bluuebunny/crossref_metadata_2025 huggingface dataset:
Increasing the Reliability of Adaptive Quadrature Using Explicit Interpolants
Authors: Gonnet Pedro
Published: September 2010

We present two new adaptive quadrature routines. Both routines differ from previously published algorithms in many aspects, most significantly in how they represent the integrand, how they treat nonnumerical values of the integrand, how they deal with improper divergent integrals, and how they estimate the integration error. The main focus of these improvements is to increase the
reliability
of the algorithms without significantly impacting their
efficiency
. Both algorithms are implemented in MATLAB and tested using both the “families” suggested by Lyness and Kaganove and the battery test used by Gander and Gautschi and Kahaner. They are shown to be more reliable, albeit in some cases less efficient, than other commonly-used adaptive integrators.
Adaptive Projection Subspace Dimension for the Thick-Restart Lanczos Method
Authors: Yamazaki Ichitaro , Bai Zhaojun , Simon Horst , Wang Lin-Wang , Wu Kesheng
Published: September 2010

The Thick-Restart Lanczos (TRLan) method is an effective method for solving large-scale Hermitian eigenvalue problems. The performance of the method strongly depends on the dimension of the projection subspace used at each restart. In this article, we propose an objective function to quantify the effectiveness of the selection of subspace dimension, and then introduce an adaptive scheme to dynamically select the dimension to optimize the performance. We have developed an open-source software package
a
--TRLan to include this adaptive scheme in the TRLan method. When applied to calculate the electronic structure of quantum dots,
a
--TRLan runs up to 2.3x faster than a state-of-the-art preconditioned conjugate gradient eigensolver.
Unified Tables for Exponential and Logarithm Families
Authors: Anand Christopher Kumar , Sharma Anuroop
Published: September 2010

Accurate table methods allow for very accurate and efficient evaluation of elementary functions. We present new single-table approaches to logarithm and exponential evaluation, by which we mean that a single table of values works for both log(
x
) and log(1 + 
x
), and a single table for
e
x
and
e
x
 − 1. This approach eliminates special cases normally required to evaluate log(1 + 
x
) and
e
x
 − 1 accurately near zero, which will significantly improve performance on architectures which use SIMD parallelism, or on which data-dependent branching is expensive.

We have implemented it on the Cell/B.E. SPU (SIMD compute engine) and found the resulting functions to be up to twice as fast as the conventional implementations distributed in the IBM Mathematical Acceleration Subsystem (MASS). We include the literate code used to generate all the variants of exponential and log functions in the article, and discuss relevant language and hardware features.
Algorithm 905
Authors: Thacker William I. , Zhang Jingwei , Watson Layne T. , Birch Jeffrey B. , Iyer Manjula A. , Berry Michael W.
Published: September 2010

Scattered data interpolation problems arise in many applications. Shepard’s method for constructing a global interpolant by blending local interpolants using local-support weight functions usually creates reasonable approximations. SHEPPACK is a Fortran 95 package containing five versions of the modified Shepard algorithm: quadratic (Fortran 95 translations of Algorithms 660, 661, and 798), cubic (Fortran 95 translation of Algorithm 791), and linear variations of the original Shepard algorithm. An option to the linear Shepard code is a statistically robust fit, intended to be used when the data is known to contain outliers. SHEPPACK also includes a hybrid robust piecewise linear estimation algorithm RIPPLE (residual initiated polynomial-time piecewise linear estimation) intended for data from piecewise linear functions in arbitrary dimension
m
. The main goal of SHEPPACK is to provide users with a single consistent package containing most existing polynomial variations of Shepard’s algorithm. The algorithms target data of different dimensions. The linear Shepard algorithm, robust linear Shepard algorithm, and RIPPLE are the only algorithms in the package that are applicable to arbitrary dimensional data.
I/O Deduplication
Authors: Koller Ricardo , Rangaswami Raju
Published: September 2010

Duplication of data in storage systems is becoming increasingly common. We introduce I/O Deduplication, a storage optimization that utilizes content similarity for improving I/O performance by eliminating I/O operations and reducing the mechanical delays during I/O operations. I/O Deduplication consists of three main techniques:
content-based caching, dynamic replica retrieval
, and
selective duplication
. Each of these techniques is motivated by our observations with I/O workload traces obtained from actively-used production storage systems, all of which revealed surprisingly high levels of content similarity for both stored and accessed data. Evaluation of a prototype implementation using these workloads showed an overall improvement in disk I/O performance of 28 to 47% across these workloads. Further breakdown also showed that each of the three techniques contributed significantly to the overall performance improvement.
DFS
Authors: Josephson William K. , Bongo Lars A. , Li Kai , Flynn David
Published: September 2010

We present the design, implementation, and evaluation of Direct File System (DFS) for virtualized flash storage. Instead of using traditional layers of abstraction, our layers of abstraction are designed for directly accessing flash memory devices. DFS has two main novel features. First, it lays out its files directly in a very large virtual storage address space provided by FusionIO's virtual flash storage layer. Second, it leverages the virtual flash storage layer to perform block allocations and atomic updates. As a result, DFS performs better and is much simpler than a traditional Unix file system with similar functionalities. Our microbenchmark results show that DFS can deliver 94,000 I/O operations per second (IOPS) for direct reads and 71,000 IOPS for direct writes with the virtualized flash storage layer on FusionIO's ioDrive. For direct access performance, DFS is consistently better than ext3 on the same platform, sometimes by 20%. For buffered access performance, DFS is also consistently better than ext3, and sometimes by over 149%. Our application benchmarks show that DFS outperforms ext3 by 7% to 250% while requiring less CPU power.
Multi-Layered Interfaces to Improve Older Adults’ Initial Learnability of Mobile Applications
Authors: Leung Rock , Findlater Leah , McGrenere Joanna , Graf Peter , Yang Justine
Published: September 2010

