bluuebunny/crossref_metadata_2025 huggingface dataset:
Adaptive set pinning
Authors: Srikantaiah Shekhar , Kandemir Mahmut , Irwin Mary Jane
Published: April 2008

As part of the trend towards Chip Multiprocessors (CMPs) for the next leap in computing performance, many architectures have explored sharing the last level of cache among different processors for better performance-cost ratio and improved resource allocation. Shared cache management is a crucial CMP design aspect for the performance of the system. This paper first presents a new classification of cache misses - CII: Compulsory, Inter-processor and Intra-processor misses - for CMPs with shared caches to provide a better understanding of the interactions between memory transactions of different processors at the level of shared cache in a CMP. We then propose a novel approach, called set pinning, for eliminating inter-processor misses and reducing intra-processor misses in a shared cache. Furthermore, we show that an adaptive set pinning scheme improves over the benefits obtained by the set pinning scheme by significantly reducing the number of off-chip accesses. Extensive analysis of these approaches with SPEComp 2001 benchmarks is performed using a full system simulator. Our experiments indicate that the set pinning scheme achieves an average improvement of 22.18% in the L2 miss rate while the adaptive set pinning scheme reduces the miss rates by an average of 47.94% as compared to the traditional shared cache scheme. They also improve the performance by 7.24% and 17.88% respectively.
Adapting to intermittent faults in multicore systems
Authors: Wells Philip M. , Chakraborty Koushik , Sohi Gurindar S.
Published: April 2008

Future multicore processors will be more susceptible to a variety of hardware failures. In particular,
intermittent faults
, caused in part by manufacturing, thermal, and voltage variations, can cause bursts of frequent faults that last from several cycles to several seconds or more. Due to practical limitations of circuit techniques, cost-effective reliability will likely require the ability to temporarily suspend execution on a core during periods of intermittent faults.

We investigate three of the most obvious techniques for adapting to the dynamically changing resource availability caused by intermittent faults, and demonstrate their different system-level implications. We show that system software reconfiguration has very high overhead, that temporarily pausing execution on a faulty core can lead to cascading livelock, and that using spare cores has high fault-free cost. To remedy these and other drawbacks of the three baseline techniques, we propose using a thin hardware/firmware layer to manage an
overcommitted system
-- one where the OS is configured to use more virtual processors than the number of currently available physical cores. We show that this proposed technique can gracefully degrade performance during intermittent faults of various duration with low overhead, without involving system software, and without requiring spare cores.
Feedback-driven threading
Authors: Suleman M. Aater , Qureshi Moinuddin K. , Patt Yale N.
Published: April 2008

Extracting high-performance from the emerging Chip Multiprocessors (CMPs) requires that the application be divided into multiple threads. Each thread executes on a separate core thereby increasing concurrency and improving performance. As the number of cores on a CMP continues to increase, the performance of some multi-threaded applications will benefit from the increased number of threads, whereas, the performance of other multi-threaded applications will become limited by data-synchronization and off-chip bandwidth. For applications that get limited by data-synchronization, increasing the number of threads significantly degrades performance and increases on-chip power. Similarly, for applications that get limited by off-chip bandwidth, increasing the number of threads increases on-chip power without providing any performance improvement. Furthermore, whether an application gets limited by data-synchronization, or bandwidth, or neither depends not only on the application but also on the input set and the machine configuration. Therefore, controlling the number of threads based on the run-time behavior of the application can significantly improve performance and reduce power.

This paper proposes
Feedback-Driven Threading (FDT)
, a framework to dynamically control the number of threads using run-time information. FDT can be used to implement
Synchronization-Aware Threading (SAT)
, which predicts the optimal number of threads depending on the amount of data-synchronization. Our evaluation shows that SAT can reduce both execution time and power by up to 66% and 78% respectively. Similarly, FDT can be used to implement
Bandwidth-Aware Threading (BAT)
, which predicts the minimum number of threads required to saturate the off-chip bus. Our evaluation shows that BAT reduces on-chip power by up to 78%. When SAT and BAT are combined, the average execution time reduces by 17% and power reduces by 59%. The proposed techniques leverage existing performance counters and require minimal support from the threading library.
How low can you go?
Authors: McCune Jonathan M. , Parno Bryan , Perrig Adrian , Reiter Michael K. , Seshadri Arvind
Published: April 2008

We explore the extent to which newly available CPU-based security technology can reduce the Trusted Computing Base (TCB) for security-sensitive applications. We find that although this new technology represents a step in the right direction, significant performance issues remain. We offer several suggestions that leverage existing processor technology, retain security, and improve performance. Implementing these recommendations will finally allow application developers to focus exclusively on the security of their own code, enabling it to execute in isolation from the numerous vulnerabilities in the underlying layers of legacy code.
Improving the performance of object-oriented languages with dynamic predication of indirect jumps
Authors: Joao Jose A. , Mutlu Onur , Kim Hyesoon , Agarwal Rishi , Patt Yale N.
Published: April 2008

Indirect jump instructions are used to implement increasingly-common programming constructs such as virtual function calls, switch-case statements, jump tables, and interface calls. The performance impact of indirect jumps is likely to increase because indirect jumps with multiple targets are difficult to predict even with specialized hardware.

