabolism. Recently there is much evidence showing an involvement of SIRT6 in tumorigenesis. At present, relatively little is known about the role of SIRT6 in regulating prostate cancer or metastasis. In our study, we have used both prostate tumor tissues and prostate cancer cell lines to study the roles of SIRT6 in the development and progression of PCa. From deposited gene profiling studies we found that SIRT6 was overexpressed in prostate tumors, compared with normal prostate tissues. Tissue microarray studies confirmed the higher levels of SIRT6 in both prostate tumor tissues and prostate cancer cells than in their normal counterparts. Depletion of SIRT6 by siRNA inhibited PCa cell proliferation. Bioinformatics analysis of the databases revealed that the high SIRT6 expression was associated with markedly shorter window of clinical recurrence, and the expression level of SIRT6 was significantly higher in PCa tissue with Gleason grade greater than seven. Further analysis indicated that SIRT6 expression increased along with the metastasis of PCa. We used PC-3 and DU145 cells to study whether SIRT6 could play a role in the migration and invasion of PCa cells. Indeed, SIRT6-deficiency markedly reduced cell migration and invasion. Compared with control siRNA treated cells, the protein level of N-cadherin reduced while E-cadherin level showed an increase after SIRT6 knockdown. We further revealed that SIRT6 regulated EMT-inducing transcription factor expression in PCa cells. Taken together, our findings indicate that SIRT6 is up-regulated in PCa, and the high expression of SIRT6 plays an important role in the progression of PCa as it facilitates cancer cell migration and invasion, and possibly metastasis. These data also suggest the therapeutic value of targeting SIRT6 in the treatment of metastatic PCa.

Citation Format: Qian Xie, Alice ST Wong, Weiliang Xia. SIRT6 induces EMT and promotes cancer cell invasion and migration in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1151. doi:10.1158/1538-7445.AM2014-1151
Abstract 1159: A novel HGF-MET paracrine signaling pathway promotes growth and resistance to chemotherapy in lung cancer
Authors: Choi Hyejin , Gao Ding Cheng , Lee Sharrell B. , Durrans Anna , Ryu Seongho , Elemento Olivier , Wong Stephen , Altorki Nasser K. , Mittal Vivek
Published: May 2015

Lung cancer is a leading cause of deaths from cancer among men and women worldwide with an estimated 1.5 million deaths each year. Available molecularly targeted therapies benefit a limited number of patients and even in these patients acquired resistance is a major impediment to effective therapeutic response. To address the need for additional therapeutic targets, we used a unique approach to identify and target tumor-stroma paracrine crosstalk pathways in non-small cell lung cancer (NSCLC).

To explore paracrine crosstalk in NSCLC, we analyzed transcriptomes of specific stromal and epithelial compartments that were sorted from Kras driven mouse model of NSCLC. Transcriptome analysis and computational modeling of multi-cellular network identified potential tumor-stroma crosstalk signaling pathways. We have selected the hepatocyte growth factor (HGF)-MET tyrosine kinase receptor signaling pathway because both HGF and MET are associated with poor survival in many cancer types including lung cancer. Notably, we identified reprogrammed intratumoral macrophages as unique source of HGF, while the expression of MET receptor was confined to tumor epithelial compartment. Importantly, we have observed elevated HGF in chemoresistant tumors both in mouse and human. Previous studies have implicated MET receptor amplification or mutations as the main mechanism of acquired resistance to EGFR TKIs, but little is known about the contribution of HGF ligand-dependent activation of MET signaling in NSCLC growth and resistance to chemotherapeutic regimens that are widely used. We have used a combination of culture experiments and in vivo genetic approaches to show that macrophage-derived HGF interacts with the MET receptor on tumor epithelial cells in a paracrine fashion, to activate downstream signaling pathways that promote tumor progression and mediate resistance to standard chemotherapies. Our investigations on this relatively unexplored HGF-MET paracrine interaction as a key mechanism of resistance to standard-of-care chemotherapeutic regimens-and not just EGFR targeted therapies-have the potential to benefit the NSCLC population as whole rather than a small subset of patients.

Citation Format: Hyejin Choi, Ding Cheng Gao, Sharrell B. Lee, Anna Durrans, Seongho Ryu, Olivier Elemento, Stephen Wong, Nasser K. Altorki, Vivek Mittal. A novel HGF-MET paracrine signaling pathway promotes growth and resistance to chemotherapy in lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1159. doi:10.1158/1538-7445.AM2014-1159