bluuebunny/crossref_metadata_2025 huggingface dataset:
Scratchpad allocation for concurrent embedded software
Authors: Suhendra Vivy , Roychoudhury Abhik , Mitra Tulika
Published: May 2010

Software-controlled scratchpad memory is increasingly employed in embedded systems as it offers better timing predictability compared to caches. Previous scratchpad allocation algorithms typically consider single-process applications. But embedded applications are mostly multitasking with real-time constraints, where the scratchpad memory space has to be shared among interacting processes that may preempt each other. In this work, we develop a novel dynamic scratchpad allocation technique that takes these process interferences into account to improve the performance and predictability of the memory system. We model the application as a Message Sequence Chart (MSC) to best capture the interprocess interactions. Our goal is to optimize the Worst-Case Response Time (WCRT) of the application through runtime reloading of the scratchpad memory content at appropriate execution points. We propose an iterative allocation algorithm that consists of two critical steps: (1) analyze the MSC along with the existing allocation to determine potential interference patterns, and (2) exploit this interference information to tune the scratchpad reloading points and content so as to best improve the WCRT. We present various alternative scratchpad allocation heuristics and evaluate their effectiveness in reducing the WCRT. The scheme is also extended to work on Message Sequence Graph models. We evaluate our memory allocation scheme on two real-world embedded applications controlling an Unmanned Aerial Vehicle (UAV) and an in-orbit monitoring instrument, respectively.
Detecting bugs in register allocation
Authors: Huang Yuqiang , Childers Bruce R. , Soffa Mary Lou
Published: May 2010

Although register allocation is critical for performance, the implementation of register allocation algorithms is difficult, due to the complexity of the algorithms and target machine architectures. It is particularly difficult to detect register allocation errors if the output code runs to completion, as bugs in the register allocator can cause the compiler to produce incorrect output code. The output code may even execute properly on some test data, but errors can remain. In this article, we propose novel data flow analyses to statically check that the value flow of the output code from the register allocator is the same as the value flow of its input code. The approach is accurate, fast, and can identify and report error locations and types. It is independent of the register allocator and uses only the input and output code of the register allocator. It can be used with different register allocators, including those that perform coalescing and rematerialization. The article describes our approach, called SARAC, and a tool that statically checks a register allocation and reports the errors and their types that it finds. The tool has an average compile-time overhead of only 8% and a modest average memory overhead of 85KB. Our techniques can be used by compiler developers during regression testing and as a command-line-enabled debugging pass for mysterious compiler behavior.
Route oracle
Authors: Zhu Yaping , Rexford Jennifer , Sen Subhabrata , Shaikh Aman
Published: May 2010

Many network-management problems in large backbone networks need the answer to a seemingly simple question: where does a given IP packet, entering the network at a particular place and time, leave the network to continue on its path to the destination? Answering this question at scale and in real time is challenging for several reasons: (i) a destination IP address could match several IP prefixes, (ii) the longest-matching prefix may change over time, (iii) the number of IP prefixes and routing protocol messages is very large, and (iv) network-management applications often require answers to this question for a large number of destination IP addresses in real time. In this paper, we present an efficient algorithm for tracking prefix-match changes for ranges of IP addresses. We then present the design, implementation, and evaluation of the Route Oracle tool that answers queries about routing changes on behalf of network management applications. Our design of Route Oracle includes several performance optimizations, such as pre-processing of BGP update messages, and parallelization of query processing. Experiments with BGP measurement data from a large ISP backbone demonstrate that our system answers queries in real time and at scale.
Towards versatile performance models for complex, popular applications
Authors: Doebel Bjoern , Nobel Peter , Thereska Eno , Zheng Alice
Published: May 2010

Perhaps surprisingly, no practical performance models exist for popular (and complex) client applications such as Adobe's Designer suite, Microsoft's Office suite and Visual Studio, Mozilla, Halo 3, etc. There is currently no tool that automatically answers program developers', IT administrators' and end-users' simple what-if questions like "what happens to the performance of my favorite application X if I upgrade from Windows Vista to Windows 7?". This paper describes directions we are taking for constructing practical, versatile performance models to address this problem.

The directions we have taken have two paths. The first path involves instrumenting applications better to export their state and associated metrics. This application-specific monitoring is always on and interesting data is collected from real, "in-the-wild" deployments. The second path involves statistical modeling techniques. The models we are experimenting with require no modifications to the OS or applications beyond the above instrumentation, and no explicit
a priori
model on how an OS or application should behave. We are in the process of learning from models we have constructed for several Microsoft products, including the Office suite, Visual Studio and Media Player. This paper presents preliminary findings from a large user deployment (several hundred thousand user sessions) of these applications that show the coverage and limitations of such models.

