bluuebunny/crossref_metadata_2025 huggingface dataset:
JIT compilation policy for modern machines
Authors: Kulkarni Prasad A.
Published: December 2011

Dynamic or Just-in-Time (JIT) compilation is crucial to achieve acceptable performance for applications (written in managed languages, such as Java and C#) distributed as intermediate language binary codes for a virtual machine (VM) architecture. Since it occurs at runtime, JIT compilation needs to carefully tune its compilation policy to make effective decisions regarding 'if' and 'when' to compile different program regions to achieve the best overall program performance. Past research has extensively tuned JIT compilation policies, but mainly for VMs with a single compiler thread and for execution on single-processor machines.

This work is driven by the need to explore the most effective JIT compilation strategies in their modern operational environment, where (a) processors have evolved from single to multi/many cores, and (b) VMs provide support for multiple concurrent compiler threads. Our results confirm that changing 'if' and 'when' methods are compiled have significant performance impacts. We construct several novel configurations in the HotSpot JVM to facilitate this study. The new configurations are necessitated by modern Java benchmarks that impede traditional static whole-program discovery, analysis and annotation, and are required for simulating future many-core hardware that is not yet widely available. We study the effects on performance of increasing compiler aggressiveness for VMs with multiple compiler threads running on existing single/multi-core and future many-core machines. Our results indicate that although more aggressive JIT compilation policies show no benefits on single-core machines, these can often improve program performance for multi/many-core machines. However, accurately prioritizing JIT method compilations is crucial to realize such benefits.
Reducing trace selection footprint for large-scale Java applications without performance loss
Authors: Wu Peng , Hayashizaki Hiroshige , Inoue Hiroshi , Nakatani Toshio
Published: December 2011

When optimizing large-scale applications, striking the balance between steady-state performance, start-up time, and code size has always been a grand challenge. While recent advances in trace compilation have significantly improved the steady-state performance of trace JITs for large-scale Java applications, the size control aspect of a trace compilation system remains largely overlooked. For instance, using the DaCapo 9.12 benchmarks, we observe that 40% of traces selected by a state-of-the-art trace selection algorithm are short-lived and, on average, each selected basic block is replicated 13 times in the trace cache.

This paper studies the size control problem for a class of commonly used trace selection algorithms and proposes six techniques to reduce the footprint of trace selection without incurring any performance loss. The crux of our approach is to target redundancies in trace selection in the form of either short-lived traces or unnecessary trace duplication.

Using one of the best performing selection algorithms as the baseline, we demonstrate that, on the DaCapo 9.12 benchmarks and DayTrader 2.0 on WebSphere Application Server 7.0, our techniques reduce the code size and compilation time by 69% and the start-up time by 43% while retaining the steady-state performance. On DayTrader 2.0, an example of large-scale application, our techniques also improve the steady-state performance by 10%.
Safe and atomic run-time code evolution for Java and its application to dynamic AOP
Authors: Würthinger Thomas , Ansaloni Danilo , Binder Walter , Wimmer Christian , Mössenböck Hanspeter
Published: December 2011

Dynamic updates to running programs improve development productivity and reduce downtime of long-running applications. This feature is however severely limited in current virtual machines for object-oriented languages. In particular, changes to classes often apply only to methods invoked after a class change, but not to active methods on the call stack of threads. Additionally, adding and removing methods as well as fields is often not supported.

We present a novel programming model for safe and atomic code updates of Java programs that also updates methods that are currently executed. We introduce safe update regions and pause threads only there before an update. We automatically convert the stack frames to suit the new versions of the methods. Our implementation is based on a production-quality Java virtual machine.

Additionally, we present SafeWeave, a dynamic aspect-oriented programming system that exposes the atomic code updates through a high-level programming model. AspectJ advice can be added to and removed from a running application.Changes are atomic and correctness is guaranteed even though weaving happens in parallel to program execution, and the system fully supports the dynamic class loading of Java. We show that the enhanced evolution features do not incur any performance penalty before and after version changes.
Backstage Java
Authors: Palmer Zachary , Smith Scott F.
Published: December 2011

We propose Backstage Java (BSJ), a Java language extension which allows algorithmic, contextually-aware generation and transformation of code. BSJ explicitly and concisely represents design patterns and other encodings by employing compile-time metaprogramming: a practice in which the programmer writes instructions which are executed over the program's AST during compilation. While compile-time metaprogramming has been successfully used in functional languages such as Template Haskell, a number of language properties (scope, syntactic structure, mutation, etc.) have thus far prevented this theory from translating to the imperative world. BSJ uses the novel approach of difference-based metaprogramming to provide an imperative programming style amenable to the Java community and to enforce that metaprograms are consistent and semantically unambiguous. To make the feasibility of BSJ metaprogramming evident, we have developed a compiler implementation and numerous working code examples.
Type checking modular multiple dispatch with parametric polymorphism and multiple inheritance
Authors: Allen Eric , Hilburn Justin , Kilpatrick Scott , Luchangco Victor , Ryu Sukyoung , Chase David , Steele Guy
Published: December 2011

In previous work, we presented rules for defining overloaded functions that ensure type safety under symmetric multiple dispatch in an object-oriented language with multiple inheritance, and we showed how to check these rules without requiring the entire type hierarchy to be known, thus supporting modularity and extensibility. In this work, we extend these rules to a language that supports parametric polymorphism on both classes and functions.

