bluuebunny/crossref_metadata_2025 huggingface dataset:
(Invited) A 1-mG MEMS Sensor
Authors: Yamane Daisuke , Konishi Toshifumi , Toshiyoshi Hiroshi , Masu Kazuya , Machida Katsuyuki
Published: May 2016

This paper presents a 1-mG MEMS (microelectromechanical systems) capacitive inertial sensor developed by multi-layer metal technology. The sensor is designed to detect acceleration below 1 mG. A proof-of-concept device is fabricated by using a post-CMOS gold electroplating process. Measurement results suggest that the actual Brownian noise (BN
) is estimated to be lower than the target BN
of 1 μG/Hz1/2. Acceleration responses are also experimentally evaluated, which shows the potential of sensing acceleration below 1 mG. Those results reveal that the proposed sensor design could be a promising way to improve the sensitivity and the sensing range of integrated CMOS-MEMS accelerometers
Light Sensing of a-Si:H P
in Diode - Wavelength and Intensity Effects
Authors: Kim Kibum , Kuo Yue
Published: May 2016

The light sensing of the a-Si:H pin photodiode with respect to the wavelength and power intensity of the illumination light has been investigated. With the decrease of the wavelength, the diode’s external quantum efficiency is dependent on the competition of electron-hole pairs generation from the light absorption and recombination from defects in the structure. Both the series resistance and the shunt resistance decreased with the increase of the light intensity following the power law, which are contributed by the combination of changes of photocurrent and leakage current. The light sensing is a complicated function of the incident light and the film properties.
(Invited) Near-Field Coupling Integration Technology
Authors: Kuroda Tadahiro
Published: May 2016

Invention of IC was driven by “Tyranny of Numbers”, a challenge implied by large number of interconnects in a large-scale system. Modern ICs integrate many miles of wiring and billions of contacts. Moore's Law, however, will die, and we cannot rely just on integration on a chip. A revolutionary solution of the connection problem is now needed for further integration. Our proposal, as More-Than-Moore, is to replace mechanical connection using wiring, solder, and connectors by electrical one using near-field coupling. Transmission Line Coupler by electromagnetic coupling for module connection and ThruChip Interface by inductive coupling for chip stacking is presented and discussed in this paper.
(Invited) Challenges and Solutions for Future Internet-of-Things Semiconductor Technologies
Authors: Schaeffer Jamie K.
Published: May 2016

Emerging IoT edge-node applications demand new capabilities from semiconductor technologies including unparalleled energy efficiency, reduced package form factor via increased integration, wireless connectivity across a range of low-power wireless protocols, embedded memory for operating systems with smaller footprint and longer battery life, and low cost. This paper will detail these challenges and show why future fully-depleted silicon-on-insulator technologies, such as 22FDX technology, possess the salient features to satisfy these requirements and enable future generations of IoT devices.
(Invited) Evaluation of Stacked Nanowires Transistors for CMOS: Performance and Technology Opportunities
Authors: Gaben Loïc , Barraud Sylvain , Samson Marie-Pierre , Jaud Marie-Anne , Martinie Sébastien , Rozeau Olivier , Lacord Joris , Arvet Christian , Vizioz Christian , Bustos Jessy , Dallery Jacques-Alexandre , Pauliac Sébastien , Balan Viorel , Euvrard-Colnat Catherine , Perrot Cédric , Loup Virginie , Besson Pascal , Hartmann Jean-Michel , Monfray Stéphane , Boeuf Frédéric , Skotnicki Thomas , Balestra Francis , Vinet Maud
Published: May 2016

Stacked-NW FETs pave the way for significant increase in device effective width over FinFET and FDSOI. An increase of performance and/or a decrease of device footprint is expected by using thin and wide NW channels also known as nanosheets or nanoplates. This paper points out Gate Last integration issues of stacked-NWs. Two solutions labeled as NW First and NW Last are presented featuring internal spacer formation. A demonstration of self-aligned gate and spacers is proposed, involving Hydrogen Silsesquioxane (HSQ) lithography through silicon channels.
(Invited) The (R)Evolution of the Junctionless Transistor
Authors: Duffy Ray
Published: May 2016

In the junctionless transistor the doping type and concentration in the channel region is essentially equal to that in the source and drain, or at least to that in the source and drain extensions. This paper will first focus on the Revolution of the junctionless transistor, concentrating on the initial reports and studies in 2009. Then the Evolution of the junctionless transistor will be discussed since those early reports in 2009. A variety of studies will be reviewed, as junctionless transistors are being reported in many more materials other than Si, such as in Ge and InGaAs, and very recently in MoS2 and in other transition-metal-dichalcogenide semiconductors.
Formation of Low-Resistivity Metal/Germanium Contact with Ultra-Thin Interlayer and Plasma Oxidation for n-Channel Germanium FET
Authors: Kim Gwang-Sik , Kim Seung-Hwan , Park June , Kim Sun-Woo , Yu Hyun-Yong
Published: May 2016