Mobile computing devices can offer older adults (ages 65+) support in their daily lives, but older adults often find such devices difficult to learn and use. One potential design approach to improve the learnability of mobile devices is a Multi-Layered (ML) interface, where novice users start with a reduced-functionality interface layer that only allows them to perform basic tasks, before progressing to a more complex interface layer when they are comfortable. We studied the effects of a ML interface on older adults’ performance in learning tasks on a mobile device. We conducted a controlled experiment with 16 older (ages 65--81) and 16 younger participants (age 21--36), who performed tasks on either a 2-layer or a nonlayered (control) address book application, implemented on a commercial smart phone. We found that the ML interface’s Reduced-Functionality layer, compared to the control’s Full-Functionality layer, better helped users to master a set of basic tasks and to retain that ability 30 minutes later. When users transitioned from the Reduced-Functionality to the Full-Functionality interface layer, their performance on the previously learned tasks was negatively affected, but no negative impact was found on learning new, advanced tasks. Overall, the ML interface provided greater benefit for older participants than for younger participants in terms of task completion time during initial learning, perceived complexity, and preference. We discuss how the ML interface approach is suitable for improving the learnability of mobile applications, particularly for older adults.
Fast, Efficient Floating-Point Adders and Multipliers for FPGAs
Authors: Hemmert K. Scott , Underwood Keith D.
Published: September 2010

Floating-point applications are a growing trend in the FPGA community. As such, it has become critical to create floating-point units optimized for standard FPGA technology. Unfortunately, the FPGA design space is very different from the VLSI design space; thus, optimizations for FPGAs can differ significantly from optimizations for VLSI. In particular, the FPGA environment constrains the design space such that only limited parallelism can be effectively exploited to reduce latency. Obtaining the right balances between clock speed, latency, and area in FPGAs can be particularly challenging. This article presents implementation details for an IEEE-754 standard floating-point adder and multiplier for FPGAs. The designs presented here enable a Xilinx Virtex4 FPGA (-11 speed grade) to achieve 270 MHz IEEE compliant double precision floating-point performance with a 9-stage adder pipeline and 14-stage multiplier pipeline. The area requirement is approximately 500 slices for the adder and under 750 slices for the multiplier.
Implementation Approaches Trade-Offs for WiMax OFDM Functions on Reconfigurable Platforms
Authors: Sghaier Ahmad , Areibi Shawki , Dony Robert
Published: September 2010

This work investigates several approaches for implementing the OFDM functions of the fixed-WiMax standard on reconfigurable platforms. In the first phase, a custom RTL approach, using VHDL, is investigated. The approach shows the capability of a medium-size FPGA to accommodate the OFDM functions of a fixed-WiMax transceiver with only 50% occupation rate. In the second phase, a high-level approach based on the AccelDSP tool is used and compared to the custom RTL approach. The approach presents an easy flow to transfer MATLAB floating-point code into synthesizable cores. The AccelDSP approach shows an area overhead of 10%, while allowing early architectural exploration and accelerating the design time by a factor of two. However, the performance figure obtained is almost 1/4 of that obtained in the custom RTL approach. In the third phase, the Tensilica Xtensa configurable processor is targeted, which presents remarkable figures in terms of power, area, and design time. Comparing the three approaches indicates that the custom RTL approach has the lead in terms of performance. However, both the AccelDSP and the Tensilica Xtensa approaches show fast design time and early architectural exploration capability. In terms of power, the obtained estimation results show that the configurable Xtensa processor approach has the lead, where approximately the total power consumed is about 12--15 times less than those results obtained by the other two approaches.
Runtime Reconfiguration of Multiprocessors Based on Compile-Time Analysis
Authors: Purnaprajna Madhura , Porrmann Mario , Rueckert Ulrich , Hussmann Michael , Thies Michael , Kastens Uwe
Published: September 2010

In multiprocessors, performance improvement is typically achieved by exploring parallelism with fixed granularities, such as instruction-level, task-level, or data-level parallelism. We introduce a new reconfiguration mechanism that facilitates variations in these granularities in order to optimize resource utilization in addition to performance improvements. Our reconfigurable multiprocessor QuadroCore combines the advantages of reconfigurability and parallel processing. In this article, a unified hardware-software approach for the design of our QuadroCore is presented. This design flow is enabled via compiler-driven reconfiguration which matches application-specific characteristics to a fixed set of architectural variations. A special reconfiguration mechanism has been developed that alters the architecture within a single clock cycle.

