bluuebunny/crossref_metadata_2025 huggingface dataset:
FISH SOI MOSFET: An Evolution of the Diamond SOI Transistor for Digital ICs Applications
Authors: Gimenez Salvador P. , Alati Daniel M.
Published: April 2011

This work introduces and studies a new transistor layout style, called Fish SOI MOSFET using 3D numerical simulations, where two trapezes compose the transistor gate area, generating a "smaller than (<)" mathematical signal shape. This innovative layout structure is an evolution of the Diamond SOI MOSFET. The Fish structure was carefully designed to be used in the digital integrated circuits applications, because now its channel length can be implemented with the minimum dimension allowed by the manufacture process, in contrast to Diamond transistor in which this is not possible. The Fish transistor also uses the Longitudinal Corner Effect (LCE) to increase the resultant longitudinal electric field along to the channel length, that results in an improvement in the average carriers drift velocity in the channel, in the drain current, in the transconductance and in the on-state series resistance parameters.
Silicon Photonics Devices Based on SOI Structures
Authors: Itabashi Seiichi , Yamada Koji , Fukuda Hiroshi , Tsuchizawa Tai , Watanabe Toshifume , Shinojima Hiroyuki , Nishi Hideaki , Takahashi R. , Ishikawa Y. , Wada K.
Published: April 2011

This paper presents our recent progress with the development of silicon (Si) photonic devices utilizing Silicon-on-insulator (SOI) wafers. Si-photonics has emerged as attractive technology for developing innovative and inexpensive optoelectronic devices. Si-photonics enables us to optical components small due to high index contrast of silicon and SiO2. Therefore, ultra-small electrical and optical components can be fabricated and integrated on SOI wafers. And Si-photonic devices will have a lot of applications in telecommunications, optical interconnections and recently in quantum information systems such as quantum key distribution.
Performance of SOI MOSFETs with Ultra-Thin Body and Buried-Oxide
Authors: Ohata Akiko , Bae Y. , Cristoloveanu Sorin , Fenouillet-Beranger C. , Perreau P. , Faynot O.
Published: April 2011

The electrical characteristics in ultra-thin (8 nm) SOI-MOSFETs with 10 nm buried oxide thickness were studied. Threshold voltage was effectively controlled for both of N-channel and P-channel SOI-MOSFETs even in the short devices (45 nm). No degradation of the mobility due to the use of thin buried oxide could be detected. Through appropriate back-gate biasing, the performance of ultra-thin SOI-MOSFETs can be improved dramatically. In P-channel SOI-MOSFETs, the hole mobility measured in volume conduction regime is higher than when only one interface (Si/high-K or Si/SiO2) is activated. This gain makes the hole mobility comparable with the universal mobility law and is promising for performance enhancement in CMOS circuits.
Thermoelectric Properties of Silicon-On-Insulator Nanostructures
Authors: Aksamija Zlatan , Knezevic Irena
Published: April 2011

Hotspots in integrated circuits degrade the performance and reliability of devices and pose a challenge to further device scaling. Thermoelectric (TE) refrigeration using Si-based nanowires and nanoribbons is an attractive approach for targeted cooling of local hotspots due to the ease of on-chip integration and the nanowires' enhanced TE figure of merit, given by ZT=S^2σ/κ. Silicon-on-insulator (SOI) membranes and membrane-based nanowires and ribbons show promise for application as efficient thermoelectrics, which requires both high power factor S^2σ and low thermal conductivity κ. The design of efficient semiconductor thermocouples requires a thorough understanding of both charge and heat transport; therefore, thermoelectricity in silicon-based nanostructures requires that both electronic and thermal transport are treated on equal footing.
The Roles of the Electric Field and the Density of Carriers in the Improved Output Conductance of Junctionless Nanowire Transistors
Authors: Doria Rodrigo T. , Pavanello Marcelo A. , Trevisoli Renan D. , De Souza Michelly , Lee Chi-Woo , Ferain Isabelle , Dehdashti Akhavan Nima , Yan Ran , Razavi Pedram , Yu Ran , Kranti Abhinav , Colinge Jean-Pierre
Published: April 2011

This paper evaluates the roles of the electric field (E) and the density of carries (n) in the drain conductance of Junctionless Nanowire Transistors (JNTs). The behavior of E and n presented by JNTs with the variation of the gate and the drain voltages has been compared to the one presented by Inversion Mode (IM) Trigate devices of similar dimensions. It has been shown that the lower drain output conductance exhibited by Junctionless transistors with respect to the IM ones is correlated not only to the differences in the mobility and its degradation but also to the electric field, the density of carries and the first order derivative of these variables with respect the drain voltage.
Transport-Confined Multi-Barrier FETs: A New Paradigm for Low-Leakage High On-Current Transistors
Authors: Afzalian Aryan , Flandre Denis
Published: April 2011

Physics and performances of a new concept of nanoscale MOSFET, the Gate-Modulated Resonant-Tunneling (RT)-FET, are investigated through 3D Non-Equilibrium Green's Function simulations. Owing to the additional barriers and the related longitudinal confinement, the density of states in a RT-FET is reduced in its off state, while remaining comparable, in its on state, to that of a MOS transistor without barriers. The RT-FET thus features both a lower RT-limited off current and a faster increase of the current with gate voltage, i.e. an improved slope characteristic, and hence an improved ION/IOFF ratio, along with high on current and therefore good speed performance. RT-FETs could therefore be promising devices for future generation low power, high speed applications owing to superior delay-power trade-off than a MOSFET. In addition, RT-FETs are intrinsically immune to source-drain tunneling and appear promising candidate for extending the roadmap below 10nm.
(Invited) III-Nitride Nanowires: Emerging Materials for Lighting and Energy Applications
Authors: Wang George T. , Li Qiming , Huang Jianyu , Wierer Jonathan , Armstrong Andrew , Lin Yong , Upadhya Prashanth , Prasankumar Rohit
Published: April 2011

