bluuebunny/crossref_metadata_2025_split huggingface dataset:
A generalized theory of collaborative caching
Authors: Gu Xiaoming , Ding Chen 
Published: January 2013

Collaborative caching allows software to use hints to influence cache management in hardware. Previous theories have shown that such hints observe the inclusion property and can obtain optimal caching if the access sequence and the cache size are known ahead of time. Previously, the interface of a cache hint is limited, e.g., a binary choice between LRU and MRU.
In this paper, we generalize the hint interface, where a hint is a number encoding a priority. We show the generality in a hierarchical relation where collaborative caching subsumes non-collaborative caching, and within collaborative caching, the priority hint subsumes the previous binary hint. We show two theoretical results for the general hint. The first is a new cache replacement policy, priority LRU, which permits the complete range of choices between MRU and LRU. We prove a new type of inclusion property---non-uniform inclusion---and give a one-pass algorithm to compute the miss rate for all cache sizes. Second, we show that priority hints can enable the use of the same hints to obtain optimal caching for all cache sizes, without having to know the cache size beforehand.
Senescence Sensitivity of Breast Cancer Cells Is Defined by Positive Feedback Loop between CIP2A and E2F1
Authors: Laine Anni , Sihto Harri , Come Christophe , Rosenfeldt Mathias T. , Zwolinska Aleksandra , Niemelä Minna , Khanna Anchit , Chan Edward K. , Kähäri Veli-Matti , Kellokumpu-Lehtinen Pirkko-Liisa , Sansom Owen J. , Evan Gerard I. , Junttila Melissa R. , Ryan Kevin M. , Marine Jean-Christophe , Joensuu Heikki , Westermarck Jukka 
Published: January 2013

Abstract
Senescence induction contributes to cancer therapy responses and is crucial for p53-mediated tumor suppression. However, whether p53 inactivation actively suppresses senescence induction has been unclear. Here, we show that E2F1 overexpression, due to p53 or p21 inactivation, promotes expression of human oncoprotein CIP2A, which in turn, by inhibiting PP2A activity, increases stabilizing serine 364 phosphorylation of E2F1. Several lines of evidence show that increased activity of E2F1-CIP2A feedback renders breast cancer cells resistant to senescence induction. Importantly, mammary tumorigenesis is impaired in a CIP2A-deficient mouse model, and CIP2A-deficient tumors display markers of senescence induction. Moreover, high CIP2A expression predicts for poor prognosis in a subgroup of patients with breast cancer treated with senescence-inducing chemotherapy. Together, these results implicate the E2F1-CIP2A feedback loop as a key determinant of breast cancer cell sensitivity to senescence induction. This feedback loop also constitutes a promising prosenescence target for therapy of cancers with an inactivated p53–p21 pathway.
Significance: It has been recently realized that most currently used chemotherapies exert their therapeutic effect at least partly by induction of terminal cell arrest, senescence. However, the mechanisms by which cell-intrinsic senescence sensitivity is determined are poorly understood. Results of this study identify the E2F1-CIP2A positive feedback loop as a key determinant of breast cancer cell sensitivity to senescence and growth arrest induction. Our data also indicate that this newly characterized interplay between 2 frequently overexpressed oncoproteins constitutes a promising prosenescence target for therapy of cancers with inactivated p53 and p21. Finally, these results may also facilitate novel stratification strategies for selection of patients to receive senescence-inducing cancer therapies. Cancer Discov; 3(2); 182–97. ©2013 AACR.
This article is highlighted in the In This Issue feature, p. 125
Omi/HtrA2 and XIAP are components of platelet apoptosis signalling
Authors: Winkler Jeannine , Rand Margaret , Schmugge Markus , Speer Oliver 
Published: January 2013

SummaryAlthough platelets possess the hallmarks of apoptosis such as activation of caspases, cytochrome c release and depolarisation of the mitochondrial transmembrane potential (ΔΨm), their entire apoptotic-signalling pathway is not totally understood. Therefore we studied the expression of various apoptotic proteins and found that platelets contain the pro-apoptotic proteins Omi/HtrA2 and Smac/Diablo, as well as their target the X-linked inhibitor of apoptosis XIAP. Omi/HtrA2 and Smac/Diablo were released from mitochondria into the platelet cytosol together with cytochrome c after induction of apoptosis by the Ca2+ ionophore A23187 or the BH3 mimetic ABT-737, and to a lesser extent, after platelet stimulation with collagen and thrombin. Inhibition of Omi/HtrA2 led to decreased levels of activated caspase-3/7 and caspase-9, but did not abolish loss of ΔΨm or prevent release of Omi/HtrA2 from mitochondria. These results indicate that platelets have a functional intrinsic apoptotic-signalling pathway including the pro-apoptotic protease Omi/HtrA2 and its target protein XIAP.
Zinc: An important cofactor in haemostasis and thrombosis
Authors: Vu Trang , Fredenburgh James , Weitz Jeffrey 
Published: January 2013