In a multiple-inheritance language in which any type may be extended by types in other modules, some overloaded functions that might seem valid are correctly rejected by our rules. We explain how these functions can be permitted in a language that additionally supports an exclusion relation among types, allowing programmers to declare "nominal exclusions" and also implicitly imposing exclusion among different instances of each polymorphic type. We give rules for computing the exclusion relation, deriving many type exclusions from declared and implicit ones.

We also show how to check our rules for ensuring the safety of overloaded functions. In particular, we reduce the problem of handling parametric polymorphism to one of determining subtyping relationships among universal and existential types. Our system has been implemented as part of the open-source Fortress compiler.
Iterative data-parallel mark&sweep on a GPU
Authors: Veldema Ronald , Philippsen Michæl
Published: December 2011

Automatic memory management makes programming easier. This is also true for general purpose GPU computing where currently no garbage collectors exist. In this paper we present a parallel mark-and-sweep collector to collect GPU memory on the GPU and tune its performance. Performance is increased by: (1) data-parallel marking and sweeping of regions of memory, (2) marking all elements of large arrays in parallel, (3) trading recursion over parallelism to match deeply linked data structures.

(1) is achieved by coarsely processing all potential objects in a region of memory in parallel. When during (1) a large array is detected, it is put aside and a parallel-for is later issued on the GPU to mark its elements. For a data-structure that is a large linked list, we dynamically switch to a marking version with less overhead by performing a few recursive steps sequentially (and multiple lists in parallel).

The collector achieves a speedup of a factor of up-to 11 over a sequential collector on the same GPU.
Waste not, want not
Authors: Hertz Matthew , Kane Stephen , Keudel Elizabeth , Bai Tongxin , Ding Chen , Gu Xiaoming , Bard Jonathan E.
Published: December 2011

To achieve optimal performance, garbage-collected applications must balance the sizes of their heaps dynamically. Sizing the heap too small can reduce throughput by increasing the number of garbage collections that must be performed. Too large a heap, however, can cause the system to page and drag down the overall throughput. In today's multicore, multiprocessor machines, multiple garbage-collected applications may run simultaneously. As a result, each virtual machine (VM) must adjust its memory demands to reflect not only the behavior of the application it is running, but also the behavior of the peer applications running on the system.

We present a memory management system that enables VMs to react to memory demands dynamically. Our approach allows the applications' heaps to remain small enough to avoid the negative impacts of paging, while still taking advantage of any memory that is available within the system. This memory manager, which we call
Poor Richard's Memory Manager
, focuses on optimizing overall system performance by allowing applications to share data and make system-wide decisions. We describe the design of our memory management system, show how it can be added to existing VMs with little effort, and document that it has almost no impact on performance when memory is plentiful. Using both homogenous and heterogenous Java workloads, we then show that Poor Richard's memory manager improves average performance by up to a factor 5.5 when the system is paging. We further show that this result is not specific to any garbage collection algorithm, but that this improvement is observed for every garbage collector on which we test it. We finally demonstrate the versatility of our memory manager by using it to improve the performance of a conservative whole-heap garbage collector used in executing .Net applications.
C4
Authors: Tene Gil , Iyengar Balaji , Wolf Michael
Published: December 2011

C4, the Continuously Concurrent Compacting Collector, an updated generational form of the Pauseless GC Algorithm [7], is introduced and described, along with details of its implementation on modern X86 hardware. It uses a read barrier to support concur- rent compaction, concurrent remapping, and concurrent incremental update tracing. C4 differentiates itself from other generational garbage collectors by supporting simultaneous-generational concurrency: the different generations are collected using concurrent (non stop-the-world) mechanisms that can be simultaneously and independently active. C4 is able to continuously perform concurrent young generation collections, even during long periods of concurrent full heap collection, allowing C4 to sustain high allocation rates and maintain the efficiency typical to generational collectors, without sacrificing response times or reverting to stop-the-world operation. Azul systems has been shipping a commercial implementation of the Pauseless GC mechanism, since 2005. Three successive generations of Azul's Vega series systems relied on custom multi-core processors and a custom OS kernel to deliver both the scale and features needed to support Pauseless GC. In 2010, Azul released its first software-only commercial implementation of C4 for modern commodity X86 hardware, using Linux kernel enhancements to support the required feature set. We discuss implementa- tion details of C4 on X86, including the Linux virtual and physical memory management enhancements that were used to support the high rate of virtual memory operations required for sustained pauseless operation. We discuss updates to the collector's manage- ment of the heap for efficient generational collection and provide throughput and pause time data while running sustained workloads.
Integrated symbol table, engine and heap memory management in multi-engine prolog
Authors: Tarau Paul
Published: December 2011

We describe an integrated solution to symbol, heap and logic engine memory management in a context where exchanges of arbitrary Prolog terms occur between multiple dynamically created engines, implemented in a new Java-based experimental Prolog system.

As our symbols represent not just Prolog atoms, but also handles to Java objects (including arbitrary size integers and decimals), everything is centered around a symbol garbage collection algorithm ensuring that external objects are shared and exchanged between logic engines efficiently.

Taking advantage of a
tag-on-data
heap representation of Prolog terms, our algorithm performs in-place updates of live symbol references directly on heap cells.

