bluuebunny/crossref_metadata_2025_split huggingface dataset:
VRSync
Authors: Miller Timothy N. , Thomas Renji , Pan Xiang , Teodorescu Radu 
Published: September 2012

Power consumption is a primary concern for microprocessor designers. Lowering the supply voltage of processors is one of the most effective techniques for improving their energy efficiency. Unfortunately, low-voltage operation faces multiple challenges going forward. One such challenge is increased sensitivity to voltage fluctuations, which can trigger so-called "voltage emergencies" that can lead to errors. These fluctuations are caused by abrupt changes in power demand, triggered by processor activity variation as a function of workload.
This paper examines the effects of voltage fluctuations on future many-core processors. With the increase in the number of cores in a chip, the effects of chip-wide activity fluctuation -- such as that caused by global synchronization in multithreaded applications -- overshadow the effects of core-level workload variability. Starting from this observation, we developed VRSync, a novel synchronization methodology that uses emergency-aware scheduling policies that reduce the slope of load fluctuations, eliminating emergencies. We show that VRSync is very effective at eliminating emergencies, allowing voltage guardbands to be significantly lowered, which reduces energy consumption by an average of 33%.
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).
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%.
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

Abstract
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

Abstract
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 (&gt;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

AbstractPurpose: 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

AbstractPurpose: 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

Abstract
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

Abstract
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.
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.
Fiber-optic intra-aortic balloon therapy and its role within cardiac surgery
Authors: Yarham G , Clements A , Morris C , Cumberland T , Bryan M , Oliver M , Burrows H , Mulholland J 
Published: September 2012

Introduction: The patient population has changed and the cardiothoracic team are now operating on patients with more co-morbidity. One of the significant aspects of this increased co-morbidity, which affects both short- and long-term outcomes, is compromised left ventricular function. Intra-aortic balloon pump (IABP) technology offers these patients and the cardiac team an easily accessible, cost-effective, mechanical assist device. Arterial pressure monitoring for IABP therapy: Fluid-filled transducers used to measure the aortic waveform can be unreliable and inconsistent. Fiber-optic manometers located in the very tip of the IAB catheters provide accurate and fast, high quality measurements. This, in turn, presents the opportunity for the hardware and algorithm to measure key markers on the arterial waveform and optimise left ventricular support. It also provides the potential for automatic in vivo calibration, further increasing the accuracy and quality of the IAB support. The effect of fiber-optic IABP therapy on clinical management: A dual centre prospective audit comparing fluid-filled versus fiber-optic arterial pressure monitoring showed a 96% reduction in IAB-related perfusion on-site call-outs (17 vs. 1, respectively) and a 94% reduction in sub-optimal timing (55/98 vs. 2/94, respectively). Conclusion: The improved timing algorithms utilise the pressure information received 50 msecs faster than with fluid-filled transducers, measuring key markers on the pressure waveform and adjusting inflation and deflation accurately on a beat per beat basis. Fiber-optic IAB technology and, specifically, these improved algorithms provide better beat per beat mechanical support. Given our evolving patient population, this technology will not only play an increased role, but will have a significant impact on cardiac surgery.