In this work, the plasma oxidation process is introduced into the metal–interlayer–semiconductor (M–I–S) structure to reduce the contact resistance of the metal/n-type germanium (n-Ge) contact. The GeOx layer formed by the plasma oxidation process acts as a good passivation layer between TiO2 and Ge, and also an additional metal induced gap states (MIGS) blocking layer. From these effects of the GeOx layer, the M–I–S structure with multi-layered interlayer stack, TiO2/GeOx, shows approximately four orders of magnitude of the reverse current density improvement from the M–S contact. This technique can be a solution of the severe Fermi-level pinning (FLP) and the high contact resistance in source/drain (S/D) regions of the n-channel germanium field-effect transistor (FET).
(Invited) Role of Interfaces in Achieving Self-Compliance Controlled Resistive Random Access Memory Devices for Low-Power Embedded Applications
Authors: Jha Rashmi , Lu Wenchao , Chen Wenbo
Published: May 2016

This paper discusses the role of interface engineering in achieving self-current compliance (SCC) controlled Resistive Random Access Memory (ReRAM) devices based on MgO switching oxides. Our results indicate that interfacial layers (IL) such as Ti and TiOx allows switching with SCC in MgO based ReRAM devices. Set/Reset voltages of 1.4V/-1.8V were obtained with 60 ns programming pulses which demonstrates potential for low voltage operations. Interestingly, both set and reset currents decreased with an increase in the TiOx layer thickness up to 7 nm. These results indicated that the optimization of MgO/TiOx stack can solve the pending issue of compliance current control circuitry requirement in high density ReRAM devices.
(Invited) III-V / Si Integration for Photonics
Authors: Reithmaier Johann Peter , Benyoucef Mohamed
Published: May 2016

A brief overview is given on different approaches how to integrate III-V materials on a silicon platform for photonics with a main focuson epitaxial techniques. Beside diverse bonding and different direct epitaxial growth techniques of III-V on Si, a new potential approach based on a III-V/Si nanocomposite will be discussed, which may allow to overcome most of the basic problems in heterogeneous integration techniques, e.g., cross-contamination between III-V and Si and cost issues related to parallel efforts in III-V and Si processing. Initial results towards this new approach will be presented, such as on optically active GaAs/InAs core-shell quantum dots directly grown on Si and on monolithic integration of InAs nanoclusters fully embedded into a defect free and planar Si matrix. Due to the minimization of the consumption of the involved III-V materials and the complete Si coverage, standard Si processes on a full wafer scale are feasible.
Effect of Ba Co-Doping on Sr5(PO4)3Cl:Ce3+ Blue Emitting Phosphor Application for White Light Emitting Diodes
Authors: Deressa Gemechu
Published: May 2016

Ce3+-activated Sr5-2x-yBay(PO4)3Cl:xCe3+,xNa+ phosphors were synthesized via the solid statereaction methods. The substitution of Ba2+ for Sr2+ ions was confirmed by Raman spectra. The broadest Raman width in Sr2.45Ba2.45(PO4)3Cl:Ce3+ phosphor supported its highest disorder of the host lattice, leading to the emission spectral broadening with a half width of 95.5 nm due to the larger variation in crystal filed strength. The thermal stability of the luminescence was evaluated by the temperature-dependent luminescence intensity. The simulating a spectra of blue-emitting Sr2.45Ba2.45(PO4)3Cl:0.05Ce3+,0.05Na+ and orange emitting Sr3SiO5:Eu2+ phosphors as light converters, an intense white GaN-based near-UV-LED (400 nm) was exhibit good color-rendering index Ra of 90.8 at a correlated color temperature of 6473 K and CIE coordinates of (0.3165, 0.3051). These characteristics makes Sr2.45Ba2.45(PO4)3Cl: 0.05Ce3+,0.05Na+ should be a promising blue-emitting phosphors for the production of white light in phosphor conversion white-LEDs.
(Invited) Why Are Nanowire BioFETs More Sensitive than Their Large-Scale Counterparts?
Authors: Shoorideh Kaveh , Chui Chi On
Published: May 2016

We have studied the electrostatics of nanowire bioFETs as their channel widths vary. It is commonly believed that smaller bioFET channel widths and heights result in better sensitivity, which is attributed to increased surface-area-to-volume ratios of the bioFET channels. The simulations and analytical arguments presented here show that this reasoning is flawed. Instead, our work suggests that the local curvature of the bioFET surface, especially the corners, affects the electrostatic potential that results from the captured target analytes. Nanowires of any width have the same number of corners, but as the nanowire width shrinks, the beneficial concave corners contain a larger fraction of the total surface area, and their relative importance increases, leading to a slight increase in the bioFET signal.
A Novel and Robust Packaging Technology for Miniaturized FET-Based Biosensors with Microfluidic Channels
Authors: Hsu Chen-Pin , Chen Pei-Chi , Wang Yu-Lin
Published: May 2016

FET devices are extensively used for sensors, including gas sensors and biosensors. In contrast to traditional resistive devices, FET has transconductance gain, which can significantly improve the S/N ratio. Recently, more applications in biosensors combine microfluidic channels and FET system. In FET-based biosensors, the wafer manufacturing process always requires a lot of cost, and it is used for metal lines as interconnects. Miniaturized chip plays a key role in reducing the manufacturing cost. However, simultaneously integrating the sensor and microfluidic channels on one chip is challenging. In this study, a novel and robust packaging method has been developed, to effectively reduce the size of the sensor chip and thereby the cost. 1 mm2 FET sensor chip has been fabricated and embedded in epoxy. Photolithography and metal deposition were done followed by lift-off process for metal interconnect. The FET-embedded chip was passivated and covered by the microfluidic channel made of PMMA.
Use of Metal Nanostructure Arrays to Develop Flexible Biosensors for Rapid Point-of-Care Diagnosis Device
Authors: Li Szu-Ying , Yi Shang-Yi , Wan Dehui
Published: May 2016