SummaryThere is mounting evidence that zinc, the second most abundant transition metal in blood, is an important mediator of haemostasis and thrombosis. Prompted by the observation that zinc deficiency is associated with bleeding and clotting abnormalities, there now is evidence that zinc serves as an effector of coagulation, anticoagulation and fibrinolysis. Zinc binds numerous plasma proteins and modulates their structure and function. Because activated platelets secrete zinc into the local microenvironment, the concentration of zinc increases in the vicinity of a thrombus. Consequently, the role of zinc varies depending on the microenvironment; a feature that endows zinc with the capacity to spatially and temporally regulate haemostasis and thrombosis. This paper reviews the mechanisms by which zinc regulates coagulation, platelet aggregation, anticoagulation and fibrinolysis and outlines how zinc serves as a ubiquitous modulator of haemostasis and thrombosis.
Significance of F8 missense mutations with respect to inhibitor formation
Authors: Pavlova Anna , Albert Thilo , Caspers Michael , Oldenburg Johannes , Schwaab Rainer 
Published: January 2013

SummaryWe have identified 1,135 haemophilia A patients with missense mutations associated with mild (46%), moderate (22%), severe (16%), and mixed haemophilia phenotypes (11%). Altogether, we detected 374 different missense mutations of which 195 are not listed in the HAMSTeRS database. While missense mutations are strongly underrepresented within the factor VIII (FVIII) B-domain, they are evenly distributed throughout the entire F8 cDNA sequence. Only 36 (5%) of 720 patients with missense mutations and known inhibitor status showed an association with inhibitor formation. Inhibitor prevalence was four-fold higher for severe haemophilia compared to mild/moderate phenotypes. Mutations associated with inhibitor formation were especially clustered within the C1/C2 domain compared to the other domains (8.7% C1/C2 domain vs. 3.6% non-C1/C2-domain; p-value: 0.01). Three different missense mutations (T314A [T295A], S2010P [S1991P], R2169H [R2150H]) were associated twice with inhibitor formation. Importantly, we found that the risk of inhibitor formation in association with FVIII missense mutations is significant higher if the amino acid substitution belongs to another physicochemical class than the original residue (p-value 0.039). For this purpose distinct classes of substitutions were grouped in association with side chains properties: class I, small/hydrophobic; class II, neutral; class III, acidic; class IV, basic. Thus, although missense mutations were associated with an overall lower risk of inhibitor formation compared to other F8 gene mutation types, different missense mutations correlate with specific risks for inhibitor formation. These differences have to be identified in assigning risk profiles to aid in choice of preventative treatments designed to prevent inhibitor formation.
The concurrent use of antithrombotic therapies and the risk of bleeding in patients with atrial fibrillation
Authors: Azoulay Laurent , Dell’Aniello Sophie , Simon Teresa , Renoux Christel , Suissa Samy 
Published: January 2013

SummaryPatients with atrial fibrillation (AF) often receive, in addition to warfarin, antithrombotic drugs to manage other comorbid conditions. To date, few population-based studies have quantified the bleeding risk associated with the concurrent use of these therapies. The United Kingdom General Practice Research Database was used to identify a cohort of 70,760 patients newly-diagnosed with AF between 1993 and 2008. A nested case-control analysis was conducted within that cohort, and conditional logistic regression was used to estimate adjusted rate ratios (RRs) of bleeding associated with current use of warfarin, aspirin, and clopidogrel in single therapy, as well as in dual and triple therapy, as compared with non-use of any therapy. A total of 10,850 patients experienced a bleeding event during follow-up. In single therapy, warfarin was associated with the highest increased risk (RR: 2.08, 95% confidence interval [CI]: 1.95–2.23), followed by clopidogrel (RR: 1.57, 95% CI: 1.37–1.81) and aspirin (RR: 1.25, 95% CI: 1.17–1.34). In dual therapy, combinations containing warfarin were associated with a higher increased risk (warfarin-aspirin: RR: 2.87, 95% CI: 2.58–3.19, and warfarin-clopidogrel: RR: 2.74, 95% CI: 2.14–3.51), than those not containing warfarin (aspirin-clopidogrel: RR: 1.68, 95% CI: 1.44–1.97). Triple therapy of warfarin-aspirin-clopidogrel was associated with the highest increased risk (RR: 3.75, 95% CI: 2.71–5.19). This large population-based study suggests that while all antithrombotic therapies are associated with an elevated risk of bleeding, the risks increase in an additive fashion with dual and triple therapy, particularly in combinations containing warfarin.
Hereditary angioedema: a bradykinin-mediated swelling disorder
Authors: Björkqvist Jenny , Sala-Cunill Anna , Renné Thomas 
Published: January 2013

