bluuebunny/crossref_metadata_2025 huggingface dataset:
COMBINING GENETIC PROGRAMMING AND MODEL-DRIVEN DEVELOPMENT
Authors: WEISE THOMAS , ZAPF MICHAEL , KHAN MOHAMMAD ULLAH , GEIHS KURT
Published: April 2009

Genetic programming (GP) is known to provide good solutions for many problems like the evolution of network protocols and distributed algorithms. In most cases it is a hardwired module of a design framework assisting the engineer in optimizing specific aspects in system development. In this article, we show how the utility of GP can be increased remarkably by isolating it as a component and integrating it into the model-driven software development process. Our GP framework produces XMI-encoded UML models that can easily be loaded into widely available modeling tools, which in turn offer code generation as well as additional analysis and test capabilities. We use the evolution of a distributed election algorithm as an example to illustrate how GP can be combined with model-driven development (MDD).
A BRANCH AND BOUND ALGORITHM FOR FINDING THE MODES IN KERNEL DENSITY ESTIMATES
Authors: WIRJADI OLIVER , BREUEL THOMAS
Published: April 2009

Kernel density estimators are established tools in nonparametric statistics. Due to their flexibility and ease of use, these methods are popular in computer vision and pattern recognition for tasks such as object tracking in video or image segmentation. The most frequently used algorithm for finding the modes in such densities (the mean shift) is a gradient ascent rule, which converges to local maxima. We propose a novel, globally optimal branch and bound algorithm for finding the modes in kernel densities. We show in experiments on datasets up to dimension five that the branch and bound method is faster than local optimization and observe linear runtime scaling of our method with sample size. Quantitative experiments on simulated data show that our method gives statistically significantly more accurate solutions than the mean shift. The mode localization accuracy is about five times more precise than that of the mean shift for all tested parameters. Applications to color image segmentation on an established benchmark test set also show measurably improved results when using global optimization.
Ranking functions for size-change termination
Authors: Lee Chin Soon
Published: April 2009

This article explains how to construct a ranking function for any program that is proved terminating by
size-change analysis
.

The “principle of size-change termination” for a first-order functional language with well-ordered data is intuitive: A program terminates on all inputs, if every infinite call sequence (following program control flow) would imply an infinite descent in some data values. Size-change analysis is based on information associated with the subject program's call-sites. This information indicates, for each call-site, strict or weak data decreases observed as a computation traverses the call-site. The set
DESC
of call-site sequences for which the size-changes imply infinite descent is ω-regular, as is the set
FLOW
of infinite call-site sequences following the program flowchart. If
FLOW
⊆
DESC
(a decidable problem), every infinite call sequence would imply infinite descent in a well-ordering—an impossibility—so the program must terminate.

This analysis accounts for termination arguments applicable to different call-site sequences, without indicating a ranking function for the program's termination. In this article, it is explained how one can be constructed whenever size-change analysis succeeds. The constructed function has an unexpectedly simple form; it is expressed using only min, max, and lexicographic tuples of parameters and constants. In principle, such functions can be tested to determine whether size-change analysis will be successful. As a corollary, if a program verified as terminating performs only multiply recursive operations, the function that it computes is multiply recursive.

The ranking function construction is connected with the determinization of the Büchi automaton for
DESC
. While the result is not practical, it is of value in addressing the scope of size-change reasoning. This reasoning has been applied broadly, in the analysis of functional and logic programs, as well as term rewrite systems.
Operational semantics for multi-language programs
Authors: Matthews Jacob , Findler Robert Bruce
Published: April 2009

Interoperability is big business, a fact to which .NET, the JVM, and COM can attest. Language designers are well aware of this, and they are designing programming languages that reflect it—for instance, SML.NET, F#, Mondrian, and Scala all treat interoperability as a central design feature. Still, current multi-language research tends not to focus on the semantics of these features, but only on how to implement them efficiently. In this article, we attempt to rectify that by giving a technique for specifying the operational semantics of a multi-language system as a composition of the models of its constituent languages. Our technique abstracts away the low-level details of interoperability like garbage collection and representation coherence, and lets us focus on semantic properties like type-safety, equivalence, and termination behavior. In doing so it allows us to adapt standard theoretical techniques such as subject-reduction, logical relations, and operational equivalence for use on multi-language systems. Generally speaking, our proofs of properties in a multi-language context are mutually referential versions of their single language counterparts.

We demonstrate our technique with a series of strategies for embedding a Scheme-like language into an ML-like language. We start by connecting very simple languages with a very simple strategy, and work our way up to languages that interact in sophisticated ways and have sophisticated features such as polymorphism and effects. Along the way, we prove relevant results such as type-soundness and termination for each system we present using adaptations of standard techniques.

Beyond giving simple expressive models, our studies have uncovered several interesting facts about interoperability. For example, higher-order function contracts naturally emerge as the glue to ensure that interoperating languages respect each other's type systems. Our models also predict that the embedding strategy where foreign values are opaque is as expressive as the embedding strategy where foreign values are translated to corresponding values in the other language, and we were able to experimentally verify this behavior using PLT Scheme's foreign function interface.
The gene evolution model and computing its associated probabilities
Authors: Arvestad Lars , Lagergren Jens , Sennblad Bengt
Published: April 2009

Phylogeny is both a fundamental tool in biology and a rich source of fascinating modeling and algorithmic problems. Today's wealth of sequenced genomes makes it increasingly important to understand evolutionary events such as duplications, losses, transpositions, inversions, lateral transfers, and domain shuffling. We focus on the gene duplication event, that constitutes a major force in the creation of genes with new function [Ohno 1970; Lynch and Force 2000] and, thereby also, of biodiversity.

