bluuebunny/crossref_metadata_2025 huggingface dataset:
Modeling human aesthetic perception of visual textures
Authors: Thumfart Stefan , Jacobs Richard H. A. H. , Lughofer Edwin , Eitzinger Christian , Cornelissen Frans W. , Groissboeck Werner , Richter Roland
Published: December 2011

Texture is extensively used in areas such as product design and architecture to convey specific aesthetic information. Using the results of a psychological experiment, we model the relationship between computational texture features and aesthetic properties of visual textures. Contrary to previous approaches, we build a layered model, which provides insights into hierarchical relationships involved in human aesthetic texture perception. This model uses a set of intermediate judgements to link computational texture features with aesthetic texture properties. We pursue two different approaches for modeling. (1) Supervised machine-learning methods are used to generate linear and nonlinear models from the experimental data automatically. The quality of these models is discussed, mainly focusing on interpretability and accuracy. (2) We apply a psychological-based approach that models the processing pathways in human perception of naturalness, introducing judgement dimensions (principal components) mediating the relationship between texture features and naturalness judgements. This multiple mediator model serves as a verification of the machine-learning approach. We conclude with a comparison of these two approaches, highlighting the similarities and discrepancies in terms of identified relationships between computational texture features and aesthetic properties of visual textures.
Domical cooperative caching for streaming media in wireless home networks
Authors: Ghandeharizadeh Shahram , Shayandeh Shahin
Published: December 2011

Wireless home networks are widely deployed due to their low cost, ease of installation, and plug-and-play capabilities with consumer electronic devices. A challenge of these environments is how to manage data across devices. This is specially true for continuous media (audio and video clips) which are large in size and delay sensitive. Caching of clips across wireless devices may improve user experience, measurable by different Quality of Service (QoS) metrics such as throughput and startup latency. Moreover, caching at the edge of the network reduces the demand for the infrastructure outside the home. In this study, we present Domical, a novel cooperative caching technique designed for streaming media in wireless home networks consisting of a handful of devices. Domical is novel because it considers both asymmetry of the available wireless link bandwidth and heterogeneity of available cache space. We provide a comprehensive description of Domical, presenting its key knobs, and the behavior of the algorithm with different granularity of data caching (block versus clip).
Group-Centric Secure Information-Sharing Models for Isolated Groups
Authors: Krishnan Ram , Niu Jianwei , Sandhu Ravi , Winsborough William H.
Published: December 2011

Group-Centric Secure Information Sharing (g-SIS) envisions bringing users and objects together in a group to facilitate agile sharing of information brought in from external sources as well as creation of new information within the group. We expect g-SIS to be orthogonal and complementary to authorization systems deployed within participating organizations. The metaphors “secure meeting room” and “subscription service” characterize the g-SIS approach.

The focus of this article is on developing the foundations of isolated g-SIS models. Groups are
isolated
in the sense that membership of a user or an object in a group does not affect their authorizations in other groups. Present contributions include the following: formal specification of core properties that at once help to characterize the family of g-SIS models and provide a “sanity check” for full policy specifications; informal discussion of policy design decisions that differentiate g-SIS policies from one another with respect to the authorization semantics of group operations; formalization and verification of a specific member of the family of g-SIS models; demonstration that the core properties are logically consistent and mutually independent; and identification of several directions for future extensions.

The formalized specification is highly abstract. Besides certain well-formedness requirements that specify, for instance, a user cannot leave a group unless she is a member, it constrains only whether user-level read and write operations are authorized and it does so solely in terms of the history of group operations; join and leave for users and add, create, and remove for objects. This makes temporal logic one of the few formalisms in which the specification can be clearly and concisely expressed. The specification serves as a reference point that is the first step in deriving authorization-system component specifications from which a programmer with little security expertise could implement a high-assurance enforcement system for the specified policy.
When Practice Doesn’t Make Perfect
Authors: Miller Craig S. , Settle Amber
Published: December 2011

Specifying file references for hypertext links is an elementary competence that nevertheless draws upon core computational thinking concepts such as tree traversal and the distinction between relative and absolute references. In this article we explore the learning effects of different instructional strategies in the context of an introductory computing course. Results suggest that asking students to do targeted tasks, albeit supported with working examples, is not the best preparation. Instead, unstructured study of examples produces superior learning. Answering targeted conceptual questions can also yield comparably positive learning but only in qualified contexts. While perhaps unintuitive, these results are consistent with a long line of research on human cognition and learning. We discuss our results in the context of this previous research and recommend effective instructional strategies, which may apply to a broad range of computational concepts.
Exploiting parallelism in matrix-computation kernels for symmetric multiprocessor systems
Authors: D'alberto Paolo , Bodrato Marco , Nicolau Alexandru
Published: December 2011

We present a simple and efficient methodology for the development, tuning, and installation of matrix algorithms such as the hybrid Strassen's and Winograd's fast matrix multiply or their combination with the 3M algorithm for complex matrices (i.e., hybrid: a recursive algorithm as Strassen's until a highly tuned BLAS matrix multiplication allows performance advantages). We investigate how modern Symmetric Multiprocessor (SMP) architectures present old and new challenges that can be addressed by the combination of an algorithm design with careful and natural parallelism exploitation at the function level (optimizations) such as function-call parallelism, function percolation, and function software pipelining.