SummaryEdema is tissue swelling and is a common symptom in a variety of diseases. Edema form due to accumulation of fluids, either through reduced drainage or increased vascular permeability. There are multiple vascular signalling pathways that regulate vessel permeability. An important mediator that increases vascular leak is the peptide hormone bradykinin, which is the principal agent in the swelling disorder hereditary angioedema. The disease is autosomal dominant inherited and presents clinically with recurrent episodes of acute swelling that can be life-threatening involving the skin, the oropharyngeal, laryngeal, and gastrointestinal mucosa. Three different types of hereditary angiodema exist in patients. The review summarises current knowledge on the pathophysiology of hereditary angiodema and focuses on recent experimental and pharmacological findings that have led to a better understanding and new treatments for the disease.
Discrepancies between ADAMTS13 activity assays in patients with thrombotic microangiopathies
Authors: Langley Katy , Chitolie Andrew , Liesner Ri , Scully Marie , Machin Samuel , Peyvandi Flora , Mackie Ian 
Published: January 2013

SummaryADAMTS13 activity assays are sometimes useful in confirming the clinical diagnosis or to distinguish different thrombotic microangiopathies (TMA). We investigated the commonly used clinical assays for ADAMTS13 activity. 159 samples from normal subjects or acquired TMA patients were studied in collagen binding (CBA), Fret and chromogenic peptide substrate assays. Frozen aliquots of pooled normal plasma gave similar values by CBA, Fret-VWF73 peptide, Fret-VWF86 and chromogenic VWF73 ELISA (chr-VWF73). Two lyophilised commercial calibrants gave lower ADAMTS13 activity by CBA than peptide substrate assays. The addition of solid HEPES to normal plasma caused a significant fall in CBA, but not Fret-VWF73 activity and might partly explain the differences, since lyophilised plasmas are often HEPES buffered. Normal plasmas showed good agreement between CBA and Fret assays, although chr-VWF73 gave slightly higher values. In acquired TMA, there was reasonable agreement between assays for samples with <11% ADAMTS13 activity (83% of samples showed agreement between CBA, Fret-VWF73 and chr-VWF73), but samples with moderate deficiency frequently showed lower CBA levels (only 41–52% agreement). However, there were also some discrepancies among the peptide substrate assays, with Fret-VWF86 sometimes giving slightly higher values than the VWF73 substrate assays. An International reference plasma might improve standardisation, but is not the only problem. It is unclear which assay has greatest clinical utility, this may depend on the nature of the sample. If the activity does not match the clinical picture, an alternative method should be performed. Where therapeutic monitoring is required, the same activity assay should be used throughout.
Hirudin anticoagulation allows more rapid determination of P2Y12 inhibition by the VerifyNow P2Y12 assay
Authors: Daly Rebecca , Mehra Sonal , Dhutia Amrita , Howgego Kate , Ecob Rosemary , Judge Heather , Morton Allison , Storey Robert , Sumaya Wael 
Published: January 2013

SummaryVerifyNow (VN) P2Y12 is a point-of-care assay used to assess response to P2Y12 inhibitors. Sodium citrate (citrate) is the standard anticoagulant used for this assay but requires a pre-incubation period. Hirudin is an alternative anticoagulant for platelet function studies that maintains physiological divalent cation levels. We investigated whether hirudin anticoagulation might allow more rapid testing of P2Y12 inhibition at the time of percutaneous coronary intervention (PCI). Blood was collected from the arterial sheath of aspirin-treated patients undergoing elective, urgent or emergency coronary angiography ± PCI and aliquots were anticoagulated with either citrate or hirudin. For each anticoagulant, VN P2Y12 was performed both immediately and after 20 minutes. A total of 98 patients were included in this study following pre-treatment with clopidogrel (n = 88), prasugrel (n = 6) or no P2Y12 inhibitor (n = 4). PRU with hirudin immediately (PRU_H_Imm) and PRU with citrate 20 minutes post sampling (PRU_C_20) were very strongly correlated (R = 0.95) though PRU_H_Imm tended to be lower than PRU_C_20 so that optimal correlation was estimated by the equation PRU_H_Imm = 0.95 x PRU_C_20 (p < 0.001). Bland-Altman plots showed good agreement between PRU_H_Imm and (0.95 x PRU_C_20). Platelet reactivity was more stable over the studied time course with hirudin as compared to citrate. We therefore conclude that VN P2Y12 with hirudin anticoagulation can be performed more rapidly and results are strongly correlated with delayed citrate measurements. Further studies are warranted to assess the utility of this method for improving clinical outcomes in patients undergoing PCI.
Left Ventricular Wall Thickness and the Presence of Asymmetric Hypertrophy in Healthy Young Army Recruits
Authors: Lee Phong T. , Dweck Marc R. , Prasher Sparsh , Shah Anoop , Humphries Steve E. , Pennell Dudley J. , Montgomery Hugh E. , Payne John R. 
Published: January 2013

Background—
To use cardiovascular magnetic resonance to investigate left ventricular wall thickness and the presence of asymmetrical hypertrophy in young army recruits before and after a period of intense exercise training.