The QuadroCore has been implemented on Xilinx XC2V6000 for functional validation and on UMC’s 90nm standard cell technology for performance estimation. A diverse set of applications have been mapped onto the reconfigurable multiprocessor to meet orthogonal performance characteristics in terms of time and power. Speedup measurements show a 2--11 times performance increase in comparison to a single processor. Additionally, the reconfiguration scheme has been applied to save power in data-parallel applications. Gate-level simulations have been performed to measure the power-performance trade-offs for two computationally complex applications. The power reports confirm that introducing this scheme of reconfiguration results in power savings in the range of 15--24%.
What is the design challenge for on-chip speed-of-light communication?
Authors: Cheng C. K. , Buckwalter James
Published: September 2010

As technology scales, on-chip interconnects become one of the most critical factors in determining the system performance and power consumption [1-3]. Since the wire resistance per unit length is inversely proportional to its cross section, the wire incurs high-signal attenuation as its cross section shrinks. Current practice views the wires as RC segments. Buffers are inserted between RC segments to boost a faster full voltage swing [4,5]. The inserted buffers regenerate the voltage level from buffer inputs instead of relaying the signals as waves. The full swing of RC segments requires high latency and consumes power.
What is a configurable, extensible processor?
Authors: Martin Grant
Published: September 2010

We're all familiar with fixed Instruction Set Architecture (ISA) processors, such as Intel or AMD x86-class processors, and in the embedded design area, ARM cores, for example. As well as these general purpose cores, there are also fixed ISA processors that are more specific to a particular problem domain, such as Digital Signal Processors (DSPs). But the product requirements of many embedded applications, especially for power-sensitive and low energy mobile media devices and cellphones, open up an opportunity to use Application-Specific Instruction set Processors (ASIPs) with highly application-oriented structural parameters and specialized instructions suitable for optimizing a particular application. Audio and video applications are good examples of product areas where the use of a customized ASIP for specific tasks may reduce energy consumption by a factor of 3 to 10 or more, thus allowing portable devices to operate for greatly increased periods between battery charges. Even the field of high performance computing may make use of ASIPs as the reduction in energy consumption and gain in performance for specific high-end tasks, such as climate modelling, may make the use of thousands or even millions of ASIPs very appropriate.
What is majority/minority network synthesis?
Authors: Jha Niraj K.
Published: September 2010

Majority (minority) network synthesis uses majority (minority) gates as logic elements. A majority (minority) gate has three inputs and one output and produces an output value 1 when a majority (minority) of input values are 1. Thus, the majority function, M, corresponding to a majority gate is given by

M(x1,x2,x3) = x1x2 + x2x3 + x1x3

The minority function, m, is simply given by M' (the complement of M).
What is wireless health?
Authors: Sarrafzadeh Majid
Published: September 2010

Recent advances in the electronics industry and wireless communication have enabled innovative domains of applications to evolve. Embedded processors and systems have become widely used in people's everyday life in various applications ranging from mobile communication to automotive industries to medical applications. The groundswell of wellness healthcare programs and patient management emphasize more involvement by patients themselves. This paradigm largely requires that patient information be readily available at the point of care, regardless of which physician the patient sees. The current proliferation of broadband wireless services, along with more powerful and convenient handheld devices, is helping introduce real-time monitoring and guidance for a wide array of patients. Low-cost sensors and wireless systems can now create a constantly vigilant and pervasive monitoring capability at home, at work, and in conventional point-of-care environments [4][5] (e.g., primary care physician offices, outpatient clinics, rehabilitation centers). Indeed, a large research community and a nascent industry is beginning to connect medical care with technology developers, vendors of wireless and sensing hardware systems [1], network service providers, and enterprise data management communities. Wearable devices focusing on personal health, rehabilitation, and early disease detection are now being prototyped. All these have led us to the new notion of "Wireless Health"
What is Bluespec?
Authors: Nikhil Rishiyur S. , Arvind
Published: September 2010

Bluespec refers to a language and associated tools which are being used for all aspects of hardware system design . specification, synthesis, modeling, and verification. The language, BSV (Bluespec SystemVerilog), is based on a new model of computation for hardware, where all behavior is described as a set of rewrite rules, or Guarded Atomic Actions. Unlike the process/thread model of Verilog, VHDL and SystemC, or the sequential model of C/C++, all behavior of a BSV program can be understood in terms of atomic rule firings. This computational model has a long pedigree in formal specification and verification systems (e.g., Dijkstra's Guarded Commands, UNITY, TLA+, and EventB), and BSV makes it available for hardware design.
What is the first open source 45nm standard-cell library?
Authors: Cheung Ken
Published: September 2010

Nangate, the leading provider of tools for design-specific digital cell library development, announced that it has donated an open source 45nm standard-cell library to the Silicon Integration Initiative (Si2) - an organization of industry-leading companies in the semiconductor, electronic systems and EDA tool industries.
What is post-silicon debug?
Authors: Markov Igor
Published: September 2010

Due to the complexity of modern IC designs and increasingly sophisticated manufacturing technologies, some of the steps in the design and optimization of ICs result in errors. A prime example of a design error is the Pentium IV FDIV bug --- a miscalculation when dividing certain rarely-occurring numbers, --- which resulted in the costly recalls of millions of CPUs in mid-1990s. Only rare errors escape extensive simulation used to verify designs, but they may jeopardize mission-critical applications and lead to class-action lawsuits. Some computer viruses escalate and exploit subtle hardware errors. Intel's response to the FDIV bug was to invest heavily in formal verification, so as to catch even the bugs that evade simulation. While very successful, this effort has always been limited to individual on-chip modules rather than entire chips. If bugs arising from the interaction between modules are not caught by extensive simulation, they show up in manufactured chips.
What is double patterning lithography and its impact on nanometer design?
Authors: Pan David Z.
Published: September 2010