We have three contributions: first, we present a performance overview for double- and double-complex-precision matrices for state-of-the-art SMP systems; second, we introduce new algorithm implementations: a variant of the 3M algorithm and two new different schedules of Winograd's matrix multiplication (achieving up to 20% speedup with respect to regular matrix multiplication). About the latter Winograd's algorithms: one is designed to minimize the number of matrix additions and the other to minimize the computation latency of matrix additions; third, we apply software pipelining and threads allocation to all the algorithms and we show how this yields up to 10% further performance improvements.
Algorithm 914
Authors: Gil Amparo , Segura Javier , Temme Nico M.
Published: December 2011

A Fortran 90 program for the computation of the real parabolic cylinder functions
W
(
a
, ±
x
),
x
≥ 0 and their derivatives is presented. The code also computes scaled functions for
a
> 50. The functions
W
(
a
, ±
x
) are a numerically satisfactory pair of solutions of the parabolic cylinder equation
y
′ + (
x
2
/4 −
a
)
y
= 0,
x
≥ 0. Using Wronskian tests, we claim a relative accuracy better than 5 10
−13
in the computable range of unscaled functions, while for scaled functions the aimed relative accuracy is better than 5 10
−14
. This code, together with the algorithm and related software described in Gil et al. [2006a, 2006b], completes the set of software for Parabolic Cylinder Functions (PCFs) for real arguments.
Semantic relations in bilingual lexicons
Authors: Peirsman Yves , Padó Sebastian
Published: December 2011

Bilingual lexicons, essential to many NLP applications, can be constructed automatically on the basis of parallel or comparable corpora. In this article, we make two contributions to their induction from comparable corpora. The first one concerns the creation of these lexicons. We show that seed lexicons can be improved by adding a bootstrapping procedure that uses cross-lingual distributional similarity. The second contribution concerns the evaluation of bilingual lexicons. It is generally based on translation lexicons, which corresponds to the implicit assumption that (cross-lingual) synonymy is the semantic relation of primary interest, even though other semantic relations like (cross-lingual) hyponymy or cohyponymy make up a considerable portion of translation pair candidates proposed by distributional methods.

We argue that the focus on synonymy is an oversimplification and that many applications can profit from the inclusion of other semantic relations. We study what effect these semantic relations have on two cross-lingual tasks: the cross-lingual projection of polarity scores and the cross-lingual modeling of selectional preferences. We find that the presence of non-synonymous semantic relations may negatively affect the former of these tasks, but benefit the latter.
Edupunks Revisited
Authors: Kamenetz Anya
Published: December 2011

Edupunk refers to a style of teaching and learning that's part of a storm of disruption invading higher education.
Gigabit wireless LANs
Authors: Perahia Eldad , Gong Michelle X.
Published: December 2011

This paper gives an overview of the upcoming IEEE Gigabit Wireless LAN amendments, i.e. IEEE 802.11ac and 802.11ad. Both standard amendments advance wireless networking throughput beyond gigabit rates. 802.11ac adds multi-user access techniques in the form of downlink multi-user (DL MU) multiple input multiple output (MIMO)and 80 and 160 MHz channels in the 5 GHz band for applications such as multiple simultaneous video streams throughout the home. 802.11ad takes advantage of the large swath of available spectrum in the 60 GHz band and defines protocols to enable throughput intensive applications such as wireless I/O or uncompressed video. New waveforms for 60 GHz include single carrier and orthogonal frequency division multiplex (OFDM). Enhancements beyond the new 60 GHz PHY include Personal Basic Service Set (PBSS) operation, directional medium access, and beamforming. We describe 802.11ac channelization, PHY design, MAC modifications, and DL MU MIMO. For 802.11ad, the new PHY layer, MAC enhancements, and beamforming are presented.
WiSec 2011 demo
Authors: Hummen René , Wirtz Hanno , Viol Nicolai , Heer Tobias , Wehrle Klaus
Published: December 2011

Municipal Wi-Fi networks aim at city-wide wireless access to selected city services for a variety of users. Collaborative Muni-Fi approaches use existing private access points and provide controlled access to these services. However, the distributed and decentralized nature of a network comprised of strangers makes access control challenging. We present two design options for including mobile clients in such system: a client and a network centric design. For both designs we briefly discuss aspects of security and device mobility.
WiSec 2011 demo
Authors: Wilhelm Matthias , Martinovic Ivan , Schmitt Jens B. , Lenders Vincent
Published: December 2011

We present RFReact, a USRP2-based platform that enables selective and reactive RF jamming. We demonstrate that RFReact is both powerful and versatile with a jamming system that can demodulate the header of an IEEE 802.15.4 packet, decide whether to jam it based on its content, and carry out the decision all while the packet is still on the air.
WiSec 2011 poster
Authors: Jaeger Attila , Stübing Hagen , Huss Sorin A.
Published: December 2011