We introduce the probabilistic
gene evolution model
, which describes how a gene tree evolves within a given species tree with respect to speciation, gene duplication, and gene loss. The actual relation between gene tree and species tree is captured by a reconciliation, a concept which we generalize for more expressiveness. The model is a canonical generalization of the classical linear birth-death process, obtained by replacing the interval where the process takes place by a tree.

For the
gene evolution model
, we derive efficient algorithms for some associated probability distributions: the probability of a reconciled tree, the probability of a gene tree, the maximum probability reconciliation, the posterior probability of a reconciliation, and sampling reconciliations with respect to the posterior probability. These algorithms provides the basis for several applications, including species tree construction, reconciliation analysis, orthology analysis, biogeography, and host-parasite co-evolution.
Multi-linear formulas for permanent and determinant are of super-polynomial size
Authors: Raz Ran
Published: April 2009

An arithmetic formula is multilinear if the polynomial computed by each of its subformulas is multilinear. We prove that any multilinear arithmetic formula for the permanent or the determinant of an
n
×
n
matrix is of size super-polynomial in
n
. Previously, super-polynomial lower bounds were not known (for any explicit function) even for the special case of multilinear formulas of constant depth.
Checking timed Büchi automata emptiness on simulation graphs
Authors: Tripakis Stavros
Published: April 2009

Timed automata [Alur and Dill 1994] comprise a popular model for describing real-time and embedded systems and reasoning formally about them. Efficient model-checking algorithms have been developed and implemented in tools such as Kronos [Daws et al. 1996] or Uppaal [Larsen et al. 1997] for checking safety properties on this model, which amounts to reachability. These algorithms use the so-called zone-closed simulation graph, a finite graph that admits efficient representation and has been recently shown to preserve reachability [Bouyer 2004]. Building upon Bouyer [2004] and our previous work [Bouajjani et al. 1997; Tripakis et al. 2005], we show that this graph can also be used for checking liveness properties, in particular, emptiness of timed Büchi automata.
Simultaneous checking of completeness and ground confluence for algebraic specifications
Authors: Bouhoula Adel
Published: April 2009

Algebraic specifications provide a powerful method for the specification of abstract data types in programming languages and software systems. Completeness and ground confluence are fundamental notions for building algebraic specifications in a correct and modular way. Related works for checking ground confluence are based on the completion techniques or on the test that all critical pairs between axioms are valid with respect to a sufficient criterion for ground confluence. It is generally accepted that such techniques may be very inefficient, even for very small specifications. Indeed, the completion procedure often diverges and there often exist many critical pairs of the axioms. In this article, we present a procedure for simultaneously checking completeness and ground confluence for specifications with free/nonfree constructors and parameterized specifications. If the specification is not complete or not ground confluent, then our procedure will output the set of patterns on whose ground instances a function is not defined and it can easily identify the rules that break ground confluence. In contrast to previous work, our method does not rely on completion techniques and does not require the computation of critical pairs of the axioms. The method is entirely implemented and allowed us to prove the completeness and the ground confluence of many specifications in a completely automatic way, where related techniques diverge or generate very complex proofs. Our system offers two main components: (i) a completeness and ground confluence analyzer that computes pattern trees of defined functions and may generate some proof obligations; and (ii) a procedure to prove (joinable) inductive conjectures which is used to discharge these proof obligations.
Hacking social networks
Authors: Greiner Lynn
Published: April 2009

The more users trust the community the more they risk having their trust compromised.
The tech behind universal broadband
Authors: Weiss Aaron
Published: April 2009

Any realistic solution to America's broadband gap requires a technological patchwork, wired and wireless, old and new, costly and economical.
Optimization of store performance using personalized pricing
Authors: Baydar Cem
Published: April 2009

Currently, most of the grocery stores provide special discounts to their customers under different loyalty card programs. However, since each individual's shopping behavior is not taken into consideration, these discounts do not help optimize the store performance. We believe that a more determined approach such as individual pricing could enable retailers to optimize their store performance by giving special discounts to each customer. Our approach requires each customer is modeled as an agent and his/her shopping behavior is obtained from transaction data. Then, the overall shopping behavior is simulated and the store performance is optimized using Monte-Carlo simulations and evolutionary computation. The results showed that individual pricing outperforms the traditional product-centered approach significantly.
GEVA
Authors: O'Neill Michael , Hemberg Erik , Gilligan Conor , Bartley Eliott , McDermott James , Brabazon Anthony
Published: April 2009

We are delighted to announce the release of
GEVA
[1], an open source software implementation of Grammatical Evolution (GE) in Java. Grammatical Evolution in Java (GEVA) was developed at UCD's Natural Computing Research & Applications group (http://ncra.ucd.ie).
A comparison of 2H2O and phenylalanine flooding dose to investigate muscle protein synthesis with acute exercise in rats
Authors: Gasier Heath G. , Riechman Steven E. , Wiggs Michael P. , Previs Stephen F. , Fluckey James D.
Published: April 2009

