bluuebunny/crossref_metadata_2025 huggingface dataset:
A first-order mechanistic model for architectural vulnerability factor
Authors: Nair Arun Arvind , Eyerman Stijn , Eeckhout Lieven , John Lizy Kurian
Published: September 2012

Soft error reliability has become a first-order design criterion for modern microprocessors. Architectural Vulnerability Factor (AVF) modeling is often used to capture the probability that a radiation-induced fault in a hardware structure will manifest as an error at the program output. AVF estimation requires detailed microarchitectural simulations which are time-consuming and typically present aggregate metrics. Moreover, it requires a large number of simulations to derive insight into the impact of microarchitectural events on AVF. In this work we present a first-order mechanistic analytical model for computing AVF by estimating the occupancy of correct-path state in important microarchitecture structures through inexpensive profiling. We show that the model estimates the AVF for the reorder buffer, issue queue, load and store queue, and functional units in a 4-wide issue machine with a mean absolute error of less than 0.07. The model is constructed from the first principles of out-of-order processor execution in order to provide novel insight into the interaction of the workload with the microarchitecture to determine AVF. We demonstrate that the model can be used to perform design space explorations to understand trade-offs between soft error rate and performance, to study the impact of scaling of microarchitectural structures on AVF and performance, and to characterize workloads for AVF.
LOT-ECC
Authors: Udipi Aniruddha N. , Muralimanohar Naveen , Balsubramonian Rajeev , Davis Al , Jouppi Norman P.
Published: September 2012

Memory system reliability is a serious and growing concern in modern servers. Existing chipkill-level memory protection mechanisms suffer from several drawbacks. They activate a large number of chips on every memory access -- this increases energy consumption, and reduces performance due to the reduction in rank-level parallelism. Additionally, they increase access granularity, resulting in wasted bandwidth in the absence of sufficient access locality. They also restrict systems to use narrow-I/O x4 devices, which are known to be less energy-efficient than the wider x8 DRAM devices. In this paper, we present LOT-ECC, a localized and multi-tiered protection scheme that attempts to solve these problems. We separate error detection and error correction functionality, and employ simple checksum and parity codes effectively to provide strong fault-tolerance, while simultaneously simplifying implementation. Data and codes are localized to the same DRAM row to improve access efficiency. We use system firmware to store correction codes in DRAM data memory and modify the memory controller to handle data mapping. We thus build an effective fault-tolerance mechanism that provides strong reliability guarantees, activates as few chips as possible (reducing power consumption by up to 44.8% and reducing latency by up to 46.9%), and reduces circuit complexity, all while working with commodity DRAMs and operating systems. Finally, we propose the novel concept of a heterogeneous DIMM that enables the extension of LOT-ECC to x16 and wider DRAM parts.
FLEXclusion
Authors: Sim Jaewoong , Lee Jaekyu , Qureshi Moinuddin K. , Kim Hyesoon
Published: September 2012

Exclusive last-level caches (LLCs) reduce memory accesses by effectively utilizing cache capacity. However, they require excessive on-chip bandwidth to support frequent insertions of cache lines on eviction from upper-level caches. Non-inclusive caches, on the other hand, have the advantage of using the on-chip bandwidth more effectively but suffer from a higher miss rate. Traditionally, the decision to use the cache as exclusive or non-inclusive is made at design time. However, the best option for a cache organization depends on application characteristics, such as working set size and the amount of traffic consumed by LLC insertions.

This paper proposes FLEXclusion, a design that dynamically selects between exclusion and non-inclusion depending on workload behavior. With FLEXclusion, the cache behaves like an exclusive cache when the application benefits from extra cache capacity, and it acts as a non-inclusive cache when additional cache capacity is not useful, so that it can reduce on-chip bandwidth. FLEXclusion leverages the observation that both non-inclusion and exclusion rely on similar hardware support, so our proposal can be implemented with negligible hardware changes. Our evaluations show that a FLEXclusive cache reduces the on-chip LLC insertion traffic by 72.6% compared to an exclusive design and improves performance by 5.9% compared to a non-inclusive design.
Setting an error detection infrastructure with low cost acoustic wave detectors
Authors: Upasani Gaurang , Vera Xavier , González Antonio
Published: September 2012

The continuing decrease in dimensions and operating voltage of transistors has increased their sensitivity against radiation phenomena making soft errors an important challenge in future chip multiprocessors (CMPs). Hence, new techniques for detecting errors in the logic and memories that allow meeting the desired failures-in-time (FIT) budget in CMPs are required.

This paper proposes a low-cost dynamic particle strike detection mechanism through acoustic wave detectors. Our results show that our mechanism can protect both the logic and the memory arrays. As a case study, we also show how this technique can be combined with error codes to protect the last-level cache at low cost.
Viper
Authors: Pellegrini Andrea , Greathouse Joseph L. , Bertacco Valeria
Published: September 2012

The reliability of future processors is threatened by decreasing transistor robustness. Current architectures focus on delivering high performance at low cost; lifetime device reliability is a secondary concern. As the rate of permanent hardware faults increases, robustness will become a first class constraint for even low-cost systems. Current research into reliable architectures has focused on ad-hoc solutions to improve designs without altering their centralized control logic. Unfortunately, this centralized control presents a single point of failure, which limits long-term robustness.