In this work the design of a security module is presented providing FPGA based hardware acceleration for Elliptic Curve Cryptography which, meets the requirements of Car-to-X Communication. The module is pluggable via USB to a Car-to-X system and therefore easily deployable within currently running or planed Field Operational Tests.
Testing atomicity of composed concurrent operations
Authors: Shacham Ohad , Bronson Nathan , Aiken Alex , Sagiv Mooly , Vechev Martin , Yahav Eran
Published: December 2011

We address the problem of testing atomicity of composed concurrent operations. Concurrent libraries help programmers exploit parallel hardware by providing scalable concurrent operations with the illusion that each operation is executed atomically. However, client code often needs to compose atomic operations in such a way that the resulting composite operation is also atomic while preserving scalability. We present a novel technique for testing the atomicity of client code composing scalable concurrent operations. The challenge in testing this kind of client code is that a bug may occur very rarely and only on a particular interleaving with a specific thread configuration. Our technique is based on modular testing of client code in the presence of an adversarial environment; we use commutativity specifications to drastically reduce the number of executions explored to detect a bug. We implemented our approach in a tool called COLT, and evaluated its effectiveness on a range of 51 real-world concurrent Java programs. Using COLT, we found 56 atomicity violations in Apache Tomcat, Cassandra, MyFaces Trinidad, and other applications.
Synthesis of first-order dynamic programming algorithms
Authors: Pu Yewen , Bodik Rastislav , Srivastava Saurabh
Published: December 2011

To solve a problem with a dynamic programming algorithm, one must reformulate the problem such that its solution can be formed from solutions to overlapping subproblems. Because overlapping subproblems may not be apparent in the specification, it is desirable to obtain the algorithm directly from the specification. We describe a semi-automatic synthesizer of linear-time dynamic programming algorithms. The programmer supplies a declarative specification of the problem and the operators that might appear in the solution. The synthesizer obtains the algorithm by searching a space of candidate algorithms; internally, the search is implemented with constraint solving. The space of candidate algorithms is defined with a program template reusable across all linear-time dynamic programming algorithms, which we characterize as first-order recurrences. This paper focuses on how to write the template so that the constraint solving process scales to real-world linear-time dynamic programming algorithms. We show how to reduce the space with (i)~symmetry reduction and (ii)~domain knowledge of dynamic programming algorithms. We have synthesized algorithms for variants of maximal substring matching, an assembly-line optimization, and the extended Euclid algorithm. We have also synthesized a problem outside the class of first-order recurrences, by composing three instances of the algorithm template.
Catch me if you can
Authors: Jovic Milan , Adamoli Andrea , Hauswirth Matthias
Published: December 2011

Profilers help developers to find and fix performance problems. But do they find performance bugs -- performance problems that real users actually notice? In this paper we argue that -- especially in the case of interactive applications -- traditional profilers find irrelevant problems but fail to find relevant bugs.

We then introduce lag hunting, an approach that identifies perceptible performance bugs by monitoring the behavior of applications deployed in the wild. The approach transparently produces a list of performance issues, and for each issue provides the developer with information that helps in finding the cause of the problem.

We evaluate our approach with an experiment where we monitor an application used by 24 users for 1958 hours over the course of 3-months. We characterize the resulting 881 issues, and we find and fix the causes of a set of representative examples.
Synthesizing method sequences for high-coverage testing
Authors: Thummalapenta Suresh , Xie Tao , Tillmann Nikolai , de Halleux Jonathan , Su Zhendong
Published: December 2011

High-coverage testing is challenging. Modern object-oriented programs present additional challenges for testing. One key difficulty is the generation of proper method sequences to construct desired objects as method parameters. In this paper, we cast the problem as an instance of program synthesis that automatically generates candidate programs to satisfy a user-specified intent. In our setting, candidate programs are method sequences, and desired object states specify an intent. Automatic generation of desired method sequences is difficult due to its large search space---sequences often involve methods from multiple classes and require specific primitive values. This paper introduces a novel approach, called Seeker, to intelligently navigate the large search space. Seeker synergistically combines static and dynamic analyses: (1) dynamic analysis generates method sequences to cover branches; (2) static analysis uses dynamic analysis information for not-covered branches to generate candidate sequences; and (3) dynamic analysis explores and eliminates statically generated sequences. For evaluation, we have implemented Seeker and demonstrate its effectiveness on four subject applications totalling 28K LOC. We show that Seeker achieves higher branch coverage and def-use coverage than existing state-of-the-art approaches. We also show that Seeker detects 34 new defects missed by existing tools.
Two for the price of one
Authors: Burckhardt Sebastian , Leijen Daan , Sadowski Caitlin , Yi Jaeheon , Ball Thomas
Published: December 2011

Parallel or incremental versions of an algorithm can significantly outperform their counterparts, but are often difficult to develop. Programming models that provide appropriate abstractions to decompose data and tasks can simplify parallelization. We show in this work that the same abstractions can enable both parallel and incremental execution. We present a novel algorithm for parallel self-adjusting computation. This algorithm extends a deterministic parallel programming model (concurrent revisions) with support for recording and repeating computations. On record, we construct a dynamic dependence graph of the parallel computation. On repeat, we reexecute only parts whose dependencies have changed.

