bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adaptive timekeeping replacement
Authors: Wu Carole-Jean , Martonosi Margaret 
Published: May 2011

In chip multiprocessors (CMPs), several high-performance cores typically compete for capacity in a shared last-level cache. This causes degraded and unpredictable memory performance for multiprogrammed and parallel workloads. In response, recent schemes apportion cache bandwidth and capacity in ways that offer better aggregate performance for the workloads. These schemes, however, focus primarily on relatively coarse-grained capacity management without concern for operating system process priority levels.
In this work, we explore capacity management approaches that are both temporally and spatially more fine-grained than prior work. We also consider operating system priority levels as part of capacity management. We propose a capacity management mechanism based on timekeeping techniques that track the time interval since the last access to cached data. This Adaptive Timekeeping Replacement (ATR) scheme maintains aggregate cache occupancies that reflect the priority and footprint of each application. The key novelties of our work are (1) ATR offers a complete cache capacity management framework taking into account application priorities and memory characteristics, and (2) ATR's fine-grained cache capacity control is demonstrated to be effective and important in improving the performance of parallel workloads in addition to sequential ones.
We evaluate our ideas using a full-system simulator and multiprogrammed workloads of both sequential and parallel applications. This is the first detailed study of shared cache capacity management considering thread behaviors in parallel applications. ATR outperforms an unmanaged system by as much as 1.63X and by an average of 1.19X. ATR's fine-grained temporal control is particularly important for parallel applications, which are expected to be increasingly prevalent in years to come.
TNFα Accelerates Monocyte to Endothelial Transdifferentiation in Tumors by the Induction of Integrin α5 Expression and Adhesion to Fibronectin
Authors: Li Bin , Pozzi Ambra , Young Pampee P. 
Published: May 2011

AbstractTumor-associated myeloid cells are believed to promote tumor development by stimulating tumor growth, angiogenesis, invasion, and metastasis. Tumor-associated myeloid cells that coexpress endothelial and myeloid markers represent a proangiogenic subpopulation known as vascular leukocytes. Recently, we and others had shown that tumor-derived TNFα promotes local tumor growth and vascularity. Our data suggested that tumor growth is in part due to TNFα-mediated increased numbers of tumor-associated vascular leukocytes (i.e., myeloid–endothelial biphenotypic cells). The work detailed herein explored the mechanism by which TNFα mediates endothelial differentiation of myeloid cells. Our studies showed that fibronectin is a robust facilitator of endothelial differentiation of blood mononuclear cells in vitro. We have found that TNFα treatment of monocytes significantly increased expression of α5β1 integrin, a major fibronectin receptor enriched on endothelial cells, leading to a consequent fourfold increase in fibronectin adhesion. Furthermore, TNFα-treated monocytes upregulated expression of endothelial markers, flk-1(VEGFR2/KDR) and VE-cadherin. Integrin α5 subunit inhibitory antibodies blocked adhesion to fibronectin as well as consequent upregulation of flk-1 and VE-cadherin transcripts, implying a role for outside-in signaling by the α5β1 integrin after binding fibronectin. Finally, treatment of mouse tumors with anti-α5 antibodies reduced accumulation of tumor vascular leukocytes in vivo. Our studies suggest that tumor cell–derived TNFα constitutes a tumor microenvironment signal that promotes differentiation of tumor-associated monocytes toward a proangiogenic/provasculogenic myeloid–endothelial phenotype via upregulation of the fibronectin receptor α5β1. Mol Cancer Res; 9(6); 702–11. ©2011 AACR.
Declining Stroke and Vascular Event Recurrence Rates in Secondary Prevention Trials Over the Past 50 Years and Consequences for Current Trial Design
Authors: Hong Keun-Sik , Yegiaian Sharon , Lee Meng , Lee Juneyoung , Saver Jeffrey L. 
Published: May 2011

Background—
It is widely supposed, but not well-demonstrated, that cumulative advances in standard care have reduced recurrent stroke and cardiovascular events in secondary prevention trials.