The primary objective of this investigation was to determine whether 2H2O and phenylalanine (Phe) flooding dose methods yield comparable fractional rates of protein synthesis (FSR) in skeletal muscle following a single bout of high-intensity resistance exercise (RE). Sprague-Dawley rats were assigned by body mass to either 4-h control (CON 4 h; n = 6), 4-h resistance exercise (RE 4 h; n = 6), 24-h control (CON 24 h; n = 6), or 24-h resistance exercise (RE 24 h; n = 6). The RE groups were operantly conditioned to engage in a single bout of high-intensity, “squat-like” RE. All rats were given an intraperitoneal injection of 99.9% 2H2O and provided 4.0% 2H2O drinking water for either 24 ( n = 12) or 4 h ( n = 12) prior to receiving a flooding dose of l-[2,3,4,5,6-3H]Phe 16 h post-RE. Neither method detected an effect of RE on FSR in the mixed gastrocnemius, plantaris, or soleus muscle. Aside from the qualitative similarities between methods, the 4-h 2H2O FSR measurements, when expressed in percent per hour, were quantitatively greater than the 24-h 2H2O and Phe flooding in all muscles ( P < 0.001), and the 24-h 2H2O was greater than the Phe flooding dose in the mixed gastrocnemius and plantaris ( P < 0.05). In contrast, the actual percentage of newly synthesized protein was significantly higher in the 24- vs. 4-h 2H2O and Phe flooding dose groups ( P < 0.001). These results suggest that the methodologies provide “qualitatively” similar results when a perturbation such as RE is studied. However, due to potential quantitative differences between methods, the experimental question should determine what approach should be used.
Dysregulated glutathione metabolism links to impaired insulin action in adipocytes
Authors: Kobayashi Hironori , Matsuda Morihiro , Fukuhara Atsunori , Komuro Ryutaro , Shimomura Iichiro
Published: April 2009

Oxidative stress plays an important role in obesity-related metabolic diseases. Glutathione peroxidase (GPX) is an antioxidant enzyme downregulated in adipose tissue of obese mice. However, the role of GPX in adipocytes remains elusive. The objective of this study was to clarify the pathophysiological changes in GPX activity and glutathione metabolism and their roles in the pathogenesis of insulin resistance in adipocytes. To achieve this goal, we measured cellular GPX activity, glutathione (GSH) contents, GSH/GSSG ratio, and mRNA expression of γ-glutamylcysteine synthetase (γ-GCS), a rate-limiting enzyme for de novo GSH synthesis, in adipose tissue of control and ob/ob mice and in 3T3-L1 adipocytes treated with insulin, H2O2, free fatty acid (FFA), or TNFα. Furthermore, we investigated the effects of GPX inhibition with a specific GPX inhibitor or RNA interference against GPX, H2O2, and reduced GSH on insulin signaling in 3T3-L1 adipocytes. ob/ob Mice showed not only a decrease in cellular activity of GPXs (GPX1, -4, and -7) but also an increase in γ-GCS expression, resulting in increased GSH contents in adipose tissue. These alterations in glutathione metabolism were also observed during differentiation of 3T3-L1 cells and their exposure to insulin, FFA, or H2O2. Inhibition of GPX activity, addition of GSH, and H2O2resulted in impaired insulin signaling in 3T3-L1 adipocytes. These results suggest that decreased GPX activity and increased γ-GCS expression lead to overaccumulation of GSH, which might be involved in the pathogenesis of insulin resistance in obesity.
Altered expression and insulin-induced trafficking of Na+-K+-ATPase in rat skeletal muscle: effects of high-fat diet and exercise
Authors: Galuska Dana , Kotova Olga , Barrès Romain , Chibalina Daria , Benziane Boubacar , Chibalin Alexander V.
Published: April 2009

Skeletal muscle Na+-K+-ATPase plays a central role in the clearance of K+from the extracellular fluid, therefore maintaining blood [K+]. Na+-K+-ATPase activity in peripheral tissue is impaired in insulin resistant states. We determined effects of high-fat diet (HFD) and exercise training (ET) on skeletal muscle Na+-K+-ATPase subunit expression and insulin-stimulated translocation. Skeletal muscle expression of Na+-K+-ATPase isoforms and transcription factor DNA binding was determined before or after 5 days of swim training in Wistar rats fed chow or HFD for 4 or 12 wk. Skeletal muscle insulin resistance was observed after 12 wk of HFD. Na+-K+-ATPase α1-subunit protein expression was increased 1.6-fold ( P < 0.05), whereas α2- and β1-subunits and protein expression were decreased twofold ( P < 0.01) in parallel with decrease in plasma membrane Na+-K+-ATPase activity after 4 wk of HFD. Exercise training restored α1-, α2-, and β1-subunit expression and Na+-K+-ATPase activity to control levels and reduced β2-subunit expression 2.2-fold ( P < 0.05). DNA binding activity of the α1-subunit-regulating transcription factor ZEB (AREB6) and α1mRNA expression were increased after HFD and restored by ET. DNA binding activity of Sp-1, a transcription factor involved in the regulation of α2- and β1-subunit expression, was decreased after HFD. ET increased phosphorylation of the Na+-K+-ATPase regulatory protein phospholemman. Phospholemman mRNA and protein expression were increased after HFD and restored to control levels after ET. Insulin-stimulated translocation of the α2-subunit to plasma membrane was impaired by HFD, whereas α1-subunit translocation remained unchanged. Alterations in sodium pump function precede the development of skeletal muscle insulin resistance. Disturbances in skeletal muscle Na+-K+-ATPase regulation, particularly the α2-subunit, may contribute to impaired ion homeostasis in insulin-resistant states such as obesity and type 2 diabetes.
Structured Variability of Muscle Activations Supports the Minimal Intervention Principle of Motor Control
Authors: Valero-Cuevas Francisco J. , Venkadesan Madhusudhan , Todorov Emanuel
Published: April 2009