This paper proposes a new way of handling hard-to-predict indirect jumps: dynamically predicating them. The compiler (static or dynamic) identifies indirect jumps that are suitable for predication along with their control-flow merge (CFM) points. The hardware predicates theinstructions between different targets of the jump and its CFM point if the jump turns out to be hard-to-predict at run time. If the jump would actually have been mispredicted, its dynamic predication eliminates a pipeline flush, thereby improving performance.

Our evaluations show that Dynamic Indirect jump Predication (DIP) improves the performance of a set of object-oriented applications including the Java DaCapo benchmark suite by 37.8% compared to a commonly-used branch target buffer based predictor, while also reducing energy consumption by 24.8%. We compare DIP to three previously proposed indirect jump predictors and find that it provides the best performance and energy-efficiency.
Hardware counter driven on-the-fly request signatures
Authors: Shen Kai , Zhong Ming , Dwarkadas Sandhya , Li Chuanpeng , Stewart Christopher , Zhang Xiao
Published: April 2008

Today's processors provide a rich source of statistical informationon application execution through hardware counters. In this paper, we explore the utilization of these statistics as request signaturesin server applications for identifying requests and inferring high-level request properties (
e.g.
, CPU and I/O resource needs). Our key finding is that effective request signatures may be constructed using a small amount of hardware statistics while the request is still in an early stage of its execution. Such
on-the-fly
request identification and property inference allow guided operating system adaptation at request granularity (
e.g.
, resource-aware request scheduling and on-the-fly request classification). We address the challenges of selecting hardware counter metrics for signature construction and providing necessary operating system support for per-request statistics management. Our implementation in the Linux 2.6.10 kernel suggests that our approach requires low overhead suitable for runtime deployment. Our on-the-fly request resource consumption inference (averaging 7%, 3%, 20%, and 41% prediction errors for four server workloads, TPC-C, TPC-H, J2EE-based RUBiS, and a trace-driven index search, respectively) is much more accurate than the online running-average based prediction (73-82% errors). Its use for resource-aware request scheduling results in a 15-70% response time reduction for three CPU-bound applications. Its use for on-the-fly request classification and anomaly detection exhibits high accuracy for the TPC-H workload with synthetically generated anomalous requests following a typical SQL-injection attack pattern.
Parallelizing security checks on commodity hardware
Authors: Nightingale Edmund B. , Peek Daniel , Chen Peter M. , Flinn Jason
Published: April 2008

Speck (Speculative Parallel Check) is a system thataccelerates powerful security checks on commodity hardware by executing them in parallel on multiple cores. Speck provides an infrastructure that allows
sequential
invocations of a particular security check to run in parallel without sacrificing the safety of the system. Speck creates parallelism in two ways. First, Speck decouples a security check from an application by continuing the application, using speculative execution, while the security check executes in parallel on another core. Second, Speck creates parallelism between sequential invocations of a security check by running later checks in parallel with earlier ones. Speck provides a process-level replay system to deterministically and efficiently synchronize state between a security check and the original process.We use Speck to parallelize three security checks: sensitive data analysis, on-access virus scanning, and taint propagation. Running on a 4-core and an 8-core computer, Speck improves performance 4x and 7.5x for the sensitive data analysis check, 3.3x and 2.8x for theon-access virus scanning check, and 1.6x and 2x for the taint propagation check.
New problem
Authors: Polivka Ray
Published: April 2008

Let us have some fun selecting out diagonals from rank 2 and 3 arrays. It is really an exercise in using some of the lesser-used but powerful primitive APL functions. There are probably several ways to arrive at the solutions. Let's see what we get.
A solution to the diagonal sums on spiral matrices
Authors: Fornallaz Andrew W.
Published: April 2008

This paper refers to the section Exercises and Problems, published in the September 2007 APL Quote Quad issue, Volume 35, Number 3, and to the problem Diagonal Sums on Spiral Matrices, proposed by Ray Polivka.
Serial experiments online
Authors: Ramos-Munoz Juan J. , Yamamoto Lidia , Tschudin Christian
Published: April 2008

Current network protocols must comply with rigid interfaces and rules of behavior to fit into well defined, vertical protocol stacks. It is difficult for network designers to offer a wide spectrum of alternative protocols suitable for diverse situations, and to make the stack evolve to match new needs. The tendency is to design protocols that can adapt to the widest possible spread of use. However, even the best adaptive protocols cannot possibly cope with all situations. When their adaptivity limits are reached, the ability to switch to other protocols becomes a clear advantage

Our aim in this paper is to present Lightweight Autonomous resIlient Networks (LAIN), a framework that exploits the multiplicity of alternative protocol, and exposes the spectrum of choice to the advantage of the applications. The system runs continuous experiments with alternative protocols online, in parallel as well as serially, in order to select automatically those that best match the application's needs under the current network conditions. We report first results on the feasibility of the approach and point out the need for such a system in network and protocol evolution
My ten favorite "practical theory" papers
Authors: Rexford Jennifer
Published: April 2008

As the saying goes, "In theory there is no difference between theory and practice. But, in practice, there is." Networking research has a wealth of good papers on both sides of the theory-practice divide. However, many practical papers stop short of having a sharp problem formulation or a rigorously considered solution, and many theory papers overlook or assume away some key aspect of the system they intend to model. Still, every so often, a paper comes along that nails a practical question with just the right bit of theory. When that happens, it's a thing of beauty. These are my ten favorite examples. In some cases, I mention survey papers that cover an entire body of work, or a journal paper that presents a more mature overview of one or more conference papers, rather than single out an individual research result. (As an aside, I think good survey papers are a wonderful contribution to the community, and wish more people invested the considerable time and energy required to write them
Modeling internet topology dynamics
Authors: Haddadi Hamed , Uhlig Steve , Moore Andrew , Mortier Richard , Rio Miguel
Published: April 2008

Despite the large number of papers on network topology modeling and inference, there still exists ambiguity about the real nature of the Internet AS and router level topology. While recent findings have illustrated the inaccuracies in maps inferred from BGP peering and traceroute measurements, existing topology models still produce static topologies, using simplistic assumptions about power law observations and preferential attachment.