The aligned growth of III-nitride nanowires, along with results providing insights into the nanowire properties obtained using electrical, optical and structural characterization techniques, are discussed. A new "top-down" approach for fabricating ordered arrays of high quality GaN-based nanorods with controllable height, pitch and diameter is also presented, along with results from preliminary LEDs grown on these nanorod arrays. Additionally, a novel application of aligned nanowire arrays as strain-relief templates for the growth of high quality GaN is demonstrated.
(Invited) High Thermal Dissipation Apparatus for UV LEDs Application
Authors: Horng Ray-Hua , Hu Hung-Lieh , Lin Re-Ching , Chiang Yi-Chen
Published: April 2011

In this study, composite electroplating technique is used to fabricate the diamond-added copper heat spreader for UV LED applications. Thermal dissipation characteristic and optical performance are improved as the composite diamond-added copper heat spreader adoption. The low thermal resistance of 18.4 K/W with UV LED using diamond-added copper heat spreader was measured. Surface temperature of UV LED using the diamond-added copper heat spreader is 50.42 oC at 500 mA injecting current lower than pure copper heat spreader of 59.9 oC and original heat spreader of 90.4 oC. The thermal diffusivity of the diamond-added copper is 0.7179 cm2/s measurement by laser flash method. Output power and power efficiency of UV LEDs are also enhanced to 71.81 mW and 4.32 %, respectively, at 400 mA injection current. The optimal structure design and materials fabrication will be discussed.
Growth and Characterization of p-InGaN/i-InGaN/n-GaN Double Heterojunction Solar Cell on Patterned Sapphire Substrates
Authors: Chu Mu-Tao , Liao Wen-Yih , Wu Ming-Hsien , Horng Ray-Hua , Tsai Tsung-Yen , Liu Shu-Ping
Published: April 2011

InGaN-based solar cells with p-InGaN/i-InGaN/n-GaN double heterojunction structure have been fabricated and characterized in our study. Two kinds of sapphire substrate, conventional sapphire substrate and pattern sapphire substrate, were used for epitaxial growth of the heterojunction structure. Both the solar cells grown on conventional sapphire substrate and pattern sapphire substrate demonstrated high open-circuit voltage (VOC) of 2.05 V and 2.08 V, respectively. However, short-circuit current density (JSC) of solar cell grown on pattern sapphire substrate shown an improvement of 27.6% when comparing to its grown on conventional sapphire substrate. Such an enhancement could be contributed to the increase of effective light absorption path due to the incident light scattering from textured surface on pattern sapphire substrate.
A Novel InGaN Blue Light-Emitting Diode with a Self-Textured Oxide Mask Structure
Authors: Lin Wen-Yu , Wuu Dong-Sing , Huang Shih-Cheng , Lo Shih-Yung , Liu C. M. , Horng Ray-Hua
Published: April 2011

A 460 nm InGaN/GaN blue light-emitting diode (LED) with a self-textured oxide mask (STOM) structure was fabricated and demonstrated. The design of the STOM on the GaN/sapphire substrate could be used to reduce the threading dislocation density in the epitaxial template and enhance the light extraction efficiency via the light scattering or deflection from the corrugated STOM. Under an injection current of 20 mA, the forward voltage of the STOM-LED and conventional LED (C-LED) was nearly identical at 3.41 V. Moreover, the leakage current of the STOM-LED was lower than the C-LED. Furthermore, the light output power of the STOM-LED was approximately 43% higher (at 20 mA) than the C-LED. This significant improvement was attributed to the enhanced light extraction via the STOM mask.
Advanced Residual Stress Analysis on the Heteroepitaxial Growth of 3C-SiC/Si for MEMS Application
Authors: Anzalone Ruggero , Camarda Massimo , D'Arrigo Giuseppe , Piluso Nicolò , Severino Andrea , Canino Andrea , La Magna Antonino , La Via Francesco
Published: April 2011

In this article, helped by finite element simulations, we show that, properly designed, planar-rotator microstructures can be used to simultaneously determine the uniform and gradient residual stresses in thin films in the limit of linear residual stress form. TEM characterization studies on the defect formation and propagation as a function of 3C-SiC/Si thickness revealed that the linear stress approximation in such a hetero-epitaxial thin film is wrong. With finite element modeling four different stress relationships were studied and compared. This study shows that the new approximation forms of the total residual stress function result in a better fit of the experimental data and reduces the disagreement between theory and experiments.
Vertically Configured Nanodiamond Vacuum Field Emission Transistor Arrays
Authors: Hsu S. H. , Kang W. P. , Davidson J. L , Huang Jin-Hua
Published: April 2011

The design, fabrication and device characteristics of a vertically configured nanodiamond vacuum field emission transistor array are reported. The device is fabricated by a simple dual-mask process, involving mold transfer technique, growth of chemical vapor deposited nanodiamond and formation of self-aligning gate structure from a silicon-on-insulator (SOI) substrate. The gate controlled emission current modulation was achieved at a relatively low gate turn-on voltage of 25 V. The device demonstrates transistor characteristics with high emission anode current of 160 uA and negligible gate intercepted current of less than 3 uA at gate voltage of 34 V. This nanodiamond VFET promises potential applications in vacuum microelectronics, including vacuum integrated circuits.
Microfluidics for Detection of Myoglobin in Blood Samples
Authors: Gunda Naga Siva Kumar , Mitra Sushanta K.
Published: April 2011

