bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of the Retention Characteristic in Three dimensional Junction-less Charge Trapping Memory
Authors: Jiang Dandan , Xia Zhiliang , Jin Lei , Zou Xingqi , Zhang Yu , Tang Zhaoyun , Li Xinkai , Huo Zongliang
Published: May 2016

This work studied the retention characteristic of three dimensional cylindrical junction-less charge trapping memory. Both trapped charge and electron concentration distributions along the channel direction are observed by using sentaurus 3D device simulator. Lateral charge migration is significant after programming with 10 years retention. For vertical direction, charge loss toward block layer is more serious than tunnel layer. Nearly no trapped hole loss even after erasing 10 years.
High-K Metal-Gate Nanowire Junctionless FinFET with Nickel Silicide by Microwave Annealing
Authors: Tsai Wan-Ting , Lin Yu-Hsien
Published: May 2016

This work presents the structure Junctionless Fin-FET(JL-FinFET) based on ultra-thin body (UTB) with nickel silicide. The experiment will show the structure between silicide and non-silicide junctionless Fin-FET. The experiment results show superior performance including steep sub-threshold swing (SS) of 103 mV/dec and Ion/Ioff ratio (>105).The simulation results show that the nanowire junctionless field-effect transistor with silicide has better drain current than non-silicide. Both experimental and simulation results show that the silicide sample has two times of Ion value comparing to non-silicide sample.
High Performance Tri-Gate Germanium-on-insulator Based Junctionless Nanowire Transistors
Authors: Sun Chuanchuan , Liang Ren Rong , Wang Jing , Xu Jun
Published: May 2016

We fabricated high performance junctionless nanowire transistors (JNTs) directly on ultrathin-body Ge-on-insulator (GOI) substrates using a simple Si-compatible process. We reported the detailed fabrication process employing both optical lithography (OL) and electron beam lithography (EBL) to reduce costs and improve efficiency. These JNTs have gate lengths and channel widths that are both less than 100 nm and exhibit good electrical properties. The JNT with W/L=40 nm/70 nm, Na=1018 cm-3, and Ge-thickness dGe= 10 nm has Ion/Ioff ratio of approximately 105 at Vd=-1 V. The subthreshold slope and the drain-induced- barrier lowering (DIBL) are estimated to be 110 mV/dec at Vd=-0.1 V and 140 mV/V, respectively. The influence of Ge film thickness and temperature on electrical properties of these JLTs were investigated. Finally, we extracted the mobility of these JNTs and a peak mobility larger than 200 cm2V-1s-1 was observed.
(Invited) Transistors, Integrated Circuits and Nano-Technology: A Historical Review
Authors: Huff Howard R.
Published: May 2016

Bardeen and Brattain, following a suggestion by Gibney on Nov. 17th, 1947, successfully negated the influence of surface states on Nov 21st and, on Dec 16th, achieved transistor action – point-contact semiconductor amplification (of minority-carriers) in polycrystalline Ge. Bardeen and Brattain’s Magic Month was followed by Shockley’s Magic Month, which culminated with Shockley’s minority-carrier injection (Jan 23rd 1948) over the electrostatic barrier at the source / base interface, into the base where the minority-carriers were transported across the base en route to being accumulated at the collector in the polycrystalline Ge sample. Indeed, although all the principals involved were looking to develop a majority-carrier device, their minds were amply prepared to absorb the lessons they learned with the minority-carriers and the resulting new solid-state electronics era was initiated.
On the Origin of the 4.7 eV Absorption and 2.8 eV Emission Bands in Bulk AlN Substrates
Authors: Alden Dorian , Bryan Zachary , Gaddy Benjamin , Bryan Isaac , Callsen Gordon , Koukitu Akinori , Kumagai Yoshinao , Hoffmann Axel , Irving Doug , Sitar Zlatko , Collazo Ramon
Published: May 2016

One of the main limitations based on point defects in AlN is related to the UV absorption band present at 265 nm. This relatively broad absorption band limits the use of bulk substrates within the deep UV range and several complicated fabrication procedures have been devised to overcome this limitation. The origin for this absorption band along with corresponding photoluminescence signatures will be reviewed. CN
-
and VN
+
were identified as the point defects directly associated with the main absorption at 4.7 eV and the emission at 2.8 eV. The main absorption is due to a transition between the CN
-
state and conduction band, while the emission arises from a DAP transition between the donor VN
+
and acceptor CN
-
through the 4.7 eV excitation channel. New observations based on photoluminescence excitation are presented to further support the assignments previously made.
Channel Scaling Behavior of Amorphous In-Zn-O Thin Film Transistors with High Mobility over 35 cm2/Vsec
Authors: Lee Sunghwan , Paine David C.
Published: May 2016

We report on the channel scaling behavior of amorphous In-Zn-O (a-IZO) thin film transistor (TFT) devices. The TFTs were fabricated at room temperature where a-IZO channel and Mo metallization were deposited using dc magnetron sputtering. Both channel length (L) and width (W) of the devices were scaled down in order to maintain the aspect ratio, W/L of 20. The channel scaling of a-IZO TFTs leads to an increase in on-state drain current. However, a decrease in field effect mobility and an increase in threshold voltage and off-state current are also observed with decreasing channel length, known as short channel effects which are mainly attributed to an increase in the longitudinal electric field applied to channel IZO.
Investigation on Alumina Passivation for Improved IGZO TFT Performance
Authors: Mudgal Tarun , Edwards Nicholas , Ganesh Prashant , Bharadwaj Anish , Manley Robert G. , Hirschman Karl D
Published: May 2016