With appropriate fine tuning of collection policies our algorithm provides an integrated memory management solution for Prolog systems, with amortized cost dominated by normally occurring heap garbage collection costs.
Conservative Management of Paediatric Clavicle Fractures
Authors: O'Neill Barry J. , Molloy Alan P. , Curtin William
Published: December 2011

Paediatric clavicle fractures have traditionally been treated nonoperatively. Recent studies have recommended operative management for displaced midshaft fractures. We conducted a retrospective review of all clavicle fractures in children aged one to sixteen over a two-year period. We classified fractures and evaluated followup and clinical outcome. We identified 190 fractures. There were 135 boys and 55 girls. 65% of fractures were displaced and 35% undisplaced. Mean radiographic and clinical followup was 35 days and 44 days, respectively. Clavicle fractures in children heal with nonoperative management. Radiographs of clavicle fractures in children are unnecessary in the absence of clinical symptoms.
Analysis of Intergranular Precipitation in Isothermally Aged Nitrogen-Containing Austenitic Stainless Steels by an Electrochemical Method and Its Relation to Cryogenic Toughness
Authors: Saucedo-Muñoz Maribel L. , Lopez-Hirata Victor M. , Dorantes-Rosales Hector J. , Avila-Davila Erika O.
Published: December 2011

The precipitation process in two N-containing austenitic stainless steels, aged at temperatures between 873 and 1173 K for times from 10 to 1000 min, was analyzed by an electrochemical method based on the anodic polarization test with an electrolyte of 1 N KOH solution. The anodic polarization curves showed the following intergranular precipitation sequence: austenite austenite + Cr23C6austenite + Cr23C6 + Cr2N. Besides, the fastest precipitation kinetics was detected in the aged steel with the highest content of nitrogen and carbon due to its higher driving force for precipitation. The higher the aging temperature, the higher volume fraction of precipitates. The precipitation fraction can be associated with the current density of the dissolution peaks of each phase. The Charpy-V-Notch impact energy of the aged specimens decreased with the increase in the volume fraction of precipitates.
Semidigital PLL Design for Low-Cost Low-Power Clock Generation
Authors: Xu Ni , Rhee Woogeun , Wang Zhihua
Published: December 2011

This paper describes recent semidigital architectures of the phase-locked loop (PLL) systems for low-cost low-power clock generation. With the absence of the time-to-digital converter (TDC), the semi-digital PLL (SDPLL) enables low-power linear phase detection and does not necessarily require advanced CMOS technology while maintaining a technology scalability feature. Two design examples in 0.18 μm CMOS and 65 nm CMOS are presented with hardware and simulation results, respectively.
Interferon Lambda: A New Sword in Cancer Immunotherapy
Authors: Lasfar Ahmed , Abushahba Walid , Balan Murugabaskar , Cohen-Solal Karine A.
Published: December 2011

The discovery of the interferon-lambda (IFN-λ) family has considerably contributed to our understanding of the role of interferon not only in viral infections but also in cancer. IFN-λproteins belong to the new type III IFN group. Type III IFN is structurally similar to type II IFN (IFN-γ) but functionally identical to type I IFN (IFN-α/β). However, in contrast to type I or type II IFNs, the response to type III IFN is highly cell-type specific. Only epithelial-like cells and to a lesser extent some immune cells respond to IFN-λ. This particular pattern of response is controlled by the differential expression of the IFN-λreceptor, which, in contrast to IFN-α, should result in limited side effects in patients. Recently, we and other groups have shown in several animal models a potent antitumor role of IFN-λthat will open a new challenging era for the current IFN therapy.
Stability and Superstability of Generalized (θ, ϕ)‐Derivations in Non‐Archimedean Algebras: Fixed Point Theorem via the Additive Cauchy Functional Equation
Authors: Gordji M. Eshaghi , Ghaemi M. B. , Kim G. H. , Alizadeh Badrkhan
Published: December 2011

Let A be an algebra, and let θ, ϕ be ring automorphisms of A. An additive
mapping H : A → A is called a (θ, ϕ)‐derivation if H(xy) = H(x)θ(y) + ϕ(x)H(y) for all x, y ∈ A. Moreover, an additive mapping F : A → A is said to be a generalized (θ, ϕ)‐derivation if there exists a (θ, ϕ)‐derivation H : A → A such that F(xy) = F(x)θ(y) + ϕ(x)H(y) for all x, y ∈ A. In this paper, we investigate the superstability of generalized (θ, ϕ)‐derivations in non‐Archimedean algebras by using a version of fixed point theorem via Cauchy’s functional equation.
Generalized Hyers‐Ulam Stability of the Second‐Order Linear Differential Equations
Authors: Javadian A. , Sorouri E. , Kim G. H. , Gordji M. Eshaghi
Published: December 2011

We prove the generalized Hyers‐Ulam stability of the 2nd‐order linear differential
equation of the form y′′ + p(x)y′ + q(x)y = f(x), with condition that there exists a nonzero y1 : I → X in C2(I) such that and I is an open
interval. As a consequence of our main theorem, we prove the generalized Hyers‐Ulam
stability of several important well‐known differential equations.
Primary Biliary Cirrhosis Associated with Systemic Sclerosis: Diagnostic and Clinical Challenges
Authors: Rigamonti Cristina , Bogdanos Dimitrios P. , Mytilinaiou Maria G. , Smyk Daniel S. , Rigopoulou Eirini I. , Burroughs Andrew K.
Published: December 2011