Numerous observations of structured motor variability indicate that the sensorimotor system preferentially controls task-relevant parameters while allowing task-irrelevant ones to fluctuate. Optimality models show that controlling a redundant musculo-skeletal system in this manner meets task demands while minimizing control effort. Although this line of inquiry has been very productive, the data are mostly behavioral with no direct physiological evidence on the level of muscle or neural activity. Furthermore, biomechanical coupling, signal-dependent noise, and alternative causes of trial-to-trial variability confound behavioral studies. Here we address those confounds and present evidence that the nervous system preferentially controls task-relevant parameters on the muscle level. We asked subjects to produce vertical fingertip force vectors of prescribed constant or time-varying magnitudes while maintaining a constant finger posture. We recorded intramuscular electromyograms (EMGs) simultaneously from all seven index finger muscles during this task. The experiment design and selective fine-wire muscle recordings allowed us to account for a median of 91% of the variance of fingertip forces given the EMG signals. By analyzing muscle coordination in the seven-dimensional EMG signal space, we find that variance-per-dimension is consistently smaller in the task-relevant subspace than in the task-irrelevant subspace. This first direct physiological evidence on the muscle level for preferential control of task-relevant parameters strongly suggest the use of a neural control strategy compatible with the principle of minimal intervention. Additionally, variance is nonnegligible in all seven dimensions, which is at odds with the view that muscle activation patterns are composed from a small number of synergies.
Central Lateral Thalamic Neurons Receive Noxious Visceral Mechanical and Chemical Input in Rats
Authors: Ren Yong , Zhang Liping , Lu Ying , Yang Hong , Westlund Karin N.
Published: April 2009

Thalamic intralaminar and medial nuclei participate mainly in affective and motivational aspects of pain processing. Unique to the present study were identification and characterization of spontaneously active neurons in the central lateral nucleus (CL) of the intralaminar thalamus, which were found to respond only to viscerally evoked noxious stimuli in animals under pentobarbital anesthesia. Responses to noxious colorectal distention, intrapancreatic bradykinin, intraperitoneal dilute acetic acid, and greater splanchnic nerve electrical stimulation were characterized. Electrophysiological recordings revealed activity in most CL neurons (93%) was excited (69%) or inhibited (31%) in response to noxious visceral stimulation of visceral nerves. Expression of c-Fos observed in CL nucleus after intensive visceral stimulation confirmed the activation. However, excited CL neurons did not have somatic fields, except in 3 of 43 (7%) CL neurons tested for responses to somatic stimulation (innocuous brush and noxious pinch). Intrathecal administration of morphine significantly reduced the increased responses of CL neurons to colorectal and pancreatic stimuli and was naloxone reversible. High-level thoracic midline dorsal column (DC) myelotomy also dramatically reduced responses, identifying the DC as a major route of travel from the spinal cord for CL input, in addition to input traveling ventromedially in the spinothalamic tract identified anatomically in a previous study. Spinal cord and lower brain stem cells providing input to medial thalamus were mapped after stereotaxic injections of a retrograde dye. These data combined with our previous data suggest that the CL nucleus is an important component of a medial visceral nociceptive system that may mediate attentional, affective, endocrine, motor, and autonomic responses to noxious visceral stimuli.
Lung evolution as a cipher for physiology
Authors: Torday J. S. , Rehan V. K.
Published: April 2009

In the postgenomic era, we need an algorithm to readily translate genes into physiologic principles. The failure to advance biomedicine is due to the false hope raised in the wake of the Human Genome Project (HGP) by the promise of systems biology as a ready means of reconstructing physiology from genes. like the atom in physics, the cell, not the gene, is the smallest completely functional unit of biology. Trying to reassemble gene regulatory networks without accounting for this fundamental feature of evolution will result in a genomic atlas, but not an algorithm for functional genomics. For example, the evolution of the lung can be “deconvoluted” by applying cell-cell communication mechanisms to all aspects of lung biology development, homeostasis, and regeneration/repair. Gene regulatory networks common to these processes predict ontogeny, phylogeny, and the disease-related consequences of failed signaling. This algorithm elucidates characteristics of vertebrate physiology as a cascade of emergent and contingent cellular adaptational responses. By reducing complex physiological traits to gene regulatory networks and arranging them hierarchically in a self-organizing map, like the periodic table of elements in physics, the first principles of physiology will emerge.
Generalized Caristi's Fixed Point Theorems
Authors: Latif Abdul
Published: April 2009