A study of the influence of back-channel alumina passivation on the operation of bottom-gate IGZO TFTs is presented. TFTs without any passivation material deposited typically exhibit best-case initial results. Regardless a passivation layer is required for device stability and process integration. The impact of passivation using alumina deposited via electron beam evaporation and atomic layer deposition (ALD) has been investigated. A decrease in subthreshold slope and channel mobility on certain treatment combinations is attributed to an inferior IGZO/alumina back-channel interface. A two-step passivation process has been developed which offers back-channel protection during device fabrication, and remains compatible with an oxidizing ambient anneal. Modifications in the passivation and annealing procedures and process integration details have resulted in a marked improvement in the performance of alumina passivated devices, with demonstrated resistance to aging.
(Invited) Surface Composition and Oxygen Exchange Properties of Alkaline Earth-Free Perovskites; LaCo0.6Ni0.4O3
Authors: Druce John , Téllez Helena , Ishihara Tatsumi , Kilner John A.
Published: May 2016

It is well known that alkaline earth additives in conventional perovskite-based solid oxide electrode materials tend to segregate rapidly to the outer surfaces, which is associated with degradation in device performance. It may be possible to avoid these problems by developing materials which do not contain alkaline earth dopants; however, without the oxygen vacancies introduced by alkaline earth doping, the oxygen transport and electro-catalytic properties may suffer. Here, we investigate oxygen transport in the nickel doped lanthanum cobaltite system, and find that the relatively low oxygen diffusivity is dominated by grain boundary transport. Despite this, at higher temperatures, the surface exchange coefficient is comparable to state-of-the-art Sr doped cobaltites. The surface composition of the annealed samples measured by Low Energy Ion Scattering spectroscopy does not appear different from the as-polished samples, suggesting that the surface composition is indeed more stable for this alkaline earth free material.
Microstructure and Compositional Defects Affects Proton Conductivity and Reactions in Y-doped BaZrO3 Thin Films
Authors: Yang Nan , Di Bartolomeo Elisabetta , Foglietti Vittorio , Cantoni Claudia , Belianinov Alex , Tebano Antonello , Licoccia Silvia , Lee Tien-Lin , Schlueter Christoph , Kalinin Sergei V. , Balestrino Giuseppe , Aruta Carmela
Published: May 2016

In this paper, we report on BaZr0.8Y0.2O3-x (BZY) thin films grown on highly mismatched NdGaO3 (110) substrates by RHEED assisted pulsed laser deposition. The conduction and electrochemical performances are studied by Electrochemical Impedance Spectroscopy and Electrochemical Strain Microscopy respectively. Conductivity, as well as electrochemical response improves while decreasing the thickness, indicating that the proton movement is prompt at the defective interface region. Structural defects at the interface between film and substrate are clearly displayed by x-ray diffraction, RHEED patterns and transmission electron microscopy. The role of chemical defects on BZY film properties is elucidated by Hard X-ray Photoelectron Spectroscopy. Our results demonstrate that both structural dislocations and chemical defects influence the proton conduction and reaction process in BZY thin films.
Electrochemical Frequency Modulation for Estimating Exchange Current Density in Solid Oxide Fuel Cells
Authors: Das Debanjan , Hall Derek M. , Lvov Serguei N.
Published: May 2016

Electrochemical frequency modulation (EFM) was applied for the first time to solid oxide fuel cells (SOFC) to obtain effective exchange current density and transfer coefficient values. Values obtained from EFM data were compared to values obtained from electrochemical impedance spectroscopy (EIS) and linear sweep voltammetry (LSV). A kinetic model based on Butler-Volmer (B-V) equation was used as the basis for the analysis. It was found that the values obtained via EFM were in good agreement with EIS and Tafel analyses. The obtained values for a cell within a SOFC stack closely ranged from 11 - 16 mA cm-2 for effective exchange current density and 0.88 – 1.3 for transfer coefficient with good repeatability.
Blind Source Parameters for Performance Evaluation of Despeckling Filters
Authors: Biradar Nagashettappa , Dewal M. L. , Rohit ManojKumar , Gowre Sanjaykumar , Gundge Yogesh
Published: May 2016

The speckle noise is inherent to transthoracic echocardiographic images. A standard noise-free reference echocardiographic image does not exist. The evaluation of filters based on the traditional parameters such as peak signal-to-noise ratio, mean square error, and structural similarity index may not reflect the true filter performance on echocardiographic images. Therefore, the performance of despeckling can be evaluated using blind assessment metrics like the speckle suppression index, speckle suppression and mean preservation index (SMPI), and beta metric. The need for noise-free reference image is overcome using these three parameters. This paper presents a comprehensive analysis and evaluation of eleven types of despeckling filters for echocardiographic images in terms of blind and traditional performance parameters along with clinical validation. The noise is effectively suppressed using the logarithmic neighborhood shrinkage (NeighShrink) embedded with Stein’s unbiased risk estimation (SURE). The SMPI is three times more effective compared to the wavelet based generalized likelihood estimation approach. The quantitative evaluation and clinical validation reveal that the filters such as the nonlocal mean, posterior sampling based Bayesian estimation, hybrid median, and probabilistic patch based filters are acceptable whereas median, anisotropic diffusion, fuzzy, and Ripplet nonlinear approximation filters have limited applications for echocardiographic images.
Integrated Nanozero Valent Iron and Biosurfactant-Aided Remediation of PCB-Contaminated Soil
Authors: Zhang He , Zhang Baiyu , Liu Bo
Published: May 2016