Deep sub-wavelength lithography, i.e., using the 193nm lithography to print feature sizes/densities (e.g., for 45nm, 32nm, 22nm nodes) much smaller than the wavelength (193nm), is one of the most fundamental challenges for the nanometer CMOS scaling. Many intriguing techniques have been developed to push the limit of the 193nm lithography, from immersion lithography to computational lithography. However, even with these exotic techniques, the single patterning 193nm lithography is approaching its ultimate limit around the 22nm node. On the other hand, the so-called next generation lithography (NGL), including extreme ultraviolet (EUV) lithography, nano- imprint lithography (NIL), multiple e-beam direct-write (MEBDW) is still "next-generation" (i.e., not ready for primetime in 22nm or perhaps even the 16nm node) due to many technology challenges (not to mention the economical barriers to adopt them).
Cortical Control of Adaptive Locomotion in Wild-Type Mice and Mutant Mice Lacking the Ephrin-Eph Effector Protein α2-Chimaerin
Authors: Asante Curtis Oware , Chu Amy , Fisher Mark , Benson Leora , Beg Asim , Scheiffele Peter , Martin John
Published: September 2010

In voluntary control, supraspinal motor systems select the appropriate response and plan movement mechanics to match task constraints. Spinal circuits translate supraspinal drive into action. We studied the interplay between motor cortex (M1) and spinal circuits during voluntary movements in wild-type (WT) mice and mice lacking the α2-chimaerin gene (Chn1−/−), necessary for ephrinB3-EphA4 signaling. Chn1−/− mice have aberrant bilateral corticospinal systems, aberrant bilateral-projecting spinal interneurons, and disordered voluntary control because they express a hopping gait, which may be akin to mirror movements. We addressed three issues. First, we determined the role of the corticospinal system in adaptive control. We trained mice to step over obstacles during treadmill locomotion. We compared performance before and after bilateral M1 ablation. WT mice adaptively modified their trajectory to step over obstacles, and M1 ablation increased substantially the incidence of errant steps over the obstacle. Chn1−/− mice randomly stepped or hopped during unobstructed locomotion but hopped over the obstacle. Bilateral M1 ablation eliminated this obstacle-dependent hop selection and increased forelimb obstacle contact errors. Second, we characterized the laterality of corticospinal action in Chn1−/− mice using pseudorabies virus retrograde transneuronal transport and intracortical microstimulation. We showed bilateral connections between M1 and forelimb muscles in Chn1−/− and unilateral connections in WT mice. Third, in Chn1−/− mice, we studied adaptive responses before and after unilateral M1 ablation. We identified a more important role for contralateral than ipsilateral M1 in hopping over the obstacle. Our findings suggest an important role for M1 in the mouse in moment-to-moment adaptive control, and further, using Chn1−/− mice, a role in mediating task-dependent selection of mirror-like hopping movements over the obstacle. Our findings also stress the importance of subcortical control during adaptive locomotion because key features of the trajectory remained largely intact after M1 ablation.
Angiotensin II-regulated transcription regulatory genes in adrenal steroidogenesis
Authors: Romero Damian G. , Gomez-Sanchez Elise P. , Gomez-Sanchez Celso E.
Published: September 2010

Transcription regulatory genes are crucial modulators of cell physiology and metabolism whose intracellular levels are tightly controlled in response to extracellular stimuli. We previously reported a set of 29 transcription regulatory genes modulated by angiotensin II in H295R human adrenocortical cells and their roles in regulating the expression of the last and unique enzymes of the glucocorticoid and mineralocorticoid biosynthetic pathways, 11β-hydroxylase and aldosterone synthase, respectively, using gene expression reporter assays. To study the effect of this set of transcription regulatory genes on adrenal steroidogenesis, H295R cells were transfected by high-efficiency nucleofection and aldosterone and cortisol were measured in cell culture supernatants under basal and angiotensin II-stimulated conditions. BCL11B, BHLHB2, CITED2, ELL2, HMGA1, MAFF, NFIL3, PER1, SERTAD1, and VDR significantly stimulated aldosterone secretion, while EGR1, FOSB, and ZFP295 decreased aldosterone secretion. BTG2, HMGA1, MITF, NR4A1, and ZFP295 significantly increased cortisol secretion, while BCL11B, NFIL3, PER1, and SIX2 decreased cortisol secretion. We also report the effect of some of these regulators on the expression of endogenous aldosterone synthase and 11β-hydroxylase under basal and angiotensin II-stimulated conditions. In summary, this study reports for the first time the effects of a set of angiotensin II-modulated transcription regulatory genes on aldosterone and cortisol secretion and the expression levels of the last and unique enzymes of the mineralocorticoid and glucocorticoid biosynthetic pathways. Abnormal regulation of mineralocorticoid or glucocorticoid secretion is involved in several pathophysiological conditions. These transcription regulatory genes may be involved in adrenal steroidogenesis pathologies; thus they merit additional study as potential candidates for therapeutic intervention.
Geno-transcriptomic dissection of proteinuria in the uninephrectomized rat uncovers a molecular complexity with sexual dimorphism
Authors: Yagil Yoram , Hessner Martin , Schulz Herbert , Gosele Claudia , Lebedev Larissa , Barkalifa Ronit , Sapojnikov Marina , Hubner Norbert , Yagil Chana
Published: September 2010