We present generalized versions of Caristi's fixed point theorem for multivalued maps. Our results either improve or generalize the corresponding generalized Caristi's fixed point theorems due to Bae (2003), Suzuki (2005), Khamsi (2008), and others.
The Potential Use of Intrauterine Insemination as a Basic Option for Infertility: A Review for Technology-Limited Medical Settings
Authors: Abdelkader Abdelrahman M. , Yeh John
Published: April 2009

Objective. There is an asymmetric allocation of technology and other resources for infertility services. Intrauterine insemination (IUI) is a process of placing washed spermatozoa transcervically into the uterine cavity for treatment of infertility. This is a review of literature for the potential use of IUI as a basic infertility treatment in technology-limited settings.Study design. Review of articles on treatment of infertility using IUI.Results. Aspects regarding the use of IUI are reviewed, including ovarian stimulation, semen parameters associated with good outcomes, methods of sperm preparation, timing of IUI, and number of inseminations. Implications of the finding in light of the needs of low-technology medical settings are summarized.Conclusion. The reviewed evidence suggests that IUI is less expensive, less invasive, and comparably effective for selected patients as a first-line treatment for couples with unexplained or male factor infertility. Those couples may be offered three to six IUI cycles in technology-limited settings.
Epithelioid Sarcoma of the Forearm Arising from Perineural Sheath of Median Nerve Mimicking Carpal Tunnel Syndrome
Authors: Fujii Hiromasa , Honoki Kanya , Yajima Hiroshi , Kido Akira , Kobata Yasunori , Kaji Daisuke , Takakura Yoshinori
Published: April 2009

We report here a case of epithelioid sarcoma in the forearm of a 33-year-old male presenting with symptoms and signs of carpal tunnel syndrome originating from the direct involvement of the median nerve. Due to the slow growing of the tumor, the patient noticed the presence of tumor mass in his forearm after several months from the initial onset of the symptoms. Magnetic resonance imaging showed an8×4 cm mass involving the median nerve in the middle part of the forearm, and histological analysis of the biopsy specimen revealed the diagnosis of epithelioid sarcoma. Radical surgical resection was performed in conjunction with adjuvant chemotherapy. The function of the flexors were restored by the multiple tendon transfers (EIP→FDS;ECRL→FDP;BrR→FPL;EDM→opponens) with superficial cutaneous branch of radial nerve transfer to the resected median nerve. The function of the affected hand showed excellent with the DASH disability/symptom score of 22.5, and both the grasp power and sensory of the median nerve area has recovered up to 50% of the normal side. The patient returned to his original vocation and alive with continuous disease free at 3.5-year follow-up since initial treatment.
The Renin-Angiotensin System Modulates Inflammatory Processes in Atherosclerosis: Evidence from Basic Research and Clinical Studies
Authors: Montecucco Fabrizio , Pende Aldo , Mach François
Published: April 2009

Recent evidence shows that the renin-angiotensin system is a crucial player in atherosclerotic processes. The regulation of arterial blood pressure was considered from its first description of the main mechanism involved. Vasoconstriction (mediated by angiotensin II) and salt and water retention (mainly due to aldosterone) were classically considered as pivotal proatherosclerotic activities. However, basic research and animal studies strongly support angiotensin II as a proinflammatory mediator, which directly induces atherosclerotic plaque development and heart remodeling. Furthermore, angiotensin II induces proatherosclerotic cytokine and chemokine secretion and increases endothelial dysfunction. Accordingly, the pharmacological inhibition of the renin-angiotensin system improves prognosis of patients with cardiovascular disease even in settings of normal baseline blood pressure. In the present review, we focused on angiotensin-convertingenzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and renin inhibitors to update the direct activities of the renin-angiotensin system in inflammatory processes governing atherosclerosis.
Preferential Induction of EphB4 over EphB2 and Its Implication in Colorectal Cancer Progression
Authors: Kumar S. Ram , Scehnet Jeffrey S. , Ley Eric J. , Singh Jasbir , Krasnoperov Valery , Liu Ren , Manchanda Parmeet K. , Ladner Robert D. , Hawes Debra , Weaver Fred A. , Beart Robert W. , Singh Gagandeep , Nguyen Cu , Kahn Michael , Gill Parkash S.
Published: April 2009

The receptor tyrosine kinase EphB2 is expressed by colon progenitor cells; however, only 39% of colorectal tumors express EphB2 and expression levels decline with disease progression. Conversely, EphB4 is absent in normal colon but is expressed in all 102 colorectal cancer specimens analyzed, and its expression level correlates with higher tumor stage and grade. Both EphB4 and EphB2 are regulated by the Wnt pathway, the activation of which is critically required for the progression of colorectal cancer. Differential usage of transcriptional coactivator cyclic AMP-responsive element binding protein–binding protein (CBP) over p300 by the Wnt/β-catenin pathway is known to suppress differentiation and increase proliferation. We show that the β-catenin-CBP complex induces EphB4 and represses EphB2, in contrast to the β-catenin-p300 complex. Gain of EphB4 provides survival advantage to tumor cells and resistance to innate tumor necrosis factor-related apoptosis-inducing ligand–mediated cell death. Knockdown of EphB4 inhibits tumor growth and metastases. Our work is the first to show that EphB4 is preferentially induced in colorectal cancer, in contrast to EphB2, whereby tumor cells acquire a survival advantage. [Cancer Res 2009;69(9):3736–45]
Treatment-Dependent Androgen Receptor Mutations in Prostate Cancer Exploit Multiple Mechanisms to Evade Therapy
Authors: Steinkamp Mara P. , O'Mahony Orla A. , Brogley Michele , Rehman Haniya , LaPensee Elizabeth W. , Dhanasekaran Saravana , Hofer Matthias D. , Kuefer Rainer , Chinnaiyan Arul , Rubin Mark A. , Pienta Kenneth J. , Robins Diane M.
Published: April 2009