Patients with primary biliary cirrhosis (PBC) often have concurrent limited systemic sclerosis (SSc). Conversely, up to one-fourth of SSc patients are positive for PBC-specific antimitochondrial antibodies (AMA). The mechanisms responsible for the co-occurrence of these diseases are largely unknown. Genetic, epigenetic, environmental, and infectious factors appear to be important for the pathogenesis of the disease, but the hierarchy of events are not well defined. Patients with SSc and PBC have an increased morbidity and mortality compared with the general population, but whether the presence of both diseases in an affected individual worsens the prognosis and/or outcome of either disease is not clear. Some case reports suggested that the presence of SSc in PBC patents is associated with a more favorable prognosis of the liver disease, whereas others report an increased mortality in patients with PBC and SSc compared to patients with PBC alone. This paper discusses the features of patients with PBC-associated SSc. Our aims are to clarify some of the pathogenetic, diagnostic, and clinical challenges that are currently faced in the routine management of these patients. We also intend to provide some practical hints for practitioners that will assist in the early identification of patients with PBC-associated SSc.
Temperature-Driven Models for Insect Development and Vital Thermal Requirements
Authors: Damos Petros , Savopoulou-Soultani Matilda
Published: December 2011

Since 1730 when Reaumut introduced the concept of heat units, many methods of calculating thermal physiological time heat have been used to simulate the phenology of poikilothermic organisms in biological and agricultural sciences. Most of these models are grounded on the concept of the “law of total effective temperatures”, which abstracts the temperature responses of a particular species, in which a specific amount of thermal units should be accumulated above a temperature threshold, to complete a certain developmental event. However, the above temperature summation rule is valid within the species-specific temperature range of development and therefore several empirical linear and nonlinear regression models, including the derivation of the biophysical models as well, have been proposed to define these critical temperatures for development. Additionally, several statistical measures based on ordinary least squares instead of likelihoods, have been also proposed for parameter estimation and model comparison. Given the importance of predicting distribution of insects, for insect ecology and pest management, this article reviews representative temperature-driven models, heat accumulation systems and statistical model evaluation criteria, in an attempt to describe continuous and progressive improvement of the physiological time concept in current entomological science and to infer the ecological consequences for insect spatiotemporal arrangements.
Signaling Required for Blood Vessel Maintenance: Molecular Basis and Pathological Manifestations
Authors: Murakami Masahiro
Published: December 2011

As our understanding of molecular mechanisms leading to vascular formation increases, vessel maintenance including stabilization of new vessels and prevention of vessel regression began to be considered as an active process that requires specific cellular signaling. While signaling pathways such as VEGF, FGF, and angiopoietin-Tie2 are important for endothelial cell survival and junction stabilization, PDGF and TGF-βsignaling modify mural cell (vascular smooth muscle cells and pericytes) functions, thus they fortify vessel integrity. Breakdown of these signaling systems results in pathological hyperpermeability and/or genetic vascular abnormalities such as vascular malformations, ultimately progressing to hemorrhage and edema. Hence, blood vessel maintenance is fundamental to controlling vascular homeostasis and tissue functions. This paper discusses signaling pathways essential for vascular maintenance and clinical conditions caused by deterioration of vessel integrity.
The Evolution of Endothelial Regulatory Paradigms in Cancer Biology and Vascular Repair
Authors: Franses Joseph W. , Edelman Elazer R.
Published: December 2011

Although the roles of endothelial cells in cancer have primarily been considered to be related to tumor perfusion, the emerging appreciation of “angiocrine” regulation adds stromal regulatory capabilities to the expanding list of endothelial functions in tumors. We posit that an understanding of the state-dependent paracrine regulatory paradigms established in vascular disease and repair will be critical for a deep understanding of tumor biology, as endothelial cells regulate diverse processes in all vascularized tissues. Here, we outline the historical developments that led to the appreciation of the paracrine regulatory functions of endothelial cells, summarize classical views of blood vessels and stroma in cancer, and attempt to merge these ideas to include the stromal regulatory endothelial cell as a critical regulator of cancer. The notion of the endothelial cell as a biochemical regulator of cancer state in constant dynamic balance with its tumor could impact diagnosis, prognosis, and treatment of cancer. Such concepts might well explain the mixed results from antiangiogenic cancer therapeutics and how certain drugs that improve vascular health correlate with improved cancer prognosis. Cancer Res; 71(24); 7339–44. ©2011 AACR.
Tumor Infiltration by T Lymphocytes Expressing Chemokine Receptor 7 (CCR7) Is Predictive of Favorable Outcome in Patients with Advanced Colorectal Carcinoma
Authors: Correale Pierpaolo , Rotundo Maria Saveria , Botta Cirino , Del Vecchio Maria Teresa , Ginanneschi Chiara , Licchetta Antonella , Conca Raffaele , Apollinari Serena , De Luca Fabio , Tassone Pierfrancesco , Tagliaferri Pierosandro
Published: December 2011

Purpose: An efficient adaptive immunity is critical for a longer survival in cancer. We investigated the prognostic value of tumor infiltration by CD8+ T cells expressing the chemokine-receptor-7 (Tccr7) and the correlation between tumor infiltration by Tccr7 and regulatory CD4+FoxP3+ T cells (Treg) in 76 metastatic colorectal cancer (mCRC) patients enrolled in a phase III trial.