We implement and evaluate our idea by studying five example programs, including a realistic multi-pass CSS layout algorithm. We describe programming techniques that proved particularly useful to improve the performance of self-adjustment in practice. Our final results show significant speedups on all examples (up to 37x on an 8-core machine). These speedups are well beyond what can be achieved by parallelization alone, while requiring a comparable effort by the programmer.
Product lines of theorems
Authors: Delaware Benjamin , Cook William , Batory Don
Published: December 2011

Mechanized proof assistants are powerful verification tools, but proof development can be difficult and time-consuming. When verifying a family of related programs, the effort can be reduced by proof reuse. In this paper, we show how to engineer product lines with theorems and proofs built from feature modules. Each module contains proof fragments which are composed together to build a complete proof of correctness for each product. We consider a product line of programming languages, where each variant includes metatheory proofs verifying the correctness of its semantic definitions. This approach has been realized in the Coq proof assistant, with the proofs of each feature independently certifiable by Coq. These proofs are composed for each language variant, with Coq mechanically verifying that the composite proofs are correct. As validation, we formalize a core calculus for Java in Coq which can be extended with any combination of casts, interfaces, or generics.
Null dereference verification via over-approximated weakest pre-conditions analysis
Authors: Madhavan Ravichandhran , Komondoor Raghavan
Published: December 2011

Null dereferences are a bane of programming in languages such as Java. In this paper we propose a sound, demand-driven, inter-procedurally context-sensitive dataflow analysis technique to verify a given dereference as safe or potentially unsafe. Our analysis uses an abstract lattice of formulas to find a pre-condition at the entry of the program such that a null-dereference can occur only if the initial state of the program satisfies this pre-condition. We use a simplified domain of formulas, abstracting out integer arithmetic, as well as unbounded access paths due to recursive data structures. For the sake of precision we model aliasing relationships explicitly in our abstract lattice, enable strong updates, and use a limited notion of path sensitivity. For the sake of scalability we prune formulas continually as they get propagated, reducing to true conjuncts that are less likely to be useful in validating or invalidating the formula. We have implemented our approach, and present an evaluation of it on a set of ten real Java programs. Our results show that the set of design features we have incorporated enable the analysis to (a) explore long, inter-procedural paths to verify each dereference, with (b) reasonable accuracy, and (c) very quick response time per dereference, making it suitable for use in desktop development environments.
Memory management in NUMA multicore systems
Authors: Majo Zoltan , Gross Thomas R.
Published: December 2011

Multiprocessors based on processors with multiple cores usually include a non-uniform memory architecture (NUMA); even current 2-processor systems with 8 cores exhibit non-uniform memory access times. As the cores of a processor share a common cache, the issues of memory management and process mapping must be revisited. We find that optimizing only for data locality can counteract the benefits of cache contention avoidance and vice versa. Therefore, system software must take
both
data locality and cache contention into account to achieve good performance, and memory management cannot be decoupled from process scheduling. We present a detailed analysis of a commercially available NUMA-multicore architecture, the Intel Nehalem. We describe two scheduling algorithms: maximum-local, which optimizes for maximum data locality, and its extension,
N-MASS
, which reduces data locality to avoid the performance degradation caused by cache contention. N-MASS is fine-tuned to support memory management on NUMA-multicores and improves performance up to 32%, and 7% on average, over the default setup in current Linux implementations.
The Desmoplastic Stroma Plays an Essential Role in the Accumulation and Modulation of Infiltrated Immune Cells in Pancreatic Adenocarcinoma
Authors: Tjomsland Vegard , Niklasson Lina , Sandström Per , Borch Kurt , Druid Henrik , Bratthäll Charlotte , Messmer Davorka , Larsson Marie , Spångeus Anna
Published: December 2011

Tumor microenvironment is composed of tumor cells, fibroblasts, and infiltrating immune cells, which all work together and create an inflammatory environment favoring tumor progression. The present study aimed to investigate the role of the desmoplastic stroma in pancreatic ductal adenocarcinoma (PDAC) regarding expression of inflammatory factors and infiltration of immune cells and their impact on the clinical outcome. The PDAC tissues examined expressed significantly increased levels of immunomodulatory and chemotactic factors (IL-6, TGFβ, IDO, COX-2, CCL2, and CCL20) and immune cell-specific markers corresponding to macrophages, myeloid, and plasmacytoid dendritic cells (DCs) as compared to controls. Furthermore, short-time survivors had the lowest levels of DC markers. Immunostainings indicated that the different immune cells and inflammatory factors are mainly localized to the desmoplastic stroma. Therapies modulating the inflammatory tumor microenvironment to promote the attraction of DCs and differentiation of monocytes into functional DCs might improve the survival of PDAC patients.
Ovarian Surface Epithelium in Patients with Severe Ovarian Infertility: A Potential Source of Cells Expressing Markers of Pluripotent/Multipotent Stem Cells
Authors: Virant-Klun Irma , Skutella Thomas , Stimpfel Martin , Sinkovec Jasna
Published: December 2011

