bluuebunny/crossref_metadata_2025_split huggingface dataset:
Understanding the behavior and implications of context switch misses
Authors: Liu Fang , Solihin Yan 
Published: January 2011

One of the essential features in modern computer systems is context switching, which allows multiple threads of execution to time-share a limited number of processors. While very useful, context switching can introduce high performance overheads, with one of the primary reasons being the cache perturbation effect. Between the time a thread is switched out and when it resumes execution, parts of its working set in the cache may be perturbed by other interfering threads, leading to (context switch) cache misses to recover from the perturbation.
The goal of this article is to understand how cache parameters and application behavior influence the number of context switch misses the application suffers from. We characterize a previously unreported type of context switch misses that occur as the artifact of the interaction of cache replacement policy and an application's temporal reuse behavior. We characterize the behavior of these “reordered misses” for various applications, cache sizes, and various amount of cache perturbation. As a second contribution, we develop an analytical model that reveals the mathematical relationship between cache design parameters, an application's temporal reuse pattern, and the number of context switch misses the application suffers from. We validate the model against simulation studies and find that it is sufficiently accurate in predicting the trends of context switch misses with regard to various cache perturbation amount.
The mathematical relationship provided by the model allows us to derive insights into precisely why some applications are more vulnerable to context switch misses than others. Through a case study on prefetching, we find that prefetching tends to aggravate the number of context switch misses and a less aggresive prefetching technique can reduce the number of context switch misses the application suffers from. We also investigate how cache sizes affect context switch misses. Our study shows that under relatively heavy workloads in the system, the worst-case number of context switch misses an application suffers from tends to increase proportionally with cache sizes, to the extent that may completely negate the reduction in other types of cache misses.
Ibuprofen Inhibits Activation of Nuclear β-Catenin in Human Colon Adenomas and Induces the Phosphorylation of GSK-3β
Authors: Greenspan Emily J. , Madigan James P. , Boardman Lisa A. , Rosenberg Daniel W. 
Published: January 2011

Abstract
Nonselective cyclooxygenase (COX) inhibitors target many of the same cancer-associated molecular pathways as COX-2–specific inhibitors. Although these nonsteroidal anti-inflammatory drugs (NSAIDs) are often associated with gastrointestinal toxicity, there is renewed interest in their use as colorectal cancer (CRC) chemopreventive agents due to the adverse side effects associated with long-term use of selective COX-2 inhibitors. In this study, we investigated the effects of long-term use (up to 25 years) of NSAIDs (ibuprofen or aspirin) on adenoma pathology and β-catenin–mediated signaling in sporadic human colon adenomas. Although NSAID use did not impact overall adenoma size or degree of dysplasia, it did cause a significant inhibition of nuclear β-catenin localization, which correlated with suppression of cyclin D1 expression. To further elucidate the effect of these agents in regulating β-catenin, we treated SW480 colon cancer cells with a panel of NSAIDs and determined their effects on β-catenin levels and cellular localization. In agreement with our in vivo results, both S-ibuprofen and aspirin were found to decrease total levels of β-catenin while increasing its phosphorylation. In addition, S-ibuprofen induced both degradation of IκBα and nuclear localization of NF-κB. Despite its nuclear localization, however, the activation of the NF-κB target genes, Bcl-2, survivin, and cyclin D1, was suppressed. This reduction in NF-κB transcriptional activity may be due to increased phosphorylation of GSK-3β following S-ibuprofen treatment. These data suggest that ibuprofen can effectively target both the Wnt/β-catenin and NF-κB pathways, and potentially uncovers a novel mechanism through which NSAIDS may exert their chemopreventive efficacy. Cancer Prev Res; 4(1); 161–71. ©2011 AACR.
Mcs5c: A Mammary Carcinoma Susceptibility Locus Located in a Gene Desert that Associates withTenascin CExpression
Authors: Veillet Adeline L. , Haag Jill D. , Remfert Jane L. , Meilahn Amanda L. , Samuelson David J. , Gould Michael N. 
Published: January 2011