Polychlorobiphenyls (PCBs) have been identified as environmental hazards for years. Due to historical issues, a considerable amount of PCBs was released deep underground in Canada. In this research, a nanoscale zero valent iron- (nZVI-) aided dechlorination followed by biosurfactant enhanced soil washing method was developed to remove PCBs from soil. During nZVI-aided dechlorination, the effects of nZVI dosage, initial pH level, and temperature were evaluated, respectively. Five levels of nZVI dosage and two levels of initial pH were experimented to evaluate the PCB dechlorination rate. Additionally, the temperature changes could positively influence the dechlorination process. In soil washing, the presence of nanoiron particles played a key role in PCB removal. The crude biosurfactant was produced using a bacterial stain isolated from the Atlantic Ocean and was applied for soil washing. The study has led to a promising technology for PCB-contaminated soil remediation.
Peripapillary Choroidal Thickness and Open-Angle Glaucoma: A Meta-Analysis
Authors: Lin Zhongjing , Huang Shouyue , Xie Bing , Zhong Yisheng
Published: May 2016

Purpose. To investigate the potential relationship between open-angle glaucoma (OAG) and peripapillary choroidal thickness (PPCT).Materials and Methods. Relevant publications were searched systematically through various databases from inception to January 2016. Studies comparing PPCT in OAG patients and healthy controls were retrieved. All qualified articles were analyzed using Stata 14.0 and Revman 5.3 software.Results. A total of 13 studies were identified for inclusion. There was a significant reduction of average PPCT in OAG patients compared to control participants (WMD = −24.07, 95% CI: −34.29, −13.85). Reduction of PPCT was significant in the superior (WMD = −28.87, 95% CI: −44.96, −12.78) and nasal (WMD = −21.75, 95% CI: −41.52, −1.98) sectors, but there was no significant reduction of PPCT in the inferior (WMD = −9.57, 95% CI: −36.55, 17.40) and temporal (WMD = −13.85, 95% CI: −35.40, 7.70) sectors. No obvious publication bias was detected.Conclusions. This meta-analysis suggests that open-angle glaucoma patients have significantly decreased peripapillary choroidal thickness compared to healthy individuals. Peripapillary choroidal thickness measured by optical coherence tomography may be an important parameter to consider in open-angle glaucoma.
Comparison of Experimental and Calculated Ion Mobilities of Small Molecules in Air
Authors: Gunzer Frank
Published: May 2016

Ion mobility spectrometry is a well-known technique for analyzing gases. Examples are military applications, but also safety related applications, for example, for protection of employees in industries working with hazardous gases. In the last 15 years, this technique has been further developed as a tool for structural analysis, for example, in pharmaceutical applications. In particular, the collision cross section, which is related to the mobility, is of interest here. With help of theoretic principles, it is possible to develop molecular models that can be verified by the comparison of their calculated cross sections with experimental data. In this paper, it is analyzed how well the ion trajectory method is suitable to reproduce the measured ion mobility of small organic molecules such as the water clusters forming the positively charged reactant ions, simple aromatic substances, and n-alkanes.
Unilateral Eyelid Edema as Initial Sign of Orbital Sarcoidosis
Authors: Petrarolha Sílvia Miguéis Picado , Rodrigues Bruna Suda , Filho Flávio David Haddad , Dedivitis Rogério Aparecido , Petrarolha Samuel Brunini , Morais Pedro Martins Tavares Scianni
Published: May 2016

Introduction. Sarcoidosis is a rare multisystemic granulomatous inflammatory disease of unknown etiology affecting the respiratory system, skin, and eyes. Sarcoidosis outside the lacrimal gland is rare. The case study concerns a patient with a final diagnosis of orbital sarcoidosis.Case Report. A 37-year-old male patient went to the ophthalmic emergency room complaining of pain in the left eye, diplopia, and decreased visual acuity. An external eye examination showed hard and cold edema of the lower eyelid, ocular motility with limitation of adduction, and discreet ipsilateral proptosis. Magnetic resonance of the orbit showed left eye proptosis and thickening and increase of soft tissues associated with heterogeneous impregnation of contrast in the infralateral region of the left eyelid. A biopsy of the lesion showed a chronic inflammatory process, with numerous compact nonnecrotizing granulomas surrounded by lamellar hyaline collagen, providing histological confirmation of sarcoidosis.Discussion. A biopsy of the orbital tumor is essential for the diagnosis of sarcoidosis, in addition to the search for systemic findings such as hilar adenopathy or parenchymal lung disease found in 90% of patients.
Nonvisualization of the Internal Carotid Artery on Computed Tomography Angiography: Discussion of Two Cases with Review of Literature
Authors: Saran Sonal , Rajagopal Rengarajan , Khera Pushpinder S. , Mehta Neeraj
Published: May 2016