To address this issue, we introduce Viper, an architecture built from a redundant collection of fine-grained hardware components. Instructions are perceived as customers that require a sequence of services in order to properly execute. The hardware components vie to perform what services they can, dynamically forming virtual pipelines that avoid defective hardware. This is done using distributed control logic, which avoids a single point of failure by construction.

Viper can tolerate a high number of permanent faults due to its inherent redundancy. As fault counts increase, its performance degrades more gracefully than traditional centralized-logic architectures. We estimate that fault rates higher than one permanent faults per 12 million transistors, on average, cause the throughput of a classic CMP design to fall below that of a Viper design of similar size.
Buffer-on-board memory systems
Authors: Cooper-Balis Elliott , Rosenfeld Paul , Jacob Bruce
Published: September 2012

The design and implementation of the commodity memory architecture has resulted in significant performance and capacity limitations. To circumvent these limitations, designers and vendors have begun to place intermediate logic between the CPU and DRAM. This additional logic has two functions: to control the DRAM and to communicate with the CPU over a fast and narrow bus. The benefit provided by this logic is a reduction in pin-out to the memory system and increased signal integrity to the DRAM, allowing faster clock rates while maintaining capacity. While the few vendors utilizing this design have used the same general approach, their implementations vary greatly in their nontrivial details.

A hardware-verified simulation suite is developed to accurately model and evaluate the behavior of this buffer-onboard memory system. A study of this design space is used to determine optimal use of the resources involved. This includes DRAM and bus organization, queue storage, and mapping schemes. Various constraints based on implementation costs are placed on simulated configurations to confirm that these optimizations apply to viable systems. Finally, full system simulations are performed to better understand how this memory system interacts with an operating system executing an application with the goal of uncovering behaviors not present in simple limit case simulations. When applying insights gleaned from these simulations, optimal performance can be achieved while still considering outside constraints (i.e., pin-out, power, and fabrication costs).
Physically addressed queueing (PAQ)
Authors: Jung Myoungsoo , Wilson Ellis H. , Kandemir Mahmut
Published: September 2012

NAND flash storage has proven to be a competitive alternative to traditional disk for its properties of high random-access speeds, low-power and its presumed efficacy for random-reads. Ironically, we demonstrate that when packaged in SSD format, there arise many barriers to reaching full parallelism in reads, resulting in random writes out-performing them. Motivated by this, we propose Physically Addressed Queuing (PAQ), a request scheduler that avoids resource contention resultant from shared SSD resources. PAQ makes the following major contributions: First, it exposes the physical addresses of requests to the scheduler. Second, I/O clumping is utilized to select groups of operations that can be simultaneously executed without major resource conflict. Third, inter-request NAND transaction packing empowers multi-plane-mode operations. We implement PAQ in a cycle-accurate simulator and demonstrate bandwidth and IOPS improvements greater than 62% and latency decreases as much as 41.6% for random reads, without degrading performance of other access types.
Probabilistic shared cache management (PriSM)
Authors: Manikantan R , Rajan Kaushik , Govindarajan R
Published: September 2012

Effective sharing of the last level cache has a significant influence on the overall performance of a multicore system. We observe that existing solutions control cache occupancy at a coarser granularity, do not scale well to large core counts and in some cases lack the flexibility to support a variety of performance goals.

In this paper, we propose Probabilistic Shared Cache Management (PriSM), a framework to manage the cache occupancy of different cores at cache block granularity by controlling their eviction probabilities. The proposed framework requires only simple hardware changes to implement, can scale to larger core count and is flexible enough to support a variety of performance goals. We demonstrate the flexibility of PriSM, by computing the eviction probabilities needed to achieve goals like hit-maximization, fairness and QOS.

PriSM-HitMax improves performance by 18.7% over LRU and 11.8% over previously proposed schemes in a sixteen core machine. PriSM-Fairness improves fairness over existing solutions by 23.3% along with a performance improvement of 19.0%. PriSM-QOS successfully achieves the desired QOS targets.
Revisiting hardware-assisted page walks for virtualized systems
Authors: Ahn Jeongseob , Jin Seongwook , Huh Jaehyuk
Published: September 2012

Recent improvements in architectural supports for virtualization have extended traditional hardware page walkers to traverse nested page tables. However, current two-dimensional (2D) page walkers have been designed under the assumption that the usage patterns of guest and nested page tables are similar. In this paper, we revisit the architectural supports for nested page table walks to incorporate the unique characteristics of memory management by hypervisors. Unlike page tables in native systems, nested page table sizes do not impose significant overheads on the overall memory usage. Based on this observation, we propose to use flat nested page tables to reduce unnecessary memory references for nested walks.