Early indications from this work point towards future modeling strategies based on large amounts of data collected in the field. We present our thoughts on what this could imply for the SIGMETRICS community.
Product environmental metrics for printers
Authors: Ord Jason , Chappell Ellen , Canonico Scott , Strecker Tim
Published: May 2010

Hewlett-Packard's Imaging & Printing Group (IPG) is charting a course towards environmental leadership in its markets. To do this, IPG must look beyond just satisfying the regulations and identify opportunities for groundbreaking improvement. Carefully designed metrics are necessary to guide design, chart progress and set goals in this effort. IPG's Environmental Strategy Team is leading an initiative to establish these metrics internally. This paper describes the development process the authors followed to construct the initial metrics, which are focused on the "carbon footprint" of products under development. The paper also discusses the lessons learned developing the initial metrics, the results achieved thus far, implementation details, challenges, and future opportunities for improvement.
The sustainability hub
Authors: Cayzer Steve , Preist Chris
Published: May 2010

Sustainability is becoming an increasingly important driver for which decision makers -- consumers, corporate and government -- rely on principled, accurate and provenanced metrics to make appropriate behavior changes. Our assertion here is that a Sustainability Hub which manages such metrics together with their context and chains of reasoning will be of great benefit to the global community. In this paper we explain the Hub vision and explain its triple value proposition of context, chains of reasoning and community. We propose a data model and describe our existing prototype.
The Prosecution of Human Rights Violations
Authors: Nobles Melissa
Published: May 2010

This article analyzes the central arguments and findings of “transitional justice,” the study of how incoming rulers address the human rights abuses of outgoing regimes. A scholarly consensus suggests the balance of political power matters most for explanations of transitional justice decision making. However, other important influences include international factors and the passage of time combined with democratic governance and/or emotions. Our review finds no consensus on the efficacy of transitional justice measures, in part because few studies currently exist. However, existing studies suggest that trials and truth commissions neither destabilize democracy nor foster animosity, respectively. Finally, this article considers whether restricting the study of transitional justice to third-wave democracies is appropriate in light of recent developments in long-established democracies.
Bioenergetic characterization of mouse podocytes
Authors: Abe Yoshifusa , Sakairi Toru , Kajiyama Hiroshi , Shrivastav Shashi , Beeson Craig , Kopp Jeffrey B.
Published: May 2010

Mitochondrial dysfunction contributes to podocyte injury, but normal podocyte bioenergetics have not been characterized. We measured oxygen consumption rates (OCR) and extracellular acidification rates (ECAR), using a transformed mouse podocyte cell line and the Seahorse Bioscience XF24 Extracellular Flux Analyzer. Basal OCR and ECAR were 55.2 ± 9.9 pmol/min and 3.1 ± 1.9 milli-pH units/min, respectively. The complex V inhibitor oligomycin reduced OCR to ∼45% of baseline rates, indicating that ∼55% of cellular oxygen consumption was coupled to ATP synthesis. Rotenone, a complex I inhibitor, reduced OCR to ∼25% of the baseline rates, suggesting that mitochondrial respiration accounted for ∼75% of the total cellular respiration. Thus ∼75% of mitochondrial respiration was coupled to ATP synthesis and ∼25% was accounted for by proton leak. Carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP), which uncouples electron transport from ATP generation, increased OCR and ECAR to ∼360% and 840% of control levels. FCCP plus rotenone reduced ATP content by 60%, the glycolysis inhibitor 2-deoxyglucose reduced ATP by 35%, and 2-deoxyglucose in combination with FCCP or rotenone reduced ATP by >85%. The lactate dehydrogenase inhibitor oxamate and 2-deoxyglucose did not reduce ECAR, and 2-deoxyglucose had no effect on OCR, although 2-deoxyglucose reduced ATP content by 25%. Mitochondrial uncoupling induced by FCCP was associated with increased OCR with certain substrates, including lactate, glucose, pyruvate, and palmitate. Replication of these experiments in primary mouse podocytes yielded similar data. We conclude that mitochondria play the primary role in maintaining podocyte energy homeostasis, while glycolysis makes a lesser contribution.
Diurnal variation in time to presyncope and associated circulatory changes during a controlled orthostatic challenge
Authors: Lewis N. C. S. , Atkinson G. , Lucas S. J. E. , Grant E. J. M. , Jones H. , Tzeng Y. C. , Horsman H. , Ainslie P. N.
Published: May 2010

Epidemiological data indicate that the risk of neurally mediated syncope is substantially higher in the morning. Syncope is precipitated by cerebral hypoperfusion, yet no chronobiological experiment has been undertaken to examine whether the major circulatory factors, which influence perfusion, show diurnal variation during a controlled orthostatic challenge. Therefore, we examined the diurnal variation in orthostatic tolerance and circulatory function measured at baseline and at presyncope. In a repeated-measures experiment, conducted at 0600 and 1600, 17 normotensive volunteers, aged 26 ± 4 yr (mean ± SD), rested supine at baseline and then underwent a 60° head-up tilt with 5-min incremental stages of lower body negative pressure until standardized symptoms of presyncope were apparent. Pretest hydration status was similar at both times of day. Continuous beat-to-beat measurements of cerebral blood flow velocity, blood pressure, heart rate, stroke volume, cardiac output, and end-tidal Pco2 were obtained. At baseline, mean cerebral blood flow velocity was 9 ± 2 cm/s (15%) lower in the morning than the afternoon ( P < 0.0001). The mean time to presyncope was shorter in the morning than in the afternoon (27.2 ± 10.5 min vs. 33.1 ± 7.9 min; 95% CI: 0.4 to 11.4 min, P = 0.01). All measurements made at presyncope did not show diurnal variation ( P > 0.05), but the changes over time (from baseline to presyncope time) in arterial blood pressure, estimated peripheral vascular resistance, and α-index baroreflex sensitivity were greater during the morning tests ( P < 0.05). These data indicate that tolerance to an incremental orthostatic challenge is markedly reduced in the morning due to diurnal variations in the time-based decline in blood pressure and the initial cerebral blood flow velocity “reserve” rather than the circulatory status at eventual presyncope. Such information may be used to help identify individuals who are particularly prone to orthostatic intolerance in the morning.
Saving energy to fuel exercise: swimming suppresses oocyte development and downregulates ovarian transcriptomic response of rainbow troutOncorhynchus mykiss
Authors: Palstra Arjan P. , Crespo Diego , van den Thillart Guido E. E. J. M. , Planas Josep V.
Published: May 2010