Nonvisualization of the internal carotid artery (ICA) on cross-sectional imaging studies can be due to congenital (dysgenesis of the ICA) or acquired (complete occlusion of ICA) causes. We report two cases, one with absent carotid canal on bone window setting of computed tomography (CT) suggestive of congenital cause and the other with normal carotid canal, suggesting acquired cause. Development of aortic arches with six pathways of collateral circulation in brain is also discussed.
Maternal Vitamin D Level Is Associated with Viral Toll-Like Receptor Triggered IL-10 Response but Not the Risk of Infectious Diseases in Infancy
Authors: Liao Sui-Ling , Lai Shen-Hao , Tsai Ming-Han , Hua Man-Chin , Yeh Kuo-Wei , Su Kuan-Wen , Chiang Chi-Hsin , Huang Shih-Yin , Kao Chuan-Chi , Yao Tsung-Chieh , Huang Jing-Long
Published: May 2016

Reports on the effect of prenatal vitamin D status on fetal immune development and infectious diseases in childhood are limited. The aim of this study was to investigate the role of maternal and cord blood vitamin D level in TLR-related innate immunity and its effect on infectious outcome. Maternal and cord blood 25 (OH)D level were examined from 372 maternal-neonatal pairs and their correlation with TLR-triggered TNF-α, IL-6, and IL-10 response at birth was assessed. Clinical outcomes related to infection at 12 months of age were also evaluated. The result showed that 75% of the pregnant mothers and 75.8% of the neonates were vitamin deficient. There was a high correlation between maternal and cord 25(OH)D levels (r=0.67,p<0.001). Maternal vitamin D level was inversely correlated with IL-10 response to TLR3 (p=0.004) and TLR7-8 stimulation (p=0.006). However, none of the TLR-triggered cytokine productions were associated with cord 25(OH)D concentration. There was no relationship between maternal and cord blood vitamin D status with infectious diseases during infancy. In conclusion, our study had shown that maternal vitamin D, but not cord vitamin D level, was associated with viral TLR-triggered IL-10 response.
Nodular Scleritis Associated with Herpes Zoster Virus: An Infectious and Immune-Mediated Process
Authors: Loureiro Mónica , Rothwell Renata , Fonseca Sofia
Published: May 2016

Purpose.To describe a case of anterior nodular scleritis, preceded by an anterior hypertensive uveitis, which was primarily caused by varicella zoster virus (VZV).Case Report. A 54-year-old woman presented with anterior uveitis of the right eye presumably caused by herpetic viral disease and was successfully treated. Two months later, she developed a nodular scleritis and started oral nonsteroidal anti-inflammatory without effect. A complete laboratory workup revealed positivity for HLA-B27; the infectious workup was negative. Therapy was changed to oral prednisolone and an incomplete improvement occurred. Therefore, a diagnostic anterior paracentesis was performed and the polymerase chain reaction (PCR) analysis revealed VZV. She was treated with valacyclovir and the oral prednisolone began to decrease; however, a marked worsening of the scleritis occurred with the reduction of the daily dose; subsequently, methotrexate was introduced allowing the suspension of the prednisolone and led to clinical resolution of the scleritis.Conclusion.This report of anterior nodular scleritis caused by VZV argues in favor of an underlying immune-mediated component, requiring immunosuppressive therapy for clinical resolution. The PCR analysis of the aqueous humor was revealed to be a valuable technique and should be considered in cases of scleritis with poor response to treatment.
Characterization of Nora Virus Structural Proteins via Western Blot Analysis
Authors: Ericson Brad L. , Carlson Darby J. , Carlson Kimberly A.
Published: May 2016

Nora virus is a single stranded RNA picorna-like virus with four open reading frames (ORFs). The coding potentials of the ORFs are not fully characterized, but ORF3 and ORF4 are believed to encode the capsid proteins (VP3, VP4a, VP4b, and VP4c) comprising the virion. To determine the polypeptide composition of Nora virus virions, polypeptides from purified virus were compared to polypeptides detected in Nora virus infectedDrosophila melanogaster. Nora virus was purified from infected flies and used to challenge mice for the production of antisera.ORF3,ORF4a,ORF4b, andORF4cwere individually cloned and expressed inE. coli; resultant recombinant proteins purified and were used to make monospecific antisera. Antisera were evaluated via Western blot against whole virus particles and Nora virus infected fly lysates. Viral purification yielded two particle types with densities of ~1.31 g/mL (empty particles) and ~1.33 g/mL (complete virions). Comparison of purified virus polypeptide composition to Nora virus infectedD. melanogasterlysate showed the number of proteins in infected cell lysates is less than purified virus. Our results suggest the virion is composed of 6 polypeptides, VP3, VP4a, two forms of VP4b, and two forms of VP4c. This polypeptide composition is similar to other small RNA insect viruses.
Outcomes of Patients with Intestinal Failure after the Development and Implementation of a Multidisciplinary Team
Authors: Furtado Sabrina , Ahmed Najma , Forget Sylviane , Sant’Anna Ana
Published: May 2016