A competing mechanism to HW 2D page walkers is shadow paging, which duplicates guest page tables but provides direct translations from guest virtual to system physical addresses. However, shadow paging has been suffering from the overheads of synchronization between guest and shadow page tables. The second mechanism we propose is a speculative shadow paging mechanism, called speculative inverted shadow paging, which is backed by non-speculative flat nested page tables. The speculative mechanism provides a direct translation with a single memory reference for common cases, and eliminates the page table synchronization overheads. We evaluate the proposed schemes with the real Xen hypervisor running on a full system simulator. The flat page tables improve a state-of-the-art 2D page walker with a page walk cache and nested TLB by 7%. The speculative shadow paging improves the same 2D page walker by 14%.
Managing distributed ups energy for effective power capping in data centers
Authors: Kontorinis Vasileios , Zhang Liuyi Eric , Aksanli Baris , Sampson Jack , Homayoun Houman , Pettis Eddie , Tullsen Dean M. , Rosing Tajana Simunic
Published: September 2012

Power over-subscription can reduce costs for modern data centers. However, designing the power infrastructure for a lower operating power point than the aggregated peak power of all servers requires dynamic techniques to avoid high peak power costs and, even worse, tripping circuit breakers. This work presents an architecture for distributed per-server UPSs that stores energy during low activity periods and uses this energy during power spikes. This work leverages the distributed nature of the UPS batteries and develops policies that prolong the duration of their usage. The specific approach shaves 19.4% of the peak power for modern servers, at no cost in performance, allowing the installation of 24% more servers within the same power budget. More servers amortize infrastructure costs better and, hence, reduce total cost of ownership per server by 6.3%.
The dynamic granularity memory system
Authors: Yoon Doe Hyun , Jeong Min Kyu , Sullivan Michael , Erez Mattan
Published: September 2012

Chip multiprocessors enable continued performance scaling with increasingly many cores per chip. As the throughput of computation outpaces available memory bandwidth, however, the system bottleneck will shift to main memory. We present a memory system, the dynamic granularity memory system (DGMS), which avoids unnecessary data transfers, saves power, and improves system performance by dynamically changing between fine and coarse-grained memory accesses. DGMS predicts memory access granularities dynamically in hardware, and does not require software or OS support. The dynamic operation of DGMS gives it superior ease of implementation and power efficiency relative to prior multi-granularity memory systems, while maintaining comparable levels of system performance.
Computational geometry in the parallel external memory model
Authors: Sitchinava Nodari
Published: September 2012

Continued advances in VLSI scaling combined with unsustainable power consumption of frequency scaling resulted in parallel processors having become mainstream as demonstrated by modern multicores. Current off-the-shelf processors already contain up to 16 cores and the prototypes boast up to 48 cores on a single chip.
Revisiting the need for mobile MAC protocols in wireless sensor networks
Authors: Hassanzadeh Navid , Landsiedel Olaf , Hermans Frederik , Rensfelt Olof , Voigt Thiemo
Published: September 2012

There exists a number of MAC protocols targeted for mobile scenarios. These include MMAC, MS-MAC and AM-MAC. These MAC protocols have in common that they seem to be evaluated only in simulation. This might indicate that these MAC are either too complex to use or they are not needed, at least for data collection, the major task of sensor networks. In this paper we show that extending a traditional data collection protocol with lightweight, carefully selected mechanisms is sufficient to provide reliable data collection at low energy cost for mobile sensor networks where both sinks and sources move.
A lightweight approach to online detection and classification of interference in 802.15.4-based sensor networks
Authors: Hermans Frederik , Larzon Lars-Åke , Rensfelt Olof , Gunningberg Per
Published: September 2012

With a rapidly increasing number of devices sharing access to the 2.4 GHz ISM band, interference becomes a serious problem for 802.15.4-based, low-power sensor networks. Consequently, interference mitigation strategies are becoming commonplace. In this paper, we consider the step that precedes interference mitigation: interference detection. We have performed extensive measurements to characterize how different types of interferers affect individual 802.15.4 packets. From these measurements, we define a set of features which we use to train a neural network to classify the source of interference of a corrupted packet. Our approach is sufficiently lightweight for online use in a resource-constrained sensor network. It does not require additional hardware, nor does it use active spectrum sensing or probing packets. Instead, all information about interferers is gathered from inspecting corrupted packets that are received during the sensor network's regular operation. Even without considering a history of earlier packets, our approach reaches a mean classification accuracy of 79.8%, with per interferer accuracies of 64.9% for WiFi, 82.6% for Bluetooth, 72.1% for microwave ovens, and 99.6% for packets that are corrupted due to insufficient signal strength.
Zooming into radio events by bus snooping
Authors: He Zhitao , Voigt Thiemo
Published: September 2012

In this position paper, we advocate the use of bus snooping to trace radio events. Highly precise and unintrusive, the technique leads to potentially more efficient code and enables more insightful protocol analysis than conventional code instrumentation techniques.
Enhanced Growth Inhibition of Osteosarcoma by Cytotoxic Polymerized Liposomal Nanoparticles Targeting the Alcam Cell Surface Receptor
Authors: Federman Noah , Chan Jason , Nagy Jon O. , Landaw Elliot M. , McCabe Katelyn , Wu Anna M. , Triche Timothy , Kang HyungGyoo , Liu Bin , Marks James D. , Denny Christopher T.
Published: September 2012

Osteosarcoma is the most common primary malignancy of bone in children, adolescents, and adults. Despite extensive surgery and adjuvant aggressive high-dose systemic chemotherapy with potentially severe bystander side effects, cure is attainable in about 70% of patients with localized disease and only 20%–30% of those patients with metastatic disease. Targeted therapies clearly are warranted in improving our treatment of this adolescent killer. However, a lack of osteosarcoma-associated/specific markers has hindered development of targeted therapeutics. We describe a novel osteosarcoma-associated cell surface antigen, ALCAM. We, then, create an engineered anti-ALCAM-hybrid polymerized liposomal nanoparticle immunoconjugate (α-AL-HPLN) to specifically target osteosarcoma cells and deliver a cytotoxic chemotherapeutic agent, doxorubicin. We have demonstrated thatα-AL-HPLNs have significantly enhanced cytotoxicity over untargeted HPLNs and over a conventional liposomal doxorubicin formulation. In this way,α-AL-HPLNs are a promising new strategy to specifically deliver cytotoxic agents in osteosarcoma.
Clonal Populations of Amniotic Cells by Dilution and Direct Plating: Evidence for Hidden Diversity
Authors: Wilson Patricia G. , Devkota Lorna , Payne Tiffany , Crisp Laddie , Winter Allison , Wang Zhan
Published: September 2012