Metabolic processes and sexual maturation closely interact during the long-distance reproductive migration of many fish species to their spawning grounds. In the present study, we have used exercise experimentally to investigate the effects on sexual maturation in rainbow trout. Pubertal autumn-spawning seawater-raised female rainbow trout Oncorhynchus mykiss ( n = 26; 50 cm, 1.5 kg) were rested or swum at a near optimal speed of 0.75 body lengths per second in a 6,000-liter swim flume under natural reproductive conditions (16°C fresh-water, starvation, 8:16-h light-dark photoperiod). Fish were sampled after arrival and subsequently after 10 days (resting or swimming 307 km) and 20 days (resting or swimming 636 km). Ovarian development was significantly reduced in the swimmers. Analysis of the expression of key factors in the reproductive axis included pituitary kiss1-receptor, lh, and fsh and ovarian lh-receptor, fsh-receptor, aromatase, and vitellogenin-receptor ( vtgr). Swimmers had lower pituitary lh and ovarian vtgr expression than resters. Furthermore, the number of late vitellogenic oocytes was lower in swimmers than in resters, probably resulting from the lower vtgr expression, and vitellogenin plasma levels were higher. Therefore, swimming exercise suppresses oocyte development possibly by inhibiting vitellogenin uptake. Transcriptomic changes that occurred in the ovary of exercised fish were investigated using a salmonid cDNA microarray platform. Protein biosynthesis and energy provision were among the 16 functional categories that were all downregulated in the ovary. Downregulation of the transcriptomic response in the ovary illustrates the priority of energy reallocation and will save energy to fuel exercise. A swimming-induced ovarian developmental suppression at the start of vitellogenesis during long-term reproductive migration may be a strategy to avoid precocious muscle atrophy.
Effects of Leg Pedaling on Early Latency Cutaneous Reflexes in Upper Limb Muscles
Authors: Sasada Syusaku , Tazoe Toshiki , Nakajima Tsuyoshi , Zehr E. Paul , Komiyama Tomoyoshi
Published: May 2010

The functional coupling of neural circuits between the upper and lower limbs involving rhythmic movements is of interest to both motor control research and rehabilitation science. This coupling can be detected by examining the effect of remote rhythmic limb movement on the modulation of reflex amplitude in stationary limbs. The present study investigated the extent to which rhythmic leg pedaling modulates the amplitude of an early latency (peak 30–70 ms) cutaneous reflex (ELCR) in the upper limb muscles. Thirteen neurologically intact volunteers performed leg pedaling (60 or 90 rpm) while simultaneously contracting their arm muscles isometrically. Control experiments included isolated isometric contractions and discrete movements of the leg. ELCRs were evoked by stimulation of the superficial radial nerve with a train of rectangular pulses (three pulses at 333 Hz, intensity 2.0- to 2.5-fold perceptual threshold). Reflex amplitudes were significantly increased in the flexor carpi radialis and posterior deltoid and significantly decreased in the biceps brachii muscles during leg pedaling compared with that during stationary isometric contraction of the lower leg muscles. This effect was also sensitive to cadence. No significant modulation was seen during the isometric contractions or discrete movements of the leg. Additionally, there was no phase-dependent modulation of the ELCR. These findings suggest that activation of the rhythm generating system of the legs affects the excitability of the early latency cutaneous reflex pathways in the upper limbs.
Resonant Perturbation Theory of Decoherence and Relaxation of Quantum Bits
Authors: Merkli M. , Berman G. P. , Sigal I. M.
Published: May 2010

We describe our recent results on the resonant perturbation theory of decoherence
and relaxation for quantum systems with many qubits. The approach
represents a rigorous analysis of the phenomenon of decoherence and relaxation
for general N‐level systems coupled to reservoirs of bosonic fields. We derive
a representation of the reduced dynamics valid for all times t ≥ 0 and for small
but fixed interaction strength. Our approach does not involve master equation
approximations and applies to a wide variety of systems which are not explicitly
solvable.
Adaptive Watermarking Scheme Using Biased Shift of Quantization Index
Authors: Seo Young-Ho , Choi Hyun-Jun , Yoo Ji-Sang , Kim Dong-Wook
Published: May 2010

We propose a watermark embedding and extracting method for blind watermarking. It uses the characteristics of a scalar quantizer to comply with the recommendation in JPEG, MPEG series, or JPEG2000. Our method performs embedding of a watermark bit by shifting the corresponding frequency transform coefficient (the watermark position) to a quantization index according to the value of the watermark bit, which prevents from losing the watermark information during the data compression process. The watermark can be embedded simultaneously to the quantization process without an additional process for watermarking, which means it can be performed at the same speed to the compression process. In the embedding process, a Linear Feedback Shift Register (LFSR) is used to hide the watermark informations and the watermark positions. The experimental results showed that the proposed method satisfies enough robustness and imperceptibility that are the major requirements for watermarking.
New Types of Almost Countable Dense Homogeneous Space
Authors: Tallafha Abdalla , Al-Rawashdeh Ahmed
Published: May 2010