Aim. A multidisciplinary team was created in our institution to manage patients with intestinal failure (INFANT: INtestinal Failure Advanced Nutrition Team). We aimed to evaluate the impact of the implementation of the team on the outcomes of this patient population.Methods. Retrospective chart review of patients with intestinal failure over a 6-year period was performed. Outcomes of patients followed up by INFANT (2010–2012) were compared to a historical cohort (2007–2009).Results. Twenty-eight patients with intestinal failure were followed up by INFANT while the historical cohort was formed by 27 patients. There was no difference between the groups regarding remaining length of small and large bowel, presence of ICV, or number of infants who reached full enteral feeds. Patients followed up by INFANT took longer to attain full enteral feeds and had longer duration of PN, probably reflecting more complex cases. Overall mortality (14.8%/7.1%) was lower than other centers, probably illustrating our population of “early” intestinal failure patients.Conclusions. Our data demonstrates that the creation and implementation of a multidisciplinary program in a tertiary center without an intestinal and liver transplant program can lead to improvement in many aspects of their care.
Oral Hygiene and Risk of Nasopharyngeal Carcinoma—A Population-Based Case–Control Study in China
Authors: Liu Zhiwei , Chang Ellen T. , Liu Qing , Cai Yonglin , Zhang Zhe , Chen Guomin , Xie Shang-Hang , Cao Su-Mei , Shao Jian-Yong , Jia Wei-Hua , Zheng Yuming , Liao Jian , Chen Yufeng , Ernberg Ingemar , Vaughan Thomas L. , Adami Hans-Olov , Huang Guangwu , Zeng Yi , Zeng Yi-Xin , Ye Weimin
Published: May 2016

Background: The association between oral health and risk of nasopharyngeal carcinoma (NPC) is largely unknown. Further understanding could shed light on potential pathogenic mechanisms and preventive measures.

Methods: We conducted a population-based case–control study in southern China between 2010 and 2014. We enrolled 2,528 incident NPC cases, aged 20–74 years, and 2,596 controls, randomly selected from the total population registers, with frequency matching to the 5-year age and sex distribution of the cases by geographic region. We interviewed subjects using a structured questionnaire inquiring about oral health indicators and potential confounding factors. We used unconditional logistic regression to estimate multivariate-adjusted ORs with 95% confidence intervals (CI).

Results: A higher number of filled teeth was associated with an elevated risk of NPC. Individuals with 1 to 3 and more than 3 teeth filled versus none had adjusted ORs of 1.25 (95% CI, 1.06–1.49) and 1.55 (95% CI, 1.13–2.12), respectively (Ptrend = 0.002). Conversely, the adjusted OR for those who brushed teeth twice or more per day versus once or less per day was 0.62 (95% CI, 0.55–0.70). We detected a borderline significant positive association with earlier age at first adult tooth loss.

Conclusion: Our study suggested a positive association between some indicators of poor oral health and risk of NPC. Further studies are needed to confirm whether the findings are causal and, if so, to further explain the underlying mechanisms.

Impact: Improvement of oral hygiene might contribute to reducing NPC risk. Cancer Epidemiol Biomarkers Prev; 25(8); 1201–7. ©2016 AACR.
Abstract A115: A novel therapy targeting Wnt receptor in metastatic solid tumors
Authors: Gujral Taran , Kirschner Marc
Published: May 2016

Metastasis is responsible for as much as 90% of cancer-associated mortality; yet progress has remained slow in developing effective drugs either specifically targeting metastasis or targeting cells with metastatic potential. To date, surgical resection is considered the best treatment for most cancers; however, it provides limited benefit in metastatic cancers. Although there are numerous studies showing the migratory potential of metastatic cells and relating metastasis to the biology of the epithelial-mesenchymal transition (EMT), little is known about how tumor cells engage this fundamental cellular program. We have recently discovered a new non-canonical Wnt pathway through Wnt5-Fzd2 that drives EMT, cellular migration, invasion in vitro and tumor growth and metastasis in vivo. Using focused proteomics approaches, we have identified several novel signaling proteins downstream of Fzd2, including Fyn, Stat3, Mek-Erk-S6k, and Pyk2 kinase. Our new findings highlight critical nodes in the Fzd2 pathway that are linked to metastatic phenotypes such as increased motility, and EMT. Overall, these findings establish the driver role of Fzd2 signaling in diverse solid tumors and make Fzd2 a potential first-in-class therapeutic target for metastatic cancers.

Citation Format: Taran Gujral, Marc Kirschner. A novel therapy targeting Wnt receptor in metastatic solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A115.
Abstract A139: Targeting cholesterol with beta-cyclodextrins disrupt PI3K-AKT, sensitizing cancer cells for chemotherapeutics
Authors: Yamaguchi Ryuji
Published: May 2016

Activated PI3K-AKT pro-survival signal is the major obstacle to successful chemotherapies. Activated growth-factors receptors such as EGFR and IGF1R generate two signal transduction cascades; RTK-Ras-MAPK cascades generating proliferation signals, and RTK-PI3K-AKT cascades generating pro-survival signals that enhance glucose-uptake and stimulate energy production at mitochondria and at the same time, protecting mitochondria from mitochondria-dependent apoptotic signals. When we depleted cholesterol from plasma membranes with beta-cyclodextrins (beta-CDs) in tissue culture cells, we found that RTKs were activated normally in the absence of cholesterol, and activating Ras-MAPK pathways. However, beta-CD disrupted the signal transduction between PI3K and AKT, attenuating PI3K-AKT pro-survival signal in cancer cells and sensitizing them for mitochondria-dependent apoptosis. Injected into mice, beta-CD blocked IGF1-induced hypoglycemia in 5-hour starved mice, suggesting that the IGF1R-PI3K-AKT pathway was disrupted. Injected into mice carrying human cancer cells, it enhanced the efficacies of chemotherapeutics that could trigger mitochondria-dependent apoptosis quickly such as the combination of 2-dexoyglucose and Bcl2 antagonists or TNF-related apoptosis-inducing ligand (TRAIL).