To determine the amount of hydrogen peroxide (H2O2), we have developed two novel, low-cost, easy-to-use, and sensitive H2O2 biosensors. In this study, we could detect H2O2 without complicated equipment. Our first system utilizes an enzymatic approach by using a hollow palladium nanostructure (PdNS) to catalyze the oxidization of ABTS by H2O2. The formation of ox-ABTS shows an obvious green color. In another system, the silver atoms in Au-Ag nanoshell (AuNS) would be oxidized to silver ions and the AuNS would be transformed to a more porous shell due to the strong oxidizing ability of H2O2. We could distinguish the color change with increasing H2O2 concentration in the two systems with naked eyes. For developing point-of-care (POC) device of clinical diagnosis, we fabricated the low-cost disposable sensing platforms by immobilizing the nanoparticle onto the polyethylene terephthalate (PET) plate.
Developing Low-Intermediate Temperature Fuel Cells for Direct Conversion of Methane to Methanol Fuel
Authors: Torabi Alireza , Barton Joseph , Willman Carl , Ghezel-Ayagh Hossein , Li Na , Poozhikunnath Abhinav , Maric Radenka , Marina Olga A
Published: May 2016

The objective of this project is development of a durable, low-cost, and high performance Low Temperature Solid Oxide Fuel Cell (LT-SOFC) for direct conversion of methane to methanol and other liquids, characterized by: a) operating temperature < 500oC, b) current density of > 100 mA/cm2 in liquid hydrocarbon production mode, c) continuous operation of > 100 h, d) cell area > 100 cm2, e) cell cost per rate of product output < 100,000/bpd, f) process intensity of > 0.1 bpd/ft3, g) product yield and carbon efficiency > 50%, and h) volumetric output per cell > 30 L/day
Structure, Mechanism, and Application of Vacuum Insulation Panels in Chinese Buildings
Authors: Peng Changhai , Yang Jianqiang
Published: May 2016

Thermal insulation is one of the most used approaches to reduce energy consumption in buildings. Vacuum insulation panels (VIPs) are new thermal insulation materials that have been used in the domestic and overseas market in the last 20 years. Due to the vacuum thermal insulation technology of these new materials, their thermal conductivity can be as low as 0.004 W/(m·K) at the center of panels. In addition, VIPs that are composites with inorganic core and an envelope out of commonly three metallized PET layers and a PE sealing layer can provide B class fire resistance (their core materials are not flammable and are classified as A1). Compared with other conventional thermal insulation materials, the thermal insulation and fire resistance performances form the foundation of VIP’s applications in the construction industry. The structure and thermal insulation mechanism of VIP and their application potential and problems in Chinese buildings are described in detail.
Comparison of the Characteristics of Solid Type and Annular Type Nuclear Fuels Using Thermoelastic-Plastic-Creep FEM
Authors: Kwon Young-Doo , Lee Dae-Suep , Yun Tae-Hyeok
Published: May 2016

The purpose of this study is to compare the characteristics of two types of nuclear fuel using the finite element program of thermoelastic-plastic-creep analysis. The analyzed fuel rods are of two types, solid and annular ones, and their thermomechanical characteristics are compared. Thermoelastic-plastic-creep analyses were made using an in-house finite element analysis program that adopts the “effective-stress-function” algorithm. The temperature-dependent material properties, which were obtained from the experiments for actual nuclear reactors, are adopted. The effects of type of fuel systems are revealed in both stresses and temperature distributions. The maximum tensile and compressive hoop stress of pellet and cladding are monitored to evaluate the mechanical behavior, and the maximum temperature is used to evaluate the thermal behavior. Although the annular type of fuel has certain disadvantage, it would be used very effectively or safely in future nuclear power plants.
Sedation Monitoring and Management during Percutaneous Endoscopic Lumbar Discectomy
Authors: Oksar Menekse , Gumus Tulin , Kanbak Orhan
Published: May 2016

Percutaneous endoscopic laser discectomy (PELD) is a painful intervention that requires deep sedation and analgesia. However, sedation should be light at some point because cooperation by the patient during the procedure is required for successful surgical treatment. Light sedation poses a problem for endotracheal intubation, while patients placed in the prone position during percutaneous endoscopic discectomy pose a problem for airway management. Therefore, under these conditions, sedation should be not deeper than required. Here we report the sedation management of three cases that underwent PELD, with a focus on deep and safe sedation that was monitored using bispectral index score and observer’s assessment of alertness/sedation score.
Quantitative Clinical Diagnostic Analysis of Acetone in Human Blood by HPLC: A Metabolomic Search for Acetone as Indicator
Authors: Akgul Kalkan Esin , Sahiner Mehtap , Ulker Cakir Dilek , Alpaslan Duygu , Yilmaz Selehattin
Published: May 2016