In the present work we investigated the applicability of microfluidics for detection of myoglobin in blood samples using a dielectrophoresis (DEP) technique. We have proposed a new method of detecting myoglobin using immunoassay assisted by DEP. This paper focuses on the fabrication of the proposed device as well as the sample preparation for myoglobin detection.
Use of Electroporation for Efficacious Gene Delivery to the Lungs
Authors: Dean David A. , Barravecchia Michael , Danziger Benjamin , Lin Xin
Published: April 2011

We are interested in developing gene therapy treatments for pulmonary diseases, including acute lung injury. Recent research from our laboratory and others has demonstrated that electroporation can be used to efficiently deliver genes to the lung, in vivo with no apparent damage and yields high level gene expression. The method is simple, fast, and safe: DNA is delivered to the airways and electrodes placed externally on either side of the chest are used to deliver the field. In studies in mice and rats, we have demonstrated that transfer of genes for the Na+,K+-ATPase and/or the Epithelial Sodium Channel protects from subsequent endotoxin-induced lung injury, but more importantly, we have also shown that this approach can be used in lungs with established lung injury and pulmonary edema to treat the disease and lessen the severity of the injury. To move this toward clinical use, we have evaluated these techniques in a large animal pig model that closely resembles the human situation. The approach is safe and effective, paving the way to clinical use.
Negative Charge in Plasma Oxidized SiO2 Layers
Authors: Boogaard Arjen , Kovalgin Alexey Y. , Wolters Rob
Published: April 2011

SiO2 gate dielectric layers were deposited on n-type Si by inductively-coupled plasma-enhanced chemical vapor deposition (ICPECVD) at 150°C. In contrast to the well-accepted positive charge for thermally grown SiO2, the net oxide charge was negative and a function of the layer thickness. Our experiments suggested that the negative charge was created due to unavoidable oxidation of the silicon surface by plasma species. The CVD component added a positive space charge to the oxide. Additional measurements showed that the negative charge in SiO2 also persisted on p-type substrates. We suggest that plasma oxidation of the silicon surface results in SiO2 with a surplus of oxygen, which is able to accumulate a negative charge. This assumption is addressed by a series of experiments wherein oxygen is implanted into thermal SiO2. It is shown that the implantation can result in a negative charge to the bulk oxide layer.
Quantitative Discussion on Electron-Hole Universal Tunnel Mass in Ultrathin Dielectric of Oxide and Oxide-Nitride
Authors: Watanabe Hiroshi
Published: April 2011

MOS and MIS capacitor has been extensively studied in past several decades by many authors. It has been expected to reveal how basic physics relate electron device operation. In this structure, several physical phenomena co-work and then exhibit the electrical properties measured in IV- and CV-characteristics. On the other hand, the conventional models were established separately for the inversion layer (positive gate voltage), the depletion region (negative-low gate voltage), and the accumulation region (negative-high gate voltage). In addition, actual MOS/MIS samples have interfacial transition layer where physical properties are gradually changed from Si to oxide or other dielectric, the varying composition ratio of molecules and local traps owing to atomistic dangling bonds through dielectric layer. What will happen if we self-consistently unify all the physical models that are separately developed?
Intrinsic Variability and Reliability in Nano-CMOS
Authors: Velamala Jyothi , Wang Chi-Chao , Zheng Rui , Ye Yun , Cao Yu
Published: April 2011

Intrinsic device variability and reliability, such as dopant and geometry fluctuations, as well as temporal degradation, poses a fundamental challenge to CMOS scaling and IC design. Their importance is rapidly increasing as device feature size approaches the atom dimension. Predictive modeling helps benchmark its impact on circuit performance, indicating the trend, priority and techniques of variability control. Furthermore, statistical interaction between static variation and temporal shift is investigated.
Bias-Temperature Instabilities and Radiation Effects on SiC MOSFETs
Authors: Zhang Enxia , Zhang Cher Xuan , Fleetwood Daniel M , Schrimpf Ronald D. , Dhar Sarit , Ryu Sei-Hyung , Shen Xiao , Pantelides Sokrates T.
Published: April 2011

Bias-temperature-instabilities (BTIs) are investigated for 4H-SiC based nMOSFETs before and after total ionizing dose irradiation. We find that the threshold voltage shifts of unirradiated devices decrease significantly with elevated-temperature stress under accumulation bias; in contrast, devices stressed under inversion bias do not exhibit significant threshold voltage shifts. Threshold voltage shifts due to BTI for unirradiated devices stressed under accumulation bias may well be enhanced significantly as a result of the additional ionization of deep dopants in SiC at elevated temperatures. The BTIs are caused by charge carriers are captured by deep interface traps (more than 0.6 eV away from the SiC conduction or valence bands) and O vacancies in the SiO2. Hole trapping at O vacancies dominates the ionizing radiation response. The magnitudes of the changes in threshold voltage shifts increase with switched bias-temperature stress after irradiation, relative to those in unirradiated devices.
Role of Oxygen Transfer for High-k/SiO2/Si Stack Structure on Flatband Voltage Shift
Authors: Nabatame Toshihide , Ohi Akihiko , Chikyow Toyohiro
Published: April 2011