Today, topology generators are tightly bound to the observed data used to validate them. Given that the actual properties of the Internet topology are not known, topology generators should strive to reproduce the variability that characterizes the evolution of the Internet topology over time. Future topology generators should be able to express the variations in local connectivity that makes today's Internet: peering relationships, internal AS topology and routing policies each changing over time due to failures, maintenance, upgrades and business strategies of the network. Topology generators should capture those dimensions, by allowing a certain level of randomness in the outcome, rather than enforcing structural assumptions as the truths about Internet's evolving structure, which may never be discovered
OpenFlow
Authors: McKeown Nick , Anderson Tom , Balakrishnan Hari , Parulkar Guru , Peterson Larry , Rexford Jennifer , Shenker Scott , Turner Jonathan
Published: April 2008

This whitepaper proposes OpenFlow: a way for researchers to run experimental protocols in the networks they use every day. OpenFlow is based on an Ethernet switch, with an internal flow-table, and a standardized interface to add and remove flow entries. Our goal is to encourage networking vendors to add OpenFlow to their switch products for deployment in college campus backbones and wiring closets. We believe that OpenFlow is a pragmatic compromise: on one hand, it allows researchers to run experiments on heterogeneous switches in a uniform way at line-rate and with high port-density; while on the other hand, vendors do not need to expose the internal workings of their switches. In addition to allowing researchers to evaluate their ideas in real-world traffic settings, OpenFlow could serve as a useful campus component in proposed large-scale testbeds like GENI. Two buildings at Stanford University will soon run OpenFlow networks, using commercial Ethernet switches and routers. We will work to encourage deployment at other schools; and We encourage you to consider deploying OpenFlow in your university network too
Gender in African Population Research: The Fertility/Reproductive Health Example
Authors: Dodoo F. Nii-Amoo , Frost Ashley E.
Published: April 2008

We survey the literature on sub-Saharan Africa to identify how gender has factored into explaining fertility levels and behavior. Tracing the development of male role theory, we argue that despite increasing awareness of men's authority, fertility research continues to focus almost exclusively on women and treats gender as a property of individuals instead of as a system of inequality. The mainstream fertility literature generally overlooks the decision-making nexus wherein men's authority seemingly overrides women's preferences. Positing that male authority in the reproductive and sexual arenas is predicated on cultural rights negotiated at marriage—and undergirded by bridewealth payments—we contend that attempts to understand (and change) reproductive behavior will hardly be sustainable without attention to this contextual realm. In that vein, we speculate that efforts to empower women (via increased education, occupational opportunities, microcredit schemes, etc.) may hardly yield sustainable outcomes without concurrent efforts to alter cultural distributions of gendered power.
Telomeres and Aging
Authors: Aubert Geraldine , Lansdorp Peter M.
Published: April 2008

Telomeres play a central role in cell fate and aging by adjusting the cellular response to stress and growth stimulation on the basis of previous cell divisions and DNA damage. At least a few hundred nucleotides of telomere repeats must “cap” each chromosome end to avoid activation of DNA repair pathways. Repair of critically short or “uncapped” telomeres by telomerase or recombination is limited in most somatic cells and apoptosis or cellular senescence is triggered when too many “uncapped” telomeres accumulate. The chance of the latter increases as the average telomere length decreases. The average telomere length is set and maintained in cells of the germline which typically express high levels of telomerase. In somatic cells, telomere length is very heterogeneous but typically declines with age, posing a barrier to tumor growth but also contributing to loss of cells with age. Loss of (stem) cells via telomere attrition provides strong selection for abnormal and malignant cells, a process facilitated by the genome instability and aneuploidy triggered by dysfunctional telomeres. The crucial role of telomeres in cell turnover and aging is highlighted by patients with 50% of normal telomerase levels resulting from a mutation in one of the telomerase genes. Short telomeres in such patients are implicated in a variety of disorders including dyskeratosis congenita, aplastic anemia, pulmonary fibrosis, and cancer. Here the role of telomeres and telomerase in human aging and aging-associated diseases is reviewed.
Nonsynaptic Chemical Transmission Through Nicotinic Acetylcholine Receptors
Authors: Lendvai Balázs , Vizi E. Sylvester
Published: April 2008

This review attempts to organize the different aspects of nicotinic transmission in the context of nonsynaptic interactions. Nicotinic acetylcholine receptors (nAChRs) dominantly operate in the nonsynaptic mode in the central nervous system despite their ligand-gated ion-channel nature, which would otherwise be better suited for fast synaptic transmission. This fast form of nonsynaptic transmission, most likely unique to nAChRs, represents a new avenue in the communication platforms of the brain. Cholinergic messages received by nAChRs, arriving at a later phase following synaptic activation, can interfere with dendritic signal integration. Nicotinic transmission plays a role in both neural plasticity and cellular learning processes, as well as in long-term changes in basic activity through fast activation, desensitization of receptors, and fluctuations of the steady-state levels of ACh. ACh release can contribute to plastic changes via activation of nAChRs in neurons and therefore plays a role in learning and memory in different brain regions. Assuming that nAChRs in human subjects are ready to receive long-lasting messages from the extracellular space because of their predominantly nonsynaptic distribution, they offer an ideal target for drug therapy at low, nontoxic drug levels.
CLC-0 and CFTR: Chloride Channels Evolved From Transporters
Authors: Chen Tsung-Yu , Hwang Tzyh-Chang
Published: April 2008