In 1972, Bennett studied the countable dense homogeneous (CDH) spaces
and in 1992, Fitzpatrick, White, and Zhou proved that every CDH
space is a T1 space. Afterward Bsoul, Fora, and Tallafha gave another
proof for the same result, also they defined the almost CDH spaces and
almost T1, T0 spaces, indeed they prove that every ACDH space is an almost T1 space. In this paper we introduce a new type of almost CDH
spaces called ACDH‐1, we characterize the ACDH spaces, the almost
T0 spaces, we also give relations between different types of CDH spaces.
We define new type of almost T1 (AT1) spaces, and we study the relations between the old and new definitions. By extending the techniques
given by Tallafha, Bsoul, and Fora, we prove that every ACDH‐1 is an AT1.
Permanence and Positive Periodic Solutions of a Discrete Delay Competitive System
Authors: Qin Wenjie , Liu Zhijun
Published: May 2010

A discrete time non‐autonomous two‐species competitive system with delays is proposed, which involves the influence of many generations on the density of species population. Sufficient conditions for permanence of the system are given. When the system is periodic, by using the continuous theorem of
coincidence degree theory and constructing a suitable Lyapunov discrete function, sufficient conditions which guarantee the existence and global attractivity of positive periodic solutions are obtained. As an application, examples and their numerical simulations are presented to illustrate the feasibility of our main results.
Applied LPV Control with Full Block Multipliers and Regional Pole Placement
Authors: Ghersin Alejandro S. , Sánchez Peña Ricardo S.
Published: May 2010

A formulation of an LPV control problem with regional pole placement constraints is presented, which is suitable for the application of a Full Block S-Procedure. It is demonstrated that improved bounds can be obtained on the inducedL2norm of closed loop systems, while satisfying pole placement constraints. An application consisting in the 6 degrees of freedom (DOF) control of a space vehicle is developed as an example, with hardware in the loop (HIL) simulation. This shows that the method is appealing from the practical point of view, considering that the synthesized control law can be implemented satisfactorily in standard flight control systems. Conclusions with remarks towards the practical use of the method are presented as well.
Chimeric Antigen Receptor-Engineered T Cells for Immunotherapy of Cancer
Authors: Cartellieri Marc , Bachmann Michael , Feldmann Anja , Bippes Claudia , Stamova Slava , Wehner Rebekka , Temme Achim , Schmitz Marc
Published: May 2010

CD4+andCD8+T lymphocytes are powerful components of adaptive immunity, which essentially contribute to the elimination of tumors. Due to their cytotoxic capacity, T cells emerged as attractive candidates for specific immunotherapy of cancer. A promising approach is the genetic modification of T cells with chimeric antigen receptors (CARs). First generation CARs consist of a binding moiety specifically recognizing a tumor cell surface antigen and a lymphocyte activating signaling chain. The CAR-mediated recognition induces cytokine production and tumor-directed cytotoxicity of T cells. Second and third generation CARs include signal sequences from various costimulatory molecules resulting in enhanced T-cell persistence and sustained antitumor reaction. Clinical trials revealed that the adoptive transfer of T cells engineered with first generation CARs represents a feasible concept for the induction of clinical responses in some tumor patients. However, further improvement is required, which may be achieved by second or third generation CAR-engrafted T cells.
A Single-Institution Review of Portosystemic Shunts in Children: An Ongoing Discussion
Authors: Lillegard J. B. , Hanna A. M. , McKenzie T. J. , Moir C. R. , Ishitani M. B. , Nagorney D. M.
Published: May 2010

Purpose. Review the safety and long-term success with portosystemic shunts in children at a single institution. Methods. An IRB-approved, retrospective chart review of all children ages 19 and undergoing surgical portosystemic shunt from January 1990–September 2008. Results. Ten patients were identified, 8 females and 2 males, with a mean age of 15 years (range 5–19 years). Primary diagnoses were congenital hepatic fibrosis (5), hepatic vein thrombosis (2), portal vein thrombosis (2), and cystic fibrosis (1). Primary indications were repeated variceal bleeding (6), symptomatic hypersplenism (2), and significant liver dysfunction (2). Procedures performed were distal splenorenal bypass (4), side-to-side portocaval shunt (3), proximal splenorenal shunt (2), and an interposition H-graft portocaval shunt (1). There was no perioperative mortality and only minor morbidity. Seventy percent of patients had improvement of their symptoms. Eighty percent of shunts remained patent. Two were occluded at a median follow-up of 50 months (range 0.5–13.16 years). Two patients underwent subsequent liver transplantation. Two patients died at 0.5 and 12.8 years postoperatively, one from multisystem failure with cystic fibrosis and one from post-operative transplant complications. Conclusions. The need for portosystemic shunts in children is rare. However, in the era of liver transplantation, portosystemic shunts in selected patients with well-preserved liver function remains important. We conclude that portosystemic shunts are safe and efficacious in the control of variceal hemorrhage and symptoms related to hypersplenism.
Role of RUNX3 in Bone Morphogenetic Protein Signaling in Colorectal Cancer
Authors: Lee Cecilia Wei Lin , Ito Kosei , Ito Yoshiaki
Published: May 2010