We investigate the difference of flatband voltage (Vfb) behavior in high-k/SiO2/Si stack structure due to oxygen vacancy (Vo) and additional oxygen generated by the reduction and oxidation annelaing process, respectively. The Vfb of Mg and La-incorporated Hf-based high-k dielectrics is also influenced by Vo generation in high-k layer. We found that the non-linear relationships of Vfb behavior appears in HfSiOx, Mg2+- and La3+-HfSiOx dielectrics as a function of the oxidation annealing temperature, while the HfO2, N3+-HfSiOx, Mg2+- HfO2, and La3+-HfO2 dielectrics show the linear relationships of Vfb shift by introducing additional oxygen. Furthermore, it is clear that the Vfb shift of all high-k materials satisfies the diffusion equation; which indicates that the oxygen transfer in high-k layer is a dominant factor in determining Vfb. We found that the oxygen diffusion in high-k materials can be ordered as follow: Mg2+- and La3+-HfO2 > HfO2 >> N3+-HfSiOx and La3+-HfSiOx > HfSiOx and Mg2+-HfSiOx.
An Electron Paramagnetic Resonance Study of Defects in Interlayer Dielectrics
Authors: Bittel Brad C. , Pomorski Thomas , Lenahan Patrick M. , King Sean
Published: April 2011

The electronic properties of thin film low-κ interlayer dielectric (ILD) and etch stop layers (ESL) are important issues in present day ULSI development (1-6). Low-κ ILD and ESLs with dielectric constants significantly less then those of SiO2 and SiN are utilized to reduce capacitance induced RC delays in ULSI circuits. Leakage currents, time dependent dielectric breakdown (TDDM) and stress induced leakage currents (SILC) are critical problems that are not yet well understood in ILD. A topic of current interest is ultraviolet light (UV curing) of low-k materials (5,6). We have made electron spin resonance (ESR) and current density versus voltage measurements on a moderately extensive set of dielectric/silicon structures involving materials of importance to low-k interconnect systems. Most of the dielectrics studied involve various compo-sitions of SiOC:H. In addition we have also made measurements on other dielectrics including SiO2, SiCN:H and SiN:H.
Salt sensitivity in experimental thyroid disorders in rats
Authors: Perez-Abud Rocío , Rodríguez-Gómez Isabel , Villarejo Ana Belén , Moreno Juan Manuel , Wangensteen Rosemary , Tassi Mohamed , O'Valle Francisco , Osuna Antonio , Vargas Félix
Published: April 2011

This study assessed salt sensitivity, analyzing the effects of an increased saline intake on hemodynamic, morphological, and oxidative stress and renal variables in experimental thyroid disorders. Six groups of male Wistar rats were used: control, hypothyroid, hyperthyroid, and the same groups treated with salt (8% via food intake). Body weight, blood pressure (BP), and heart rate (HR) were recorded weekly for 6 wk. Finally, BP and HR were recorded directly, and morphological, metabolic, plasma, and renal variables were measured. High-salt intake increased BP in thyroxine-treated rats but not in control or hypothyroid rats. High-salt intake increased cardiac mass in all groups, with a greater increase in hyperthyroid rats. Urinary isoprostanes and H2O2were higher in hyperthyroid rats and were augmented by high-salt intake in all groups, especially in hyperthyroid rats. High-salt intake reduced plasma thyroid hormone levels in hyperthyroid rats. Proteinuria was increased in hyperthyroid rats and aggravated by high-salt intake. Urinary levels of aminopeptidases (glutamyl-, alanyl-, aspartyl-, and cystinylaminopeptidase) were increased in hyperthyroid rats. All aminopeptidases were increased by salt intake in hyperthyroid rats but not in hypothyroid rats. In summary, hyperthyroid rats have enhanced salt sensitivity, and high-salt intake produces increased BP, cardiac hypertrophy, oxidative stress, and signs of renal injury. In contrast, hypothyroid rats are resistant to salt-induced BP elevation and renal injury signs. Urinary aminopeptidases are suitable biomarkers of renal injury.
An Effective Generalization of the Direct Support Method
Authors: Radjef Sonia , Bibi Mohand Ouamer
Published: April 2011

The main objective of our paper is to solve a problem which was
encountered in an industrial firm. It concerns the conception of a weekly
production planning with the aim to optimize the quantities to be launched.
Indeed, one of the problems raised in that company could be modeled as a linear multiobjective program where the decision variables are of two kinds: the
first ones are upper and lower bounded, and the second ones are nonnegative.
During the resolution process of the multiobjective case, we were faced with the
necessity of developing an effective method to solve the mono‐objective case
without any increase in the linear program size, since the industrial case to
solve is already very large. So, we propose an extension of the direct support
method presented in this paper. Its particularity is that it avoids the preliminary transformation of the decision variables. It handles the bounds as
they are initially formulated. The method is really effective, simple to use, and
permits speeding up the resolution process.
Effect of Tumor Necrosis Factor-α on Neutralization of Ventricular Fibrillation in Rats with Acute Myocardial Infarction
Authors: Chen Yu , Zhang Qing , Liao Yu-Hua , Cao Zhe , Du Yi-Mei , Xia Jia-Ding , Yang Hua , Chen Zhi-Jian
Published: April 2011