AbstractGenetic factors have been estimated to account for at least 30% of a woman's risk to develop breast cancer. We have developed a rat model using Wistar Furth (WF) and Wistar Kyoto (WKy) strains to genetically identify mammary cancer susceptibility loci. The WKy allele of the mammary carcinogenesis susceptibility locus Mcs5c, was previously shown to reduce carcinoma multiplicity after 7,12-dimethylbenz-[a]anthracene (DMBA) exposure. In this study, Mcs5c was fine-mapped using WF.WKy congenic lines. Mcs5c was located to a region of approximately 176 kb on rat chromosome 5. One of the Mcs5c congenic lines containing a narrow Mcs5c WKy interval displayed a 40% decrease in average carcinoma number compared with WF-homozygous congenic controls after mammary carcinogenesis induction using two different models. As genetically mapped, the Mcs5c locus is located in a gene desert and thus is devoid of genes and annotated RNAs; thus, a genetic element in Mcs5c was hypothesized to regulate the expression of genes outside the locus. Tenascin c (Tnc) was identified as a candidate gene due to its reduced expression in thymus and ovarian tissues of Mcs5c WKy-homozygous congenic females compared with WF-homozygous congenic controls. This allele-specific differential expression is environmentally controlled. Cancer Prev Res; 4(1); 97–106. ©2011 AACR.
Resveratrol-Induced Apoptosis Is Mediated by Early Growth Response-1, Krüppel-Like Factor 4, and Activating Transcription Factor 3
Authors: Whitlock Nichelle C. , Bahn Jae Hoon , Lee Seong-Ho , Eling Thomas E. , Baek Seung Joon 
Published: January 2011

Abstract
Resveratrol, a dietary phytoalexin readily available in the diet, is reported to possess antitumorigenic properties in several cancers, including colorectal. However, the underlying mechanism(s) involved is not completely understood. In the present study, we investigated the effect of resveratrol treatment on gene modulation in human colorectal cancer cells and identified activating transcription factor 3 (ATF3) as the most highly induced gene after treatment. We confirmed that resveratrol upregulates ATF3 expression, both at the mRNA and protein level, and showed resveratrol involvement in ATF3 transcriptional regulation. Analysis of the ATF3 promoter revealed the importance of early growth response-1 (Egr-1; located at −245 to −236) and Krüppel-like factor 4 (KLF4; located at −178 to −174) putative binding sites in resveratrol-mediated ATF3 transactivation. Specificity of these sites to the Egr-1 and KLF4 protein was confirmed by electrophoretic mobility shift and chromatin immunoprecipitation assays. Resveratrol increased Egr-1 and KLF4 expression, which preceded ATF3 expression, and further suggests Egr-1 and KLF4 involvement in resveratrol-mediated activity. We provide evidence for Egr-1 and KLF4 interaction in the presence of resveratrol, which may facilitate ATF3 transcriptional regulation by this compound. Furthermore, we demonstrate that induction of apoptosis by resveratrol is mediated, in part, by increased ATF3 expression. Taken together, these results provide a novel mechanism by which resveratrol induces ATF3 expression and represent an additional explanation of how resveratrol exerts its antitumorigenic effects in human colorectal cancer cells. Cancer Prev Res; 4(1); 116–27. ©2011 AACR.
Time to Think Outside the (Genetic) Box
Authors: Issa Jean-Pierre J. , Garber Judy E. 
Published: January 2011

Abstract
Many patients develop cancers that have clinical features of inherited syndromes (e.g., young age of onset and unique pathology) but lack mutations in the genes characteristic of the disease. In this issue of the journal, Wong et al. report that somatic epigenetic inactivation could explain some such cases in the setting of BRCA1-associated breast cancer. Here, we discuss the implications of this work in terms of the etiology, risk, and potential prevention of cancer. Cancer Prev Res; 4(1); 6–8. ©2011 AACR.
Glucose-Insulin-Potassium Reduces the Incidence of Low Cardiac Output Episodes After Aortic Valve Replacement for Aortic Stenosis in Patients With Left Ventricular Hypertrophy
Authors: Howell Neil J. , Ashrafian Houman , Drury Nigel E. , Ranasinghe Aaron M. , Contractor Hussain , Isackson Henrik , Calvert Melanie , Williams Lynne K. , Freemantle Nick , Quinn David W. , Green David , Frenneaux Michael , Bonser Robert S. , Mascaro Jorge G. , Graham Timothy R. , Rooney Stephen J. , Wilson Ian C. , Pagano Domenico 
Published: January 2011

Background—
Patients undergoing aortic valve replacement for critical aortic stenosis often have significant left ventricular hypertrophy. Left ventricular hypertrophy has been identified as an independent predictor of poor outcome after aortic valve replacement as a result of a combination of maladaptive myocardial changes and inadequate myocardial protection at the time of surgery. Glucose-insulin-potassium (GIK) is a potentially useful adjunct to myocardial protection. This study was designed to evaluate the effects of GIK infusion in patients undergoing aortic valve replacement surgery.