Methods and Results—

Systematic search identified all randomized, controlled trials of medical secondary stroke prevention therapies published from 1960 to 2009. Randomized, controlled trials narrowly focused on single stroke mechanisms, including atrial fibrillation, cervical carotid stenosis, and intracranial stenosis, were excluded. From control arms of individual trials, we extracted data for baseline characteristics and annual event rates for recurrent stroke, fatal stroke, and major vascular events and analyzed trends over time. Fifty-nine randomized controlled trials were identified, enrolling 66 157 patients in control arms. Over the 5 decade periods, annual event rates declined, per decade, for recurrent stroke by 0.996% (
P
=0.001), fatal stroke by 0.282% (
P
=0.003), and major vascular events by 1.331% (
P
=0.001). Multiple regression analyses identified increasing antithrombotic use and lower blood pressures as major contributors to the decline in recurrent stroke. For recurrent stroke, annual rates fell from 8.71% in trials launched in the 1960s to 6.10% in the 1970s, 5.41% in the 1980s, 4.04% in the 1990s, and 4.98% in the 2000s. The sample size required for a trial to have adequate power to detect a 20% reduction in recurrent stroke increased 2.2-fold during this period.

Conclusions—
Recurrent stroke and vascular event rates have declined substantially over the last 5 decades, with improved blood pressure control and more frequent use of antiplatelet therapy as the leading causes. Considerably larger sample sizes are now needed to demonstrate incremental improvements in medical secondary prevention.
Pomalidomide augments fetal hemoglobin production without the myelosuppressive effects of hydroxyurea in transgenic sickle cell mice
Authors: Meiler Steffen E. , Wade Marlene , Kutlar Ferdane , Yerigenahally Shobha D. , Xue Yongjun , Moutouh-de Parseval Laure A. , Corral Laura G. , Swerdlow Paul S. , Kutlar Abdullah 
Published: May 2011

AbstractPharmacologic induction of fetal hemoglobin (HbF) expression is an effective treatment strategy for sickle cell disease (SCD) and β-thalassemia. Pomalidomide is a potent structural analog of thalidomide and member of a new class of immunomodulatory drugs. Recent reports demonstrated that pomalidomide reduced or eliminated transfusion requirements in certain hematologic malignancies and induced HbF ex vivo in CD34+ progenitor cells from healthy and SCD donors. We investigated the effects of pomalidomide on erythropoiesis and hemoglobin synthesis in a transgenic mouse model of SCD. We found that 8 weeks of treatment with pomalidomide induced modest increases of HbF with similar efficacy as hydroxyurea. However, in stark contrast to hydroxyurea's myelosuppressive effects, pomalidomide augmented erythropoiesis and preserved bone marrow function. Surprisingly, combinatory therapy with both drugs failed to mitigate hydroxyurea's myelotoxic effects and caused loss of HbF induction. These findings support further evaluation of pomalidomide as a novel therapy for SCD.
DCIR-mediated enhancement of HIV-1 infection requires the ITIM-associated signal transduction pathway
Authors: Lambert Alexandra A. , Barabé Frédéric , Gilbert Caroline , Tremblay Michel J. 
Published: May 2011

AbstractDendritic cell immunoreceptor (DCIR) is a C-type lectin receptor expressed at high levels on dendritic cells (DCs). This surface molecule acts as an attachment factor for HIV-1 on DCs and contributes to trans- and cis-infection pathways. Moreover, DICR is induced by HIV-1 in CD4+ T cells and promotes virus replication in this cell type. Nothing is known hitherto about the DCIR-dependent signaling, which is induced following HIV-1 ligation. First, specific pharmacologic inhibitors were tested on HIV-1 binding/entry and, second, specific antisense oligonucleotides targeted, more specifically kinases and phosphatases, were used. Our results show that SHP-1, SHP-2, Syk, and Src kinases (ie, Src, Fyn, and Hck) as well as PKC-α and MAP kinases (ie, Erk1/2 and p38) are all involved in the DCIR-mediated signal transduction pathway triggered by HIV-1. By mutagenesis and through the use of intracellular phosphorylated peptides, we show as well a pivotal role for the tyrosine and threonine residues of the DCIR immunoreceptor tyrosine-based inhibitory motif (ITIM). Our data suggest for the first time an involvement of ITIM domain in HIV-1–mediated signaling events and a relationship between phosphorylation events and DCIR function with respect to HIV-1 biology.
A study of toxicity and differential gene expression in murine liver following exposure to anti-malarial drugs: amodiaquine and sulphadoxine-pyrimethamine
Authors: Mishra Shrawan Kumar , Singh Prabhat , Rath Srikanta Kumar 
Published: May 2011

Abstract

Background
Amodiaquine (AQ) along with sulphadoxine-pyrimethamine (SP) offers effective and cheaper treatment against chloroquine-resistant falciparum malaria in many parts of sub-Saharan Africa. Considering the previous history of hepatitis, agranulocytosis and neutrocytopenia associated with AQ monotherapy, it becomes imperative to study the toxicity of co-administration of AQ and SP. In this study, toxicity and resulting global differential gene expression was analyzed following exposure to these drugs in experimental Swiss mice.