Investigation of proteinuria, whose pathophysiology remains incompletely understood, is confounded by differences in the phenotype between males and females. We initiated a sex-specific geno-transcriptomic dissection of proteinuria in uninephrectomized male and female Sabra rats that spontaneously develop focal and segmental glomerulosclerosis, testing the hypothesis that different mechanisms might underlie the pathophysiology of proteinuria between the sexes. In the genomic arm, we scanned the genome of 136 male and 111 female uninephrectomized F2 populations derived from crosses between SBH/y and SBN/y. In males, we identified proteinuria-related quantitative trait loci (QTLs) on RNO2 and 20 and protective QTLs on RNO6 and 9. In females, we detected proteinuria-related QTLs on RNO11, 13, and 20. The only QTL overlap between the sexes was on RNO20. Using consomic strains, we confirmed the functional significance of this QTL in both sexes. In the transcriptomic arm, we searched on a genomewide scale for genes that were differentially expressed in kidneys of SBH/y and SBN/y with and without uninephrectomy. These studies identified within each sex differentially expressed genes of relevance to proteinuria. Integrating genomics with transcriptomics, we identified differentially expressed genes that mapped within the boundaries of the proteinuria-related QTLs, singling out 24 transcripts in males and 30 in females, only 4 of which ( Tubb5, Ubd, Psmb8, and C2) were common to both sexes. Data mining revealed that these transcripts are involved in multiple molecular mechanisms, including immunity, inflammation, apoptosis, matrix deposition, and protease activity, with no single molecular pathway predominating in either sex. These results suggest that the pathophysiology of proteinuria is highly complex and that some of the underlying mechanisms are shared between the sexes, while others are sex specific and may account for the difference in the proteinuric phenotype between males and females.
Silencing of Thrombospondin-1 Is Critical for Myc-Induced Metastatic Phenotypes in Medulloblastoma
Authors: Zhou Limei , Picard Daniel , Ra Young-Shin , Li Meihua , Northcott Paul A. , Hu Yaqi , Stearns Duncan , Hawkins Cynthia , Taylor Michael D. , Rutka James , Der Sandy D. , Huang Annie
Published: September 2010

Mechanisms by which c-Myc (Myc) amplification confers aggressive medulloblastoma phenotypes are poorly defined. Here, we show using orthotopic models that high Myc expression promotes cell migration/invasion and induces metastatic tumors, which recapitulate aggressive histologic features of Myc-amplified primary human medulloblastoma. Using ChIP-chip analysis, we identified cell migration and adhesion genes, including Tsp-1/THBS1, ING4, PVRL3, and PPAP2B, as Myc-bound loci in medulloblastoma cells. Expression of Tsp-1 was most consistently and robustly diminished in medulloblastoma cell lines and primary human tumors with high Myc expression (n = 101, P = 0.032). Strikingly, stable Tsp-1 expression significantly attenuated in vitro transformation and invasive/migratory properties of high Myc-expressing medulloblastoma cells without altering cell proliferation, whereas RNA interference–mediated Myc knockdown was consistently accompanied by increased Tsp-1 levels and reduced cell migration and invasion in medulloblastoma cells. Chromatin immunoprecipitation (ChIP) assays revealed colocalization of Myc and obligate partner Max and correlated diminished RNA polymerase II occupancy (∼3-fold decrease, P < 0.01) with increased Myc binding at a core Tsp-1 promoter. Reporter gene and/or gel shift assays confirmed direct repression of Tsp-1 transcription by Myc and also identified JPO2, a Myc interactor associated with metastatic medulloblastoma, as a cofactor in Myc-mediated Tsp-1 repression. These findings indicate the Myc-regulatory network targets Tsp-1 via multiple mechanisms in medulloblastoma transformation, and highlight a novel critical role for Tsp-1 in Myc-mediated aggressive medulloblastoma phenotypes. Cancer Res; 70(20); 8199–210. ©2010 AACR.
Apatinib (YN968D1) Reverses Multidrug Resistance by Inhibiting the Efflux Function of Multiple ATP-Binding Cassette Transporters
Authors: Mi Yan-jun , Liang Yong-ju , Huang Hong-bing , Zhao Hong-yun , Wu Chung-Pu , Wang Fang , Tao Li-yang , Zhang Chuan-zhao , Dai Chun-Ling , Tiwari Amit K. , Ma Xiao-xu , To Kenneth Kin Wah , Ambudkar Suresh V. , Chen Zhe-Sheng , Fu Li-wu
Published: September 2010

Apatinib, a small-molecule multitargeted tyrosine kinase inhibitor, is in phase III clinical trial for the treatment of patients with non–small-cell lung cancer and gastric cancer in China. In this study, we determined the effect of apatinib on the interaction of specific antineoplastic compounds with P-glycoprotein (ABCB1), multidrug resistance protein 1 (MRP1, ABCC1), and breast cancer resistance protein (BCRP, ABCG2). Our results showed that apatinib significantly enhanced the cytotoxicity of ABCB1 or ABCG2 substrate drugs in KBv200, MCF-7/adr, and HEK293/ABCB1 cells overexpressing ABCB1 and in S1-M1-80, MCF-7/FLV1000, and HEK293/ABCG2-R2 cells overexpressing ABCG2 (wild-type). In contrast, apatinib did not alter the cytotoxicity of specific substrates in the parental cells and cells overexpressing ABCC1. Apatinib significantly increased the intracellular accumulation of rhodamine 123 and doxorubicin in the multidrug resistance (MDR) cells. Furthermore, apatinib significantly inhibited the photoaffinity labeling of both ABCB1 and ABCG2 with [125I]iodoarylazidoprazosin in a concentration-dependent manner. The ATPase activity of both ABCB1 and ABCG2 was significantly increased by apatinib. However, apatinib, at a concentration that produced a reversal of MDR, did not significantly alter the ABCB1 or ABCG2 protein or mRNA expression levels or the phosphorylation of AKT and extracellular signal–regulated kinase 1/2 (ERK1/2). Importantly, apatinib significantly enhanced the effect of paclitaxel against the ABCB1-resistant KBv200 cancer cell xenografts in nude mice. In conclusion, apatinib reverses ABCB1- and ABCG2-mediated MDR by inhibiting their transport function, but not by blocking the AKT or ERK1/2 pathway or downregulating ABCB1 or ABCG2 expression. Apatinib may be useful in circumventing MDR to other conventional antineoplastic drugs. Cancer Res; 70(20); 7981–91. ©2010 AACR.
Hepatocyte Nuclear Factor 4α Suppresses the Development of Hepatocellular Carcinoma
Authors: Ning Bei-Fang , Ding Jin , Yin Chuan , Zhong Wei , Wu Kun , Zeng Xin , Yang Wen , Chen Yue-Xiang , Zhang Jun-Ping , Zhang Xin , Wang Hong-Yang , Xie Wei-Fen
Published: September 2010