Using high-performance liquid chromatography (HPLC) and 2,4-dinitrophenylhydrazine (2,4-DNPH) as a derivatizing reagent, an analytical method was developed for the quantitative determination of acetone in human blood. The determination was carried out at 365 nm using an ultraviolet-visible (UV-Vis) diode array detector (DAD). For acetone as its 2,4-dinitrophenylhydrazone derivative, a good separation was achieved with a ThermoAcclaim C18column (15 cm×4.6 mm×3 μm) at retention time (tR) 12.10 min and flowrate of 1 mL min−1using a (methanol/acetonitrile) water elution gradient. The methodology is simple, rapid, sensitive, and of low cost, exhibits good reproducibility, and allows the analysis of acetone in biological fluids. A calibration curve was obtained for acetone using its standard solutions in acetonitrile. Quantitative analysis of acetone in human blood was successfully carried out using this calibration graph. The applied method was validated in parameters of linearity, limit of detection and quantification, accuracy, and precision. We also present acetone as a useful tool for the HPLC-based metabolomic investigation of endogenous metabolism and quantitative clinical diagnostic analysis.
Macrophage Migration Inhibitory Factor and Malondialdehyde as Potential Predictors of Vascular Risk Complications in Type 2 Diabetes Mellitus: Cross-Sectional Case Control Study in Saudi Arabia
Authors: Morsi Heba Kamal , Ismail Manar Mohammad , Gaber Hassan Abdelaziz Hassan , Elbasmy Amani Abdelhamid
Published: May 2016

Background. Malondialdehyde (MDA) has been implicated in the development of many acute inflammatory, autoimmune diseases as well as chronic inflammatory metabolic disorders. Involvement of inflammatory response and oxidative stress is currently suggested as a mechanism underlying development of diabetes and its complications.Objective. To evaluate the clinical utility of MDA, macrophage migration inhibitory factor (MIF), LDL-C/HDL-C, and TG/HDL-C ratio as noninvasive laboratory markers for prediction of T2DM vascular complications.Method. 63 Saudi T2DM patients and 16 age and sex matched controls were included. Serum MDA and MIF were assayed by thiobarbituric acid reactive substances and ELISA, respectively. TG/HDL-C and LDL-C/HDL-C ratios were calculated.Results. Uncontrolled DM patients had significantly higher levels of MDA, MIF, TG/HDL-C, and LDL-C/HDL-C ratios when compared with controlled DM patients and control group (p<0.001). MDA had 100% sensitivity and 88% specificity. MIF showed 97% sensitivity and 100% specificity and LDL-C/HDL-C had 97% sensitivity and 95% specificity. Meanwhile, TG/HDL-C had the lowest sensitivity and specificity in identifying diabetic patients who would suffer from vascular complications.Conclusion. MDA, MIF, and LDL-C/HDL-C could be new predictors of metabolic disturbance which promote vascular complications in T2DM.
Erythropoietin Dose and Mortality in Hemodialysis Patients: Marginal Structural Model to Examine Causality
Authors: Streja Elani , Park Jongha , Chan Ting-Yan , Lee Janet , Soohoo Melissa , Rhee Connie M. , Arah Onyebuchi A. , Kalantar-Zadeh Kamyar
Published: May 2016

It has been previously reported that a higher erythropoiesis stimulating agent (ESA) dose in hemodialysis patients is associated with adverse outcomes including mortality; however the causal relationship between ESA and mortality is still hotly debated. We hypothesize ESA dose indeed exhibits a direct linear relationship with mortality in models of association implementing the use of a marginal structural model (MSM), which controls for time-varying confounding and examines causality in the ESA dose-mortality relationship. We conducted a retrospective cohort study of 128 598 adult hemodialysis patients over a 5-year follow-up period to evaluate the association between weekly ESA (epoetin-α) dose and mortality risk. A MSM was used to account for baseline and time-varying covariates especially laboratory measures including hemoglobin level and markers of malnutrition-inflammation status. There was a dose-dependent positive association between weekly epoetin-αdoses ≥18 000 U/week and mortality risk. Compared to ESA dose of <6 000 U/week, adjusted odds ratios (95% confidence interval) were 1.02 (0.94–1.10), 1.08 (1.00–1.18), 1.17 (1.06–1.28), 1.27 (1.15–1.41), and 1.52 (1.37–1.69) for ESA dose of 6 000 to <12 000, 12 000 to <18 000, 18 000 to <24 000, 24 000 to <30 000, and ≥30 000 U/week, respectively. High ESA dose may be causally associated with excessive mortality, which is supportive of guidelines which advocate for conservative management of ESA dosing regimen in hemodialysis patients.
Basic Hand Gestures Classification Based on Surface Electromyography
Authors: Palkowski Aleksander , Redlarski Grzegorz
Published: May 2016

This paper presents an innovative classification system for hand gestures using 2-channel surface electromyography analysis. The system developed uses the Support Vector Machine classifier, for which the kernel function and parameter optimisation are conducted additionally by the Cuckoo Search swarm algorithm. The system developed is compared with standard Support Vector Machine classifiers with various kernel functions. The average classification rate of 98.12% has been achieved for the proposed method.
Self-Shrinkage Behaviors of Waste Paper Fiber Reinforced Cement Paste considering Its Self-Curing Effect at Early-Ages
Authors: Jiang Zhengwu , Guo Xiuyan , Li Wenting , Chen Qing
Published: May 2016