The purpose of this study was to explore the effects of tumor necrosis factor-α (TNF-α) on ventricular fibrillation (VF) in rats with acute myocardial infarction (AMI). Rats were randomly classified into AMI group, sham operation group and recombinant human tumor necrosis factor receptor:Fc fusion protein (rhTNFR:Fc) group. Spontaneous and induced VFs were recorded. Monophasic action potentials (MAPs) among different zones of myocardium were recorded at eight time points before and after ligation and MAP duration dispersions (MAPDds) were calculated. Then expression of TNF-α among different myocardial zones was detected. After ligation of the left anterior descending coronary artery, total TNF-α expression in AMI group began to markedly increase at 10 min, reached a climax at 20–30min, and then gradually decreased. The time-windows of VFs and MAPDds in the border zone performed in a similar way. At the same time-point, the expression of TNF-α in the ischemia zone was greater than that in the border zone, and little in the non-ischemia zone. Although the time windows of TNF-α expression, the MAPDds in the border zone and the occurrence of VFs in the rhTNFR:Fc group were similar to those in the AMI group, they all decreased in the rhTNFR:Fc group. Our findings demonstrate that TNF-α could enlarge the MAPDds in the border zone, and promote the onset of VFs.
A Joint Vehicle-Vehicle/Vehicle-Roadside Communication Protocol for Highway Traffic Safety
Authors: Hu Bin , Gharavi Hamid
Published: April 2011

A joint vehicle-vehicle/vehicle-roadside communication protocol is proposed
for cooperative collision avoiding in Vehicular Ad Hoc Networks (VANETs). In this protocol,
emergency warning messages are simultaneously transmitted via Vehicle-to-Vehicle (V2V) and
Vehicle-to-Roadside (V2R) communications in order to achieve multipath diversity routing. In
addition, to further improve communication reliability and achieve low latency, a Multi-Channel
(MC) technique based on two nonoverlapping channels for Vehicle-Vehicle (V2V) and V2R (or
R2V) is proposed. The simulation results demonstrate that the proposed joint V2V/V2R (R2V)
communication protocol is capable of improving the message delivery ratio and obtaining low latency,
which are very important merits for highway traffic safety.
STAT3 Inhibition Is a Therapeutic Strategy for ABC-like Diffuse Large B-Cell Lymphoma
Authors: Scuto Anna , Kujawski Maciej , Kowolik Claudia , Krymskaya Ludmila , Wang Lin , Weiss Lawrence M. , DiGiusto David , Yu Hua , Forman Stephen , Jove Richard
Published: April 2011

Persistent STAT3 signaling contributes to malignant progression in many diverse types of human cancer. STAT3 is constitutively active in activated B-cell (ABC)–like diffuse large B-cell lymphomas (DLBCL), a class of nongerminal center derived DLBCL cells for which existing therapy is weakly effective. In this report, we provide a preclinical proof of concept that STAT3 is an effective molecular target for ABC-like DLBCL therapy. Direct inhibition of STAT3 with short hairpin RNA suppressed the growth of human ABC-like DLBCL in mouse models in a manner associated with apoptosis, repression of STAT3 target genes, and inhibition of a tumor-promoting microenvironment. Together, these results suggest that STAT3 is essential to maintain the pathophysiology of ABC-like DLBCL and therefore that STAT3 inhibition may offer a promising approach in its therapy. Cancer Res; 71(9); 3182–8. ©2011 AACR.
Abstract BSF1-2: Understanding Stem Cells To Get Abreast of Breast Cancer
Authors: Lindeman GJ
Published: April 2011

Gene profiling studies have provided a basis for classifying breast cancer into at least six molecular subtypes and stimulated interest in identifying the cell type in which these distinct subtypes arise. Elucidating the normal cellular hierarchy within breast tissue is essential for identifying the ‘cell of origin’ that is targeted for neoplastic transformation. Stem cells, which lie at the apex of the normal tissue hierarchy, represent strong candidates, given that they are long-lived and capable of self-renewal. Alternatively, committed progenitor cells (stem cell descendants) or even mature progeny could also serve as cells of origin in breast cancer. Under these circumstances, cells would need to acquire certain stem cell-like properties (such as self-renewal) during tumorigenesis.

Our group (and others) have isolated discrete subpopulations of mouse and human mammary epithelial cells on the basis of cell-surface markers and defined subsets that are highly enriched for basal/mammary stem cells, committed luminal progenitor cells and mature luminal cells. Gene profiling revealed remarkable similarities between their molecular signatures and certain subtypes of breast cancer. Notably, the luminal progenitor signature (and not the basal/stem cell signature) was most similar to basal-like breast cancer. Moreover, breast tissue from breast cancer prone BRCA1 mutation carriers was found to contain increased numbers of luminal progenitors, which had aberrant growth and differentiation properties. Taken together, these findings suggest that luminal progenitors (and not basal/stem cells) are the likely target that give rise to basal-like breast cancer. Key markers (such as KIT) expressed by luminal progenitor cells could serve as therapeutic targets for breast cancer prevention or therapy. The cancer stem cell (CSC) hypothesis is in many ways distinct from the ‘cell of origin’ concept. This model proposes that established tumors are hierarchically organised (like normal tissue) and contain a subpopulation of cells with tumor propagating ability. CSCs are not necessarily derived from transformed stem cells. However, CSCs do need to acquire key stem cell properties (such as self-renewal capability). Breast CSCs have now been identified by several groups using xenograft models. Our laboratory has studied syngeneic mouse models of mammary tumorigenesis and found that a subset (but not all) appear to conform to the CSC hypothesis. The luminal progenitor marker (CD61/≥3-integrin) was found to identify a CSC population in mammary tumor-prone MMTV-wnt-1 and BALB/c-p53+/−, but not in MMTV-neu/erbB2 mice. We speculate that the CSC model may not necessarily apply to all breast tumors. Rather, the conventional ‘clonal evolution’ model (or perhaps a hybrid model) may also be relevant in some cases of breast cancer.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr BSF1-2.
Abstract BSF2-1: Molecular Chaperones: Cancer Dependence and Druggability
Authors: Workman P
Published: April 2011