The aim of this study was to confirm the presence of stem cells in the ovarian surface epithelium of patients with premature ovarian failure and no mature follicles and oocytes. In these patients, small round cells of unknown origin expressing SOX‐2 marker of pluripotency were observed among the epithelial cells just after the ovarian surface epithelium scraping. These cells were an integral part of the ovarian surface epithelium. When the scraped cells were cultured in a medium with added follicular fluid to provide some ovarian niche, primitive oocyte‐like cells and typical round‐shaped cell clusters positively stained on alkaline phosphatase, and markers of pluripotency, such as SOX‐2 and SSEA‐4, were developed. These markers were expressed early and also later in the culture. Single oocyte‐like cells expressed genes OCT4A, SOX-2, NANOG, NANOS, STELLA, CD9, LIN28, KLF4, GDF3, and MYC, characteristic for pluripotent stem cells. The results of this study confirmed the presence of putative stem cells in the ovarian surface epithelium of these patients and provided some basis to create a stem cell line in the future.
Progenitors for the Corneal Endothelium and Trabecular Meshwork: A Potential Source for Personalized Stem Cell Therapy in Corneal Endothelial Diseases and Glaucoma
Authors: Yu Wing Yan , Sheridan Carl , Grierson Ian , Mason Sharon , Kearns Victoria , Lo Amy Cheuk Yin , Wong David
Published: December 2011

Several adult stem cell types have been found in different parts of the eye, including the corneal epithelium, conjunctiva, and retina. In addition to these, there have been accumulating evidence that some stem‐like cells reside in the transition area between the peripheral corneal endothelium (CE) and the anterior nonfiltering portion of the trabecular meshwork (TM), which is known as the Schwalbe′s Ring region. These stem/progenitor cells may supply new cells for the CE and TM. In fact, the CE and TM share certain similarities in terms of their embryonic origin and proliferative capacity in vivo. In this paper, we discuss the putative stem cell source which has the potential for replacement of lost and nonfunctional cells in CE diseases and glaucoma. The future development of personalized stem cell therapies for the CE and TM may reduce the requirement of corneal grafts and surgical treatments in glaucoma.
Induction of Human Squamous Cell-Type Carcinomas by Arsenic
Authors: Martinez Victor D. , Becker-Santos Daiana D. , Vucic Emily A. , Lam Stephen , Lam Wan L.
Published: December 2011

Arsenic is a potent human carcinogen. Around one hundred million people worldwide have potentially been exposed to this metalloid at concentrations considered unsafe. Exposure occurs generally through drinking water from natural geological sources, making it difficult to control this contamination. Arsenic biotransformation is suspected to have a role in arsenic-related health effects ranging from acute toxicities to development of malignancies associated with chronic exposure. It has been demonstrated that arsenic exhibits preference for induction of squamous cell carcinomas in the human, especially skin and lung cancer. Interestingly, keratins emerge as a relevant factor in this arsenic-related squamous cell-type preference. Additionally, both genomic and epigenomic alterations have been associated with arsenic-driven neoplastic process. Some of these aberrations, as well as changes in other factors such as keratins, could explain the association between arsenic and squamous cell carcinomas in humans.
On the Uncontrollability of Nonabelian Group Codes with Uncoded Group ℤp
Authors: Arpasi Jorge Pedraza
Published: December 2011

Error‐correcting encoding is a mathematical manipulation of the information against transmission errors over noisy communications channels. One class of error‐correcting codes is the so‐called group codes. Presently, there are many good binary group codes which are abelian. A group code is a family of bi‐infinite sequences produced by a finite state machine (FSM) homomorphic encoder defined on the extension of two finite groups. As a set of sequences, a group code is a dynamical system and it is known that well‐behaved dynamical systems must be necessarily controllable. Thus, a good group code must be controllable. In this paper, we work with group codes defined over nonabelian groups. This necessity on the encoder is because it has been shown that the capacity of an additive white Gaussian noise (AWGN) channel using abelian group codes is upper bounded by the capacity of the same channel using phase shift keying (PSK) modulation eventually with different energies per symbol. We will show that when the trellis section group is nonabelian and the input group of the encoder is a cyclic group with, p elements, p prime, then the group code produced by the encoder is noncontrollable.
IT-141, a Polymer Micelle Encapsulating SN-38, Induces Tumor Regression in Multiple Colorectal Cancer Models
Authors: Carie Adam , Rios-Doria Jonathan , Costich Tara , Burke Brian , Slama Richard , Skaff Habib , Sill Kevin
Published: December 2011

Polymer micelles are promising drug delivery vehicles for the delivery of anticancer agents to tumors. Often, anticancer drugs display potent cytotoxic effects towards cancer cells but are too hydrophobic to be administered in the clinic as a free drug. To address this problem, a polymer micelle was designed using a triblock copolymer (ITP-101) that enables hydrophobic drugs to be encapsulated. An SN-38 encapsulated micelle, IT-141, was prepared that exhibited potent in vitro cytotoxicity against a wide array of cancer cell lines. In a mouse model, pharmacokinetic analysis revealed that IT-141 had a much longer circulation time, plasma exposure, and tumor exposure compared to irinotecan. IT-141 was also superior to irinotecan in terms of antitumor activity, exhibiting greater tumor inhibition in HT-29 and HCT116 colorectal cancer xenograft models at half the dose of irinotecan. The antitumor effect of IT-141 was dose-dependent and caused complete growth inhibition and tumor regression at well-tolerated doses. Varying the specific concentration of SN-38 within the IT-141 micelle had no detectible effect on this antitumor activity, indicating no differences in activity between different IT-141 formulations. In summary, IT-141 is a potent micelle-based chemotherapy that holds promise for the treatment of colorectal cancer.
Liquefaction Mitigation Using Lateral Confinement Technique
Authors: Azzam W. R. , Nazir A. K.
Published: December 2011