The aim of this paper was to study how the early-age self-shrinkage behavior of cement paste is affected by the addition of the waste paper fibers under sealed conditions. Although the primary focus was to determine whether the waste paper fibers are suitable to mitigate self-shrinkage as an internal curing agent under different adding ways, evaluating their strength, pore structure, and hydration properties provided further insight into the self-cured behavior of cement paste. Under the wet mixing condition, the waste paper fibers could mitigate the self-shrinkage of cement paste and, at additions of 0.2% by mass of cement, the waste paper fibers were found to show significant self-shrinkage cracking control while providing some internal curing. In addition, the self-curing efficiency results were analyzed based on the strength and the self-shrinkage behaviors of cement paste. Results indicated that, under a low water cement ratio, an optimal dosage and adding ways of the waste paper fibers could enhance the self-curing efficiency of cement paste.
Abstract A100: In vivo models of pancreatic cancer for translational medicine
Authors: Behrens Diana , Anders Diana , Hallas Cora , Pahle Jessica , Fichtner Iduna
Published: May 2016

In Germany pancreatic cancer remains a lethal disease with only 3 - 8% of patients surviving 5 years after diagnosis of the tumor (2005). Reasons for this poor situation are advanced and inoperable tumor stages at time of diagnosis and resistance to conventional therapies. One bottleneck in the development of novel therapies is the restricted availability of preclinical models with a high clinical relevance.

The aim of our study was to develop well-defined in vivo xenografts derived from patient pancreatic carcinomas to address translational questions. These xenografts can be used for identification of biomarkers and cancer related pathways as well as for the evaluation of targeted therapies. The genesis of pancreatic neoplasm, the progression of tumor growth as wells as the development of resistance can be elucidated with animal models of patient-derived material. And last but not least preclinical data can be used prospectively for efficient stratification of patients.

57 patient tumors were collected from the clinical cooperation partner and transplanted immediately into immune-deficient mice.

14 out of 57 samples could be established so far as passagable pancreatic cancer xenografts (PDX), 5 were identified as inflammations of the pancreas. Interestingly, we observed 4 out of 57 as post-transplant lymphoproliferative disorders (PLTD); 29 failed to grow in mice. All of the engrafted PDX are poor or moderate differentiated adenocarcinomas. Global gene expression analysis and determination of cancer associated mutations were performed from engrafted tumor models. According to clinical data we found K-ras mutations in 13 and additionally p53 mutations in 9 out of 14 PDX.

Chemosensitivity was evaluated by transplanting tumor material into cohorts of immune-deficient mice. Beginning from palpable tumor sizes mice were treated with clinically relevant therapies (Gemcitabine, Abraxane, 5FU, Oxaliplatin, Erlotinib as monotherapy or combinations) as well as PDAC untypical drugs like Irinotecan, Vincristine, Avastin and Sorafenib at optimized schedules and doses. The response to Gemcitabine was moderate within the PDX panel. The most efficient therapeutic was Abraxane. Additionally, we could establish a luciferase expressing PDX for in vivo imaging of orthotopic tumor grafts.

Patient-derived xenografts are a crucial tool for the prediction of therapy and potentially relevant for the implication into clinical decisions. We have successfully developed a panel of 14 pancreatic cancer PDX for translational research projects.

Citation Format: Diana Behrens, Diana Anders, Cora Hallas, Jessica Pahle, Iduna Fichtner. In vivo models of pancreatic cancer for translational medicine. [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 A100.
Abstract A164: The small molecule UAE inhibitor TAK-243 (MLN7243) prevents DNA damage repair and reduces cell viability/tumor growth when combined with radiation, carboplatin and docetaxel
Authors: Milhollen Michael A. , Shi Judi , Traore Tary , Huck Jessica , Sappal Darshan , Duffy Jennifer , Lightcap Eric , Ishii Yuko , Ciavarri Jeff , Fleming Paul , Bence Neil , Hyer Marc L.
Published: May 2016

Clinical results of VELCADE® (bortezomib) For Injection have prompted evaluation of other enzymes within the ubiquitin proteasome system (UPS) as druggable targets for human cancer. We have identified a first in class investigational drug, TAK-243 (MLN7243), which targets the ubiquitin activating enzyme, UAE (UBA1), an essential cellular enzyme responsible for activating > 99% of all cellular ubiquitin. Ubiquitin is involved in multiple cellular processes including ubiquitin-dependent protein turnover, cell cycle progression, regulation of apoptosis, protein localization and response to DNA damage. Experiments combining targeted siRNA knockdown with TAK-243 identified DNA damage repair genes necessary for UAE inhibitor-induced cell death. A more focused approach revealed TAK-243 treatment blocked essential monoubiquitination events within the Translesion synthesis (TLS), Fanconi Anemia (FA) and Homologous recombination (HR) pathways. Inhibition of UAE prevented mono-ubiquitin signaling of key mediators within these pathways, including PCNA and FANCD2, by blocking formation of their specific E2-ubiquitin thioesters. In vitro cell-based assays combining TAK-243 with ultraviolet (UV) and radiation, both known to induce DNA damage, yielded inhibition of cell growth and enhanced DNA damage as observed through colony formation assays and Comet assay detection, respectively. Xenograft tumor bearing mice were treated with carboplatin or docetaxel, combined with TAK-243, to evaluate combination benefits in vivo. Synergistic and additive anti-tumor combination benefits were observed in animals treated with TAK-243 + carboplatin and TAK-243 + docetaxel. These important mechanistic in vitro and in vivo studies indicate the dependency of ubiquitination signaling in DNA damage repair and provide a mechanistic rationale for combining radiation, carboplatin or docetaxel with TAK-243 in the clinical setting. Currently, TAK-243 is being evaluated in a solid tumor phase I clinical trial evaluating safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumor activity (ClinicalTrials.gov identifier: NCT02045095).