Experimental Design: Tccr7 and Treg cell infiltration in tumor samples was quantified by immunohistochemistry. The correlation among Tccr7, Treg tumor infiltration, and patients' outcome was evaluated.

Results: High Tccr7 tumor infiltration was predictive of prolonged OS [high vs. low Tccr7 score: median 38 months (95% CI: 24.5–51.4) vs. 20 months (95% CI: 11.4–28.5); HR = 0.48 (95% CI: 0.24–0.96); P = 0.03] and prolonged progression-free survival [PFS; high vs. low Tccr7 score: median 12 months (95% CI: 7.7–16.2) vs. 7 months (95% CI: 5.2–8.7); HR = 0.54 (95% CI: 0.28–1.01); P = 0.01] after front-line chemotherapy. Regression analysis did not show correlation between Tccr7 and Treg infiltration levels. However, the cluster of patients showing concomitant high infiltration by both Tccr7 and Treg disclosed a favorable outcome [double high vs. double low tumor infiltration score: median OS = 35 months (95% CI: 20.8–49.1) vs. 17 months (95% CI: 4.6–29.3); HR = 0.32 (95% CI: 0.12–0.87); P = 0.02 and median PFS = 11 months (95% CI: 9.4–12.5) vs. 5 months (95% CI: 2.2–7.7); HR = 0.43 (95% CI: 0.17–1.06); P = 0.01].

Conclusions: High Tccr7 tumor infiltration score is a favorable prognostic factor for mCRC. Our findings underline the relevance of microenvironment-related immunologic events for patient outcome. Clin Cancer Res; 18(3); 850–7. ©2011 AACR.
Targeting the mTOR/4E-BP Pathway in Endometrial Cancer
Authors: Korets Sharmilee Bansal , Czok Sarah , Blank Stephanie V. , Curtin John P. , Schneider Robert J.
Published: December 2011

Endometrial cancer is the most common gynecologic malignancy. Although it is highly treatable in the early stages of disease, therapies for advanced and recurrent disease are rarely curative. A molecular and genetic understanding of endometrial cancer involves the mTOR signaling pathway, an emerging target for treatment of type I disease (the most common presentation). Endometrial cancers show a significant reliance on the mTOR pathway for survival, and studies to date have revealed a clinical advantage in targeting this pathway. Less well developed in the study of endometrial cancer is an understanding of mTOR signaling to its major downstream effector, translational control. Given the poor rate of success for treatment of late-stage endometrial cancer, increasing attention is being directed to the development of new therapeutic approaches, including targeting the mTOR pathway. Here, we discuss the potential benefit of targeting mTOR combined with existing chemotherapies by monitoring its impact on translational regulatory pathways and key translation targets in endometrial cancer. We also highlight laboratory and clinical research findings that will provide new avenues for future research and clinical development. Clin Cancer Res; 17(24); 7518–28. ©2011 AACR.
MEK1/2 Inhibitor Selumetinib (AZD6244) Inhibits Growth of Ovarian Clear Cell Carcinoma in a PEA-15–Dependent Manner in a Mouse Xenograft Model
Authors: Bartholomeusz Chandra , Oishi Tetsuro , Saso Hitomi , Akar Ugur , Liu Ping , Kondo Kimie , Kazansky Anna , Krishnamurthy Savitri , Lee Jangsoon , Esteva Francisco J. , Kigawa Junzo , Ueno Naoto T.
Published: December 2011

Clear cell carcinoma (CCC) of the ovary tends to show resistance to standard chemotherapy, which results in poor survival for patients with CCC. Developing a novel therapeutic strategy is imperative to improve patient prognosis. Epidermal growth factor receptor (EGFR) is frequently expressed in epithelial ovarian cancer. One of the major downstream targets of the EGFR signaling cascade is extracellular signal–related kinase (ERK). PEA-15, a 15-kDa phosphoprotein, can sequester ERK in the cytoplasm. MEK1/2 plays a central role in integrating mitogenic signals into the ERK pathway. We tested the hypothesis that inhibition of the EGFR–ERK pathway suppresses tumorigenicity in CCC, and we investigated the role of PEA-15 in ERK-targeted therapy in CCC. We screened a panel of 4 CCC cell lines (RMG-I, SMOV-2, OVTOKO, and KOC-7c) and observed that the EGFR tyrosine kinase inhibitor erlotinib inhibited cell proliferation of EGFR-overexpressing CCC cell lines through partial dependence on the MEK/ERK pathway. Furthermore, erlotinib-sensitive cell lines were also sensitive to the MEK inhibitor selumetinib (AZD6244), which is under clinical development. Knockdown of PEA-15 expression resulted in reversal of selumetinib-sensitive cells to resistant cells, implying that PEA-15 contributes to selumetinib sensitivity. Both selumetinib and erlotinib significantly suppressed tumor growth (P < 0.0001) in a CCC xenograft model. However, selumetinib was better tolerated; erlotinib-treated mice exhibited significant toxic effects (marked weight loss and severe skin peeling) at high doses. Our findings indicate that the MEK–ERK pathway is a potential target for EGFR-overexpressing CCC and indicate that selumetinib and erlotinib are worth exploring as therapeutic agents for CCC. Mol Cancer Ther; 11(2); 360–9. ©2011 AACR.
Cancer Risks for the Relatives of Colorectal Cancer Cases with a Methylated MLH1 Promoter Region: Data from the Colorectal Cancer Family Registry
Authors: Levine A. Joan , Win Aung Ko , Buchanan Daniel D. , Jenkins Mark A. , Baron John A. , Young Joanne P. , Long Tiffany I. , Weisenberger Daniel J. , Laird Peter W. , McCall Rebecca L. , Duggan David J. , Haile Robert W.
Published: December 2011