Bone morphogenetic proteins (BMPs), members of the transforming growth factor-β (TGF-β) superfamily, are multifunctional cytokines regulating a broad spectrum of biological functions. Recent studies show the presence of BMP receptor 1a mutations in juvenile polyposis and frequent Smad4 mutations in colon cancer, suggesting that aberrations in BMP signaling play an important role in intestinal cancer pathogenesis. However, the exact molecular mechanisms remain poorly understood. The Runt domain transcription factor RUNX3 is an integral component of signaling pathways mediated by TGF-β and BMPs. RUNX3 is a gastric and colon tumor suppressor, functioning downstream of TGF-β. Recently, we showed the tumor-suppressive effects of RUNX3 by its ability to attenuate β-catenin/T-cell factors (TCFs) transactivation in intestinal tumorigenesis. Here, we explore the molecular basis of the tumor-suppressive function of the BMP pathway through RUNX3 in colorectal carcinogenesis. BMP exerted a growth-suppressive effect in HT-29, a human colorectal cancer cell line. c-Myc oncogene was found to be downregulated by BMP and/or RUNX3. We show that upregulation of RUNX3 by BMP reduces c-Myc expression. Evidence is presented suggesting that RUNX3 downregulates c-Myc expression by two parallel pathways—directly at the transcriptional level and through attenuation of β-catenin/TCFs, downstream of BMPs in colorectal cancer cells. Cancer Res; 70(10); 4243–52. ©2010 AACR.
Heterogeneity of Regional Redox Status and Relation of the Redox Status to Oxygenation in a Tumor Model, Evaluated Using Electron Paramagnetic Resonance Imaging
Authors: Takeshita Keizo , Kawaguchi Kumiko , Fujii-Aikawa Kaori , Ueno Megumi , Okazaki Shoko , Ono Mitsuhiro , Krishna Murali C. , Kuppusamy Periannan , Ozawa Toshihiko , Ikota Nobuo
Published: May 2010

It is widely accepted that redox status, along with the partial pressure of oxygen (pO2), determines the efficacy of some therapeutic methods applied to treat tumors, including radiation. Redox status, evaluated by the reduction of a nitroxyl probe, was reportedly heterogeneous in a mouse tumor model. However, neither variation of heterogeneity of the redox status among mice nor the relation of the redox status to pO2 in tumors has been characterized sufficiently. In this study, the regional reduction status in a mouse radiation-induced fibrosarcoma tumor model was evaluated using sequential three-dimensional electron paramagnetic resonance (EPR) imaging after i.v. injection of a tissue-permeable nitroxyl probe, HM-PROXYL. The regional decay of HM-PROXYL signal obeyed first-order kinetics, and the amplitude of the reduction rate and extent of its heterogeneity in a tumor varied among six mice. The tissue pO2 was measured using EPR oximetry with lithium phthalocyanine (LiPc) microcrystals implanted within the tumor. The location of LiPc was determined with EPR imaging. A sequential image was obtained following the injection of HM-PROXYL, even after LiPc implantation, by choosing an HM-PROXYL signal peak which does not overlap with the signal of LiPc. The relationship between pO2 and the reduction rate at the region of pO2 measurement was found to be low (r = 0.357) in 13 tumor-bearing mice, indicating that the extent of oxygenation does not necessarily affect the redox status under air-breathing conditions. The results strongly indicate the necessity of measurements of both redox status and oxygenation in every tumor to characterize tumor physiology. Cancer Res; 70(10); 4133–40. ©2010 AACR.
Deficiency in p53 but not Retinoblastoma Induces the Transformation of Mesenchymal Stem Cells In vitro and Initiates Leiomyosarcoma In vivo
Authors: Rubio Ruth , García-Castro Javier , Gutiérrez-Aranda Iván , Paramio Jesús , Santos Mirentxu , Catalina Purificación , Leone Paola E. , Menendez Pablo , Rodríguez René
Published: May 2010

Sarcomas have been modeled in mice by the expression of specific fusion genes in mesenchymal stem cells (MSC), supporting the concept that MSCs might be the target initiating cell in sarcoma. In this study, we evaluated the potential oncogenic effects of p53 and/or retinoblastoma (Rb) deficiency in MSC transformation and sarcomagenesis. We derived wild-type, p53−/−, Rb−/−, and p53−/−Rb−/− MSC cultures and fully characterized their in vitro growth properties and in vivo tumorigenesis capabilities. In contrast with wild-type MSCs, Rb−/−, p53−/−, and p53−/−Rb−/− MSCs underwent in vitro transformation and showed severe alterations in culture homeostasis. More importantly, p53−/− and p53−/−Rb−/− MSCs, but not Rb−/− MSCs, were capable of tumor development in vivo after injection into immunodeficient mice. p53−/− or p53−/−Rb−/− MSCs originated leiomyosarcoma-like tumors, linking this type of smooth muscle sarcoma to p53 deficiency in fat tissue–derived MSCs. Sca1+ and Sca1 low/− cell populations isolated from ex vivo–established, transformed MSC lines from p53−/−Rb−/− tumors showed identical sarcomagenesis potential, with 100% tumor penetrance and identical latency, tumor weight, and histologic profile. Our findings define the differential roles of p53 and Rb in MSC transformation and offer proof-of-principle that MSCs could provide useful tools to dissect the sarcoma pathogenesis. Cancer Res; 70(10); 4185–94. ©2010 AACR.
Plasma Folate, Related Genetic Variants, and Colorectal Cancer Risk in EPIC
Authors: Eussen Simone J.P.M. , Vollset Stein Emil , Igland Jannicke , Meyer Klaus , Fredriksen Åse , Ueland Per Magne , Jenab Mazda , Slimani Nadia , Boffetta Paolo , Overvad Kim , Tjønneland Anne , Olsen Anja , Clavel-Chapelon Françoise , Boutron-Ruault Marie-Christine , Morois Sophie , Weikert Cornelia , Pischon Tobias , Linseisen Jakob , Kaaks Rudolf , Trichopoulou Antonia , Zilis Demosthenes , Katsoulis Michael , Palli Domenico , Berrino Franco , Vineis Paolo , Tumino Rosario , Panico Salvatore , Peeters Petra H.M. , Bueno-de-Mesquita H. Bas , van Duijnhoven Fränzel J.B. , Gram Inger Torhild , Skeie Guri , Lund Eiliv , González Carlos A. , Martínez Carmen , Dorronsoro Miren , Ardanaz Eva , Navarro Carmen , Rodríguez Laudina , Guelpen Bethany Van , Palmqvist Richard , Manjer Jonas , Ericson Ulrika , Bingham Sheila , Khaw Kay-Tee , Norat Teresa , Riboli Elio
Published: May 2010