Citation Format: Ryuji Yamaguchi. Targeting cholesterol with beta-cyclodextrins disrupt PI3K-AKT, sensitizing cancer cells for chemotherapeutics. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A139.
Abstract A142: The effect of beta2-glycoprotein I on anti-tumor cell migration
Authors: Chiang An-Na , Li Wan-Chun , Yeh Shu-Hau , Cheng Shu-Wei , Lin Yu-Shan
Published: May 2016

β2-glycoprotein I (β2-GPI) is a multifaceted protein with diverse biological functions, including triglyceride metabolism, blood coagulation and homeostasis. We previously reported that β2-GPI exhibits significant anti-migration effect on human aortic endothelial cells through the NF-κB/eNOS/NO signalling pathway. Migration of endothelial cells has known to be involved in vascular physiology and pathology, such as angiogenesis and tumorigenesis. We thus hypothesize that β2-GPI may also play a critical role in the regulation of tumor cell migration and invasion. Human plasma protein was precipitated by 3% (v/v) perchloric acid and β2-GPI was purified by heparin-Sepharose affinity chromatography. The purity of β2-GPI was determined by SDS/PAGE and Western blot analysis. The influence of β2-GPI on tumor cell migration was analyzed by wound healing and trans-well migration analysis. Using wound healing assay, we found that purified β2-GPI was able to inhibit cell migration in various tumor cancers, such as A375 human melanoma cancer cells, B16-F10 mouse melanoma cells, oral squamous cell carcinoma (OSCC)-derived cell line human tongue squamous carcinoma (SAS), and human head neck squamous cell carcinoma (HNSCC) cell lines FaDu (hypopharyngeal) carcinoma. In the trans-well assay, β2-GPI also showed markedly inhibition of tumor cell migration from the upper chamber to the lower chamber. Furthermore, β2-GPI revealed dose-dependently anti-invasion effect on melanoma cancer cells. The findings of the present study provide insight into the ability of β2-GPI to inhibit tumor cell migration, which indicates a novel direction for its application in anti-cancer therapy.

Citation Format: An-Na Chiang, Wan-Chun Li, Shu-Hau Yeh, Shu-Wei Cheng, Yu-Shan Lin. The effect of beta2-glycoprotein I on anti-tumor cell migration. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A142.
Abstract A148: Developing a baculovirus expression system to evaluate the role of B2-glycoprotein I in anti-tumor cell growth
Authors: Lin Yu-Shan , Leu Shr-Jeng , Chiang An-Na
Published: May 2016

β2-glycoprotein I (β2-GPI) is a human plasma protein which has been reported to elicit an anti-cell migration effect on human aortic endothelial cells in our previous study. Migration of endothelial cells has been found to be involved in tumorigenesis, however, whether β2-GPI regulates tumor cell growth is unknown. In this study, we investigated the biological effect of β2-GPI on anti-cell migration and proliferation in tumor cells using a baculovirus expression system. Based on Bac-to-Bac Baculovirus Expression system, the cDNA encoding B2-GPI gene has been constructed and cloned into the pFastBac vector with additionally designed sequences, including a Honeybee Melittin Secretion Signal, a dual Flag/StrepII affinity tag and a Tabacco Etch Virus cleavage site at N terminal end and a C-terminal IgG1 Fc fusion protein sequences. This recombinant bacmid DNA containing a complete B2-GPI gene was transfected into insect Sf9 cells to generate recombinant baculovirus. Expression of these chimeric proteins in insect cells resulted in efficient assembly and release of hybrid recombinant B2-GPI protein into cultured media. The fusion proteins containing IgG1-Fc sequences can be purified by the protein A affinity column. Finally, we collected the recombinant B2-GPI in high purity and expression yield. Direct administration of recombinant B2-GPI protein resulted in an effective inhibition of the melanoma cell migration and tumor growth. Development of this baculoviral-based system provides an option for investigation in the anti-tumor cell growth function of B2-GPI in vitro and in vivo. Our study provides a baculoviral-based approach which opens a new perspective for developing B2-GPI as an agent in anti-cancer therapy.

Citation Format: Yu-Shan Lin, Shr-Jeng Leu, An-Na Chiang. Developing a baculovirus expression system to evaluate the role of B2-glycoprotein I in anti-tumor cell growth. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A148.
Abstract A19: Network analysis of gene essentiality in CRISPR screens
Authors: Jiang Peng , Liu Xiaole Shirley
Published: May 2016

CRISPR screen is a powerful technique to study gene essentiality at genome scale. Based on our analysis of public CRISPR screen data, the essential genes selected in CRISPR screens can be predicted by the expression level of their neighboring genes in the protein interaction network. Meanwhile, the quality of CRISPR screen results can be significantly enhanced through network neighbor information. Through analysis of tumor-profiling data, we found the network neighbor expression to be a significantly better predictor of survival than gene expression alone. Thus, our study provides a reliable method for CRISPR screen analysis and gene essentiality study. The source code and web application of our method is available at http://nest.dfci.harvard.edu.