Methylation of the MLH1 gene promoter region is an underlying cause of colorectal cancer (CRC) with high microsatellite instability (MSI-H) diagnosed in persons without a germ line mutation in a mismatch repair (MMR) gene (non–Lynch Syndrome CRC). It is unclear whether relatives of CRC cases with MLH1 methylation have an increased risk of colorectal or other cancers. In this retrospective cohort study, we assessed risk of CRC and other cancers for the first- and second-degree relatives of CRC cases with a methylated MLH1 gene, by comparing observed numbers of cases with those expected on the basis of age-, sex-, and country-specific cancer incidences (standardized incidence ratios). The cohort consisted of 3,128 first- and second-degree relatives of the 233 MLH1-methylated CRC cases with no MMR or MUTYH gene mutations. The standardized incidence ratio (SIR) for CRC was 1.60 [95% confidence interval (CI), 1.22–2.16] for first-degree relatives and 1.08 (0.74–1.60) for second-degree relatives. The SIR for gastric cancer was 2.58 (1.52–4.71) for first-degree relatives and 4.52 (2.23–10.61) for second-degree relatives and, for ovarian cancer, it was 2.16 (1.29–3.86) for first-degree relatives. The risk of liver cancer was also increased significantly in first-degree relatives but the estimate was on the basis of only two cases. These data imply that relatives of CRC cases with MLH1 methylation may be at increased risk of CRC and stomach cancer and possibly ovarian and liver cancer, suggesting that there may be a heritable factor for CRC and other cancers associated with MLH1 methylation in non–Lynch syndrome CRCs. Cancer Prev Res; 5(2); 328–35. ©2011 AACR.
Developmental Profiles and Thyroid Hormone Regulation of Brain Transcripts in Frogs: A Species Comparison with Emphasis on Physalaemus pustulosus
Authors: Duarte-Guterman Paula , Ryan Michael J. , Hogan Natacha S. , Trudeau Vance L.
Published: December 2011

In amphibians, thyroid hormones (THs) are considered key regulators of brain remodeling during metamorphosis, while sex steroids (estrogens and androgens) control sexual differentiation and gonadal development. However, these two endocrine axes can interact during tadpole brain development. Previously, we demonstrated that THs affect sex steroid-related gene expression in the developing brain of Silurana tropicalis and Rana pipiens; however, the gene expression changes differed between species. We chose to study a third anuran species, Physalaemuspustulosus, to test new hypotheses about the role of THs in the regulation of brain gene expression. We first established developmental transcript profiles of TH- and sex steroid-related genes in the brain of P. pustulosus. Then, following the same protocols as in our previous studies, we investigated triiodothyronine (T3) regulation of brain transcripts in premetamorphic P.pustulosus and then compared the results with our previous two studies. In the case of TH-related genes, TH receptor beta (trbeta) and deiodinase type 3 (dio3), mRNA developmental profiles were similar in the three species and with respect to other species in the published literature. However, the profiles of TH receptor alpha (tralpha) and deiodinase type 2 (dio2) mRNA revealed differences between anuran species. Among the three anurans we have studied, the direction of the T3 regulation of TH-related genes was overall similar, but the magnitude of gene expression change differed depending on the rate of metamorphosis in a given species. For the sex steroid-related genes, each species exhibited similar developmental profiles but differed in their response to T3. In P. pustulosus, T3 reduced the expression of aromatase (cyp19) while increasing mRNA levels of androgen and estrogen receptors. These results are similar to previous research in R. pipiens but differ from data for S. tropicalis, for which we found an increase in androgen synthesis enzymes but no effect on cyp19. Together, we propose that T3 has the potential to induce the brain androgen system in anurans. This could be achieved by increasing androgen synthesis enzymes (S. tropicalis) or by decreasing estrogen synthesis (due to a decrease in cyp19 in P. pustulosus and R. pipiens). In conclusion, we demonstrated that mechanisms of hormone interactions differ between anuran species, but in all cases T3 appears to affect the balance of sex steroids in the brain, stimulating the androgen system. We have shown that the regulation of sex steroid-related genes by T3 is more similar among closely related species than species with similar reproductive and developmental characteristics.
The Retinal Wholemount Technique: A Window to Understanding the Brain and Behaviour
Authors: Ullmann Jeremy F.P. , Moore Bret A. , Temple Shelby E. , Fernández-Juricic Esteban , Collin Shaun P.
Published: December 2011