Methods and Results—

Patients undergoing aortic valve replacement for aortic stenosis with evidence of left ventricular hypertrophy were randomly assigned to GIK or placebo. The trial was double-blind and conducted at a single center. The primary outcome was the incidence of low cardiac output syndrome. Left ventricular biopsies were analyzed to assess changes in 5′ adenosine monophosphate–activated protein kinase (AMPK), Akt phosphorylation, and protein O-linked β-
N
-acetylglucosamination (O-GlcNAcylation). Over a 4-year period, 217 patients were randomized (107 control, 110 GIK). GIK treatment was associated with a significant reduction in the incidence of low cardiac output state (odds ratio, 0.22; 95% confidence interval, 0.10 to 0.47;
P
=0.0001) and a significant reduction in inotrope use 6 to 12 hours postoperatively (odds ratio, 0.30; 95% confidence interval, 0.15 to 0.60;
P
=0.0007). These changes were associated with a substantial increase in AMPK and Akt phosphorylation and a significant increase in the O-GlcNAcylation of selected protein bands.

Conclusions—
Perioperative treatment with GIK was associated with a significant reduction in the incidence of low cardiac output state and the need for inotropic support. This benefit was associated with increased signaling protein phosphorylation and O-GlcNAcylation. Multicenter studies and late follow-up will determine whether routine use of GIK improves patient prognosis.

Clinical Trial Registration—

URL:
http://www.controlled-trials.com
. Reference number: ISRCTN 05758301.
Long-Term Outcomes of Endoscopic Vein Harvesting After Coronary Artery Bypass Grafting
Authors: Dacey Lawrence J. , Braxton John H. , Kramer Robert S. , Schmoker Joseph D. , Charlesworth David C. , Helm Robert E. , Frumiento Carmine , Sardella Gerald L. , Clough Robert A. , Jones Stephan R. , Malenka David J. , Olmstead Elaine M. , Ross Cathy S. , O'Connor Gerald T. , Likosky Donald S. 
Published: January 2011

Background—
Use of endoscopic saphenous vein harvesting has developed into a routine surgical approach at many cardiothoracic surgical centers. The association between this technique and long-term morbidity and mortality has recently been called into question. The present report describes the use of open versus endoscopic vein harvesting and risk of mortality and repeat revascularization in northern New England during a time period (2001 to 2004) in which both techniques were being performed.

Methods and Results—

From 2001 to 2004, 8542 patients underwent isolated coronary artery bypass grafting procedures, 52.5% with endoscopic vein harvesting. Surgical discretion dictated the vein harvest approach. The main outcomes were death and repeat revascularization (percutaneous coronary intervention or coronary artery bypass grafting) within 4 years of the index admission. The use of endoscopic vein harvesting increased from 34% in 2001 to 75% in 2004. In general, patients undergoing endoscopic vein harvesting had greater disease burden. Endoscopic vein harvesting was associated with an increased adjusted risk of bleeding requiring a return to the operating room (2.4 versus 1.7;
P
=0.03) but a decreased risk of leg wound infections (0.2 versus 1.1;
P
<0.001). Use of endoscopic vein harvesting was associated with a significant reduction in long-term mortality (adjusted hazard ratio, 0.74; 95% confidence interval, 0.60 to 0.92) but a nonsignificant increased risk of repeat revascularization (adjusted hazard ratio, 1.29; 95% confidence interval, 0.96 to 1.74). Similar results were obtained in propensity-stratified analysis.

Conclusions—
During 2001 to 2004 in northern New England, the use of endoscopic vein harvesting was not associated with harm. There was a nonsignificant increase in repeat revascularization, and survival was not decreased.
Depot-Specific Differences and Insufficient Subcutaneous Adipose Tissue Angiogenesis in Human Obesity
Authors: Gealekman Olga , Guseva Nina , Hartigan Celia , Apotheker Sarah , Gorgoglione Matthew , Gurav Kunal , Tran Khanh-Van , Straubhaar Juerg , Nicoloro Sarah , Czech Michael P. , Thompson Michael , Perugini Richard A. , Corvera Silvia 
Published: January 2011

Background—
Adipose tissue expands in response to excess caloric intake, but individuals prone to deposit visceral instead of subcutaneous adipose tissue have higher risk of metabolic disease. The role of angiogenesis in the expandability of human adipose tissue depots is unknown. The objective of this study was to measure angiogenesis in visceral and subcutaneous adipose tissue and to establish whether there is a relationship between obesity, metabolic status, and the angiogenic properties of these depots.

