bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overshadow
Authors: Chen Xiaoxin , Garfinkel Tal , Lewis E. Christopher , Subrahmanyam Pratap , Waldspurger Carl A. , Boneh Dan , Dwoskin Jeffrey , Ports Dan R.K. 
Published: April 2008

Commodity operating systems entrusted with securing sensitive data are remarkably large and complex, and consequently, frequently prone to compromise. To address this limitation, we introduce a virtual-machine-based system called Overshadow that protects the privacy and integrity of application data, even in the event of a total OScompromise. Overshadow presents an application with a normal view of its resources, but the OS with an encrypted view. This allows the operating system to carry out the complex task of managing an application's resources, without allowing it to read or modify them. Thus, Overshadow offers a last line of defense for application data.
Overshadow builds on multi-shadowing, a novel mechanism that presents different views of "physical" memory, depending on the context performing the access. This primitive offers an additional dimension of protection beyond the hierarchical protection domains implemented by traditional operating systems and processor architectures.
We present the design and implementation of Overshadow and show how its new protection semantics can be integrated with existing systems. Our design has been fully implemented and used to protect a wide range of unmodified legacy applications running on an unmodified Linux operating system. We evaluate the performance of our implementation, demonstrating that this approach is practical.
Accelerating two-dimensional page walks for virtualized systems
Authors: Bhargava Ravi , Serebrin Benjamin , Spadini Francesco , Manne Srilatha 
Published: April 2008

Nested paging is a hardware solution for alleviating the software memory management overhead imposed by system virtualization. Nested paging complements existing page walk hardware to form a two-dimensional (2D) page walk, which reduces the need for hypervisor intervention in guest page table management. However, the extra dimension also increases the maximum number of architecturally-required page table references.
This paper presents an in-depth examination of the 2D page table walk overhead and options for decreasing it. These options include using the AMD Opteron processor's page walk cache to exploit the strong reuse of page entry references. For a mix of server and SPEC benchmarks, the presented results show a 15%-38% improvement in guest performance by extending the existing page walk cache to also store the nested dimension of the 2D page walk. Caching nested page table translations and skipping multiple page entry references produce an additional 3%-7% improvement.
Much of the remaining 2D page walk overhead is due to low-locality nested page entry references, which result in additional memory hierarchy misses. By using large pages, the hypervisor can eliminate many of these long-latency accesses and further improve the guest performance by 3%-22%.
Archipelago
Authors: Lvin Vitaliy B. , Novark Gene , Berger Emery D. , Zorn Benjamin G. 
Published: April 2008

Memory errors are a notorious source of security vulnerabilities that can lead to service interruptions, information leakage and unauthorized access. Because such errors are also difficult to debug, the absence of timely patches can leave users vulnerable to attack for long periods of time. A variety of approaches have been introduced to combat these errors, but these often incur large runtime overheads and generally abort on errors, threatening availability.
This paper presents Archipelago, a runtime system that takes advantage of available address space to substantially reduce the likelihood that a memory error will affect program execution. Archipelago randomly allocates heap objects far apart in virtual address space, effectively isolating each object from buffer overflows. Archipelago also protects against dangling pointer errors by preserving the contents of freed objects after they are freed. Archipelago thus trades virtual address space---a plentiful resource on 64-bit systems---for significantly improved program reliability and security, while limiting physical memory consumption by tracking the working set of an application and compacting cold objects. We show that Archipelago allows applications to continue to run correctly in the face of thousands of memory errors. Across a suite of server applications, Archipelago's performance overhead is 6% on average (between -7% and 22%), making it especially suitable to protect servers that have known security vulnerabilities due to heap memory errors.
Accurate branch prediction for short threads
Authors: Choi Bumyong , Porter Leo , Tullsen Dean M. 
Published: April 2008

Multi-core processors, with low communication costs and high availability of execution cores, will increase the use of execution and compilation models that use short threads to expose parallelism. Current branch predictors seek to incorporate large amounts of control flow history to maximize accuracy. However, when that history is absent the predictor fails to work as intended. Thus, modern predictors are almost useless for threads below a certain length.
Using a Speculative Multithreaded (SpMT) architecture as an example of a system which generates shorter threads, this work examines techniques to improve branch prediction accuracy when a new thread begins to execute on a different core. This paper proposes a minor change to the branch predictor that gives virtually the same performance on short threads as an idealized predictor that incorporates unknowable pre-history of a spawned speculative thread. At the same time, strong performance on long threads is preserved. The proposed technique sets the global history register of the spawned thread to the initial value of the program counter. This novel and simple design reduces branch mispredicts by 29% and provides as much as a 13% IPC improvement on selected SPEC2000 benchmarks.
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.
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
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
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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 &lt; 0.0001), and expression of Six1 and cyclin A1 each correlate with Ki67, a marker of proliferation (P &lt; 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

Abstract
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

Abstract
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]