Citation Format: Michael A. Milhollen, Judi Shi, Tary Traore, Jessica Huck, Darshan Sappal, Jennifer Duffy, Eric Lightcap, Yuko Ishii, Jeff Ciavarri, Paul Fleming, Neil Bence, Marc L. Hyer. The small molecule UAE inhibitor TAK-243 (MLN7243) prevents DNA damage repair and reduces cell viability/tumor growth when combined with radiation, carboplatin and docetaxel. [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 A164.
Abstract A174: RXDX-105 demonstrates potent RET inhibitory activity with therapeutic potential in multiple preclinical models of RET-rearrangement driven cancer
Authors: Joseph James , Franovic Aleksandra , Schairer Anni , Martin Eric , Wei Ge , Murphy Danielle , Christiansen Jason , Shoemaker Robert , Multani Pratik , Wild Robert , Li Gang
Published: May 2016

Genomic alterations in RET, encoding the RET (rearranged in transformation) kinase, have been identified as bona fide oncogenic drivers in numerous tumor types. Activating RET point mutations are typically associated with multiple endocrine neoplasia (types A and B) and familial medullary thyroid carcinoma. Although activating RET rearrangements can be found in up to 40% of papillary thyroid cancers, they are only present in up to 2% of non-small cell lung cancers and at lower frequencies in multiple other malignancies. As a result of the relatively low prevalence of molecular alterations in multiple tumor types, diagnostics-driven therapeutic selection strategies are being developed to identify patients with RET alterations. There also remains a clinical need for a potent, selective and safe RET inhibitor that demonstrates robust efficacy in malignancies harboring RET rearrangements and other oncogenic alterations.

RXDX-105 (formerly CEP-32496) is a potent, orally available, small molecule kinase inhibitor that potently binds and antagonizes several known oncogenic driver proteins, including RET, while sparing VEGFR2. RXDX-105 is currently in clinical trial in patients with solid tumors. To evaluate the therapeutic potential of RXDX-105 in malignancies bearing RET alterations, we first assessed the ability of RXDX-105 to antagonize RET activity in vitro. In biochemical and cell based assays, RXDX-105 potently antagonizes the activity of RET-fusion proteins and RET activating point mutations, resulting in a dose dependent inhibition of downstream signaling events and cell proliferation. In vivo, RXDX-105 displays potent and dose dependent anti-tumor activity with significant tumor growth regressions in several patient derived xenograft models harboring RET-rearrangements.

These pre-clinical studies support the inclusion of patients bearing RET alterations in future diagnostics-based clinical trials exploring RXDX-105 efficacy across a variety of tumor types.

Citation Format: James Joseph, Aleksandra Franovic, Anni Schairer, Eric Martin, Ge Wei, Danielle Murphy, Jason Christiansen, Robert Shoemaker, Pratik Multani, Robert Wild, Gang Li. RXDX-105 demonstrates potent RET inhibitory activity with therapeutic potential in multiple preclinical models of RET-rearrangement driven cancer. [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 A174.
Abstract A185: Combined treatment strategies for microtubule interfering agent-resistant tumors
Authors: Broggini-Tenzer Angela , Sharma Ashish , Bender Sabine , Nytko-Karouzakis Katarzyna , Pruschy Martin
Published: May 2016

Treatment resistances to specific anticancer agents and radiotherapy are often linked to the mutated genetic background of tumor cells. Their activities towards co-targeted tumor microenvironment-related cells are thereby also abrogated but could be reestablished as part of rationally-designed combined treatment modalities. Here we mechanistically investigate in two clinically relevant microtubule-interfering agent (MIA)-refractory tumor models the potency of combined treatment modalities of MIAs, inhibitors of angiogenesis and ionizing radiation to overcome MIA-resistance.

Single and combined treatment regimens of ionizing radiation, microtubule stabilizing and de-stabilizing agents and anti-angiogenic compounds (everolimus, bevacizumab) were investigated in genetically defined MIA-sensitive and tubulin-mutated or P-glycoprotein/MDR1-overexpressing MIA-resistant lung and colon adenocarcinoma carcinoma cell systems (A549, SW480) and in the corresponding tumor xenografts. MIAs potently inhibited A549wt and endothelial cell proliferation, while no anti-proliferative effect was observed in the corresponding MIA-resistant tumor cells. More important, MIAs did not downregulate anymore HIF-1α transcriptional activity and subsequent secretion of HIF-1α-mediated growth factors and cytokines from these MIA-resistant tumor cells. Continuous pro-survival auto- and paracrine signaling from these resistant tumor cells resulted in an additional level of treatment resistance towards MIAs and ionizing radiation as determined in tumor xenografts derived from MIA-resistant tumor cells. However rationally-designed combined treatment of MIAs with mTOR-signaling- or VEGF-antagonists strongly re-sensitized treatment-resistant tumors to the corresponding MIA.

These data demonstrate that the interaction between the tumor cell compartment and the tumor microenvironment strongly determines the treatment response to different anticancer treatment modalities.A combined treatment modality of MIAs with antiangiogenic agents is potent to overcome tumor cell-linked MIA-resistance and should be considered as clinical strategy for MIA-refractory tumor entities.