The exploration of a series of shaking tests on circular model footing with and without cellular confinement constructed around the footing with variable depths and diameters under the effect of variable net bearing stress is studied. The effect of the confinement on the liquefaction time, final settlement, excess pore water pressure, and induced building acceleration were studied. The consequences showed that installing the cell with minimum diameter closer to footing and sufficient penetration depth significantly delayed the liquefaction time. It can be considered as an alternative technique to decrease both the lateral spreading and the final settlement below the foundation during the shaking. The results demonstrated that the cell reduced the excess pore water pressure within the confined zone and the pore water pressure migration outside the confined block where the liquefaction is induced. Moreover, the peak foundation acceleration of the confined footing soil system is reduced compared with the case of without cell confinement.
Nonlinear Dynamic Analysis of Vowels in Cleft Palate Children with or without Hypernasality
Authors: Mishima Katsuaki , Nakano Hiroyuki , Matsumura Tatsushi , Moritani Norifumi , Iida Seiji , Ueyama Yoshiya
Published: December 2011

Objectives. To clarify the difference between Lyapunov exponents (LEs) for cleft palate (CP) patients with hypernasality versus without hypernasality and to investigate the relationship between their LEs and nasalance scores (NSs).Material and Methods. Six CP patients with severe hypernasality (mean age 9.2 years) and six CP patients without hypernasality (mean age 8.0 years) were enrolled. Five Japanese vowels were recorded at 44.1 KHz, and the NSs were measured simultaneously. The mean first LE (mLE1) from all one-second intervals was computed.Results. The mLE1for /o/ in patients with hypernasality was significantly higher than that in patients without hypernasality. The correlation coefficients between the mLE1and NS for all vowels were not statistically different.Conclusion. The voice signal of /o/ for the patients with hypernasality was more instable than in those without hypernasality. The chaotic phenomenon was independent of nasal resonance in CP voice.
Community-Level Response of Fishes and Aquatic Macroinvertebrates to Stream Restoration in a Third-Order Tributary of the Potomac River, USA
Authors: Selego Stephen M. , Rose Charneé L. , Merovich George T. , Welsh Stuart A. , Anderson James T.
Published: December 2011

Natural stream channel design principles and riparian restoration practices were applied during spring 2010 to an agriculturally impaired reach of the Cacapon River, a tributary of the Potomac River which flows into the Chesapeake Bay. Aquatic macroinvertebrates and fishes were sampled from the restoration reach, two degraded control, and two natural reference reaches prior to, concurrently with, and following restoration (2009 through 2010). Collector filterers and scrapers replaced collector gatherers as the dominant macroinvertebrate functional feeding groups in the restoration reach. Before restoration, based on indices of biotic integrity (IBI), the restoration reach fish and macroinvertebrate communities closely resembled those sampled from the control reaches, and after restoration more closely resembled those from the reference reaches. Although the macroinvertebrate community responded more favorably than the fish community, both communities recovered quickly from the temporary impairment caused by the disturbance of restoration procedures and suggest rapid improvement in local ecological conditions.
Application of Autofluorescence Endoscopy for Colorectal Cancer Screening: Rationale and an Update
Authors: Aihara Hiroyuki , Tajiri Hisao , Suzuki Takeshi
Published: December 2011

As the result of basic researches, several intravital fluorophores have been determined so far in human colorectal tissue. Autofluorescence endoscopy (AFE) can detect slight alterations in their distribution and concentration during the colorectal carcinogenesis process and, thus facilitate noninvasive screening colonoscopies without the need for fluorescent substances or staining reagents to be administered. While detecting faint autofluorescence intensity by conventional fiberoptic endoscopy remains challenging, the latest AFE system with high-resolution videoendoscope capabilities enables such detection by using a false-color display algorithm. To this end, the diagnostic benefits of AFE have been reported in several multicenter randomized controlled studies of colorectal cancer (CRC) screening and differential diagnosis. CRC screening using the latest AFE technology could, therefore, lead to future reductions in CRC mortality.
Urinary Estrogens and Estrogen Metabolites and Subsequent Risk of Breast Cancer among Premenopausal Women
Authors: Eliassen A. Heather , Spiegelman Donna , Xu Xia , Keefer Larry K. , Veenstra Timothy D. , Barbieri Robert L. , Willett Walter C. , Hankinson Susan E. , Ziegler Regina G.
Published: December 2011