CLC-0 and cystic fibrosis transmembrane conductance regulator (CFTR) Cl−channels play important roles in Cl−transport across cell membranes. These two proteins belong to, respectively, the CLC and ABC transport protein families whose members encompass both ion channels and transporters. Defective function of members in these two protein families causes various hereditary human diseases. Ion channels and transporters were traditionally viewed as distinct entities in membrane transport physiology, but recent discoveries have blurred the line between these two classes of membrane transport proteins. CLC-0 and CFTR can be considered operationally as ligand-gated channels, though binding of the activating ligands appears to be coupled to an irreversible gating cycle driven by an input of free energy. High-resolution crystallographic structures of bacterial CLC proteins and ABC transporters have led us to a better understanding of the gating properties for CLC and CFTR Cl−channels. Furthermore, the joined force between structural and functional studies of these two protein families has offered a unique opportunity to peek into the evolutionary link between ion channels and transporters. A promising byproduct of this exercise is a deeper mechanistic insight into how different transport proteins work at a fundamental level.
Detection of Early Prostate Cancer Using a Hepsin-Targeted Imaging Agent
Authors: Kelly Kimberly A. , Setlur Sunita R. , Ross Robert , Anbazhagan Rajesh , Waterman Peter , Rubin Mark A. , Weissleder Ralph
Published: April 2008

Early detection and diagnosis of prostate cancer is key to designing effective treatment strategies. Microarrays have resulted in the discovery of hepsin (HPN) as a biomarker for detection of prostate cancer. In this study, we explore the development of HPN imaging probes for detection of prostate cancer. We used phage display to isolate HPN binding peptides with 190 + 2.2 nmol/L affinity in monomeric form and high specificity. The identified peptides were able to detect human prostate cancer on tissue microarrays and in cell-based assays. HPN-targeted imaging agents were synthesized by conjugating multiple peptides to fluorescent nanoparticles to further improve avidity through multivalency and to improve pharmacokinetics. When injected into mouse xenograft models, HPN-targeted nanoparticles bound specifically to HPN-expressing LNCaP xenografts compared with non–HPN-expressing PC3 xenografts. HPN imaging may provide a new method for detection of prostate cancer. [Cancer Res 2008;68(7):2286–91]
TTI-237: A Novel Microtubule-Active Compound with In vivo Antitumor Activity
Authors: Beyer Carl F. , Zhang Nan , Hernandez Richard , Vitale Danielle , Lucas Judy , Nguyen Thai , Discafani Carolyn , Ayral-Kaloustian Semiramis , Gibbons James J.
Published: April 2008

5-Chloro-6-[2,6-difluoro-4-[3-(methylamino)propoxy]phenyl]-N-[(1S)-2,2,2-trifluoro-1-methylethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine butanedioate (TTI-237) is a microtubule-active compound of novel structure and function. Structurally, it is one of a class of compounds, triazolo[1,5a]pyrimidines, previously not known to bind to tubulin. Functionally, TTI-237 inhibited the binding of [3H]vinblastine to tubulin, but it caused a marked increase in turbidity development that more closely resembled the effect observed with docetaxel than that observed with vincristine. The morphologic character of the presumptive polymer is unknown at present. When applied to cultured human tumor cells at concentrations near its IC50 value for cytotoxicity (34 nmol/L), TTI-237 induced multiple spindle poles and multinuclear cells, as did paclitaxel, but not vincristine or colchicine. Flow cytometry experiments revealed that, at low concentrations (20–40 nmol/L), TTI-237 produced sub-G1 nuclei and, at concentrations above 50 nmol/L, it caused a strong G2-M block. The compound was a weak substrate of multidrug resistance 1 (multidrug resistance transporter or P-glycoprotein). In a cell line expressing a high level of P-glycoprotein, the IC50 of TTI-237 increased 25-fold whereas those of paclitaxel and vincristine increased 806-fold and 925-fold, respectively. TTI-237 was not recognized by the MRP or MXR transporters. TTI-237 was active in vivo in several nude mouse xenograft models of human cancer, including LoVo human colon carcinoma and U87-MG human glioblastoma, when dosed i.v. or p.o. Thus, TTI-237 has a set of properties that distinguish it from other classes of microtubule-active compounds. [Cancer Res 2008;68(7):2292–300]
c-Jun NH2-Terminal Kinase Activating Kinase 1/Mitogen-Activated Protein Kinase Kinase 4–Mediated Inhibition of SKOV3ip.1 Ovarian Cancer Metastasis Involves Growth Arrest and p21 Up-regulation
Authors: Lotan Tamara , Hickson Jonathan , Souris Jeffrey , Huo Dezheng , Taylor Jennifer , Li Terry , Otto Kristen , Yamada Seiko Diane , Macleod Kay , Rinker-Schaeffer Carrie W.
Published: April 2008