Background: A potential dual role of folate in colorectal cancer (CRC) is currently subject to debate. We investigate the associations between plasma folate, several relevant folate-related polymorphisms, and CRC risk within the large European Prospective Investigation into Cancer and Nutrition cohort.

Methods: In this nested case-control study, 1,367 incident CRC cases were matched to 2,325 controls for study center, age, and sex. Risk ratios (RR) were estimated with conditional logistic regression and adjusted for smoking, education, physical activity, and intake of alcohol and fiber.

Results: Overall analyses did not reveal associations of plasma folate with CRC. The RR (95% confidence interval; Ptrend) for the fifth versus the first quintile of folate status was 0.94 (0.74-1.20; 0.44). The polymorphisms MTHFR677C→T, MTHFR1298A→C, MTR2756A→G, MTRR66A→G, and MTHFD11958G→A were not associated with CRC risk. However, in individuals with the lowest plasma folate concentrations, the MTHFR 677TT genotype showed a statistically nonsignificant increased CRC risk [RR (95% CI; Ptrend) TT versus CC = 1.39 (0.87-2.21); 0.12], whereas those with the highest folate concentrations showed a nonsignificant decreased CRC risk [RR TT versus CC = 0.74 (0.39-1.37); 0.34]. The SLC19A180G→A showed a positive association with CRC risk [RR AA versus GG 1.30 (1.06-1.59); <0.01].

Conclusions: This large European prospective multicenter study did not show an association of CRC risk with plasma folate status nor with MTHFR polymorphisms.

Impact: Findings of the present study tend to weaken the evidence that folate plays an important role in CRC carcinogenesis. However, larger sample sizes are needed to adequately address potential gene-environment interactions. Cancer Epidemiol Biomarkers Prev; 19(5); 1328–40. ©2010 AACR.
Maternal Alcohol Consumption during Pregnancy and Risk of Childhood Leukemia: Systematic Review and Meta-analysis
Authors: Latino-Martel Paule , Chan Doris S.M. , Druesne-Pecollo Nathalie , Barrandon Emilie , Hercberg Serge , Norat Teresa
Published: May 2010

Background: Leukemia is the most frequently occurring cancer in children. Although its etiology is largely unknown, leukemia is believed to result from an interaction between genetic and environmental factors. Among different potential risk factors, the possible role of maternal alcohol consumption during pregnancy has been questioned.

Methods: To assess the association between maternal alcohol consumption during pregnancy and childhood leukemia, a systematic review and meta-analysis of published studies was done.

Results: Twenty-one case-control studies were included in categorical and dose-response meta-analyses. No cohort study was identified. Analyses were conducted by type of leukemia, children's age at diagnosis, and type of alcoholic beverage and trimester of pregnancy at alcohol use. Alcohol intake during pregnancy (yes versus no) was statistically significantly associated with childhood acute myeloid leukemia (AML) [odds ratio (OR), 1.56; 95% confidence interval (CI), 1.13-2.15] but not with acute lymphoblastic leukemia (OR, 1.10; 95% CI, 0.93-1.29). Heterogeneity between studies was observed. The OR of AML for an increase of a drink per week was 1.24 (95% CI, 0.94-1.64). The association of alcohol intake during pregnancy with AML was observed for cancers diagnosed at age 0 to 4 years (OR, 2.68; 95% CI, 1.85-3.89) in five studies without heterogeneity (I2 ≤ 0.1%).

Conclusions: The results of case-control studies indicate that maternal alcohol consumption during pregnancy is associated with a significantly increased risk of AML in young children.

Impact: Avoidance of maternal alcohol drinking during pregnancy might contribute to a decrease in the risk of childhood AML. Cancer Epidemiol Biomarkers Prev; 19(5); 1238–60. ©2010 AACR.
Determinants of VIA (Visual Inspection of the Cervix After Acetic Acid Application) Positivity in Cervical Cancer Screening of Women in a Peri-Urban Area in Andhra Pradesh, India
Authors: Vedantham Haripriya , Silver Michelle I. , Kalpana B. , Rekha C. , Karuna B.P. , Vidyadhari K. , Mrudula S. , Ronnett Brigitte M. , Vijayaraghavan K. , Ramakrishna Gayatri , Sowjanya Pavani , Laxmi Shantha , Shah Keerti V. , Gravitt Patti E.
Published: May 2010

Objectives: Visual inspection of the cervix after acetic acid application (VIA) is widely recommended as the method of choice in cervical cancer screening programs in resource-limited settings because of its simplicity and ability to link with immediate treatment. In testing the effectiveness of VIA, human papillomavirus DNA testing, and Pap cytology in a population-based study in a peri-urban area in Andhra Pradesh, India, we found the sensitivity of VIA for detection of cervical intraepithelial neoplasia grade 2 and worse (CIN2+) to be 26.3%, much lower than the 60% to 90% reported in the literature. We therefore investigated the determinants of VIA positivity in our study population.