Endogenous estrogens and estrogen metabolism are hypothesized to be associated with premenopausal breast cancer risk but evidence is limited. We examined 15 urinary estrogens/estrogen metabolites and breast cancer risk among premenopausal women in a case–control study nested within the Nurses' Health Study II (NHSII). From 1996 to 1999, urine was collected from 18,521 women during the mid-luteal menstrual phase. Breast cancer cases (N = 247) diagnosed between collection and June 2005 were matched to two controls each (N = 485). Urinary estrogen metabolites were measured by liquid chromatography-tandem mass spectrometry and adjusted for creatinine level. Relative risks (RR) and 95% confidence intervals (CI) were estimated by multivariate conditional logistic regression. Higher urinary estrone and estradiol levels were strongly significantly associated with lower risk (top vs. bottom quartile RR: estrone = 0.52; 95% CI, 0.30–0.88; estradiol = 0.51; 95% CI, 0.30–0.86). Generally inverse, although nonsignificant, patterns also were observed with 2- and 4-hydroxylation pathway estrogen metabolites. Inverse associations generally were not observed with 16-pathway estrogen metabolites and a significant positive association was observed with 17-epiestriol (top vs. bottom quartile RR = 1.74; 95% CI, 1.08–2.81; Ptrend = 0.01). In addition, there was a significant increased risk with higher 16-pathway/parent estrogen metabolite ratio (comparable RR = 1.61; 95% CI, 0.99–2.62; Ptrend = 0.04). Other pathway ratios were not significantly associated with risk except parent estrogen metabolites/non–parent estrogen metabolites (comparable RR = 0.58; 95% CI, 0.35–0.96; Ptrend = 0.03). These data suggest that most mid-luteal urinary estrogen metabolite concentrations are not positively associated with breast cancer risk among premenopausal women. The inverse associations with parent estrogen metabolites and the parent estrogen metabolite/non–parent estrogen metabolite ratio suggest that women with higher urinary excretion of parent estrogens are at lower risk. Cancer Res; 72(3); 696–706. ©2011 AACR.
Bexarotene via CBP/p300 Induces Suppression of NF-κB–Dependent Cell Growth and Invasion in Thyroid Cancer
Authors: Cras Audrey , Politis Béatrice , Balitrand Nicole , Darsin-Bettinger Diane , Boelle Pierre Yves , Cassinat Bruno , Toubert Marie-Elisabeth , Chomienne Christine
Published: December 2011

Purpose: Retinoic acid (RA) treatment has been used for redifferentiation of metastatic thyroid cancer with loss of radioiodine uptake. The aim of this study was to improve the understanding of RA resistance and investigate the role of bexarotene in thyroid cancer cells.

Experimental Design: A model of thyroid cancer cell lines with differential response to RA was used to evaluate the biological effects of retinoid and rexinoid and to correlate this with RA receptor levels. Subsequently, thyroid cancer patients were treated with 13-cis RA and bexarotene and response evaluated on radioiodine uptake reinduction on posttherapy scan and conventional imaging.

Results: In thyroid cancer patients, 13-cis RA resistance can be bypassed in some tumors by bexarotene. A decreased tumor growth without differentiation was observed confirming our in vitro data. Indeed, we show that ligands of RARs or RXRs exert different effects in thyroid cancer cell lines through either differentiation or inhibition of cell growth and invasion. These effects are associated with restoration of RARβ and RXRγ levels and downregulation of NF-κB targets genes. We show that bexarotene inhibits the transactivation potential of NF-κB in an RXR-dependent manner through decreased promoter permissiveness without interfering with NF-κB nuclear translocation and binding to its responsive elements. Inhibition of transcription results from the release of p300 coactivator from NF-κB target gene promoters and subsequent histone deacetylation.

Conclusion: This study highlights dual mechanisms by which retinoids and rexinoids may target cell tumorigenicity, not only via RARs and RXRs, as expected, but also via NF-κB pathway. Clin Cancer Res; 18(2); 442–53. ©2011 AACR.
New Challenges in Endpoints for Drug Development in Advanced Melanoma
Authors: Ribas Antoni , Hersey Peter , Middleton Mark R. , Gogas Helen , Flaherty Keith T. , Sondak Vernon K. , Kirkwood John M.
Published: December 2011

During the past 3 decades, the field of clinical research for the treatment of advanced melanoma lacked significant advances. Available drugs had low antitumor activity and no proven benefit in overall survival. Recently, new drugs developed based on an in-depth understanding of the biology of this disease have shown significant benefit, with ipilimumab and vemurafenib having recently shown a positive impact in overall survival in patients with metastatic melanoma leading to approval in this indication by the U.S. Food and Drug Administration. This rapid introduction of new active agents is likely to challenge current notions on how to develop future agents for the treatment of melanoma. The strong evidence of benefit for initial agents that modulate immune regulatory checkpoints or target driver oncogenes has spurred great interest in developing other similarly acting agents. However, this will pose problems in the choice of endpoints for the future definitive clinical trials, and the hurdles for achieving these endpoints will be higher given the similar activity for comparator agents or the availability of competing agents for salvage therapy. This new reality will likely require tailoring registrational clinical trial endpoints to the patient benefits shown in early clinical testing. In this perspective article, we illustrate the challenges in the choice of endpoints for registrational trials in metastatic melanoma and that, with an improved understanding of the agent being developed, the design of the registrational programs can be informed by earlier mechanistic studies to define the assumptions for definitive clinical testing. Clin Cancer Res; 18(2); 336–41. ©2011 AACR.
Ganetespib, a Unique Triazolone-Containing Hsp90 Inhibitor, Exhibits Potent Antitumor Activity and a Superior Safety Profile for Cancer Therapy
Authors: Ying Weiwen , Du Zhenjian , Sun Lijun , Foley Kevin P. , Proia David A. , Blackman Ronald K. , Zhou Dan , Inoue Takayo , Tatsuta Noriaki , Sang Jim , Ye Shuxia , Acquaviva Jamie , Ogawa Luisa Shin , Wada Yumiko , Barsoum James , Koya Keizo
Published: December 2011