The accessibility of the vertebrate retina has provided the opportunity to assess various parameters of the visual abilities of a range of species. This thin but complex extension of the brain achieves a large proportion of the necessary visual processing of an optical image before information is delivered to the brain as neural impulses. Studies of the retina as a wholemount or a flattened sheet of neural tissue are abundant due to the large amount of information that can be analysed, as follows: the level of summation or convergence; the coverage, stratification and potential sites of synaptic connections; the spatial resolving power; the arrangement of neuronal arrays or mosaics; electrophysiological access for the recording of responses to visual stimuli; the spatial arrangement of cell dendritic fields; location of retinal ‘blind spots’ (optic nerve, falciform process and pecten); topographic differences in retinal cell sampling; spectral filters, and reflective structures. The present study examines all aspects of the wholemount technique, including enucleation, fixation, retinal extraction, flattening, staining, visualization of labelled cells and stereological mapping of cell density. Uniquely, it highlights the crucial technical and often species-specific differences encountered when examining a range of vertebrate taxa (fishes, reptiles, birds and mammals). This broad comparative approach will enable future studies to overcome technical difficulties, thus permitting larger conceptual questions to be posed regarding the diversity of visual tasks across phylogenetic boundaries.
Comparable Analysis of Outcomes for Allogeneic Peripheral Blood Stem Cell Transplantation from Matched Related and Matched Unrelated Donors in Acute Myeloid Leukemia
Authors: Lee Soo Jung , Kang Byung Woog , Moon Joon Ho , Chae Yee Soo , Kim Jong Gwang , Jung Joo Seop , Cho Goon-Jae , Jo Deog-Yeon , Kim Yeo Kyeoung , Kim Hyeoung Joon , Ryoo Hun-Mo , Eom Hyeon Seok , Le Sang Min , Joo Young-Don , Won Jong-Ho , Park Moo Rim , Kim Min Kyung , Hyun Myung Soo , Sohn Sang-Kyun
Published: December 2011

This study compared the results of allogeneic peripheral blood stem cell transplantation (PBSCT) from unrelated and related donors in 142 consecutive patients with acute myeloid leukemia (AML). The cumulative incidence of acute graft-versus-host disease (GVHD) was 37.6% in the related PBSCT group and 53.7% in the unrelated PBSCT group. The cumulative incidence of extensive chronic GVHD was also higher in the unrelated PBSCT group (19.5%) than in the related PBSCT group (8.9%). The overall survival rate at 4 years was 62.4 ± 5.4 and 53.8 ± 1.2% (p = 0.535) in the related and unrelated PBSCT group, respectively. In a multivariate analysis, unrelated PBSCT was identified as a risk factor for the development of extensive chronic GVHD (hazard ratio = 3.019, p = 0.027). Unfavorable cytogenetics and the disease status at the time of transplantation were found to be related to overall survival. In the case of high-risk AML, the survival rate and relapse incidence were significantly better in the matched unrelated PBSCT group (p = 0.047 and 0.039, respectively). In conclusion, the allogeneic PBSCT outcomes for AML were comparable in the matched related and matched unrelated groups. Nonetheless, for high-risk AML patients, matched unrelated PBSCT was found to be preferable to matched related PBSCT.
The Brainstem Is at High Risk for Recurrent Noncardioembolic Cerebral Infarction in Association with Diabetes Mellitus: A Hospital-Based Study
Authors: Ichikawa Hiroo , Shimizu Yuuki , Kuriki Ayako , Murakami Hidetomo , Mukai Masanori , Kawamura Mitsuru
Published: December 2011

The goals of the study were to investigate the importance of brainstem infarction (BSI) in recurrent noncardioembolic ischemic stroke and to examine the relevant clinical background. Data were retrospectively reviewed for 655 consecutive patients with acute noncardioembolic infarction who were admitted to our hospital from January 2004 to August 2010. The patients were divided into first-stroke (n = 592) and recurrent-stroke (n = 63) groups. Acute infarcted lesions were explored on MRI, and clinical background factors including age, sex, smoking, atrial fibrillation, coronary heart disease, hypertension, hyperlipidemia and diabetes mellitus (DM) were assessed. The frequency of BSI in the recurrent-stroke group was significantly higher than that in first-stroke patients (30.2 vs. 14.9%, p = 0.0033). No other clinical background factors differed between the two groups. Only the frequency of DM differed significantly among four subgroups formed based on stroke recurrence and BSI (p < 0.0001): DM was present in 63.2% of recurrent-stroke patients with BSI, 54.5% of first-stroke patients with BSI, 27.4% of first-stroke patients without BSI, and 20.5% of recurrent-stroke patients without BSI. We conclude that the brainstem is at high risk for recurrent cerebral infarction in patients with DM.
N-Terminal Pro-Brain Natriuretic Peptide as a Predictor of Heart Failure with Preserved Ejection Fraction in Hemodialysis Patients without Fluid Overload
Authors: Kamano Chisako , Osawa Hirokazu , Hashimoto Kazumasa , Nishimura Shungo , Saito Sabiene Kyoko , Kashiwagi Tetsuya , Iino Yasuhiko , Katayama Yasuo
Published: December 2011

Background/Aims: The diagnostic value of N-terminal pro-brain natriuretic peptide (NT-pro BNP) for heart failure with preserved ejection fraction (EF; HF-PEF) was evaluated in hemodialysis (HD) patients. Method: In total, 83 patients were analyzed. Left-ventricular (LV) function was assessed using trans-thoracic Doppler echocardiography, and indices of hydration status were assessed using bioelectrical impedance analysis. Plasma NT-pro BNP levels were measured simultaneously. Results: A moderate negative correlation was found between NT-pro BNP and LVEF. Subsequently, 77 HD patients who maintained their LVEF (LVEF >50%) were analyzed. Patients with a clinical suspicion of LV diastolic dysfunction (LVDD; E/A ≤0.75) showed higher NT-pro BNP levels (p = 0.021), but no significant differences in hydration status were observed between the two groups. Conclusions: The NT-pro BNP level may be a very helpful biomarker in screening for LVDD and HF-PEF and determining the need for echocardiography or a sophisticated cardiac study, even in HD patients.
Distinct Development of the Cerebral Cortex in Platypus and Echidna
Authors: Ashwell Ken W.S. , Hardman Craig D.
Published: December 2011