Methods and Results—
Angiogenic capacity was determined by quantifying capillary branch formation from human adipose tissue explants embedded in Matrigel, and capillary density was assessed by immunohistochemistry. Subcutaneous adipose tissue had a greater angiogenic capacity than visceral tissue, even after normalization to its higher initial capillary density. Gene array analyses revealed significant differences in expression of angiogenic genes between depots, including an increased subcutaneous expression of angiopoietin-like protein 4, which is proangiogenic in an adipose tissue context. Subcutaneous capillary density and angiogenic capacity decreased with morbid obesity, and subcutaneous, but not visceral, adipose tissue angiogenic capacity correlated negatively with insulin sensitivity.

Conclusions—
These data imply that subcutaneous adipose tissue has a higher capacity to expand its capillary network than visceral tissue, but this capacity decreases with morbid obesity. The decrease correlates with insulin resistance, suggesting that impairment of subcutaneous adipose tissue angiogenesis may contribute to metabolic disease pathogenesis.
N-RasG12D induces features of stepwise transformation in preleukemic human umbilical cord blood cultures expressing the AML1-ETO fusion gene
Authors: Chou Fu-Sheng , Wunderlich Mark , Griesinger Andrea , Mulloy James C. 
Published: January 2011

Abstract
AML1-ETO (AE) is a fusion product of t(8;21) observed in 40% French-American-British M2 type of acute myeloid leukemia (AML). Clinical data suggest that Ras mutation is a frequent cooperating event in t(8;21) AML. Whether constitutively active Ras promotes leukemogenesis on the t(8;21) background has not been demonstrated experimentally. Here, we retrovirally expressed N-RasG12D in AE-expressing human hematopoieticcells to investigate cooperativity. The AE/N-RasG12D cultures were cytokine-independent, enriched for CD34 positivity, and possessed increased colony-forming and replating abilities. N-RasG12D expression led to Bcl-2 up-regulation and reduced apoptosis. Ectopic Bcl-2 expression also resulted in enhanced colony-forming and replating abilities but was insufficient to sustain cytokine independence. AE/N-RasG12D cells were more sensitive to Bcl-2 inhibition with ABT-737 than parent AE cells. Enhanced engraftment of AE/N-RasG12D cells was observed on intrafemoral injection into immunodeficient mice, presumably because of improved survival in the bone marrow microenvironment. N-RasG12D promotes progression toward transfor-mation in AE-expressing cells, partially through up-regulating Bcl-2.
HIV disease progression correlates with the generation of dysfunctional naive CD8low T cells
Authors: Favre David , Stoddart Cheryl A. , Emu Brinda , Hoh Rebecca , Martin Jeffrey N. , Hecht Frederick M. , Deeks Steven G. , McCune Joseph M. 
Published: January 2011

AbstractHIV infection can result in depletion of total CD4+ T cells and naive CD8+ T cells, and in the generation of dysfunctional effector CD8+ T cells. In this study, we show that naive CD8+ T cells in subjects with progressive HIV disease express low levels of CD8α and CD8β chains. Such naive CD8low T cells display broad signaling defects across the T-cell receptor complex, and their appearance correlates with generalized up-regulation of major histocompatibility complex class I (MHC-I) antigens on peripheral blood mononuclear cells (PBMCs). To explore a causal link between increased MHC-I up-regulation and the generation of naive CD8low T cells, we used the humanized SCID-hu Thy/Liv mouse model to show that HIV infection of the thymus and interferon α (IFNα) treatment alone result in MHC-I up-regulation and in the generation of dysfunctional CD3highCD8+CD4− single-positive 8 (SP8) thymocytes with low expression of CD8. We suggest that dysfunctional naive CD8low T cells are generated as a result of IFNα-mediated up-regulation of MHC-I on stromal cells in the thymus and antigen-presenting cells in the periphery, and that dysfunction in this naive compartment contributes to the immunodeficiency of HIV disease. This study is registered at www.clinicaltrials.gov as NCT00187512.
COMP-Ang1 stimulates HIF-1α–mediated SDF-1 overexpression and recovers ischemic injury through BM-derived progenitor cell recruitment
Authors: Youn Seock-Won , Lee Sae-Won , Lee Jaewon , Jeong Han-Kyul , Suh Jung-Won , Yoon Chang-Hwan , Kang Hyun-Jae , Kim Hak-Zoo , Koh Gou-Young , Oh Byung-Hee , Park Young-Bae , Kim Hyo-Soo 
Published: January 2011