In many patients without clinical metastases, cancer cells have already escaped from the primary tumor and entered a distant organ. A long-standing question in metastasis research is why some disseminated cancer cells fail to complete steps of metastatic colonization for extended periods of time. Our laboratory identified c-Jun NH2-terminal kinase activating kinase 1/mitogen-activated protein kinase kinase 4 (JNKK1/MKK4) as a metastasis suppressor protein in a mouse xenograft model of experimental i.p. ovarian cancer metastasis. In this model, expression of JNKK1/MKK4 via activation of p38 delays formation of ≥1-mm implants and prolongs animal survival. Here, we elucidate the time course of this delay as well as the biological mechanisms underpinning it. Using the Gompertz function to model the net accumulation of experimental omental metastases, we show that MKK4-expressing implants arise, on average, 30 days later than controls. Quantitative real-time PCR shows that MKK4 expression does not have a substantial effect on the number of cancer cells initially adhering to the omentum, and terminal deoxyribonucleotidyl transferase–mediated dUTP nick end labeling analysis shows that there is no increase in apoptosis in these cells. Instead, immunohistochemical quantitation of cell cycle proteins reveals that MKK4-expressing cells fail to proliferate once they reach the omentum and up-regulate p21, a cell cycle inhibitor. Consistent with the time course data, in vitro kinase assays and in vivo passaging of cell lines derived from macroscopic metastases show that the eventual outgrowth of MKK4-expressing cells is not due to a discrete selection event. Rather, the population of MKK4-expressing cells eventually uniformly adapts to the consequences of up-regulated MKK4 signaling. [Cancer Res 2008;68(7):2166–75]
EWS-FLI-1 Expression Triggers a Ewing's Sarcoma Initiation Program in Primary Human Mesenchymal Stem Cells
Authors: Riggi Nicolò , Suvà Mario-Luca , Suvà Domizio , Cironi Luisa , Provero Paolo , Tercier Stéphane , Joseph Jean-Marc , Stehle Jean-Christophe , Baumer Karine , Kindler Vincent , Stamenkovic Ivan
Published: April 2008

Ewing's sarcoma family tumors (ESFT) express the EWS-FLI-1 fusion gene generated by the chromosomal translocation t(11;22)(q24;q12). Expression of the EWS-FLI-1 fusion protein in a permissive cellular environment is believed to play a key role in ESFT pathogenesis. However, EWS-FLI-1 induces growth arrest or apoptosis in differentiated primary cells, and the identity of permissive primary human cells that can support its expression and function has until now remained elusive. Here we show that expression of EWS-FLI-1 in human mesenchymal stem cells (hMSC) is not only stably maintained without inhibiting proliferation but also induces a gene expression profile bearing striking similarity to that of ESFT, including genes that are among the highest ESFT discriminators. Expression of EWS-FLI-1 in hMSCs may recapitulate the initial steps of Ewing's sarcoma development, allowing identification of genes that play an important role early in its pathogenesis. Among relevant candidate transcripts induced by EWS-FLI-1 in hMSCs, we found the polycomb group gene EZH2, which we show to play a critical role in Ewing's sarcoma growth. These observations are consistent with our recent findings using mouse mesenchymal progenitor cells and provide compelling evidence that hMSCs are candidate cells of origin of ESFT. [Cancer Res 2008;68(7):2176–85]
Six1 Overexpression in Mammary Cells Induces Genomic Instability and Is Sufficient for Malignant Transformation
Authors: Coletta Ricardo D. , Christensen Kimberly L. , Micalizzi Douglas S. , Jedlicka Paul , Varella-Garcia Marileila , Ford Heide L.
Published: April 2008

Homeoproteins are transcription factors that act as master regulators of development and are frequently dysregulated in cancers. During embryogenesis, the Six1 homeoprotein is essential for the expansion of precursor cell populations that give rise to muscle and kidney, among other organs. Six1 overexpression is observed in numerous cancers, resulting in increased proliferation, survival, and metastasis. Here, we investigate whether Six1 can play a causal role in mammary tumor initiation. We show that Six1 overexpression in MCF12A mammary epithelial cells promotes multiple properties associated with malignant transformation, including increased proliferation, genomic instability, and anchorage-independent growth. We further show that this transformation is dependent on up-regulation of its transcriptional target, cyclin A1, which is normally expressed in the embryonic mammary gland but dramatically reduced in the adult gland. Six1-transformed MCF12A cells are tumorigenic in nude mice, forming aggressive tumors that are locally invasive and exhibit peritumoral lymphovascular invasion. In human breast carcinomas, expression of Six1 and cyclin A1 mRNA correlate strongly with each other (P < 0.0001), and expression of Six1 and cyclin A1 each correlate with Ki67, a marker of proliferation (P < 0.0001 and P = 0.014, respectively). Together, our data indicate that Six1 overexpression is sufficient for malignant transformation of immortalized, nontumorigenic mammary epithelial cells, and suggest that the mechanism of this transformation involves inappropriate reexpression of cyclin A1 in the adult mammary gland. [Cancer Res 2008;68(7):2204–13]
Elevated Ornithine Decarboxylase Levels Activate Ataxia Telangiectasia Mutated–DNA Damage Signaling in Normal Keratinocytes
Authors: Wei Gang , DeFeo Karen , Hayes Candace S. , Woster Patrick M. , Mandik-Nayak Laura , Gilmour Susan K.
Published: April 2008