Fetal cells are widely considered a superior cell source for regenerative medicine; fetal cells show higher proliferative capacity and have undergone fewer replicative cycles that could generate spontaneous mutations. Fetal cells in amniotic fluid were among the first normal primary cells to be cultured ex vivo, but the undefined composition of amniotic fluid has hindered advance for regenerative applications. We first developed a highly efficient method to generate clonal populations by dilution of amniocentesis samples in media and direct plating without intervening refrigeration, centrifugation, or exposure of cells to the paracrine effects in mixed cell cultures. More than 40 clonal populations were recovered from 4 amniocentesis samples and representative clones were characterized by flow cytometry, conventional assays for differentiation potential, immunofluorescence imaging, and transcript analysis. The results revealed previously unreported diversity among stromal and epithelial cell types and identified unique cell types that could be lost or undetected in mixed cell populations. The differentiation potential of amniotic cells proved to be uncoupled from expression of definitive cell surface or cytoplasmic markers for stromal and epithelial cells. Evidence for diversity among stromal and epithelial cells in amniotic fluid bears on interpretations applied to molecular and functional tests of amniotic cell populations.
CRP and TNF-α  Induce PAPP-A Expression in Human Peripheral Blood Mononuclear Cells
Authors: Li Weiping , Li Hongwei , Gu Fusheng
Published: September 2012

Objective. The effects of C-reactive protein (CRP) and tumor necrosis factor-α(TNF-α) on pregnancy-associated plasma protein-A (PAPP-A) expression in human peripheral blood mononuclear cells (PBMCs) require further investigation.Methods. The PAPP-A levels in culture supernatants, PAPP-A mRNA expression, and cellular PAPP-A expression were measured in human PBMCs isolated from fresh blood donations provided by 6 healthy volunteers (4 donations per volunteer). Analyses were conducted by ultrasensitive ELISA, western blotting, and RT-PCR following stimulation with CRP or TNF-αcytokines.Results. PAPP-A mRNA and protein levels after CRP stimulation peaked at 24 hours, whereas peak PAPP-A mRNA and protein levels were achieved after TNF-αstimulation at only 2 and 8 hours, respectively. These findings indicate the dose-dependent effect of CRP and TNF-αstimulation. Actinomycin D treatment completely prevented CRP and TNF-αinduction of PAPP-A mRNA and protein expression. Additionally, nuclear factor- (NF-)κB inhibitor (BAY11-7082) potently inhibited both CRP and TNF-αstimulated PAPP-A mRNA and protein expression.Conclusions. Human PBMCs are capable of expressing PAPP-Ain vitro, expression that may be regulated by CRP and TNF-αthrough the NF-κB pathway. This mechanism may play a significant role in the observed increase of serum PAPP-A levels in acute coronary syndrome (ACS).
Structural, Electrical, and Optical Properties of PbTe Thin Films Prepared by Simple Flash Evaporation Method
Authors: Kungumadevi Lakshmanan , Sathyamoorthy Ramakrishnan
Published: September 2012

Lead telluride (PbTe) films have been prepared on glass substrates by flash evaporation method. Structure of the film is found to possess stable face-centered cubic (fcc) NaCl phase in which the grains predominantly grow in the direction of (200) plane. The calculated grain size was in the range 19 nm. The electrical resistivity as a function of temperature was measured using four-probe technique. The electrical conductivity was calculated, and the value is found to be from 67.11 to 344.82 S/cm in the temperature range 303–453 K. The value of mobility was evaluated, and it is found to be0.329×10-3 cm2·V−1 S−1. An optical study reveals that the PbTe thin films exhibit large blue shift. The optical constants such as absorption coefficient and refractive index have been estimated, and the results are discussed.
The Impact of Experience with a Family Member with Alzheimer’s Disease on Views about the Disease across Five Countries
Authors: Blendon Robert J. , Benson John M. , Wikler Elizabeth M. , Weldon Kathleen J. , Georges Jean , Baumgart Matthew , Kallmyer Beth A.
Published: September 2012

The objective of this paper is to understand how the public’s beliefs in five countries may change as more families have direct experience with Alzheimer’s disease. The data are derived from a questionnaire survey conducted by telephone (landline and cell) with 2678 randomly selected adults in France, Germany, Poland, Spain, and the United States. The paper analyzes the beliefs and anticipated behavior of those in each country who report having had a family member with Alzheimer’s disease versus those who do not. In one or more countries, differences were found between the two groups in their concern about getting Alzheimer’s disease, knowledge that the disease is fatal, awareness of certain symptoms, and support for increased public spending. The results suggest that as more people have experience with a family member who has Alzheimer’s disease, the public will generally become more concerned about Alzheimer’s disease and more likely to recognize that Alzheimer’s disease is a fatal disease. The findings suggest that other beliefs may only be affected if there are future major educational campaigns about the disease. The publics in individual countries, with differing cultures and health systems, are likely to respond in different ways as more families have experience with Alzheimer’s disease.
Multiple Roles of p53-Related Pathways in Somatic Cell Reprogramming and Stem Cell Differentiation
Authors: Yi Lan , Lu Chiwei , Hu Wenwei , Sun Yvonne , Levine Arnold J.
Published: September 2012