Methods
The conventional markers of toxicity in serum, oxidative stress parameters in tissue homogenates, histology of liver and alterations in global transcriptomic expression were evaluated to study the toxic effects of AQ and SP in isolation and in combination.

Results
The combination therapy of AQ and SP results in more pronounced hepatotoxicity as revealed by elevated level of serum ALT, AST with respect to their individual drug exposure regimen. Furthermore, alterations in the activity of major antioxidant enzymes (glutathione peroxidase, superoxide dismutase, catalase, glutathione reductase), indicating the development of oxidative stress, was more significant in AQ+SP combination therapy. cDNA microarray results too showed considerably more perturbed gene expression following combination therapy of AQ and SP as compared to their individual drug treatment. Moreover, a set of genes were identified whose expression pattern can be further investigated for identifying a good biomarker for potential anti-malarial hepatotoxicity.

Conclusion
These observations clearly indicate AQ+SP combination therapy is hepatotoxic in experimental Swiss mice. Microarray results provide a considerable number of potential biomarkers of anti-malarial drug toxicity. These findings hence will be useful for future drug toxicity studies, albeit implications of this study in clinical conditions need to be monitored with cautions.
The emergence of insecticide resistance in central Mozambique and potential threat to the successful indoor residual spraying malaria control programme
Authors: Abilio Ana P , Kleinschmidt Immo , Rehman Andrea M , Cuamba Nelson , Ramdeen Varsha , Mthembu David S , Coetzer Sarel , Maharaj Rajendra , Wilding Craig S , Steven Andrew , Coleman Marlize , Hemingway Janet , Coleman Michael 
Published: May 2011

Abstract

Background
Malaria vector control by indoor residual spraying was reinitiated in 2006 with DDT in Zambézia province, Mozambique. In 2007, these efforts were strengthened by the President's Malaria Initiative. This manuscript reports on the monitoring and evaluation of this programme as carried out by the Malaria Decision Support Project.

Methods
Mosquitoes were captured daily through a series of 114 window exit traps located at 19 sentinel sites, identified to species and analysed for sporozoites. Anopheles mosquitoes were collected resting indoors and tested for insecticide resistance following the standard WHO protocol. Annual cross sectional household parasite surveys were carried out to monitor the impact of the control programme on prevalence of Plasmodium falciparum in children aged 1 to 15 years.

Results
A total of 3,769 and 2,853 Anopheles gambiae s.l. and Anopheles funestus, respectively, were captured from window exit traps throughout the period. In 2010 resistance to the pyrethroids lambda-cyhalothrin and permethrin and the carbamate, bendiocarb was detected in An. funestus. In 2006, the sporozoite rate in An. gambiae s.s. was 4% and this reduced to 1% over 4 rounds of spraying. The sporozoite rate for An. funestus was also reduced from 2% to 0 by 2008. Of the 437 Anopheles arabiensis identified, none were infectious. Overall prevalence of P. falciparum in the sentinel sites fell from 60% to 32% between October 2006 and October 2008.

Conclusion
Both An. gambiae s.s. and An. funestus were controlled effectively with the DDT-based IRS programme in Zambézia, reducing disease transmission and burden. However, the discovery of pyrethroid resistance in the province and Mozambique's policy change away from DDT to pyrethroids for IRS threatens the gains made here.
Epigenetic markers for early detection of nasopharyngeal carcinoma in a high risk population
Authors: Hutajulu Susanna H , Indrasari Sagung R , Indrawati Luh PL , Harijadi Ahmad , Duin Sylvia , Haryana Sofia M , Steenbergen Renske DM , Greijer Astrid E , Middeldorp Jaap M 
Published: May 2011

Abstract

Background
Undifferentiated nasopharyngeal carcinoma (NPC) is strongly related to Epstein-Barr virus (EBV) infection, allowing aberrant antibodies against EBV and viral DNA load as screening tools in high risk populations. Methylation analysis in the promoter of tumor suppressor genes (TSGs) may serve as a complementary marker for identifying early cases. This study determined methylation status of multiple TSGs and evaluated whether it may improve early detection.