Citation Format: Peng Jiang, Xiaole Shirley Liu. Network analysis of gene essentiality in CRISPR screens. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A19.
Abstract A196: Stromal cells suppress cancer development by secreted GAPDH-E-cadherin interaction
Authors: Manabu Kawada , Yoshida Junjiro , Inoue Hiroyuki , Ohba Shun-ichi , Yamasaki Manabu , Usami Ihomi , Sakamoto Shuichi , Abe Hikaru , Watanabe Takumi , Nomoto Akio , Shibasaki Masakatsu
Published: May 2016

The cancer tissue contains lots of stromal cells. Among them, fibroblast-like stromal cells regulate the growth of cancer cells positively and negatively through secreted factors and adhesion. We have been studying the interactions between cancer cells and stromal cells using small molecules that can modulate the interactions. We previously reported that gastric stromal cells enhance the growth of gastric cancer cells through secretion of IL-6, which is stimulated by gastric cancer cells through PGE2 and TNF-alpha reciprocally. Here we report that GAPDH, a house keeping protein, is a negative regulator of the interactions. By purifying the growth inhibitory activity against gastric cancer cells from secreted factors of gastric stromal cell we unexpectedly identified GAPDH as an active substance. While GAPDH is known to be secreted extracellularly, its growth inhibitory activity has not yet. As a result, GAPDH is found to be secreted from various organ-derived stromal cells and to inhibit the growth of various cancer cell lines. We have found that this growth inhibitory activity of GAPDH doesn't need its original enzymatic activity and GAPDH inhibits mTOR-p70S6 kinase pathway by binding to E-cadherin on cancer cell membranes. We propose that negative regulation of cancer growth using GAPDH could be a new anti-cancer strategy.

Citation Format: Kawada Manabu, Junjiro Yoshida, Hiroyuki Inoue, Shun-ichi Ohba, Manabu Yamasaki, Ihomi Usami, Shuichi Sakamoto, Hikaru Abe, Takumi Watanabe, Akio Nomoto, Masakatsu Shibasaki. Stromal cells suppress cancer development by secreted GAPDH-E-cadherin interaction. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A196.
Abstract A32: Accelerating biomarker discovery for companion diagnostics through mouse trials with PDX models in clinical settings
Authors: Jiang Jingjing , Yu Tengfei , Yan Ying , Du Wei , Tang Tingting , Yang Xuqin , Gu Jiali , Hua Liang , Ye Xin Katherine , Gu Zhenyu
Published: May 2016

Companion diagnostics are assays intended to find the right drug for the right patient in targeted cancer therapy. Biomarker discovery is the first step in companion diagnostics development. Currently great efforts have been devoted to biomarker discovery and validation through analysis of clinical samples. However, the quantity and quality of tumor samples from drug candidate treated patients are very limited during drug development, which has posed challenges for fast and cost-effective drug-diagnostic co-development.

Patient derived xenograft (PDX) tumor models have been demonstrated to represent cancer complexity and heterogeneity known in patients. Drug targets and responses to targeted drugs in PDX models show high correlation to those in cancer patients.

We have established over 950 PDX tumor models and around 100 resistance models to drugs of interest. To evaluate mouse trials with PDX models as biomarker discovery platform, we have been testing PDX models with SOCs and clinical drug candidates such as targeted inhibitors against FGFRs, c-Met/ALK, HER2, EGFR, cell cycle regulators, Ras/Raf pathway, PI3K/Akt pathway, as well as chemotherapy drugs in a biomarker-driven multi-drug multi-arm clinical trial setting, and have accumulated more than 1500 data sets and associated PD samples. Through analysis of drug response data and genomic profile data from PDX models, we show that many of the drug sensitivity biomarkers and drug resistance biomarkers identified in clinical studies can be faithfully found in PDX studies. Moreover, some novel predictive biomarkers for candidate drugs in relatively early clinical stage have also been identified and will be further validated in future clinical studies.

The availability of a large number of PDX models, the flexibility of designing studies and the quickness in testing new drug candidates make this type of mouse trial and its derived data sets a useful platform for biomarker discovery in companion diagnostics development.

Citation Format: Jingjing Jiang, Tengfei Yu, Ying Yan, Wei Du, Tingting Tang, Xuqin Yang, Jiali Gu, Liang Hua, Xin Katherine Ye, Zhenyu Gu. Accelerating biomarker discovery for companion diagnostics through mouse trials with PDX models in clinical settings. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A32.
Abstract A64: Human epidermal growth factor receptor 2 (HER2) directly binds and activates focal adhesion kinase (FAK) to promote oncogenesis
Authors: Marlowe Timothy , Figel Sheila , Lenzo Felicia , Golubovskaya Vita , Kurenova Elena , Tropsha Alexander , Cance William
Published: May 2016

Introduction: Human epidermal growth factor receptor 2 (HER2) is known to require focal adhesion kinase (FAK) for cellular transformation, tumor growth, invasion, and metastasis. FAK is overexpressed in nearly all types of human cancer, serving as a molecular scaffold protein to integrate oncogenic growth factor receptors with focal adhesion proteins. We have identified a novel direct protein-protein interaction between HER2 and FAK. In this study, we investigated whether the HER2-FAK direct interaction is required for HER2-dependent oncogenesis and its potential as a novel drug target.

Methods: We have taken a multidisciplinary approach (biophysics, biochemistry, molecular modeling, structural biology, and molecular biology) to map the HER2-FAK binding interface and to study the functional aspects of the interaction.