Targeted inhibition of the molecular chaperone Hsp90 results in the simultaneous blockade of multiple oncogenic signaling pathways and has, thus, emerged as an attractive strategy for the development of novel cancer therapeutics. Ganetespib (formerly known as STA-9090) is a unique resorcinolic triazolone inhibitor of Hsp90 that is currently in clinical trials for a number of human cancers. In the present study, we showed that ganetespib exhibits potent in vitro cytotoxicity in a range of solid and hematologic tumor cell lines, including those that express mutated kinases that confer resistance to small-molecule tyrosine kinase inhibitors. Ganetespib treatment rapidly induced the degradation of known Hsp90 client proteins, displayed superior potency to the ansamycin inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), and exhibited sustained activity even with short exposure times. In vivo, ganetespib showed potent antitumor efficacy in solid and hematologic xenograft models of oncogene addiction, as evidenced by significant growth inhibition and/or regressions. Notably, evaluation of the microregional activity of ganetespib in tumor xenografts showed that ganetespib was efficiently distributed throughout tumor tissue, including hypoxic regions >150 μm from the microvasculature, to inhibit proliferation and induce apoptosis. Importantly, ganetespib showed no evidence of cardiac or liver toxicity. Taken together, this preclinical activity profile indicates that ganetespib may have broad application for a variety of human malignancies, and with select mechanistic and safety advantages over other first- and second-generation Hsp90 inhibitors. Mol Cancer Ther; 11(2); 475–84. ©2011 AACR.
Development of the Olfactory Pathways in Platypus and Echidna
Authors: Ashwell Ken W.S.
Published: December 2011

The two groups of living monotremes (platypus and echidnas) have remarkably different olfactory structures in the adult. The layers of the main olfactory bulb of the short-beaked echidna are extensively folded, whereas those of the platypus are not. Similarly, the surface area of the piriform cortex of the echidna is large and its lamination complex, whereas in the platypus it is small and simple. It has been argued that the modern echidnas are derived from a platypus-like ancestor, in which case the extensive olfactory specializations of the modern echidnas would have developed relatively recently in monotreme evolution. In this study, the development of the constituent structures of the olfactory pathway was studied in sectioned platypus and echidna embryos and post-hatchlings at the Museum für Naturkunde, Berlin, Germany. The aim was to determine whether the olfactory structures follow a similar maturational path in the two monotremes during embryonic and early post-hatching ages or whether they show very different developmental paths from the outset. The findings indicate that anatomical differences in the central olfactory system between the short-beaked echidna and the platypus begin to develop immediately before hatching, although details of differences in nasal cavity architecture emerge progressively during late post-hatching life. These findings are most consistent with the proposition that the two modern monotreme lineages have followed independent evolutionary paths from a less olfaction-specialized ancestor. The monotreme olfactory pathway does not appear to be sufficiently structurally mature at birth to allow olfaction-mediated behaviour, because central components of both the main and accessory olfactory system have not differentiated at the time of hatching.
Impact of Vascular Calcification on Corrected QT Interval at the Time of Renal Transplantation
Authors: Claes Kathleen J. , Heye Sam , Nuyens Dieter , Bammens Bert , Kuypers Dirk R. , Vanrenterghem Yves , Evenepoel Pieter
Published: December 2011

Background/Aims: Sudden death is the major cause of cardiac mortality in dialysis patients, accounting for approximately 60% of cardiovascular deaths. A prolonged QT interval and arterial calcification have been associated with increased cardiovascular morbidity and mortality in different patient populations including patients with chronic kidney disease (CKD). In the present study, we aimed to elucidate the association of vascular calcification with corrected QT interval duration in patients with end-stage renal disease. Methods: We performed a single-center cross-sectional study in patients referred for renal transplantation. Patients taking QT-prolonging agents or with conduction abnormalities were excluded. Aortic calcifications were scored by means of lumbar X-rays. Results: In the final analysis, 193 patients (118 men, 52 years old) were included. A prolonged QT interval was observed in 26% of the patients. Multivariate analysis showed an independent and direct association between corrected QT duration and the extent of aortic calcifications (p = 0.0004) independent of age, gender, cardiovascular history, electrolytes and parameters of mineral metabolism. Conclusions: A prolonged QT interval is prevalent in patients with CKD stage 5D. Aortic calcification is associated with a prolonged QT duration, independent of traditional determinants.