Methods
Nasopharyngeal brushings were taken from 53 NPC patients, 22 high risk subjects and 25 healthy EBV carriers. Corresponding NPC paraffin tissue was included. DNA was bisulfite-modified preceding analysis by methylation-specific PCR (MSP). Ten TSGs were studied.

Results
NPC paraffin and brushing DNA revealed an 81.8% concordance so that MSP analysis was done using either one of both specimens. NPC samples showed methylation for individual TSGs (DAPK1 79.2%, CDH13 77.4%, DLC1 76.9%, RASSF1A 75.5%, CADM1 69.8%, p16 66.0%, WIF1 61.2%, CHFR 58.5%, RIZ1 56.6% and RASSF2A 29.2%). High risk individuals, having elevated EBV IgA and viral load, showed high frequency of methylation of CDH13, DAPK1, DLC1 and CADM1, but low frequency of methylation of p16 and WIF1 and undetectable methylation of RASSF1A, CHFR, RIZ1 and RASSF2A. Healthy subjects showed similar patterns as high risk individuals. A combination of RASSF1A and p16 gave good discrimination between NPC and non-NPC, but best results were combined analysis of five methylation markers (RASSF1A, p16, WIF1, CHFR and RIZ1) with detection rate of 98%.

Conclusion
Multiple marker MSP is proposed as a complementary test for NPC risk assessment in combination with EBV-based markers.
Tetherin inhibits prototypic foamy virus release
Authors: Xu Fengwen , Tan Juan , Liu Ruikang , Xu Dan , Li Yue , Geng Yunqi , Liang Chen , Qiao Wentao 
Published: May 2011

Abstract

Background
Tetherin (also known as BST-2, CD317, and HM1.24) is an interferon- induced protein that blocks the release of a variety of enveloped viruses, such as retroviruses, filoviruses and herpesviruses. However, the relationship between tetherin and foamy viruses has not been clearly demonstrated.

Results
In this study, we found that tetherin of human, simian, bovine or canine origin inhibits the production of infectious prototypic foamy virus (PFV). The inhibition of PFV by human tetherin is counteracted by human immunodeficiency virus type 1 (HIV-1) Vpu. Furthermore, we generated human tetherin transmembrane domain deletion mutant (delTM), glycosyl phosphatidylinositol (GPI) anchor deletion mutant (delGPI), and dimerization and glycosylation deficient mutants. Compared with wild type tetherin, the delTM and delGPI mutants only moderately inhibited PFV production. In contrast, the dimerization and glycosylation deficient mutants inhibit PFV production as efficiently as the wild type tetherin.

Conclusions
These results demonstrate that tetherin inhibits the release and infectivity of PFV, and this inhibition is antagonized by HIV-1 Vpu. Both the transmembrane domain and the GPI anchor of tetherin are important for the inhibition of PFV, whereas the dimerization and the glycosylation of tetherin are dispensable.
Dynamic distribution and tissue tropism of classical swine fever virus in experimentally infected pigs
Authors: Liu Jun , Fan Xue-Zheng , Wang Qin , Xu Lu , Zhao Qi-Zu , Huang Wei , Zhou Yuan-Cheng , Tang Bo , Chen Lei , Zou Xing-Qi , Sha Sha , Zhu Yuan-Yuan 
Published: May 2011

Abstract

Background

Classical swine fever (CSF), caused by the Classical swine fever virus (CSFV), is an Office International des Epizooties (OIE) notifiable disease. However, we are far from fully understand the distribution, tissue tropism, pathogenesis, replication and excretion of CSFV in pigs. In this report, we investigated the dynamic distribution and tissue tropism of the virus in internal organs of the experimentally infected pigs using real-time RT-PCR and immunohistochemistry (IHC).

Results
A relative quantification real-time PCR was established and used to detect the virus load in internal organs of the experimentally infected pigs. The study revealed that the virus was detected in all 21 of the internal organs and blood collected from pigs at day 1 to day 8 post infections, and had an increasing virus load from day 1 to day 8 post infections. However, there was irregular distribution virus load in most internal organs over the first 2 days post infection. Blood, lymphoid tissue, pancreas and ileum usually contain the highest viral loads, while heart, duodenum and brain show relatively low viral loads.