We examined the effect of increased expression of ornithine decarboxylase (ODC), a key rate-limiting enzyme in polyamine biosynthesis, on cell survival in primary cultures of keratinocytes isolated from the skin of K6/ODC transgenic mice (Ker/ODC) and their normal littermates (Ker/Norm). Although elevated levels of ODC and polyamines stimulate proliferation of keratinocytes, Ker/ODC undergo apoptotic cell death within days of primary culture unlike Ker/Norm that continue to proliferate. Phosphorylation of ataxia telangiectasia mutated (ATM) and its substrate p53 are significantly induced both in Ker/ODC and in K6/ODC transgenic skin. Chromatin immunoprecipitation analyses show that the increased level of p53 in Ker/ODC is accompanied by increased recruitment of p53 to the Bax proximal promoter. ATM activation is polyamine dependent because α-difluoromethylornithine, a specific inhibitor of ODC activity, blocks its phosphorylation. Ker/ODC also displays increased generation of H2O2, acrolein-lysine conjugates, and protein oxidation products as well as polyamine-dependent DNA damage, as measured by the comet assay and the expression of the phosphorylated form of the histone variant γH2AX. Both reactive oxygen species generation and apoptotic cell death of Ker/ODC may, at least in part, be due to induction of a polyamine catabolic pathway that generates both H2O2 and cytotoxic aldehydes, because spermine oxidase (SMO) levels are induced in Ker/ODC. In addition, treatment with MDL 72,527, an inhibitor of SMO, blocks the production of H2O2 and increases the survival of Ker/ODC. These results show a novel activation of the ATM-DNA damage signaling pathway in response to increased ODC activity in nontumorigenic keratinocytes. [Cancer Res 2008;68(7):2214–22]
Therapeutic Efficacy of ABT-737, a Selective Inhibitor of BCL-2, in Small Cell Lung Cancer
Authors: Hann Christine L. , Daniel Vincent C. , Sugar Elizabeth A. , Dobromilskaya Irina , Murphy Sara C. , Cope Leslie , Lin Xue , Hierman Jared S. , Wilburn Daniel L. , Watkins D. Neil , Rudin Charles M.
Published: April 2008

Bcl-2 is a central regulator of cell survival that is overexpressed in the majority of small cell lung cancers (SCLC) and contributes to both malignant transformation and therapeutic resistance. We compared primary SCLC xenografts prepared from de novo human tumors with standard cell line–based xenografts in the evaluation of a novel and highly potent small molecule inhibitor of Bcl-2, ABT-737. ABT-737 induced dramatic regressions in tumors derived from some SCLC cell lines. In contrast, only one of three primary xenograft SCLC tumors showed significant growth inhibition with ABT-737. Explanations for this apparent dichotomy may include relatively low expression of Bcl-2 in the primary xenografts or inherent differences in the model systems. The addition of etoposide to ABT-737 in the primary xenografts resulted in significant decreases in tumor growth, underscoring the clinical potential of ABT-737 in combination therapy. To identify factors that may contribute to resistance to ABT-737 and related inhibitors, we isolated resistant derivatives of an initially sensitive cell line–based xenograft. Acquired resistance in this model was associated with decreases in the expression of the primary target Bcl-2, of proapoptotic partners of Bcl-2 (Bax and Bim), and of Bcl-2:Bim heterodimers. Expression profiling reveals 85 candidate genes demonstrating consistent changes in gene expression with acquired resistance. Taken together, these data have specific implications for the clinical development of Bcl-2 inhibitors for SCLC and broader implications for the testing of novel anticancer strategies in relevant preclinical models. [Cancer Res 2008;68(7):2321–8]
Genetic Variation in the One-Carbon Transfer Pathway and Ovarian Cancer Risk
Authors: Kelemen Linda E. , Sellers Thomas A. , Schildkraut Joellen M. , Cunningham Julie M. , Vierkant Robert A. , Pankratz V. Shane , Fredericksen Zachary S. , Gadre Madhura K. , Rider David N. , Liebow Mark , Goode Ellen L.
Published: April 2008

Dysfunction in enzymes involved in one-carbon (1-C) metabolism can lead to increased chromosomal strand breaking and abnormal methylation patterns, which are both associated with cancer risk. Availability of 1-C units may modify risk. We investigated the association of single-nucleotide polymorphisms (SNP) in 21 genes in the 1-C transfer pathway among 829 Caucasian cases with primary epithelial ovarian cancer and 941 frequency-matched unaffected controls enrolled at Mayo Clinic (Rochester, MN) and Duke University (Durham, NC) and examined risk modification by multivitamin supplement use. Multivariable-adjusted SNP-specific logistic regression and haplotype analyses were done for 180 SNPs and false positive report probabilities (FPRP) were calculated. Each copy of the minor allele in SHMT1 intron 5 A>G (rs9909104) was associated with epithelial ovarian cancer [odds ratio (OR), 1.2; 95% confidence interval (95% CI), 1.0–1.4; P trend = 0.02; FPRP = 0.16] and a 5-SNP SHMT1 haplotype was associated with decreased risk (P = 0.01; FPRP = 0.09). Three SNPs in DNMT3A were associated with risk among multivitamin supplement users: 3′ untranslated region (UTR) C>G (rs13420827: OR, 0.8; 95% CI, 0.6–1.0; P interaction = 0.006; FPRP = 0.54), intron 6 G>A (rs11887120: OR, 0.8; 95% CI, 0.7–1.0; P interaction = 0.007; FPRP = 0.57), and intron 22 A>T (rs11695471: OR, 1.2; 95% CI, 1.0–1.5; P interaction = 0.01; FPRP = 0.66). These data extend previous findings from other cancers of a role for SHMT1 in ovarian cancer, and provide evidence that SNPs in methylation and DNA synthesis reactions are associated with risk of ovarian cancer. Interventions with modifiable factors such as multivitamin intake may reduce risk. [Cancer Res 2008;68(7):2498–506]
Loss of E-Cadherin Promotes Ovarian Cancer Metastasis via α5-Integrin, which Is a Therapeutic Target
Authors: Sawada Kenjiro , Mitra Anirban K. , Radjabi A. Reza , Bhaskar Vinay , Kistner Emily O. , Tretiakova Maria , Jagadeeswaran Sujatha , Montag Anthony , Becker Amy , Kenny Hilary A. , Peter Marcus E. , Ramakrishnan Vanitha , Yamada S. Diane , Lengyel Ernst
Published: April 2008