Hepatocyte nuclear factor 4α (HNF4α) is a transcription factor that plays a key role in hepatocyte differentiation and the maintenance of hepatic function, but its role in hepatocarcinogenesis has yet to be examined. Here, we report evidence of a suppressor role for HNF4α in liver cancer. HNF4α expression was progressively decreased in the diethylinitrosamine-induced rat model of liver carcinogenesis. In human liver tissues, HNF4α expression was decreased in cirrhotic tissue and further decreased in hepatocarcinoma relative to healthy tissue. Notably, an inverse correlation existed with epithelial-mesenchymal transition (EMT). Enforced expression of HNF4α attenuated hepatocyte EMT during hepatocarcinogenesis, alleviated hepatic fibrosis, and blocked hepatocellular carcinoma (HCC) occurrence. In parallel, stem cell marker gene expression was inhibited along with cancer stem/progenitor cell generation. Further, enforced expression of HNF4α inhibited activation of β-catenin, which is closely associated with EMT and hepatocarcinogenesis. Taken together, our results suggest that the inhibitory effect of HNF4α on HCC development might be attributed to suppression of hepatocyte EMT and cancer stem cell generation through an inhibition of β-catenin signaling pathways. More generally, our findings broaden knowledge on the biological significance of HNF4α in HCC development, and they imply novel strategies for HCC prevention through the manipulation of differentiation-determining transcription factors in various types of carcinomas. Cancer Res; 70(19); 7640–51. ©2010 AACR.
Keratinocyte-Specific Stat3 Heterozygosity Impairs Development of Skin Tumors in Human Papillomavirus 8 Transgenic Mice
Authors: De Andrea Marco , Rittà Massimo , Landini Manuela M. , Borgogna Cinzia , Mondini Michele , Kern Florian , Ehrenreiter Karin , Baccarini Manuela , Marcuzzi Gian Paolo , Smola Sigrun , Pfister Herbert , Landolfo Santo , Gariglio Marisa
Published: September 2010

Human papillomaviruses (HPV) of the genus β are thought to play a role in human skin cancers, but this has been difficult to establish using epidemiologic approaches. To gain insight into the transforming activities of β-HPV, transgenic mouse models have been generated that develop skin tumors. Recent evidence suggests a central role of signal transducer and activator of transcription 3 (Stat3) as a transcriptional node for cancer cell–autonomous initiation of a tumor-promoting gene signature associated with cell proliferation, cell survival, and angiogenesis. Moreover, high levels of phospho-Stat3 have been detected in tumors arising in HPV8-CER transgenic mice. In this study, we investigate the in vivo role of Stat3 in HPV8-induced skin carcinogenesis by combining our established experimental model of HPV8-induced skin cancer with epidermis-restricted Stat3 ablation. Stat3 heterozygous epidermis was less prone to tumorigenesis than wild-type epidermis. Three of the 23 (13%) Stat3+/−:HPV8 animals developed tumors within 12 weeks of life, whereas 54.3% of Stat3+/+:HPV8 mice already exhibited tumors in the same observation period (median age for tumor appearance, 10 weeks). The few tumors that arose in the Stat3+/−:HPV8 mice were benign and never progressed to a more malignant phenotype. Collectively, these results offer direct evidence of a critical role for Stat3 in HPV8-driven epithelial carcinogenesis. Our findings imply that targeting Stat3 activity in keratinocytes may be a viable strategy to prevent and treat HPV-induced skin cancer. Cancer Res; 70(20); 7938–48. ©2010 AACR.
A Bispecific Antibody-IFNα2b Immunocytokine Targeting CD20 and HLA-DR Is Highly Toxic to Human Lymphoma and Multiple Myeloma Cells
Authors: Rossi Edmund A. , Rossi Diane L. , Stein Rhona , Goldenberg David M. , Chang Chien-Hsing
Published: September 2010