Both lineages of the modern monotremes have distinctive features in the cerebral cortex, but the developmental mechanisms that produce such different adult cortical architecture remain unknown. Similarly, nothing is known about the differences and/or similarities between monotreme and therian cortical development. We have used material from the Hill embryological collection to try to answer key questions concerning cortical development in monotremes. Our findings indicate that gyrencephaly begins to emerge in the echidna brain shortly before birth (crown-rump length 12.5 mm), whereas the cortex of the platypus remains lissencephalic throughout development. The cortices of both monotremes are very immature at the time of hatching, much like that seen in marsupials, and both have a subventricular zone (SubV) within both the striatum and pallium during post-hatching development. It is particularly striking that in the platypus, this region has an extension from the palliostriatal angle beneath the developing trigeminoreceptive part of the somatosensory cortex of the lateral cortex. The putative SubV beneath the trigeminal part of S1 appears to accommodate at least two distinct types of cell and many mitotic figures and (particularly in the platypus) appears to be traversed by large numbers of thalamocortical axons as these grow in. The association with putative thalamocortical fibres suggests that this region may also serve functions similar to the subplate zone of Eutheria. These findings suggest that cortical development in each monotreme follows distinct paths from at least the time of birth, consistent with a long period of independent and divergent cortical evolution.
Using Stress Testing to Guide Primary Prevention of Coronary Heart Disease Among Intermediate-Risk Patients
Authors: Galper Benjamin Z. , Moran Andrew , Coxson Pamela G. , Pletcher Mark J. , Heidenreich Paul , Lazar Lawrence D. , Rodondi Nicolas , Wang Y. Claire , Goldman Lee
Published: December 2011

Background—

Noninvasive stress testing might guide the use of aspirin and statins for primary prevention of coronary heart disease, but it is unclear if such a strategy would be cost effective.

Methods and Results—

We compared the status quo, in which the current national use of aspirin and statins was simulated, with 3 other strategies: (1) full implementation of Adult Treatment Panel III guidelines, (2) a treat-all strategy in which all intermediate-risk persons received statins (men and women) and aspirin (men only), and (3) a test-and-treat strategy in which all persons with an intermediate risk of coronary heart disease underwent stress testing and those with a positive test were treated with high-intensity statins (men and women) and aspirin (men only). Healthcare costs, coronary heart disease events, and quality-adjusted life years from 2011 to 2040 were projected. Under a variety of assumptions, the treat-all strategy was the most effective and least expensive strategy. Stress electrocardiography was more effective and less expensive than other test-and-treat strategies, but it was less expensive than treat all only if statin cost exceeded $3.16/pill or if testing increased adherence from <22% to >75%. However, stress electrocardiography could be cost effective in persons initially nonadherent to the treat-all strategy if it raised their adherence to 5% and cost saving if it raised their adherence to 13%.

Conclusions—

When generic high-potency statins are available, noninvasive cardiac stress testing to target preventive medications is not cost effective unless it substantially improves adherence.
Fish, n-3 Fatty Acids, and Cardiovascular Diseases in Women of Reproductive Age
Authors: Strøm Marin , Halldorsson Thorhallur I. , Mortensen Erik L. , Torp-Pedersen Christian , Olsen Sjurdur F.
Published: December 2011

Previous studies have indicated a protective effect of long-chain n-3 polyunsaturated fatty acids (LCn3FAs) against cardiovascular disease; however, women are underrepresented in cardiovascular research. The aim of this study was to explore the association between intake of LCn3FAs and the risk of cardiovascular disease in a large prospective cohort of young women (mean age at baseline: 29.9 years [range: 15.7–46.9]). Exposure information on 48 627 women from the Danish National Birth Cohort was linked to the Danish National Patients Registry for information on events of hypertensive, cerebrovascular, and ischemic heart disease used to define a combined measure of cardiovascular diseases. Intake of fish and LCn3FAs was assessed by a food-frequency questionnaire and telephone interviews. During follow-up (1996–2008; median: 8 years), 577 events of cardiovascular disease were identified. Low LCn3FA intake was associated with an increased risk of cardiovascular disease (adjusted hazard ratio for women in lowest versus highest LCn3FA intake group: 1.91 [95% CI: 1.26–2.90]). Restricting the sample to women who had consistently reported similar frequencies of fish intake across 3 different dietary assessment occasions tended to strengthen the relationship (hazard ratio for lowest versus highest intake: 2.91 [95% CI: 1.45–5.85]). Furthermore, the observed associations were consistent in supplementary analyses where LCn3FA intake was averaged across the 3 dietary assessment occasions, and the associations were persistent for all 3 of the individual outcomes. Our findings based on a large prospective cohort of relatively young and initially healthy women indicated that little or no intake of fish and LCn3FAs was associated with an increased risk of cardiovascular disease.