The inactivation of p53 functions enhances the efficiency and decreases the latency of producing induced pluripotent stem cells (iPSC) in culture. The formation of iPSCs in culture starts with a rapid set of cell divisions followed by an epigenetic reprogramming of the DNA and chromatin. The mechanisms by which the p53 protein inhibits the formation of iPSCs are largely unknown. Using a temperature sensitive mutant of the p53 (Trp53) gene, we examined the impact of the temporal expression of wild type p53 in preventing stem cell induction from somatic cells. We also explored how different p53 mutant alleles affect the reprogramming process. We found that little or no p53 activity favors the entire process of somatic cell reprogramming. Reactivation of p53 at any time point during the reprogramming process not only interrupted the formation of iPSCs, but also induced newly formed stem cells to differentiate. Among p53-regulated genes, p21 (Cdkn1a), but not Puma (Bbc3) played a partial role in iPSCs formation probably by slowing cell division. Activation of p53 functions in iPSCs induced senescence and differentiation in stem cell populations. High rate of birth defects and increases in DNA methylation at the IGF2-H19 loci in female offspring of p53 knockout mice suggested that the absence of p53 may give rise to epigenetic instability in a stochastic fashion. Consistently, selected p53 missense mutations showed differential effects on the stem cell reprogramming efficiency in a c-Myc dependent manner. The absence of p53 activity and functions also contributed to an enhanced efficiency of iPSC production from cancer cells. The production of iPSCs in culture from normal and cancer cells, although different from each other in several ways, both responded to the inhibition of reprogramming by the p53 protein. Cancer Res; 72(21); 5635–45. ©2012 AACR.
Genetic Polymorphisms and Protein Expression of NRF2 and Sulfiredoxin Predict Survival Outcomes in Breast Cancer
Authors: Hartikainen Jaana M. , Tengström Maria , Kosma Veli-Matti , Kinnula Vuokko L. , Mannermaa Arto , Soini Ylermi
Published: September 2012

NRF2 activates several protective genes, such as sulfiredoxin (SRXN1), as a response to oxidative and xenobiotic stress. Defects in NRF2 pathway may increase cancer susceptibility. In tumor cells, activation of NRF2 may lead to chemo- and radioresistance and thus affect patient outcome. Nine single-nucleotide polymorphisms on NRF2 gene and eight on SRXN1 were genotyped in 452 patients with breast cancer and 370 controls. Protein expression of NRF2 and SRXN1 was studied in 373 breast carcinomas by immunohistochemistry. Statistical significance of the associations between genotypes, protein expression, clinicopathologic variables, and survival was assessed. A high level (>25%) of cytoplasmic NRF2 positivity was observed in 237 of 361 (66%) and SRXN1 positivity was observed in 82 of 363 (23%) cases. The NRF2 rs6721961 genotype TT was associated with increased risk of breast cancer [P = 0.008; OR, 4.656; confidence interval (CI), 1.350–16.063] and the T allele was associated with a low extent of NRF2 protein expression (P = 0.0003; OR, 2.420; CI, 1.491–3.926) and negative SRXN1 expression (P = 0.047; OR, 1.867; CI = 1.002–3.478). The NRF2 rs2886162 allele A was associated with low NRF2 expression (P = 0.011; OR, 1.988; CI, 1.162–3.400) and the AA genotype was associated with a worse survival (P = 0.032; HR, 1.687; CI, 1.047–2.748). The NRF2 rs1962142 T allele was associated with a low level of cytoplasmic NRF2 expression (P = 0.036) and negative sulfiredoxin expression (P = 0.042). The NRF2 rs2706110 AA genotype was associated with an increased risk of breast cancer, and the SRXN1 rs6053666 C allele was associated with a decrease in breast cancer risk (P = 0.011 and 0.017). NRF2 and SRXN1 genetic polymorphisms are associated with breast cancer risk and survival, implicating that mechanisms associated with reactive oxygen species and NRF2 pathway are involved in breast cancer initiation and progression. Cancer Res; 72(21); 5537–46. ©2012 AACR.
Suppression of Human Glioma Xenografts with Second-Generation IL13R-Specific Chimeric Antigen Receptor–Modified T Cells
Authors: Kong Seogkyoung , Sengupta Sadhak , Tyler Betty , Bais Anthony J. , Ma Qiangzhong , Doucette Saryn , Zhou Jinyuan , Sahin Ayguen , Carter Bob S. , Brem Henry , Junghans Richard P. , Sampath Prakash
Published: September 2012

Purpose: Glioblastoma multiforme (GBM) remains highly incurable, with frequent recurrences after standard therapies of maximal surgical resection, radiation, and chemotherapy. To address the need for new treatments, we have undertaken a chimeric antigen receptor (CAR) “designer T cell” (dTc) immunotherapeutic strategy by exploiting interleukin (IL)13 receptor α-2 (IL13Rα2) as a GBM-selective target.