Mutations in the androgen receptor (AR) that enable activation by antiandrogens occur in hormone-refractory prostate cancer, suggesting that mutant ARs are selected by treatment. To validate this hypothesis, we compared AR variants in metastases obtained by rapid autopsy of patients treated with flutamide or bicalutamide, or by excision of lymph node metastases from hormone-naïve patients. AR mutations occurred at low levels in all specimens, reflecting genetic heterogeneity of prostate cancer. Base changes recurring in multiple samples or multiple times per sample were considered putative selected mutations. Of 26 recurring missense mutations, most in the NH2-terminal domain (NTD) occurred in multiple tumors, whereas those in the ligand binding domain (LBD) were case specific. Hormone-naïve tumors had few recurring mutations and none in the LBD. Several AR variants were assessed for mechanisms that might underlie treatment resistance. Selection was evident for the promiscuous receptor AR-V716M, which dominated three metastases from one flutamide-treated patient. For the inactive cytoplasmically restricted splice variant AR23, coexpression with AR enhanced ligand response, supporting a decoy function. A novel NTD mutation, W435L, in a motif involved in intramolecular interaction influenced promoter-selective, cell-dependent transactivation. AR-E255K, mutated in a domain that interacts with an E3 ubiquitin ligase, led to increased protein stability and nuclear localization in the absence of ligand. Thus, treatment with antiandrogens selects for gain-of-function AR mutations with altered stability, promoter preference, or ligand specificity. These processes reveal multiple targets for effective therapies regardless of AR mutation. [Cancer Res 2009;69(10):4434–42]
Interleukin-15 Enhances Proteasomal Degradation of Bid in Normal Lymphocytes: Implications for Large Granular Lymphocyte Leukemias
Authors: Hodge Deborah L. , Yang Jun , Buschman Matthew D. , Schaughency Paul M. , Dang Hong , Bere William , Yang Yili , Savan Ram , Subleski Jeff J. , Yin Xiao-Ming , Loughran Thomas P. , Young Howard A.
Published: April 2009

Large granular lymphocyte (LGL) leukemia is a clonal proliferative disease of T and natural killer (NK) cells. Interleukin (IL)-15 is important for the development and progression of LGL leukemia and is a survival factor for normal NK and T memory cells. IL-15 alters expression of Bcl-2 family members, Bcl-2, Bcl-XL, Bim, Noxa, and Mcl-1; however, effects on Bid have not been shown. Using an adoptive transfer model, we show that NK cells from Bid-deficient mice survive longer than cells from wild-type control mice when transferred into IL-15-null mice. In normal human NK cells, IL-15 significantly reduces Bid accumulation. Decreases in Bid are not due to alterations in RNA accumulation but result from increased proteasomal degradation. IL-15 up-regulates the E3 ligase HDM2 and we find that HDM2 directly interacts with Bid. HDM2 suppression by short hairpin RNA increases Bid accumulation lending further support for HDM2 involvement in Bid degradation. In primary leukemic LGLs, Bid levels are low but are reversed with bortezomib treatment with subsequent increases in LGL apoptosis. Overall, these data provide a novel molecular mechanism for IL-15 control of Bid that potentially links this cytokine to leukemogenesis through targeted proteasome degradation of Bid and offers the possibility that proteasome inhibitors may aid in the treatment of LGL leukemia. [Cancer Res 2009;69(9):3986–94]
Prediction of Drug Response in Breast Cancer Using Integrative Experimental/Computational Modeling
Authors: Frieboes Hermann B. , Edgerton Mary E. , Fruehauf John P. , Rose Felicity R.A.J. , Worrall Lisa K. , Gatenby Robert A. , Ferrari Mauro , Cristini Vittorio
Published: April 2009

Nearly 30% of women with early-stage breast cancer develop recurrent disease attributed to resistance to systemic therapy. Prevailing models of chemotherapy failure describe three resistant phenotypes: cells with alterations in transmembrane drug transport, increased detoxification and repair pathways, and alterations leading to failure of apoptosis. Proliferative activity correlates with tumor sensitivity. Cell-cycle status, controlling proliferation, depends on local concentration of oxygen and nutrients. Although physiologic resistance due to diffusion gradients of these substances and drugs is a recognized phenomenon, it has been difficult to quantify its role with any accuracy that can be exploited clinically. We implement a mathematical model of tumor drug response that hypothesizes specific functional relationships linking tumor growth and regression to the underlying phenotype. The model incorporates the effects of local drug, oxygen, and nutrient concentrations within the three-dimensional tumor volume, and includes the experimentally observed resistant phenotypes of individual cells. We conclude that this integrative method, tightly coupling computational modeling with biological data, enhances the value of knowledge gained from current pharmacokinetic measurements, and, further, that such an approach could predict resistance based on specific tumor properties and thus improve treatment outcome. [Cancer Res 2009;69(10):4484–92]