Cancer cells live in a stressed state caused by genomic abnormalities, deregulated biochemical pathways and microenvironmental pressures. As a result they evolve, during malignant transformation and progression, a dependency on a range of molecular chaperone systems that provide essential protein folding, oncoprotein activation and anti-apoptotic functions. This chaperone dependence creates a specific vulnerability in cancer cells that is now being actively exploited in drug discovery. Our own work has focused on using a combination of genetic techniques and chemical probes (a powerful combination, see Workman P, Collins I. Probing the probes: fitness factors for small molecule tools. Chem Biol 17 561-577 2010) to enhance our understanding of the cancer biology of molecular chaperone systems. At the same time we are heavily involved in the discovery and clinical evaluation of drugs that act on these cancer-supportive molecular machines. The trail has been blazed by HSP90 inhibitors, of which at least 13 are now in clinical development. Signs of clinical activity have been seen, most notably with 17-AAG (tanespimycin) in trastuzumab-refractory, ERRB2-positive breast cancer. The new HSP90 inhibitor NVP-AUY922, which we discovered with Vernalis and is being developed by Novartis, shows good activity in breast tumour models (Eccles SA et al NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumour growth, angiogenesis, and metastasis. Cancer Res 68 2850-2860 2008). The activity of HSP90 inhibitors is self-limited by the mechanism-based activation of the protective, HSF1-dependent heat shock response. This presentation will provide an update on the discovery, development and use of HSP90 inhibitors and will describe emerging data on the identification and validation of new potential chaperone system targets, including AHA1, CDC37 and the HSP70 family (eg Powers MV, Clarke PA, Workman P. Dual targeting of HSC70 and HSP72 inhibits HSP90 function and induces tumour-specific apoptosis. Cancer Cell 14 250-262 2008). Molecular chaperones are overexpressed in clinical breast cancers, and in many examples their expression correlates with clinical outcome. Moreover, many oncoproteins important in breast cancer are client proteins for HSP90, including ER, PR, ERBB2, AKT/PKB/and CRAF. Thus HSP90 and other chaperone inhibitors have particular potential in breast cancer. Progress towards, and future challenges for, the potential of anti-chaperone drugs to become part of the personalized cancer medicine of the future (Yap TA, Sandhu SK, Workman P, de Bono JS. Envisioning the future of early anticancer drug development. Nat Rev Cancer 10 514-523 2010) will be highlighted.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr BSF2-1.
Abstract CSF1-2: Controversies in Screening for Breast Cancer
Authors: Esserman LJ
Published: April 2011

Over the last 10 years, we have learned a great deal about breast cancer. We now know that all breast cancers are not the same. Whether defined by receptor status or molecular subtype, we now know that there is a range of growth rates and associated risk of metastases for each breast cancer subtype. It stands to reason then that the impact of screening is likely to be different for each breast cancer subtype. And of course, every woman is not the same, and consideration of both genetic predisposition and the context of competing health risks should play a role in optimizing screening strategies for women. The goal of this talk is to integrate these considerations with the observations on breast cancer incidence over the past 25 years since the advent of screening. The rise in the incidence of early stage disease, particularly for women over the age of 50, has not been accompanied by a commensurate decline in the incidence of regional cancers. Regional or more locally advanced cancers are more likely to present at younger ages, and as interval cancers. On the other hand, indolent disease is more likely to appear in women of older age. This knowledge helps us to understand how to better personalize screening recommendations and better understand the screening trial data and the differential impact by age as well as the US Preventive Services Task Force screening guidelines. The screening trials also reflect an era when systemic treatment was quite different than it is today. Moreover, recent data suggest that the impact of optimal systemic treatment reduces the impact of screening. Finally, we must take into account the fact that screening is more likely to detect indolent cancers (IDLE tumors) when they are present. These insights present opportunities to improve our approach to screening which may in turn reduce the burden of cancer and cancer diagnosis.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr CSF1-2.
Abstract ES9-3: Balancing Risks of Deconditioning vs. Weight-Lifting for Breast Cancer Survivors
Authors: Schmitz KH , Cheville A , Ahmed RL , Troxel A
Published: April 2011

Background: Clinical guidelines for breast cancer survivors with and at-risk for lymphedema have advised against upper body exercise, preventing them from obtaining established health benefits of weight-lifting. The primary hypotheses of the Physical Activity and Lymphedema Trial were that lymphedema onset and worsening would not differ after a one-year weightlifting intervention compared to no exercise among survivors at risk for and with breast cancer-related lymphedema.

Methods: We performed a randomized controlled trial of a twice-weekly progressive weight-lifting intervention involving 141 breast cancer survivors with stable arm lymphedema at study entry and 154 survivors at-risk for lymphedema at study entry. Treatment group participants were provided a gym membership and 13 weeks of supervised instruction; the remaining nine months were unsupervised. Control group participants were provided the intervention after study completion. The primary outcome was the change in arm swelling at one year, as measured by water volumetry of the affected and unaffected arms. Secondary outcomes included the clinician defined incidence of onset and exacerbations of lymphedema, lymphedema symptoms, and muscle strength. Participants with lymphedema were required to wear a well-fitted compression garment while weight-lifting.