Experimental Design: We tested a second-generation IL13 “zetakine” CAR composed of a mutated IL13 extracellular domain linked to intracellular signaling elements of the CD28 costimulatory molecule and CD3ζ. The aim of the mutation (IL13.E13K.R109K) was to enhance selectivity of the CAR for recognition and killing of IL13Rα2+ GBMs while sparing normal cells bearing the composite IL13Rα1/IL4Rα receptor.

Results: Our aim was partially realized with improved recognition of tumor and reduced but persisting activity against normal tissue IL13Rα1+ cells by the IL13.E13K.R109K CAR. We show that these IL13 dTcs were efficient in killing IL13Rα2+ glioma cell targets with abundant secretion of cytokines IL2 and IFNγ, and they displayed enhanced tumor-induced expansion versus control unmodified T cells in vitro. In an in vivo test with a human glioma xenograft model, single intracranial injections of IL13 dTc into tumor sites resulted in marked increases in animal survivals.

Conclusions: These data raise the possibility of immune targeting of diffusely invasive GBM cells either via dTc infusion into resection cavities to prevent GBM recurrence or via direct stereotactic injection of dTcs to suppress inoperable or recurrent tumors. Systemic administration of these IL13 dTc could be complicated by reaction against normal tissues expressing IL13Ra1. Clin Cancer Res; 18(21); 5949–60. ©2012 AACR.
Quantitative Immunofluorescence Reveals the Signature of Active B-cell Receptor Signaling in Diffuse Large B-cell Lymphoma
Authors: Bogusz Agata M. , Baxter Richard H.G. , Currie Treeve , Sinha Papiya , Sohani Aliyah R. , Kutok Jeffery L. , Rodig Scott J.
Published: September 2012

Purpose: B-cell receptor (BCR)–mediated signaling is important in the pathogenesis of a subset of diffuse large B-cell lymphomas (DLBCL) and the BCR-associated kinases SYK and BTK have recently emerged as potential therapeutic targets. We sought to identify a signature of activated BCR signaling in DLBCL to aid the identification of tumors that may be most likely to respond to BCR-pathway inhibition.

Experimental Design: We applied quantitative immunofluorescence (qIF) using antibodies to phosphorylated forms of proximal BCR signaling kinases LYN, SYK, and BTK and antibody to BCR-associated transcription factor FOXO1 on BCR-cross-linked formalin-fixed paraffin-embedded (FFPE) DLBCL cell lines as a model system and on two clinical cohorts of FFPE DLBCL specimens (n = 154).

Results: A robust signature of active BCR signaling was identified and validated in BCR-cross-linked DLBCL cell lines and in 71/154 (46%) of the primary DLBCL patient specimens. Further analysis of the primary biopsy samples revealed increased nuclear exclusion of FOXO1 among DLBCL with qIF evidence of active BCR signaling compared with those without (P = 0.004). Nuclear exclusion of FOXO1 was also detected in a subset of DLBCL without evidence of proximal BCR signaling suggesting that alternative mechanisms for PI3K/AKT activation may mediate FOXO1 subcellular localization in these cases.

Conclusion: This study establishes the feasibility of detecting BCR activation in primary FFPE biopsy specimens of DLBCL. It lays a foundation for future dissection of signal transduction networks in DLBCL and provides a potential platform for evaluating individual tumors in patients receiving novel therapies targeting the BCR pathway. Clin Cancer Res; 18(22); 6122–35. ©2012 AACR.
Sangivamycin-like Molecule 6 Exhibits Potent Anti-Multiple Myeloma Activity through Inhibition of Cyclin-Dependent Kinase-9
Authors: Dolloff Nathan G. , Allen Joshua E. , Dicker David T. , Aqui Nicole , Vogl Dan , Malysz Jozef , Talamo Giampaolo , El-Deiry Wafik S.
Published: September 2012

Despite significant treatment advances over the past decade, multiple myeloma (MM) remains largely incurable. In this study we found that MM cells were remarkably sensitive to the death-inducing effects of a new class of sangivamycin-like molecules (SLM). A panel of structurally related SLMs selectively induced apoptosis in MM cells but not other tumor or nonmalignant cell lines at submicromolar concentrations. SLM6 was the most active compound in vivo, where it was well tolerated and significantly inhibited growth and induced apoptosis of MM tumors. We determined that the anti-MM activity of SLM6 was mediated by direct inhibition of cyclin-dependent kinase 9 (CDK9), which resulted in transcriptional repression of oncogenes that are known to drive MM progression (MAF, CCND1, MYC, and others). Furthermore, SLM6 showed superior in vivo anti-MM activity more than the CDK inhibitor flavopiridol, which is currently in clinical trials for MM. These findings show that SLM6 is a novel CDK9 inhibitor with promising preclinical activity as an anti-MM agent. Mol Cancer Ther; 11(11); 2321–30. ©2012 AACR.
Desmoplasia: A Response or a Niche?
Authors: DeClerck Yves A.
Published: September 2012

Summary: Desmoplasia—the presence of a rich stroma around a tumor—has long been associated with a poor clinical outcome in patients with cancer. It is considered to be a response to the presence of invasive tumor cells. There is now evidence that desmoplasia is the result of coordinated changes in several stromal cells under the control of a single gene product, CD36, whose repression leads to a decrease in fat accumulation and an increase in matrix deposition. The presence of these changes in tumor-free human breast tissue strongly suggests that desmoplasia may precede and not always follow the presence of malignant cells. This concept has an important clinical implication for women at high risk of developing breast carcinoma, considering that the presence of desmoplasia in normal breast tissue detected in the form of mammographic density is one of the strongest risk factors. Cancer Discov; 2(9); 772–4. ©2012 AACR.