The short circulating half-life and side effects of IFNα affect its dosing schedule and efficacy. Fusion of IFNα to a tumor-targeting monoclonal antibody (MAb-IFNα) can enhance potency due to increased tumor localization and improved pharmacokinetics. We report the generation and characterization of the first bispecific MAb-IFNα, designated 20-C2-2b, which comprises two copies of IFNα2b and a stabilized F(ab)2 of hL243 (humanized anti–HLA-DR; IMMU-114) site-specifically linked to veltuzumab (humanized anti-CD20). In vitro, 20-C2-2b inhibited each of four lymphoma and eight myeloma cell lines, and was more effective than monospecific CD20-targeted MAb-IFNα or a mixture comprising the parental antibodies and IFNα in all but one (HLA-DR−/CD20−) myeloma line, suggesting that 20-C2-2b should be useful in the treatment of various hematopoietic malignancies. 20-C2-2b displayed greater cytotoxicity against KMS12-BM (CD20+/HLA-DR+ myeloma) compared with monospecific MAb-IFNα, which targets only HLA-DR or CD20, indicating that all three components in 20-C2-2b could contribute to toxicity. Our findings indicate that a given cell's responsiveness to MAb-IFNα depends on its sensitivity to IFNα and the specific antibodies, as well as the expression and density of the targeted antigens. Cancer Res; 70(19); 7600–9. ©2010 AACR.
Key Role of Phosphoinositide 3-Kinase Class IB in Pancreatic Cancer
Authors: Edling Charlotte E. , Selvaggi Federico , Buus Richard , Maffucci Tania , Di Sebastiano Pierluigi , Friess Helmut , Innocenti Paolo , Kocher Hemant M. , Falasca Marco
Published: September 2010

Purpose: Phosphoinositide 3-kinase (PI3K) signaling is well established as important in cancer. To date most studies have been focused on the PI3K/p110α isoform, which has been found to be mutated in several different cancers. The aim of our study was to determine which specific PI3K isoforms are involved in pancreatic ductal adenocarcinoma (PDAC) and investigate the effects of these isoforms on proliferation, survival, and induction of Akt activation in pancreatic cancer cells.

Experimental Design: The expression of all PI3K isoforms and downstream targets was analyzed by immunohistochemistry in human pancreatic cancer tissue and normal counterparts. Isoform selective inhibitors and short interfering RNA (siRNA) were employed to investigate the effects of the different PI3Ks on proliferation, survival, and intracellular signaling in PDAC cell lines.

Results: Immunohistochemical screening revealed high specific expression of the PI3K/p110γ isoform. Scoring indicated that 72% of the PDAC tissue stained positive for PI3K/p110γ, whereas no stain was detected in normal pancreatic ducts. Proliferation analyses after selective inhibition and siRNA downregulation of PI3K/p110γ showed that PI3K/p110γ, but not other PI3K isoforms, was required for cell proliferation. Overexpression of PI3K/p110γ indeed increased cell numbers and mediated activation of Akt in PDAC cell lines. Moreover, PI3K/p110γ was required for Akt activation via lysophosphatidic acid receptors.

Conclusions: These data represent the first identification of a tumor-specific accumulation of the PI3K isoform p110γ in human cancer. Further, our results signify a critical role for PI3K/p110γ in pancreatic cancer, and we hypothesize that PI3K/p110γ overexpression is a key event in the disease progression. Clin Cancer Res; 16(20); 4928–37. ©2010 AACR.
Preclinical Characterization of Mitochondria-Targeted Small Molecule Hsp90 Inhibitors, Gamitrinibs, in Advanced Prostate Cancer
Authors: Kang Byoung Heon , Siegelin Markus D. , Plescia Janet , Raskett Christopher M. , Garlick David S. , Dohi Takehiko , Lian Jane B. , Stein Gary S. , Languino Lucia R. , Altieri Dario C.
Published: September 2010

Purpose: This study aimed to characterize the preclinical activity of the first class of combinatorial, mitochondria-targeted, small molecule heat shock protein-90 (Hsp90) inhibitors, gamitrinibs, in models of hormone-refractory, drug-resistant, localized, and bone metastatic prostate cancer in vivo.

Experimental Design: Mitochondrial permeability transition, apoptosis, and changes in metabolic activity were examined by time-lapse videomicroscopy, multiparametric flow cytometry, MTT, and analysis of isolated mitochondria. Drug-resistant prostate cancer cells were generated by chronic exposure of hormone-refractory PC3 cells to the Hsp90 inhibitor 17-allylaminogeldanamycin (17-AAG). The effect of gamitrinibs on s.c. or intratibial prostate cancer growth was studied in xenograft models. Bone metastatic tumor growth and bone parameters were quantified by micro–computed tomography imaging.

Results: In the NCI 60-cell line screening, gamitrinibs were active against all tumor cell types tested, and efficiently killed metastatic, hormone-refractory, and multidrug-resistant prostate cancer cells characterized by overexpression of the ATP binding cassette transporter P-glycoprotein. Mechanistically, gamitrinibs, but not 17-AAG, induced acute mitochondrial dysfunction in prostate cancer cells with loss of organelle membrane potential, release of cytochrome c, and caspase activity, independently of proapoptotic Bcl-2 proteins Bax and Bak. Systemic administration of gamitrinibs to mice was well tolerated, and inhibited s.c. or bone metastatic prostate cancer growth in vivo.