Conclusions
All the data suggest that CSFV had an increasing virus load from day 1 to day 8 post infections in experimentally infected pigs detected by real-time RT-PCR, which was in consistent with the result of the IHC staining. The data also show that CSFV was likely to reproduce in blood, lymphoid tissue, pancreas and the ileum, while unlikely to replicate in the heart, duodenum and brain. The results provide a foundation for further clarification of the pathogenic mechanism of CSFV in internal organs, and indicate that blood, lymphoid tissue, pancreas and ileum may be preferred sites of acute infection.
The potential for bi-lateral agreements in medical tourism: A qualitative study of stakeholder perspectives from the UK and India
Authors: Martínez Álvarez Melisa , Chanda Rupa , Smith Richard D 
Published: May 2011

Abstract

Background
Globalisation has prompted countries to evaluate their position on trade in health services. However, this is often done from a multi-lateral, rather than a regional or bi-lateral perspective. In a previous review, we concluded that most of the issues raised could be better addressed from a bi-lateral relationship. We report here the results of a qualitative exercise to assess stakeholders' perceptions on the prospects for such a bi-lateral system, and its ability to address concerns associated with medical tourism.

Methods
30 semi-structured interviews were carried out with stakeholders, 20 in India and 10 in the UK, to assess their views on the potential offered by a bi-lateral relationship on medical tourism between both countries. Issues discussed include data availability, origin of medical tourists, quality and continuity of care, regulation and litigation, barriers to medical tourism, policy changes needed, and prospects for such a bi-lateral relationship.

Results
The majority of stakeholders were concerned about the quality of health services patients would receive abroad, regulation and litigation procedures, lack of continuity of care, and the effect of such trade on the healthcare available to the local population in India. However, when considering trade from a bi-lateral point of view, there was disagreement on how these issues would apply. There was further disagreement on the importance of the Diaspora and the validity of the UK's 'rule' that patients should not fly more than three hours to obtain care. Although the opinion on the prospects for an India-UK bi-lateral relationship was varied, there was no consensus on what policy changes would be needed for such a relationship to take place.

Conclusions
Whilst the literature review previously carried out suggested that a bi-lateral relationship would be best-placed to address the concerns regarding medical tourism, there was scepticism from the analysis provided in this paper based on the over-riding feeling that the political 'cost' involved was likely to be the major impediment. This makes the need for better evidence even more acute, as much of the current policy process could well be based on entrenched ideological positions, rather than secure evidence of impact.
Vitamin D Receptor Protein Expression in Tumor Tissue and Prostate Cancer Progression
Authors: Hendrickson Whitney K. , Flavin Richard , Kasperzyk Julie L. , Fiorentino Michelangelo , Fang Fang , Lis Rosina , Fiore Christopher , Penney Kathryn L. , Ma Jing , Kantoff Philip W. , Stampfer Meir J. , Loda Massimo , Mucci Lorelei A. , Giovannucci Edward 
Published: May 2011

Purpose Data suggest that circulating 25-hydroxyvitamin D [25(OH)D] interacts with the vitamin D receptor (VDR) to decrease proliferation and increase apoptosis for some malignancies, although evidence for prostate cancer is less clear. How VDR expression in tumor tissue may influence prostate cancer progression has not been evaluated in large studies. Patients and Methods We examined protein expression of VDR in tumor tissue among 841 patients with prostate cancer in relation to risk of lethal prostate cancer within two prospective cohorts, the Physicians' Health Study and Health Professionals Follow-Up Study. We also examined the association of VDR expression with prediagnostic circulating 25(OH)D and 1,25-dihydroxyvitamin D levels and with two VDR single nucleotide polymorphisms, FokI and BsmI. Results Men whose tumors had high VDR expression had significantly lower prostate-specific antigen (PSA) at diagnosis (P for trend < .001), lower Gleason score (P for trend < .001), and less advanced tumor stage (P for trend < .001) and were more likely to have tumors harboring the TMPRSS2:ERG fusion (P for trend = .009). Compared with the lowest quartile, men whose tumors had the highest VDR expression had significantly reduced risk of lethal prostate cancer (hazard ratio [HR], 0.17; 95% CI, 0.07 to 0.41). This association was only slightly attenuated after adjustment for Gleason score and PSA at diagnosis (HR, 0.33; 95% CI, 0.13 to 0.83) or, additionally, for tumor stage (HR, 0.37; 95% CI, 0.14 to 0.94). Neither prediagnostic plasma vitamin D levels nor VDR polymorphisms were associated with VDR expression. Conclusion High VDR expression in prostate tumors is associated with a reduced risk of lethal cancer, suggesting a role of the vitamin D pathway in prostate cancer progression.