Commentary on DeFilippis et al., p. 826.
Epigenetic Regulation of Cell Adhesion and Communication by Enhancer of Zeste Homolog 2 in Human Endothelial Cells
Authors: Dreger Henryk , Ludwig Antje , Weller Andrea , Stangl Verena , Baumann Gert , Meiners Silke , Stangl Karl
Published: September 2012

The histone methyltransferase enhancer of zeste homolog 2 (Ezh2) mediates trimethylation of lysine 27 in histone 3, which acts as a repressive epigenetic mark. Ezh2 is essential for maintaining pluripotency of stem cells, but information on its role in differentiated cells is sparse. Whole-genome mRNA expression arrays identified 964 genes that were regulated by >2-fold 72 hours after small interfering RNA-mediated silencing of Ezh2 in human umbilical vein endothelial cells. Among them, genes associated with the gene ontology terms cell communication and cell adhesion were significantly overrepresented, suggesting a functional role for Ezh2 in the regulation of angiogenesis. Indeed, adhesion, migration, and tube formation assays revealed significantly altered angiogenic properties of human umbilical vein endothelial cells after silencing of Ezh2. To identify direct target genes of Ezh2, we performed chromatin immunoprecipitation experiments followed by whole-genome promoter arrays (chromatin immunoprecipitation-on-chip) and identified 5585 genes associated with trimethylation of lysine 27 in histone 3. Comparative analysis with our mRNA expression data identified 276 genes that met our criteria for putative Ezh2 target genes, upregulation by >2-fold after Ezh2 silencing and association with trimethylation of lysine 27 in histone 3. Notably, we observed a striking overrepresentation of genes involved in wingless-type mouse mammary tumor virus integration site (WNT) signaling pathways. Epigenetic regulation of several of these genes by Ezh2 was specifically confirmed by polymerase chain reaction analysis of DNA enrichment after chromatin immunoprecipitation using an antibody specific for trimethylation of lysine 27 in histone 3. Combining mRNA expression arrays and chromatin immunoprecipitation-on-chip analysis, we identified 276 Ezh2 target genes in endothelial cells. Ezh2-dependent repression of genes involved in cell adhesion and communication contributes to the regulation of angiogenesis.
Role of the Transcription Factor Erythroblastosis Virus E26 Oncogen Homolog-1 (ETS-1) as Mediator of the Renal Proinflammatory and Profibrotic Effects of Angiotensin II
Authors: Feng Wenguang , Chumley Phillip , Hua Ping , Rezonzew Gabriel , Jaimes David , Duckworth Madison W. , Xing Dongqi , Jaimes Edgar A.
Published: September 2012

Angiotensin II (Ang II) plays a major role in the pathogenesis of end-organ injury in hypertension via its diverse hemodynamic and nonhemodynamic effects. Erythroblastosis virus E26 oncogen homolog-1 (ETS-1) is an important transcription factor recently recognized as an important mediator of cell proliferation, inflammation, and fibrosis. In the present studies, we tested the hypothesis that ETS-1 is a common mediator of the renal proinflammatory and profibrotic effects of Ang II. C57BL6 mice (n=6 per group) were infused with vehicle (control), Ang II (1.4 mg/kg per day), Ang II and an ETS-1 dominant-negative peptide (10 mg/kg per day), or Ang II and an ETS-1 mutant peptide (10 mg/kg per day) via osmotic minipump for 2 or 4 weeks. The infusion of Ang II resulted in significant increases in blood pressure and left ventricular hypertrophy, which were not modified by ETS-1 blockade. The administration of ETS-1 dominant-negative peptide significantly attenuated Ang II–induced renal injury as assessed by urinary protein excretion, mesangial matrix expansion, and cell proliferation. Furthermore, ETS-1 dominant-negative peptide but not ETS-1 mutant peptide significantly reduced Ang II–mediated upregulation of transforming growth factor-β, connective tissue growth factor, and α-smooth muscle actin. In addition, ETS-1 blockade reduced several proinflammatory effects of Ang II, including macrophage infiltration, nitrotyrosine expression, and NOX4 mRNA expression. Our studies suggest that ETS-1 is a common mediator of the proinflammatory and profibrotic effects of Ang II–induced hypertensive renal damage and may result in the development of novel strategies in the treatment and prevention of end-organ injury in hypertension.
Organizational Misfits and the Origins of Brokerage in Intrafirm Networks
Authors: Kleinbaum Adam M.
Published: September 2012