Methods: We evaluated VIA positivity by demographics and reproductive history, results of clinical examination, and results from the other screening methods.

Results: Of the 19 women diagnosed with CIN2+, only 5 were positive by VIA (positive predictive value, 3.1%). In multivariate analysis, VIA positivity (12.74%) was associated with older age, positive Pap smear, visually apparent cervical inflammation, and interobserver variation. Cervical inflammation of unknown cause was present in 21.62% of women. In disease-negative women, cervical inflammation was associated with an increase in VIA positivity from 6.1% to 15.5% (P < 0.001). Among the six gynecologists who performed VIA, the positivity rate varied from 4% to 31%.

Conclusions: The interpretation of VIA is subjective and its performance cannot be readily evaluated against objective standards.

Impact: VIA is not a robust screening test and we caution against its use as the primary screening test in resource-limited regions. Cancer Epidemiol Biomarkers Prev; 19(5); 1373–80. ©2010 AACR.
Extent of Alcohol Consumption among Adult Survivors of Childhood Cancer: The British Childhood Cancer Survivor Study
Authors: Frobisher Clare , Lancashire Emma R. , Reulen Raoul C. , Winter David L. , Stevens Michael C.G. , Hawkins Michael M.
Published: May 2010

Background: This study aimed to identify subgroups of childhood cancer survivors at highest risk of consuming alcohol, consuming above recommended weekly levels, and consuming potentially harmful amounts and compare survivor risks with those expected from the general population.

Methods: Using the British Childhood Cancer Survivor Study, a population-based cohort of 17,981 individuals diagnosed with childhood cancer (1940-1991) and surviving ≥5 years, 14,836 were eligible for a questionnaire that ascertained drinking behavior, as previously ascertained in the 2002 General Household Survey throughout Britain.

Results: Of 10,389 survivors who responded, 77.2% were alcohol drinkers, 23.8% consumed over weekly recommendations, and 3.9% consumed potentially harmful amounts. Survivors were less likely than the general population to be a current drinker {odds ratio [OR; 99% confidence interval (CI)]: 0.52 (0.46-0.60)}, consume over weekly recommended levels [OR (99% CI): 0.65 (0.58-0.73)], and consume harmful amounts [OR (99% CI): 0.40 (0.32-0.49)]. Survivors of a central nervous system neoplasm or leukemia, particularly those treated with brain irradiation, were the least likely to have adverse drinking behaviors when compared with the general population. However, survivors of Hodgkin's lymphoma, non–Hodgkin's lymphoma, Wilms' tumor, bone sarcoma, and soft tissue sarcoma had adverse drinking behaviors at levels expected from the general population.

Conclusion: Overall adverse drinking behaviors were less frequent in survivors than expected from the general population, but subgroups with adverse drinking behaviors were identified, and it is these subgroups who are most in need of intervention.

Impact: UK clinical follow-up guidelines for childhood cancer survivors need strengthening in relation to alcohol consumption. Cancer Epidemiol Biomarkers Prev; 19(5); 1174–84. ©2010 AACR.
A Prospective, Multicenter, National Cancer Institute Early Detection Research Network Study of [−2]proPSA: Improving Prostate Cancer Detection and Correlating with Cancer Aggressiveness
Authors: Sokoll Lori J. , Sanda Martin G. , Feng Ziding , Kagan Jacob , Mizrahi Isaac A. , Broyles Dennis L. , Partin Alan W. , Srivastava Sudhir , Thompson Ian M. , Wei John T. , Zhang Zhen , Chan Daniel W.
Published: May 2010

Background: The free prostate-specific antigen (PSA) isoform, [−2]proPSA, has been shown to be associated with prostate cancer. The study objective was to characterize the clinical utility of serum [−2]proPSA for prostate cancer detection and assess its association with aggressive disease.

Methods: From among 669 subjects in a prospective prostate cancer detection study at four National Cancer Institute Early Detection Research Network clinical validation centers, 566 were eligible. Serum PSA, free PSA, and [−2]proPSA were measured (Beckman Coulter Access 2 Analyzer).

Results: Two hundred and forty-five (43%) of the 566 participants had prostate cancer on biopsy. At 70% specificity, the sensitivity of %[−2]proPSA ([−2]proPSA/fPSA) was 54% [95% confidence interval (CI), 48-61%; null hypothesis, 40%]. Including %[−2]proPSA in a multivariate prediction model incorporating PSA and %fPSA improved the performance (P < 0.01). In the 2 to 4 ng/mL PSA range, %[−2]proPSA outperformed %fPSA (receiver operator characteristic-areas under the curve, 0.73 versus 0.61; P = 0.01). At 80% sensitivity, %[−2]proPSA had significantly higher specificity (51.6%; 95% CI, 41.2-61.8%) than PSA (29.9%; 95% CI, 21.0-40.0%) and %fPSA (28.9%; 95% CI, 20.1-39.0%). In the 2 to 10 ng/mL PSA range, a multivariate model had significant improvement (area under the curve, 0.76) over individual PSA forms (P < 0.01 to <0.0001). At 80% sensitivity, the specificity of %[−2]proPSA (44.9%; 95% CI, 38.4-51.5%) was significantly higher than PSA (30.8%; 95% CI, 24.9-37.1%) and relatively higher than %fPSA (34.6%; 95% CI, 28.5-41.4%). %[−2]proPSA increased with increasing Gleason score (P < 0.001) and was higher in aggressive cancers (P = 0.03).