Citation Format: Angela Broggini-Tenzer, Ashish Sharma, Sabine Bender, Katarzyna Nytko-Karouzakis, Martin Pruschy. Combined treatment strategies for microtubule interfering agent-resistant 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 A185.
Abstract A22: PanDrugsDB: Identifying druggable genetic dependencies for personalized cancer therapy
Authors: Piñeiro-Yáñez Elena , Reboiro-Jato Miguel , Perales-Patón Javier , Glez-Peña Daniel , Tejero Héctor , Shimamura Takeshi , Carretero Julián , Valencia Alfonso , Hidalgo Manuel , Al-Shahrour Fátima
Published: May 2016

The paradigm of personalized medicine is the identification of the appropriate drug for the right patient, using molecular profiles. In Oncology, it is well established that the anticancer drugs are effective in only a small subset of patients. Moreover, many of the new targeted therapies inhibit specific proteins, and they are only effective in tumors that are genetically altered. Consequently, the success of personalized treatment depends on each individual molecular profile, which a priori can be considered as very heterogeneous.

Here, we present a new computational approach (PanDrugsDB) based on the analysis and integration of genomic data (mutations, copy number variations or gene expression levels), with functional data (proteins essentiality) and pharmacological data. This tool is able to identify those molecular alterations that drive tumor progression and could be druggable based on the patient's molecular profile, and propose an individualized therapeutic strategy to guide clinical decision making for cancer patients. We have tested this approach, in publicly available data (ICGC and TCGA cancer genome projects) and patient's tumor genomic data that are analyzed in our institution as part of CNIO Personalized Medicine initiative.

Citation Format: Elena Piñeiro-Yáñez, Miguel Reboiro-Jato, Javier Perales-Patón, Daniel Glez-Peña, Héctor Tejero, Takeshi Shimamura, Julián Carretero, Alfonso Valencia, Manuel Hidalgo, Fátima Al-Shahrour. PanDrugsDB: Identifying druggable genetic dependencies for personalized cancer therapy. [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 A22.
Abstract A40: MicroRNA-494 inhibits growth of the gastrointesintal stromal tumor by targeting multiple cell cycle regulatory genes
Authors: Yun SeongJu , Kim Won Kyu , Kim Hoguen
Published: May 2016

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms occurring throughout the entire region of the gastrointestinal tract. Two oncogenes of the receptor tyrosine kinase family, KIT and PDGFRA, have gain-of-function mutations in approximately 70% and 15% of GISTs. Mutations of these 2 genes cause sustained activation, resulting in constant stimulation of the downstream signaling pathways of KIT and platelet-derived growth factor receptor, alpha polypeptide. Although KIT mutations are present in approximately 70% of GISTs,KIT overexpression is observed in more than 90% of GISTs. Dysregulation of microRNAs(miRNA)-494 was demonstrated to be a major cause for the overexppression of mutatnt KIT proteins in GISTs. It was also demonstrated that miR-494 treatment inhibits proliferation of GISTs and promotes apoptosis however, no details mechanisms are not known.

The purpose of this study was to provide evidence regarding the roles of miR-494 in GIST suppression. To elucidate the specific pathways affected by miRNA-494 treatment on GIST cell lines, transcriptome analysis of GIST430 and GIST882 cells transfected with nontargeting microRNA or with miR-494 was performed and subsequently validated by qRT-PCR. Based on the transcriptome analysis, we found that multiple cell cycle relevant pathways were down-regulated by miR-494 treatment and importantly, core genes such as KIT, CASP2, CDCA2, AURKB, CDCA8, E2F7, BIRC5 and CKS1B involved in the regulation of cell cycle pathways were identified as novel targets by miR-494. Using reporter assays, we further validated that miR-494 directly binds to the 3'UTR regions of BRAC5, CKS1B and E2F7 and induces biological alterations. To demonstrate the perturbation of cell cycle pathways by miR-494, FACS analysis using five GIST cell lines was performed and we found that all of the five GIST cell lines transfected with miR-494 subjected to cell cycle arrest and apoptosis. Colony forming and proliferation assays also demonstrated that miR-494 treatment induced the growth inhibition of GIST cells which was derived from the alterations of cell cycle pathways. Taken together, our findings suggest that the efficient suppression of GISTs by miR-494 is driven not only by targeting KIT, but also multiple genes involved in cell cycle pathways

Citation Format: SeongJu Yun, Won Kyu Kim, Hoguen Kim. MicroRNA-494 inhibits growth of the gastrointesintal stromal tumor by targeting multiple cell cycle regulatory genes. [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 A40.
Abstract A44: Inhibition of Foxm1 transcription factor diminished Kras-mutated tumor development
Authors: Wang I-Ching , Chien Hsin Chih , Chao Sheng-Yang , Li Chien-Cheng
Published: May 2016