Conclusions: Gamitrinibs have preclinical activity and favorable safety in models of drug-resistant and bone metastatic prostate cancer in vivo. Clin Cancer Res; 16(19); 4779–88. ©2010 AACR.
Wheel Running–Induced Changes in Plasma Biomarkers and Carcinogenic Response in the 1-Methyl-1-Nitrosourea–Induced Rat Model for Breast Cancer
Authors: Thompson Henry J. , Wolfe Pamela , McTiernan Anne , Jiang Weiqin , Zhu Zongjian
Published: September 2010

The purpose of this investigation was to identify pathways by which physical activity, implemented as running in an activity wheel, inhibits carcinogenesis. The focus of this analysis was on 20 plasma biomarkers for glucose homeostasis, inflammation, cytokine function, and endocrine activity, known to be affected by a physically active lifestyle. Plasma for analysis was obtained from previously reported carcinogenesis experiments in which the effects on mammary carcinogenesis, induced by i.p. injection of 1-methyl-1-nitrosurea, of running on a motorized activity wheel or a nonmotorized free wheel were compared with sedentary controls. Wheel running reduced cancer incidence (P = 0.0004) and the number of cancers per animal (P = 0.005). Principal components analysis was used to reduce the 20 plasma biomarkers to a concise index that was significantly different by treatment group assignment (P < 0.0001). Statistical analyses provided evidence that supported the hypothesis of a mediational role of these molecules in accounting for the protective effect of wheel running on the carcinogenic process. In addition, the plasma biomarker index derived from principal components analysis was a good discriminator of treatment group assignment (only 4.5% of animals were misclassified). These findings suggest that the plasma biomarkers evaluated have utility in assessing the breast cancer response to a physical activity intervention. Identification of such biomarkers is critical in clinical studies for which evaluating the effects of physical activity on cancer outcomes (diagnosis, recurrence, or mortality) is not possible. Cancer Prev Res; 3(11); 1484–92. ©2010 AACR.
Amitriptyline and Acute Inflammation: A Study Using Intravital Microscopy and the Carrageenan-Induced Paw Edema Model
Authors: Vismari L. , Alves G.J. , Palermo-Neto J.
Published: September 2010

Background/Aims: Antidepressants are reported to exhibit antiinflammatory effects. However, mechanisms involved in this action have not been elucidated. Thus, the objectives of the present study were (a) to evaluate the effects of amitriptyline on the acute inflammatory process, and (b) to investigate the participation of α1-adrenergic receptors and glucocorticoids as possible mechanisms implicated in the amitriptyline action on inflammation. Methods and Results: Single and multiple doses of amitriptyline were administered to rats submitted to the carrageenan-induced paw edema model. The results showed a significant antiedematous reaction to amitriptyline, mainly when administered at each elimination half-life. The next step was to evaluate its effects on leukocyte behavior, using intravital microscopy. Amitriptyline produced a significant effect on leukocyte behavior. To investigate possible mechanisms involved, a glucocorticoid receptor antagonist (RU-486) and an α1-adrenergic receptor antagonist (prazosin) were used. RU-486 administration lacked the ability to decrease the amitriptyline antiinflammatory effects in the carrageenan-induced paw edema model. Prazosin pretreatment potentiated the amitriptyline antiinflammatory effect without presenting an effect per se. Conclusion: The present study shows the ability of amitriptyline to decrease edema and affect leukocyte behavior in an acute inflammatory process; and, for the first time to our knowledge, we suggest the involvement of α1-adrenoceptors in the antiinflammatory effects of amitriptyline.
Incidence and Development of the Human Supracochlear Cartilage
Authors: Mérida Velasco J.R. , Rodríguez Vázquez J.F. , de la Cuadra Blanco C. , Sanz Casado J.V. , Mérida Velasco J.A.
Published: September 2010

The supracochlear cartilage is known as an accessory cartilage of the chondrocranium situated between the otic capsule and the trigeminal ganglion. Although claimed to appear regularly during human development, its incidence and development have been reported only scarcely in the literature. The aim of this study was to describe the position and relationships of the supracochlear cartilage during its development. This study was made in 96 human specimens of 7–17 weeks of development, belonging to a collection of the Embryology Institute of Complutense University of Madrid. In addition, three-dimensional reconstruction of the supracochlear cartilage was made from 1 specimen. This cartilage, spherical in shape, appeared bilaterally in 23 specimens and unilaterally (left side) in 5. In our results, the supracochlear cartilage was found in 26.5% of the cases and was related to the trigeminal ganglion, the dura mater of the trigeminal cavity and the otic capsule. In 4 specimens, bilaterally, the supracochlear cartilage was continuous with the otic capsule. This work suggests that, based on the structures to which the supracochlear cartilage is related, it could be derived from the cranial neural crest.
Decreased Apoptosis following Successful Ablation of Atrial Fibrillation
Authors: Osmancik Pavel , Peroutka Zdenek , Budera Petr , Herman Dalibor , Stros Petr , Straka Zbynek , Vondrak Karel
Published: September 2010

Objectives: Increased apoptotic processes in tissue samples from hearts in atrial fibrillation (AF) have been previously documented in animals. Whether the restoration of sinus rhythm is associated with decreased apoptosis is not known. The aim of the present study was to establish whether successful epicardial ablation of AF leads to changes in the concentration of serum markers of apoptosis. Methods: Twenty-five patients with AF were prospectively studied. All underwent epicardial isolation of pulmonary veins. The success of the ablation was assessed clinically and with 3 Holter recordings. Blood samples were drawn before surgery, and at 3 and 6 months after. Serum concentrations of Fas (apoptosis-stimulating fragment) and TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) were measured using ELISA. Results: AF was successfully ablated in 15 patients (SR group). In the other 10 patients (AF group), AF recurred during follow-up. Neither group differed with respect to age, sex, left ventricular ejection fraction, or preoperative concentrations of measured molecules. While Fas decreased in successfully ablated patients, there was no change in the Fas concentration in the AF group. Similarly, the concentrations of TRAIL decreased in the SR group, but remained unchanged in the AF group. Conclusion: The ablation of AF is associated with decreased serum markers for apoptosis.