Major Findings By extracting mathematical model parameter values for drug and nutrient delivery from monolayer (one-dimensional) experiments and using the functional relationships to compute drug delivery in MCF-7 spheroid (three-dimensional) experiments, we use the model to quantify the diffusion barrier effect, which alone can result in poor response to chemotherapy both from diminished drug delivery and from lack of nutrients required to maintain proliferative conditions.
PIK3CAandPIK3CBInhibition Produce Synthetic Lethality when Combined with Estrogen Deprivation in Estrogen Receptor–Positive Breast Cancer
Authors: Crowder Robert J. , Phommaly Chanpheng , Tao Yu , Hoog Jeremy , Luo Jingqin , Perou Charles M. , Parker Joel S. , Miller Melinda A. , Huntsman David G. , Lin Li , Snider Jacqueline , Davies Sherri R. , Olson John A. , Watson Mark A. , Saporita Anthony , Weber Jason D. , Ellis Matthew J.
Published: April 2009

Several phosphoinositide 3-kinase (PI3K) catalytic subunit inhibitors are currently in clinical trial. We therefore sought to examine relationships between pharmacologic inhibition and somatic mutations in PI3K catalytic subunits in estrogen receptor (ER)–positive breast cancer, in which these mutations are particularly common. RNA interference (RNAi) was used to determine the effect of selective inhibition of PI3K catalytic subunits, p110α and p110β, in ER+ breast cancer cells harboring either mutation (PIK3CA) or gene amplification (PIK3CB). p110α RNAi inhibited growth and promoted apoptosis in all tested ER+ breast cancer cells under estrogen deprived-conditions, whereas p110β RNAi only affected cells harboring PIK3CB amplification. Moreover, dual p110α/p110β inhibition potentiated these effects. In addition, treatment with the clinical-grade PI3K catalytic subunit inhibitor BEZ235 also promoted apoptosis in ER+ breast cancer cells. Importantly, estradiol suppressed apoptosis induced by both gene knockdowns and BEZ235 treatment. Our results suggest that PI3K inhibitors should target both p110α and p110β catalytic subunits, whether wild-type or mutant, and be combined with endocrine therapy for maximal efficacy when treating ER+ breast cancer. [Cancer Res 2009;69(9):3955–62]
Analysis of Recently Identified Prostate Cancer Susceptibility Loci in a Population-based Study: Associations with Family History and Clinical Features
Authors: FitzGerald Liesel M. , Kwon Erika M. , Koopmeiners Joseph S. , Salinas Claudia A. , Stanford Janet L. , Ostrander Elaine A.
Published: April 2009

Purpose: Two recent genome-wide association studies have highlighted several single nucleotide polymorphisms (SNPs) purported to be associated with prostate cancer risk. We investigated the significance of these SNPs in a population-based study of Caucasian men, testing the effects of each SNP in relation to family history of prostate cancer and the clinicopathologic features of the disease.

Experimental Design: We genotyped 13 SNPs in 1,308 prostate cancer patients and 1,267 unaffected controls frequency matched to cases by five-year age groups. The association of each SNP with disease risk stratified by family history of prostate cancer and clinicopathologic features of the disease was calculated with the use of logistic and polytomous regression.

Results: These results confirm the importance of multiple, previously reported SNPs in relation to prostate cancer susceptibility; 11 of the 13 SNPs were significantly associated with risk of developing prostate cancer. However, none of the SNP associations were of comparable magnitude with that associated with having a first-degree family history of the disease. Risk estimates associated with SNPs rs4242382 and rs2735839 varied by family history, whereas risk estimates for rs10993994 and rs5945619 varied by Gleason score.

Conclusions: Our results confirm that several recently identified SNPs are associated with prostate cancer risk; however, the variant alleles only confer a low to moderate relative risk of disease and are generally not associated with more aggressive disease features.
Dynamic Contrast-Enhanced Magnetic Resonance Imaging Identifies a Subgroup of Patients with Asymptomatic Monoclonal Plasma Cell Disease and Pathologic Microcirculation
Authors: Hillengass Jens , Zechmann Christian , Bäuerle Tobias , Wagner-Gund Barbara , Heiss Christiane , Benner Axel , Ho Anthony , Neben Kai , Hose Dirk , Kauczor Hans-Ulrich , Goldschmidt Hartmut , Delorme Stefan , Moehler Thomas
Published: April 2009

Purpose: The aim of our study was to investigate whether dynamic contrast–enhanced magnetic resonance imaging (DCE-MRI) allows visualization of changes in microcirculation between healthy controls on the one side and early/advanced stages of plasma cell disease on the other.

Experimental Design: We examined a group of 222 individuals consisting of 60 patients with monoclonal gammopathy of undetermined significance (MGUS), 65 patients with asymptomatic multiple myeloma (aMM), 75 patients with newly diagnosed symptomatic MM (sMM), and 22 healthy controls with DCE-MRI of the lumbar spine.