Conclusions: In this prospective study, %[−2]proPSA showed potential clinical utility for improving prostate cancer detection and was related to the risk of aggressive disease.

Impact: The addition of %[−2]proPSA could affect the early detection of prostate cancer. Cancer Epidemiol Biomarkers Prev; 19(5); 1193–200. ©2010 AACR.
International Trends in the Incidence of Testicular Cancer, 1973-2002
Authors: Chia Victoria M. , Quraishi Sabah M. , Devesa Susan S. , Purdue Mark P. , Cook Michael B. , McGlynn Katherine A.
Published: May 2010

Background: Whereas testicular cancer incidence rates have been widely reported in populations of Northern European ancestry, rates in other populations have been less frequently examined. In a prior report, global testicular cancer incidence rates and trends for the years 1973 to 1997 were summarized. The current report extends these analyses with an additional 5 years of data from Cancer Incidence in Five Continents.

Methods: Age-standardized incidence rates over successive 5-year time periods were obtained for populations in the Americas, Asia, Europe, and Oceania.

Results: In general, testicular cancer incidence remained highest in Northern European populations (8.0-9.0 per 100,000) and lowest in Asian and African populations (<1 per 100,000). One notable exception to this pattern, however, was the very high rate reported by the Valdivia, Chile registry (8.8 per 100,000). In many populations, rates rose between 1973 and 2002, although the increases were strongest and most consistent among populations of European ancestry. In certain European populations, such as those of Denmark and of Geneva, Switzerland, some recent plateauing of rates was evident. There was little evidence of increase and possible evidence of a modest decline in rates among east Asian populations. Trends by histology (seminoma and nonseminoma) were generally similar to one another.

Conclusions: Risk of testicular cancer remains relatively high in Northern European populations and low in Asian and African populations. Similar trends by histology suggest common risk factors.

Effect: Reasons for increasing rates among Northern Europeans and stable or declining rates among East Asians are unexplained, supporting the need for future etiologic studies. Cancer Epidemiol Biomarkers Prev; 19(5); 1151–9. ©2010 AACR.
Differentiation Therapy Exerts Antitumor Effects on Stem-like Glioma Cells
Authors: Campos Benito , Wan Feng , Farhadi Mohammad , Ernst Aurélie , Zeppernick Felix , Tagscherer Katrin E. , Ahmadi Rezvan , Lohr Jennifer , Dictus Christine , Gdynia Georg , Combs Stephanie E. , Goidts Violaine , Helmke Burkhard M. , Eckstein Volker , Roth Wilfried , Beckhove Philipp , Lichter Peter , Unterberg Andreas , Radlwimmer Bernhard , Herold-Mende Christel
Published: May 2010

Purpose: Stem-like tumor cells comprise a highly tumorigenic and therapy-resistant tumor subpopulation, which is believed to substantially influence tumor initiation and therapy resistance in glioma. Currently, therapeutic, drug-induced differentiation is considered as a promising approach to eradicate this tumor-driving cell population; retinoic acid is well known as a potent modulator of differentiation and proliferation in normal stem cells. In glioma, knowledge about the efficacy of retinoic acid–induced differentiation to target the stem-like tumor cell pool could have therapeutic implications.

Experimental Design: Stem-like glioma cells (SLGC) were differentiated with all-trans retinoic acid–containing medium to study the effect of differentiation on angiogenesis, invasive growth, as well as radioresistance and chemoresistance of SLGCs. In vivo effects were studied using live microscopy in a cranial window model.

Results: Our data suggest that in vitro differentiation of SLGCs induces therapy-sensitizing effects, impairs the secretion of angiogenic cytokines, and disrupts SLGCs motility. Further, ex vivo differentiation reduces tumorigenicity of SLGCs. Finally, we show that all-trans retinoic acid treatment alone can induce antitumor effects in vivo.

Conclusions: Altogether, these results highlight the potential of differentiation treatment to target the stem-like cell population in glioblastoma. Clin Cancer Res; 16(10); 2715–28. ©2010 AACR.
Delivery of 5-Azacytidine to Human Cancer Cells by Elaidic Acid Esterification Increases Therapeutic Drug Efficacy
Authors: Brueckner Bodo , Rius Maria , Markelova Maria Rivera , Fichtner Iduna , Hals Petter-Arnt , Sandvold Marit Liland , Lyko Frank
Published: May 2010

Azacytidine is an established nucleoside drug that is well known for its ability to modulate epigenetic gene regulation by inhibition of DNA methylation. Despite recent advances in the clinical development of azacytidine, the use of the drug is limited by its low bioavailability and dependency on variably expressed nucleoside transporters for cellular uptake. We show here that CP-4200, an elaidic acid derivative of azacytidine, has strong epigenetic modulatory potency in human cancer cell lines, as evidenced by efficient depletion of DNA methyltransferase protein, genome-wide DNA demethylation, and robust reactivation of epigenetically silenced tumor suppressor genes. Importantly, however, the cellular uptake of CP-4200 was substantially less dependent on the nucleoside transporters that are known to be involved in azacytidine uptake. In agreement with this notion, CP-4200 showed a significantly higher antitumoral activity than azacytidine in an orthotopic mouse tumor model for acute lymphocytic leukemia. Together, these data represent a detailed characterization of the CP-4200 mode of action and suggest that elaidic acid modification improves the therapeutic efficacy of azacytidine. Mol Cancer Ther; 9(5); 1256–64. ©2010 AACR.