Results: Among the women who entered the study with lymphedema, the proportion who experienced a 5% or greater increase in arm swelling (interlimb difference) was similar in the treatment and control groups (11% versus 12%; cumulative incidence ratio [95% confidence interval], 1.00 (0.88 to 1.13) As compared with the control group, the women in the intervention group with lymphedema had greater improvements in self-reported lymphedema symptom severity (p=0.03), and a lower incidence of lymphedema exacerbations as assessed by a certified lymphedema specialist (14% versus 29% in the control group, p= 0.04). Among the women who entered the study without lymphedema, more control than treatment group women experienced lymphedema onset defined by 5% increase in interlimb difference (17 versus 11%, p = 0.35). Among higher risk women (5+ lymph nodes removed), this comparison was statistically significant (22 versus 7%, p=0.04). Clinician-defined BCRL onset occurred in 1 treatment and 3 control group women (p=0.62).

Conclusions: Slowly progressive weight-lifting had no significant impact on arm swelling among breast cancer survivors with lymphedema, and resulted in a reduced incidence of lymphedema flares and improvement in symptoms. In breast cancer survivors at risk for lymphedema, a program of slowly progressive weight-lifting, compared with no intervention, did not result in increased incidence of lymphedema. In secondary analyses, women with 5+ nodes removed who did weight-lifting were less likely to experience increases in arm swelling.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr ES9-3.
Abstract P1-01-01: Learning Sentinel Node Biopsy in the UK: Results of the NEW START Training Program
Authors: Mansel R , Goyal A , MacNeill F , Newcombe R , Layer G , Kissin M , Horgan K , Britten A , Hilson A , Clarke D , Townson J , Ell P , Wishart G , Brown D , West N , Keshtgar M.
Published: April 2011

Background: NEW START-a structured, validated multi-professional surgical training programme, was established to allow rapid transfer of appropriate knowledge and technical skills to ensure safe and competent practice of sentinel lymph node biopsy (SLNB) across the UK.

Methods: Multi-professional teams attended a theory/skills-lab course delivering a standardized educational package, following which they performed SLNB in 30 consecutive patients, either concurrently with their standard axillary staging procedure — mentorship training model-or as stand-alone SLNB — apprenticeship training model. An accredited NEW START trainer mentored the first 5 procedures in the participants’ hospital, or all 30 if stand-alone. Validation standards were a localization rate of ≥90% and in the mentorship program where a minimum of 10 cases were node positive, a false-negative rate of ≥10%. SLNB was performed according to a standardised protocol using the combined technique of isotope (0.05-0.1ml of 99mTc-albumin colloid — Nanocoll®) and blue dye (Patent blue V) injected into the tumour quadrant peri-areolar tissue. Isotope was injected intra-dermally and static scintigraphic images were obtained, blue dye was injected sub-dermally after anaesthetic induction.

Results: From October 2004 to December 2008, 210 SLNB naive surgeons, in 103 centres, performed 6,685 SLNB procedures of which 31% (2,098/6,685) were node positive. The mentorship training model was followed in 87% (5,849/6,685). Scintigraphy identified axillary lymph node drainage in 85% (5,564/6,511) with an overall SLN localization rate of 98.9% (6,610/6,685, 95% CI 98.6% to 99.1%). Node positivity was higher (P<0.001) for failed (58.7%, 44/75) than successful (31.1%, 2054/6610) localizations. The mentorship false negative rate (FNR) was 8.9% (163/1821, 95% CI 7.7% to 10.4%). The median SLN yield was 2.0 (range 1-11).

SLN localization and FNR improved with surgeon caseload so that after 20 procedures the FNR fell below 10% but no statistically significant learning curve was identified. The FNR patients who had one SLN harvested was 14.8%. The FNR rate declined to 9.4%, 6.3%, 4.5% and 4.0% for those patients with 2, 3, 4 and more than 4 SLNs removed.

Conclusion: NEW START demonstrates that a standardized injection protocol and structured multi-professional training can abolish learning curves so ensuring patient safety during national adoption of a new technique. Tumor quadrant injection using both isotope and dye has a high localization rate and low false-negative rate. Failed localization indicates higher probability of axillary nodal involvement. It is not necessary to remove more than 4 SLNs to achieve a FNR of less than 5%.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-01-01.
Abstract P1-01-05: Clinical Significance of Tumor Burden in the Sentinel Nodes after Neoadjuvant Therapy Differs from Sentinel Nodes in the Adjuvant Setting and This May Influence the Management of the Axilla
Authors: Rubio IT , Cebrecos I , Peg V , DiCosimo S , Cortes J , Xercavins J.
Published: April 2011

Background. Lymph node metastases are the most significant prognostic factor for breast cancer patients. The use of sentinel node biopsy (SLN) has generated an increased detection of positive nodes through the identification of isolated tumor cells (ITC) and micrometastasis. The objective of this study is to evaluate the significance of SLN micrometastasis and ITC for patients undergoing neoadjuvant chemotherapy versus patients undergoing surgery first.

Material and Methods. A total of 571 patients with clinically node negative T1-T3 breast cancer underwent SLN surgery from 2004 to 2008.

Clinicopathological data were reviewed and comparison was made between results in the adjuvant and neoadjuvant setting.