Increased expression level of the Forkhead Box M1 (FOXM1) transcription factor is found in multiple types of cancers, and its expression is correlated with poor prognosis in patients with cancers, including non-small cell lung cancers and pancreatic cancers. We and others have shown that FoxM1 transcriptionally regulates a variety of genes essential for cell cycle progression, inflammation, angiogenesis, tumor cell invasiveness and survival. Published studies demonstrated that genetic deletion of Foxm1 gene from SPC-rtTA/tetO-KrasG12D/Foxm1 fl/fl mouse lung epithelial cells conferred resistance to tumorigenesis caused by oncogenic KrasG12D, indicating Foxm1 is a critical regulator of Kras signaling pathway during lung cancer initiation. When treated SPC-rtTA/tetO-KrasG12D/tetO-FOXM1 mice with Doxycycline, lung epithelial cell-specific expressed transgenic FOXM1 and Kras cooperate to promote tumor growth in mouse lungs. In the present study, we determine whether expression of FoxM1 affects proliferation of human cancer cells harboring oncogenic Kras. Here, we show that depletion of FOXM1 expression using inducible shFOXM1 diminished proliferation of Kras-mutated human non-small cell adenocarcinoma (A549 and NCI-H23) and pancreatic cancer (PANC-1 and AsPC-1) cell lines. In contrast, increased expression of FOXM1 caused increased proliferation of Kras mutated cancer cells. Scratch wound healing assay demonstrated that FOXM1 stimulates the migration of these cells, which is associated with elevated epithelial-mesenchymal transition (EMT) markers. Our studies demonstrate that FOXM1 transcription factor is required for Kras mutated human cancer cells proliferation during tumor progression.

Citation Format: I-Ching Wang, Hsin Chih Chien, Sheng-Yang Chao, Chien-Cheng Li. Inhibition of Foxm1 transcription factor diminished Kras-mutated tumor development. [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 A44.
Abstract A6: RNAseq and immune profiling analysis of syngeneic mouse models treated with immune checkpoint inhibitors enable biomarker discovery and model selection for cancer immunotherapy
Authors: Zhang Lan , Zhang Juan , Shi Qian
Published: May 2016

Background: Syngeneic tumor models have long been used in cancer research. Recently, the clinical success of anti-CTLA4 and anti-PD1 antibodies resulted in increased interests in using syngeneic models to evaluate cancer immunotherapeutics. Furthermore, as researchers discovered many of the existing or developing inhibitors of the canonical signaling pathways may interact with immune-environment, thus may synergize with cancer immunotherapies, they are looking for suitable models that may evaluate the combination of those therapies. More importantly, in the clinic it is still unknown why some patients respond to certain immunotherapies while others do not. We set out to utilize syngenetic models to address those questions.

Material and methods: Syngeneic cell lines models, such as B16, CT26, MC38, 4T1, were used to evaluate anti-PD1, PD-L1 and CTLA4 antibodies efficacies. Tumors were collected before the treatment for RNAseq analysis. Biomarkers were analyzed with the RNAseq data to predict treatment response to different immune checkpoint inhibitors.

Results: Crown has established a large collection of syngeneic models that covers most of the tumor types. Those models have been extensively profiled in vivo using anti-PD1, anti-CTLA4 antibodies, providing information necessary for selecting models and doses for combination therapy. Mostly recently, we have generated detailed maps of the expressional and mutational profiles of those models, as well as identified the alternative gene spliced transcripts, and gene fusion using RNA-seq. Mutational analysis indicated a number of syngeneic models harbor mutations that may be useful for combination studies of targeted and immuno-therapy. Using proprietary algorithms, we have also identified a set of biomarkers that may be useful to predict response to different immunotherapies in mouse models.

Conclusions: These data will enable selection of models based on researchers' specific targets for combination studies with immunotherapy. In addition, predictive biomarkers obtained from the analysis may be useful in understanding patient response in the clinic.

Citation Format: Lan Zhang, Juan Zhang, Qian Shi. RNAseq and immune profiling analysis of syngeneic mouse models treated with immune checkpoint inhibitors enable biomarker discovery and model selection for cancer immunotherapy. [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 A6.
Abstract A77: Repression of mTORC1 activity in NOTCH1 mutant T-ALL results in sensitivity to the BCL-2 inhibitor ABT-263
Authors: Dastur Anahita , Faber Anthony , Costa Carlotta , Benes Cyril
Published: May 2016

There is no effective molecularly targeted therapy for T-cell Acute Lymphoblastic Leukemias (T-ALL) and prognosis for relapsed or chemotherapeutic refractory cases remains poor. A large unbiased drug screen performed across cell lines from a broad spectrum of cancers revealed that NOTCH1 mutant T-ALL cells, including lines resistant to gamma-secretase inhibitors are very sensitive to the Bcl-2/xL inhibitor ABT-263. We found that NOTCH1 up regulates the mTOR suppressor REDD1, leading to suppression of the mTOR Complex 1. This in turn results in low MCL-1 levels and ABT-263 sensitivity. Inhibition of NOTCH1 activity in this context leads to robust and sustained up regulation of mTOR signaling which could limit the activity of gamma-secretase inhibitors. Analysis of a small set of patient samples support the findings that NOTCH1 mutant T-ALL have low MCL-1 levels. Most importantly, we show that suppression of mTORC1 by a small molecule inhibitor further sensitizes NOTCH1 mutant T-ALL to ABT-263 resulting in massive apoptosis and in vivo efficacy.

SIGNIFICANCE: This study uncovers a previously unappreciated link between two major oncogenic pathways, the NOTCH and mTOR pathways, with NOTCH1 repressing mTORC1 through REDD1. Further, we show that this suppression results in low MCL-1 levels and that combining mTORC inhibition with BCL-2 inhibition is a promising therapeutic strategy for GSI-resistantNOTCH1-mutant T-ALL.

Citation Format: Anahita Dastur, Anthony Faber, Carlotta Costa, Cyril Benes. Repression of mTORC1 activity in NOTCH1 mutant T-ALL results in sensitivity to the BCL-2 inhibitor ABT-263. [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 A77.