AbstractRecruitment and adhesion of bone marrow (BM)–derived circulating progenitor cells to ischemic tissue are important for vasculogenesis and tissue repair. Recently, we found cartilage oligomeric matrix protein (COMP)–Ang1 is a useful cell-priming agent to improve the therapeutic efficacy of progenitor cells. However, the effect and the underlying mechanisms of COMP-Ang1 on recruitment of BM-derived progenitor cells (BMPCs) to foci of vascular injury have not been well defined. Here, we found that COMP-Ang1 is a critical stimulator of stromal cell–derived factor 1 (SDF-1), the principal regulator of BM-cell trafficking. Furthermore, SDF-1 stimulation by COMP-Ang1 was blocked by small-interfering RNA (siRNA) against hypoxia-inducible factor-1α (HIF-1α). COMP-Ang1 increased the synthesis of HIF-1α by activating mammalian target of rapamycin (mTOR) in hypoxic endothelium. The intermediate mechanism transmitting the COMP-Ang1 signal to the downstream mTOR/HIF-1α/SDF-1 pathway was the enhanced binding of the Tie2 receptor with integrin-linked kinase (ILK), an upstream activator of mTOR. In the mouse ischemic model, local injection of COMP-Ang1 stimulated the incorporation of BMPCs into ischemic limb, thereby enhancing neovasculogenesis and limb salvage. Collectively, our findings identify the COMP-Ang1/HIF-1α/SDF-1 pathway as a novel inducer of BMPC recruitment and neovasculogenesis in ischemic disease.
Identification of microRNAs in the cerebrospinal fluid as marker for primary diffuse large B-cell lymphoma of the central nervous system
Authors: Baraniskin Alexander , Kuhnhenn Jan , Schlegel Uwe , Chan Andrew , Deckert Martina , Gold Ralf , Maghnouj Abdelouahid , Zöllner Hannah , Reinacher-Schick Anke , Schmiegel Wolff , Hahn Stephan A. , Schroers Roland 
Published: January 2011

Abstract
The diagnosis of primary central nervous system lymphoma (PCNSL) depends on histopathology of brain biopsies, because disease markers in the cerebrospinal fluid (CSF) with sufficient diagnostic accuracy are not available yet. MicroRNAs (miRNAs) are regulatory RNA molecules that are deregulated in many disease types, including cancer. Recently, miRNAs have shown promise as markers for cancer diagnosis. In this study, we demonstrate that miRNAs are present in the CSF of patients with PCNSL. With a candidate approach and miRNA quantification by reverse transcription polymerase chain reaction, miRNAs with significant levels in the CSF of patients with PCNSL were identified. MiR-21, miR-19, and miR-92a levels in CSF collected from patients with PCNSL and from controls with inflammatory CNS disorders and other neurologic disorders indicated a significant diagnostic value of this method. Receiver-operating characteristic analyses showed area under the curves of 0.94, 0.98, and 0.97, respectively, for miR-21, miR-19, and miR-92a CSF levels in discriminating PCNSL from controls. More importantly, combined miRNA analyses resulted in an increased diagnostic accuracy with 95.7% sensitivity and 96.7% specificity. We also demonstrated a remarkable stability of miRNAs in the CSF. In conclusion, CSF miRNAs are potentially useful tools as novel noninvasive biomarker for the diagnosis of PCNSL.
Epigenetic control of IRF1 responses in HIV-exposed seronegative versus HIV-susceptible individuals
Authors: Su Ruey-Chyi , Sivro Aida , Kimani Joshua , Jaoko Walter , Plummer Francis A. , Ball T. Blake 
Published: January 2011

AbstractNot all individuals exposed to HIV become infected. Understanding why these HIV-exposed seronegative individuals remain uninfected will help inform the development of preventative measures against HIV infection. Interferon regulatory factor-1 (IRF1) plays a critical role both in host antiviral immunity and in HIV-1 replication. This study examined IRF1 expression regulation in the ex vivo peripheral blood mononuclear cells of HIV-exposed seronegative commercial sex workers who can be epidemiologically defined as relatively resistant to HIV infection (HIV-R), versus HIV-uninfected, susceptible controls (HIV-S). Whereas HIV-susceptible individuals demonstrated a biphasic, prolonged increase in IRF1 expression after interferon-γ stimulation, HIV-R individuals demonstrated a robust, but transient response. We also found that the IRF1 promoter in HIV-R was primed by increased basal histone deacetylase-2 binding, independently of transcription regulators, STAT1 and nuclear factor-κB/p65, implicating an epigenetic silencing mechanism. Interestingly, the transitory IRF1 response in HIV-R was sufficient in comparable regulation of interleukin-12 and interleukin-4 expression compared with the HIV-susceptible controls. This is the first study characterizing IRF1 responsiveness in individuals who demonstrate altered susceptibility to HIV infection. These data suggest that transitory IRF1 responsiveness in HIV-R may be one of the key contributors to the altered susceptibility to HIV infection during the early stages of primary HIV infection.