Results. Of the 571 patients, 71 patients (12.5%) underwent SLN biopsy after neoadjuvant chemotherapy and 500 (87.5%) underwent surgery first. The SLN identification rate in the adjuvant and neoadjuvant therapy groups were similar (96.2% vs 95.8%). Mean number of sentinel nodes removed were 2,2 (range 1-15) in the adjuvant group and 2.2 (range 1-7) in the neoadjuvant group. The SLN was positive in the adjuvant group in 151 patients (30%) while in 27 patients (37.5%) in the neoadjuvant group. The SLN was the only positive node in 106 patients (70.1%) in the adjuvant group and in 6(26%) in the neoadjuvant group. Micrometastasis in the SLN was found in 39 patients (7.8%) in the adjuvant group and in 7 (9.8%) patients in the neoadjuvant group. In the adjuvant group, 7 patients (17.9%) had additional non SLN positive in the axillary dissection (ALND), while 3 (49%) in the neoadjuvant group. ALND was performed in all patients with ITC in the SLN in the neoadjuvant setting and 50% of them had additional nonSLN.

Discussion. The significance of micrometastasis or ITC in the sentinel node seems to differ in patients with neoadjuvant therapy or surgery first. Micrometastsis or ITC in patients with prior neoadjuvant therapy may reflect residual disease in the axilla, as 50% of patients will have additional positive nodes. Completion axillary node dissection should be considered in this group of patients. Even more, the majority of patients with a positive SLN in the neoadjuvant group harbored additional positive axillary nodes.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-01-05.
Abstract P1-01-08: Lymph Node Ratio as an Alternative to pN Staging in Node Positive Breast Cancer: A report from the Korean Breast Cancer Society
Authors: Kim HJ , Gong KY , Jung KH , Kim S-B , Lee JW , Ahn SH.
Published: April 2011

Background: To compare the lymph node ratio(LNR) and pN staging as a prognostic predictor and find out high risk subgroup which can not predict prognosis using pN staging.

Patients and Methods: Using information from two large databases, including Korean nationwide registry, we compared the survival using LNR and pN stage parameters by Cox regression analysis. Moreover survival data were analysed according to age subgroups and intrinsic subtypes. Results: In an analysis of 2264 node positive patients from single institution, adjusted cancer specific mortality risks of low (≥0.20), intermediate (>0.20 and ≥0.65) and high risk (>0.65) LNR groups were 1(reference), 1.9 (95%CI, 1.6 to 2.4), 4.6(95%CI, 3.6 to 5.8). The difference of mortality risk between LNR parameters were wider than that of N1, N2 and N3 in DFS, CSS, OS. In contrast to LNR risk categories, survival curve in pN1 and pN2 overlapped in the patients below 35 years old. Survival curve in pN1 and pN2 also overlapped in patients in her2/neu enriched as well as triple negative subtype. These finding were validated by an analysis of nationwide registry data on 15488 node positive patients. The patients who had N1 and LNR2-3 disease showed poor DFS (HR 1.7 95% CI 1.4 to 2.2) and CSS (HR 1.6, 95% CI 1.1 to 2.2) compared with the patients who had N2 and LNR1 disease. Conclusion: LNR define breast cancer prognosis more adequate than the pN categories especially high risk breast cancer like young age, her2/neu enriched and triple negative intrinsic subtype. It is more reasonable that treatment decision like radiotherapy might be depend on the LNR than pN staging. We argue that LNR should be considered as an alternative to pN staging.

Figures available in online version.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-01-08.
Abstract P1-01-09: Molecular Detection of Sentinel Lymph Node Metastases in Breast Cancer Patients: Correlation between Cytokeratin 19 mRNA Copy Number Detected by One Step Nucleic Acid Amplification (OSNA) and Risk of Metastases in Axillary Lymph Nodes
Authors: Buglioni S , Casini B , Marandino F , Terrenato I , Gallo E , Perri P , Botti C , Maini CL , Di Filippo F.
Published: April 2011

Background: The accuracy of the OSNA assay for metastases detection in sentinel lymph nodes (SLNs) has recently been validated in our Institute and adopted as an intra-operative test for breast cancer (BC) patient management. The aims of this study in a series of early BC patients, were: 1) to correlate the copy numbers of cytokeratin 19 (CK19) mRNA with the size of nodal metastases and with the risk of additional disease in non-sentinel lymph nodes (NSLNs); 2) to investigate the relationship between SLN status with OSNA method, and conventional bio-pathological factors taking into account the molecular BC classification: luminal A, luminal B, HER2 subtype, and triple-negative; 3) to identify a subgroup of patients with positive SLN with higher risk of NSLNs metastatic involvement. Material and Methods: 750 SLNs from 580 patients were clinically processed using both OSNA assay and post-operative histology. The results of these two methods were then compared. The correlation between the size of metastases and the copy numbers of CK19 mRNA was calculated using the Spearman correlation coefficient. Complementary axillary lymph node dissection (ALND) was performed concurrently in case of OSNA assay positivity and the probability of having a positive lymph node axillary dissection was calculated by the unconditional logistic regression model. This series of BC patients were divided into four main subtypes taking in account the BC classification based on the immunohistochemistry phenotypic patterns.

Results: OSNA positivity was reported in 24.6% of the patients for a sensitivity of 94.2%. Considering the 145 patients with SLN positivity the size of metastatic foci was significantly correlated to the copy numbers of CK19 mRNA. The complex relationships among the bio-pathological variables analyzed by multiple correspondence analysis (MCA) showed that the metastatic involvement of NSLNs is associated with SLNs with a high copy numbers of CK19 mRNA and HER2 subtype tumors. OSNA specificity (95%) and negative predictive value (98.4%) clearly demonstrated its reliability to guide ALND decision. Conclusions: Our results showed that OSNA is an excellent method for the detection of metastases in SLN and its adoption in our clinical practice has determined a significant improvement in the diagnosis of metastatic BC.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-01-09.