Results: A continuous increase in microcirculation parameters amplitude A and exchange rate constant kep reflecting vascular volume and permeability, respectively, was detected from normal controls over MGUS and aMM to sMM. For A and kep, significant differences were found between controls and aMM (P = 0.03 and P = 0.004, respectively) as well as controls and sMM (P = 0.001 and P < 0.001, respectively). Although diffuse microcirculation patterns were found in healthy controls as well as MGUS and MM, a pattern with focal hotspots was exclusively detected in 42.6% of sMM and in 3 MGUS and 3 aMM patients. MGUS and aMM patients with increased microcirculation patterns showed significantly higher bone marrow plasmocytosis compared with patients with a low microcirculation pattern.

Conclusions: Our investigations substantiate the concept of an angiogenic switch from early plasma cell disorders to sMM. Pathologic DCE-MRI findings correlate with adverse prognostic factors and DCE-MRI identifies a distinct group of patients with increased microcirculation parameters in aMM and MGUS patients.
AMG 479, a fully human anti–insulin-like growth factor receptor type I monoclonal antibody, inhibits the growth and survival of pancreatic carcinoma cells
Authors: Beltran Pedro J. , Mitchell Petia , Chung Young-A , Cajulis Elaina , Lu John , Belmontes Brian , Ho Joanne , Tsai Mei Mei , Zhu Min , Vonderfecht Steven , Baserga Renato , Kendall Richard , Radinsky Robert , Calzone Frank J.
Published: April 2009

Pancreatic carcinoma is a leading cause of cancer deaths, and recent clinical trials of a number of oncology therapeutics have not substantially improved clinical outcomes. We have evaluated the therapeutic potential of AMG 479, a fully human monoclonal antibody against insulin-like growth factor (IGF) type I receptor (IGF-IR), in two IGF-IR–expressing pancreatic carcinoma cell lines, BxPC-3 and MiaPaCa2, which also differentially express insulin receptor (INSR). AMG 479 bound to IGF-IR (KD 0.33 nmol/L) and blocked IGF-I and IGF-II binding (IC50 < 0.6 nmol/L) without cross-reacting to INSR. AMG 479 completely inhibited ligand-induced (IGF-I, IGF-II, and insulin) activation of IGF-IR homodimers and IGF-IR/INSR hybrids (but not INSR homodimers) leading to reduced cellular viability in serum-deprived cultures. AMG 479 inhibited >80% of basal IGF-IR activity in BxPC-3 and MiaPaCa2 xenografts and prevented IGF-IR and IGF-IR/INSR hybrid activation following challenge with supraphysiologic concentrations of IGF-I. As a single agent, AMG 479 inhibited (∼80%) the growth of pancreatic carcinoma xenografts, and long-term treatment was associated with reduced IGF-IR signaling activity and expression. Efficacy seemed to be the result of two distinct biological effects: proapoptotic in BxPC-3 and antimitogenic in MiaPaCa2. The combination of AMG 479 with gemcitabine resulted in additive inhibitory activity both in vitro and in vivo. These results indicate that AMG 479 is a clinical candidate, both as a single agent and in combination with gemcitabine, for the treatment of patients with pancreatic carcinoma.[Mol Cancer Ther 2009;8(5):1095–105]
Predictors of Heart Failure in Patients With Stable Coronary Artery Disease
Authors: Lewis Eldrin F. , Solomon Scott D. , Jablonski Kathleen A. , Rice Madeline Murguia , Clemenza Francesco , Hsia Judith , Maggioni Aldo P. , Zabalgoitia Miguel , Huynh Thao , Cuddy Thomas E. , Gersh Bernard J. , Rouleau Jean , Braunwald Eugene , Pfeffer Marc A.
Published: April 2009

Background—

Heart failure (HF) is a disease commonly associated with coronary artery disease. Most risk models for HF development have focused on patients with acute myocardial infarction. The Prevention of Events with Angiotensin-Converting Enzyme Inhibition population enabled the development of a risk model to predict HF in patients with stable coronary artery disease and preserved ejection fraction.

Methods and Results—

In the 8290, Prevention of Events with Angiotensin-Converting Enzyme Inhibition patients without preexisting HF, new-onset HF hospitalizations, and fatal HF were assessed over a median follow-up of 4.8 years. Covariates were evaluated and maintained in the Cox regression multivariable model using backward selection if
P
<0.05. A risk score was developed and converted to an integer-based scoring system. Among the Prevention of Events with Angiotensin-Converting Enzyme Inhibition population (age, 64�8; female, 18%; prior myocardial infarction, 55%), there were 268 cases of fatal and nonfatal HF. Twelve characteristics were associated with increased risk of HF along with several baseline medications, including older age, history of hypertension, and diabetes. Randomization to trandolapril independently reduced the risk of HF. There was no interaction between trandolapril treatment and other risk factors for HF. The risk score (range, 0 to 21) demonstrated excellent discriminatory power (c-statistic 0.80). Risk of HF ranged from 1.75% in patients with a risk score of 0% to 33% in patients with risk score ≥16.

Conclusion—

Among patients with stable coronary artery disease and preserved ejection fraction, traditional and newer factors were independently associated with increased risk of HF. Trandolopril decreased the risk of HF in these patients with preserved ejection fraction.