To extend research on the effects of networks for career outcomes, this paper examines how career processes shape network structure. I hypothesize that brokerage results from two distinct mechanisms: links with former coworkers and with friends of friends accumulated as careers unfold. Furthermore, I hypothesize that “organizational misfits”—people who followed career trajectories that are atypical in their organization—will have access to more valuable brokerage opportunities than those whose careers followed more conventional paths. I tested this hypothesis with career history data recorded longitudinally for 30,000 employees in a large information technology firm over six years and sequence-analyzed to measure individual-level fit with typical career paths in the organization. Network position was measured using a unique data set of over 250 million electronic mail messages. Empirical results support the hypotheses that diverse, and especially atypical, careers have an effect on brokerage through mechanisms rooted in social capital, even when accounting for endogeneity between networks and mobility. In theorizing about misfit from prototypical patterns, this paper offers a new, theory-driven application of sequence-analytic methods as well as a novel measure of brokerage based on interactions across observable boundaries, a complement to the structural constraint measure based on interactions across holes in social structure.
Coping With Corporatism in Decline and the Revival of Parliament
Authors: Rommetvedt Hilmar , Thesen Gunnar , Christiansen Peter Munk , Nørgaard Asbjørn Sonne
Published: September 2012

Denmark and Norway have experienced significant political changes during the past three decades, changes that affect the constraints and opportunities organized interests are facing. Corporatist representation in the policy-making process has declined, and changes in executive-legislative relations have increased the power of parliaments. Organized interests are expected to adapt to these changing circumstances to maintain their political influence. This article shows how Danish and Norwegian interest groups have coped with the decline of corporatism and the revival of parliaments. Representation in corporatist policy-making committees and lobbying toward civil servants in government ministries have been supplemented and in some cases substituted by political lobbyism directed toward elected representatives in the parliament and the government. The analysis is based on panel data from several surveys carried out among nationwide interest groups in Denmark and Norway.
Examining Willingness to Attack Critical Infrastructure Online and Offline
Authors: Holt Thomas J. , Kilger Max
Published: September 2012

The continuing adoption of technologies by the general public coupled with the expanding reliance of critical infrastructures connected through the Internet has created unique opportunities for attacks by civilians and nation-states alike. Although governments are increasingly focusing on policies to deter nation-state level attacks, it is unclear what factors may affect citizens’ decisions to engage in politically motivated cyber crime attacks against either a foreign nation-state or their own homeland. Thus, this study will explore the factors that may affect individual willingness to use technology to attack critical infrastructure online or offline using an international sample of college students. The findings compare the correlates of physical and virtual attacks, including political outlook, group equality, and involvement in cyber deviance. The implications of this research on the relationship between on- and offline infrastructure attacks will be explored in depth for policy makers, governmental agencies, and law enforcement.
Prevention-Related Research Targeting African American Alternative Education Program Students
Authors: Carswell Steven B. , Hanlon Thomas E. , Watts Amy M. , O’Grady Kevin E.
Published: September 2012

This article reports on a program of research that examined the background, planning, implementation, and evaluation of an after-school preventive intervention program within an ongoing urban alternative education program targeting African American students referred to the school because of their problematic behavior in regular schools. The research undertaken involved the examination of three separate, but interrelated, investigative components: (a) the relationship of risk and protective factors to the sexual activity of individuals in the targeted population; (b) the problems associated with the implementation of an after-school preventive intervention found to be effective within a regular school setting; and (c) determination of the effectiveness of the after-school preventive intervention, the results of which were largely compromised by the problems encountered during the implementation of the intervention.
Not Cut Out to Be an Administrator
Authors: Stone-Johnson Corrie
Published: September 2012

This article, based on qualitative interviews conducted between 2007-2008 with 12 middle-career educators in the greater Boston area in Massachusetts, details teachers’ career and leadership aspirations in a context of educational change. The findings suggest that teachers who presently are in midcareer struggle with the move toward the principalship, but that generational differences, not the changed educational context, more heavily impact their lack of attraction to the job. Using generational theory, this article offers a critique of the available literature on teachers’ career paths, the principal shortage, generational differences, and the quite different work and leadership expectations of the next generation of school leaders.
Feeling Safe in the Dark
Authors: Boomsma Christine , Steg Linda
Published: September 2012

This research examined to what extent physical factors, notably lighting and entrapment (blocked escape), and individual factors, notably gender, affect feelings of safety and the acceptability of reduced lighting levels. The authors reasoned that acceptability of reduced street lighting depends on perceived safety, which in turn depends on entrapment, lighting, and gender. Virtual representations of a residential street were used, systematically manipulating entrapment and lighting levels. As expected, people felt less safe in lower lighting and higher entrapment settings, and these settings were evaluated as less acceptable. Although women perceived a situation as less safe compared with men, the authors found no gender differences in acceptability, which extends previous research. Importantly, as hypothesized, perceived safety mediated the effect of lighting on acceptability levels, suggesting that people can accept lower lighting levels when social safety is not threatened.
Assessment of need of patients with schizophrenia: A study in Vellore, India
Authors: Ernest Sharmila , Nagarajan Guru , Jacob KS
Published: September 2012

Background and aims:

There is a dearth of studies investigating the prevalence and factors associated with unmet needs in people with schizophrenia from low- and middle-income countries. We aimed to study prevalence and risk factors for unmet need.

Method:

A case-control study design was employed. One hundred and one (101) consecutive patients attending a psychiatric hospital were assessed using Camberwell Assessment of Need Short version (CANSAS) and Positive and Negative Syndrome Scale (PANSS). Multivariate analysis was employed to adjust for confounders.

Results:

The majority of patients had many unmet needs. These unmet needs were significantly associated with lower education, poverty and persistent psychopathology on multivariate analysis.

Conclusion:

Unmet needs are associated with poverty, lower education and persistent psychopathology. There is a need to manage unmet needs, in addition to addressing psychopathology and poverty.