E-cadherin loss is frequently associated with ovarian cancer metastasis. Given that adhesion to the abdominal peritoneum is the first step in ovarian cancer dissemination, we reasoned that down-regulation of E-cadherin would affect expression of cell matrix adhesion receptors. We show here that inhibition of E-cadherin in ovarian cancer cells causes up-regulation of α5-integrin protein expression and transcription. When E-cadherin was blocked, RMUG-S ovarian cancer cells were able to attach and invade more efficiently. This greater efficiency could, in turn, be inhibited both in vitro and in vivo with an α5β1-integrin–blocking antibody. When E-cadherin is silenced, α5-integrin is up-regulated through activation of an epidermal growth factor receptor/FAK/Erk1–mitogen-activated protein kinase–dependent signaling pathway and not through the canonical E-cadherin/β-catenin signaling pathway. In SKOV-3ip1 ovarian cancer xenografts, which express high levels of α5-integrin, i.p. treatment with an α5β1-integrin antibody significantly reduced tumor burden, ascites, and number of metastasis and increased survival by an average of 12 days when compared with IgG treatment (P < 0.0005). α5-Integrin expression was detected by immunohistochemistry in 107 advanced stage ovarian cancers using a tissue microarray annotated with disease-specific patient follow-up. Ten of 107 tissues (9%) had α5-integrin overexpression, and 39% had some level of α5-integrin expression. The median survival for patients with high α5-integrin levels was 26 months versus 35 months for those with low integrin expression (P < 0.05). Taken together, we have identified α5-integrin up-regulation as a molecular mechanism by which E-cadherin loss promotes tumor progression, providing an explanation for how E-cadherin loss increases metastasis. Targeting this integrin could be a promising therapy for a subset of ovarian cancer patients. [Cancer Res 2008;68(7):2329–39]
Epidermal Growth Factor Receptor Gene Amplification Is Acquired in Association with Tumor Progression of EGFR-Mutated Lung Cancer
Authors: Yatabe Yasushi , Takahashi Takashi , Mitsudomi Tetsuya
Published: April 2008

Both mutation and amplification of epidermal growth factor receptor (EGFR) in lung cancers have been reported in association with clinical responses to tyrosine kinase inhibitors. We have reported evidence implicating mutation specifically in the “terminal respiratory unit” type of adenocarcinoma, which is characterized by expression of thyroid transcription factor 1, a lineage marker of peripheral airway cells. However, little is known about the role of gene amplification in the molecular progression of lung adenocarcinoma. In this study, we examined the topographical distribution of amplification in three microdissected portions each of 48 individual lung cancers with confirmed mutations. Relative copy number of the gene was analyzed using Taq Man–based gene dosage analysis and fluorescent in situ hybridization technique. Gene amplification was found in 11 lung cancers. Strikingly, nine of the cancers showed heterogeneous distribution, and amplification was associated with higher histologic grade or invasive growth. Because it was likely that the high-grade lesions were the origin for metastases, metastatic lymph nodes corresponding to five tumors with heterogeneous distribution were analyzed. Unexpectedly, amplification status of the metastatic sites was not always associated with gene amplification of the primary tumors, suggesting that selection of the metastatic clone may be defined by other factors. We also examined 17 precursor lesions and 21 in situ lung adenocarcinomas, and found that only one in situ carcinoma harbored gene amplification. Taken together, our results show that mutation occurs early in the development of lung adenocarcinoma, and that amplification may be acquired in association with tumor progression. [Cancer Res 2008;68(7):2106–11]
Statins Increase p21 through Inhibition of Histone Deacetylase Activity and Release of Promoter-Associated HDAC1/2
Authors: Lin Yi-Chu , Lin Jung-Hsin , Chou Chia-Wei , Chang Yu-Fan , Yeh Shu-Hao , Chen Ching-Chow
Published: April 2008