Results: Our data indicated that the N-lobe of the HER2 kinase domain directly interacts with the F1 lobe of the FAK FERM domain. In addition, molecular modeling studies have identified a putative HER2-FAK interface suitable for the binding of small molecule inhibitors. Site-directed mutagenesis studies validated this binding interface. Functional data indicated that HER2 directly transphosphorylated FAK at key tyrosine residues, Y397, Y861, and Y925, irrespective of FAK kinase activity. Additionally, kinome reprogramming analysis revealed upregulation of HER2 signaling and maintenance of FAK phosphorylation after FAK-kinase inhibitor treatment. Finally, cellular data suggested that loss of the HER2-FAK interaction, but not FAK-kinase activity, resulted in a defect in Heregulin β1-stimulated cell migration/invasion.

Conclusion: We have identified a direct interaction between HER2 and FAK that is required for HER2-dependent oncogenic signaling and is amenable to targeting by small molecule therapeutics. In addition, this interaction mediated a novel drug resistance mechanism whereby HER2 rescued and maintained FAK activation under FAK-kinase inhibition.

Citation Format: Timothy Marlowe, Sheila Figel, Felicia Lenzo, Vita Golubovskaya, Elena Kurenova, Alexander Tropsha, William Cance. Human epidermal growth factor receptor 2 (HER2) directly binds and activates focal adhesion kinase (FAK) to promote oncogenesis. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A64.
Abstract B161: Chemoproteomic profiling for target identification using chloroalkane derivatized compounds
Authors: Ford Michael , Jones Richard , Amunugama Ravi , Daniels Danette , Ohana Rachel , Levin Sergiy , Kirkland Thomas , Urh Marjeta , Wood Keith
Published: May 2016

Chemoproteomic technologies enable the quantitative and qualitative profiling of small molecule protein interactions. Here we report a new approach utilizing a chloroalkane (CA) capture tag which can be chemically attached to small molecules to enable the isolation of their respective protein targets through selective capture onto an immobilized HaloTag protein.

We have combined our chemoproteomics workflow with multiplexed chemical labeling methods to enable the analysis of dose dependent target engagement studies in a single LC-MS/MS experiment. Here we demonstrate this workflow using BIRB796-CA, a modified kinase inhibitor.

Target enrichment experiments were performed by incubating HEK293 cells with the BIRB-CA. Cells were then lysed and the BIRB-CA, together with the bound targets, was rapidly captured onto immobilized HaloTag protein. Unmodified compound was used to competitively elute putative interacting proteins. To study dose dependent effects on the protein interaction profile, cells were incubated with multiple mixtures of BIRB and BIRB-CA at varying relative concentrations. The eluted proteins were processed using SDS-PAGE and in-gel digestion. Digested material was labeled with Tandem Mass Tags (TMT) 10plex reagents and analyzed using nanoscale LC-MS/MS coupled with a Q Exactive mass spectrometer (Thermo). Protein identification was performed with MaxQuant (MaxQuant.org) and data validation and visualization was performed using Perseus (Perseus-framework.org).

We tested this chemoproteomics workflow using the interaction of MAP kinases (MAPK) with BIRB796, an allosteric kinase inhibitor. Treatment of LPS simulated THP-1 cells with BIRB796 and BIRB-CA revealed minimal impact of the CA modification on the inhibition of TNFα secretion. The interaction of BIRB-CA with known BIRB targets MAPK13, MAPK12, MAPK9 and MAPK14 has been confirmed using label free quantitative proteomic profiling. We have optimized the TMT labeling method for minimal losses and sample processing steps. We are applying the TMT method to BIRB-CA and control pull downs and extending this workflow to include the BIRB/BIRB-CA titration samples. Here we will use post-acquisition data processing of the BIRB/BIRB-CA titration pull down data to assess compound binding characteristics with the inferred extension to compounds with unknown binding specificities.

Citation Format: Michael Ford, Richard Jones, Ravi Amunugama, Danette Daniels, Rachel Ohana, Sergiy Levin, Thomas Kirkland, Marjeta Urh, Keith Wood. Chemoproteomic profiling for target identification using chloroalkane derivatized compounds. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B161.
Abstract B41: The gelatinases-stimuli nanoparticles reverse docetaxel resistance and epithelial to mesenchymal transition in lung cancer cell line
Authors: Liu Qin , Li Rutian , Liu Baorui
Published: May 2016

Drug resistance is a main obstacle for the successful cancer therapy. Emerging evidence suggests that miR-200c functions as an effective cancer stem cells (CSCs) inhibitor and restores sensitivity to microtubule-targeting drugs. In the present work, we engineered the intelligent gelatinases-stimuli nanoparticles (NPs) to co-delivery miR-200c and antitumor drug docetaxel (DOC) to verify their synergetic effects on inhibition of CSCs and cancer cells. After tumor cells were treated with miR-200c NPs, miR-200c and its targeted gene TUBB3 expression were evaluated. The effects of (miR-200c+DOC) NPs on docetaxel-resistant lung cancer cells viability as well as the expression of E-cadherin and CD44 were studied. We found that the (miR-200c+DOC) NPs significantly overcome DOC resistance, possibly by elevated miR-200c expression,low TUBB3 level, and reversed the EMT through upregulation E-cadherin and inhibition lung CSCs. The (miR-200c+DOC) NPs may provide a new modality for co-delivery of nucleic acid and drugs to inhibit CSCs and reverse drug resistance.

Citation Format: Qin Liu, Rutian Li, Baorui Liu. The gelatinases-stimuli nanoparticles reverse docetaxel resistance and epithelial to mesenchymal transition in lung cancer cell line. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B41.