Statins are 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors broadly used for the control of hypercholesterolemia. Recently, they are reported to have beneficial effects on certain cancers. In this study, we show that statins inhibited the histone deacetylase (HDAC) activity and increased the accumulation of acetylated histone-H3 and the expression of p21WAF/CIP in human cancer cells. Computational modeling showed the direct interaction of the carboxylic acid moiety of statins with the catalytic site of HDAC2. In the subsequent enzymatic assay, it was shown that lovastatin inhibited HDAC2 activity competitively with a Ki value of 31.6 μmol/L. Sp1 but not p53 sites were found to be the statins-responsive element shown by p21 luciferase-promoter assays. DNA affinity protein binding assay and chromatin immunoprecipitation assay showed the dissociation of HDAC1/2 and association of CBP, leading to the histone-H3 acetylation on the Sp1 sites of p21 promoter. In vitro cell proliferation and in vivo tumor growth were both inhibited by statins. These results suggest a novel mechanism for statins through abrogation of the HDAC activity and promoter histone-H3 acetylation to regulate p21 expression. Therefore, statins might serve as novel HDAC inhibitors for cancer therapy and chemoprevention. [Cancer Res 2008;68(7):2375–83]
An Effective Vaccine Strategy Protective against Antigenically Distinct Tumor Variants
Authors: Pavelko Kevin D. , Heckman Karin L. , Hansen Michael J. , Pease Larry R.
Published: April 2008

Antigenically distinct tumor variants can emerge in response to selective pressures inherent to host-tumor interactions. The development of successful immunotherapeutic strategies can be limited by these disparate antigenic profiles. Using the immunomodulator B7-DC XAb to activate cytolytic T cells specific for tumor-associated antigens, we found that the specificity of immune responses elicited by live tumors are distinct from the specificity of the responses elicited by soluble proteins derived from the same tumors. Remarkably, whereas the induced antitumor immunity generated against live variants of the B16 melanoma and EL4 thymic lymphoma tumors were highly specific for the original tumor variant used in the challenge, immunity generated using soluble proteins derived from tumor lysates was broadly reactive, recognizing the challenge tumor, as well as antigenically distinct variants. The antigens detected using live tumor and tumor lysate vaccines could be distinguished biochemically, demonstrating that they are structurally distinct. We show that vaccines using antigens present in tumor cell lysates induce protective immunity with strong memory against distantly related tumor variants. The existence of a class of antigens shared among tumor variants provides an attractive target for vaccine development. [Cancer Res 2008;68(7):2471–8]
Evaluation of Genetic Variants in MicroRNA-Related Genes and Risk of Bladder Cancer
Authors: Yang Hushan , Dinney Colin P. , Ye Yuanqing , Zhu Yong , Grossman H. Barton , Wu Xifeng
Published: April 2008

MicroRNAs (miRNA) are small noncoding RNA molecules involved in a diversity of cellular functions. Although it has been reported that global suppression of the miRNA biogenesis pathway leads to enhanced tumorigenesis, the effect of common genetic variants of miRNA-related genes on cancer predisposition is unclear. To better understand this effect, we genotyped 41 single-nucleotide polymorphisms (SNP) from 24 miRNA-related genes in a case-control study conducted in 746 Caucasian patients with bladder cancer and 746 matched controls. The homozygous variant genotype of a nonsynonymous SNP in the GEMIN3 gene (rs197414) was associated with a significantly increased bladder cancer risk [odds ratios (OR), 2.40; 95% confidence interval (95% CI), 1.04–5.56]. Several additional miRNA-related SNPs were also identified that showed a borderline significant association with bladder cancer risk. Haplotype analysis indicated that a common haplotype of the GEMIN4 gene was associated with a significantly increased bladder cancer risk with an OR of 1.25 (95% CI, 1.01–1.54). To assess the aggregate effects of the promising SNPs, we performed a combined unfavorable genotype analysis that included all SNPs showing at least a borderline statistical significance. We found that, compared with the low-risk reference group with less than two unfavorable genotypes, the medium-risk group with two unfavorable genotypes exhibited a 1.29-fold (0.92–1.81) increased risk whereas the high-risk group with more than two unfavorable genotypes exhibited a 1.92-fold (1.36–2.71) increased risk (Ptrend < 0.0001). Overall, this is the first epidemiologic study showing that miRNA-related genetic variants may affect bladder cancer risk individually and jointly. [Cancer Res 2008;68(7):2530–7]
Activator Protein-1 Transcription Factors Are Associated with Progression and Recurrence of Prostate Cancer
Authors: Ouyang Xuesong , Jessen Walter J. , Al-Ahmadie Hikmat , Serio Angel M. , Lin Yong , Shih Weichung-Joseph , Reuter Victor E. , Scardino Peter T. , Shen Michael M. , Aronow Bruce J. , Vickers Andrew J. , Gerald William L. , Abate-Shen Cory
Published: April 2008

To identify biomarkers that discriminate the aggressive forms of prostate cancer, we performed gene expression profiling of prostate tumors using a genetically engineered mouse model that recapitulates the stages of human prostate cancer, namely Nkx3.1; Pten mutant mice. We observed a significant deregulation of the epidermal growth factor and mitogen-activated protein kinase (MAPK) signaling pathways, as well as their major downstream effectors—the activator protein-1 transcription factors c-Fos and c-Jun. Forced expression of c-Fos and c-Jun in prostate cancer cells promotes tumorigenicity and results in activation of extracellular signal-regulated kinase (Erk) MAPK signaling. In human prostate cancer, up-regulation of c-Fos and c-Jun proteins occurs in advanced disease and is correlated with Erk MAPK pathway activation, whereas high levels of c-Jun expression are associated with disease recurrence. Our analyses reveal a hitherto unappreciated role for AP-1 transcription factors in prostate cancer progression and identify c-Jun as a marker of high-risk prostate cancer. This study provides a striking example of how accurate mouse models can provide insights on molecular processes involved in progression and recurrence of human cancer. [Cancer Res 2008;68(7):2132–44]