Methods and Results—

Using cardiovascular magnetic resonance, the left ventricular wall thickness was measured in all 17 segments and a normal range was calculated for each. The prevalence of asymmetrical wall thickening was assessed before and after training and defined by a ventricular wall thickness ≥13.0 mm that was >1.5× the thickness of the opposing myocardial segment. Five hundred forty-one men (mean age, 20±2 years) were recruited, 309 underwent repeat scanning. Considerable variation in wall thickness was observed across the ventricle with progressive thickening on moving from the apex to base (
P
<0.001) and in the basal and midcavity septum compared with the lateral wall (11.0±1.4 versus 10.1±1.3 mm;
P
<0.001). Twenty-three percent had a maximal wall thickness ≥13.0 mm, whereas the prevalence of asymmetrical wall thickening increased from 2.2% to 10% after the exercise-training program. In those who developed asymmetry, the wall thickness/diastolic volume ration remained normal (0.09±0.02 mm⋅m
2
⋅mL
−1
), indicative of a remodeling response to exercise.

Conclusions—
In a cohort of healthy young white men, we have demonstrated that wall thickness frequently measures ≥13.0 mm and that asymmetrical wall thickening is common and can develop as part of the physiological response to exercise. A diagnosis of hypertrophic cardiomyopathy in young athletic men should, therefore, not be made purely on the basis of regional wall thickening.
Molecular Imaging of the Paracrine Proangiogenic Effects of Progenitor Cell Therapy in Limb Ischemia
Authors: Ryu Jae Choon , Davidson Brian P. , Xie Aris , Qi Yue , Zha Daogang , Belcik J. Todd , Caplan Evan S. , Woda Juliana M. , Hedrick Catherine C. , Hanna Richard N. , Lehman Nicholas , Zhao Yan , Ting Anthony , Lindner Jonathan R. 
Published: January 2013

Background—
Stem cells are thought to enhance vascular remodeling in ischemic tissue in part through paracrine effects. Using molecular imaging, we tested the hypothesis that treatment of limb ischemia with multipotential adult progenitor cells (MAPCs) promotes recovery of blood flow through the recruitment of proangiogenic monocytes.

Methods and Results—

Hind-limb ischemia was produced in mice by iliac artery ligation, and MAPCs were administered intramuscularly on day 1. Optical imaging of luciferase-transfected MAPCs indicated that cells survived for 1 week. Contrast-enhanced ultrasound on days 3, 7, and 21 showed a more complete recovery of blood flow and greater expansion of microvascular blood volume in MAPC-treated mice than in controls. Fluorescent microangiography demonstrated more complete distribution of flow to microvascular units in MAPC-treated mice. On ultrasound molecular imaging, expression of endothelial P-selectin and intravascular recruitment of CX
3
CR-1-positive monocytes were significantly higher in MAPC-treated mice than in the control groups at days 3 and 7 after arterial ligation. Muscle immunohistology showed a >10-fold-greater infiltration of monocytes in MAPC-treated than control-treated ischemic limbs at all time points. Intravital microscopy of ischemic or tumor necrosis factor-α–treated cremaster muscle demonstrated that MAPCs migrate to perimicrovascular locations and potentiate selectin-dependent leukocyte rolling. In vitro migration of human CD14
+
monocytes was 10-fold greater in response to MAPC-conditioned than basal media.

Conclusions—
In limb ischemia, MAPCs stimulate the recruitment of proangiogenic monocytes through endothelial activation and enhanced chemotaxis. These responses are sustained beyond the MAPC lifespan, suggesting that paracrine effects promote flow recovery by rebalancing the immune response toward a more regenerative phenotype.
Efficacy and Safety of Oral Treprostinil Monotherapy for the Treatment of Pulmonary Arterial Hypertension
Authors: Jing Zhi-Cheng , Parikh Keyur , Pulido Tomas , Jerjes-Sanchez Carlos , White R. James , Allen Roblee , Torbicki Adam , Xu Kai-Feng , Yehle David , Laliberte Kevin , Arneson Carl , Rubin Lewis J. 
Published: January 2013

Background—
Pulmonary arterial hypertension (PAH) is a progressive, fatal disease with no cure. Parenteral and inhaled prostacyclin analogue therapies are effective for the treatment of PAH, but complicated administration requirements can limit the use of these therapies in patients with less severe disease. This study was designed to evaluate the safety and efficacy of the oral prostacyclin analogue treprostinil diolamine as initial treatment for de novo PAH.

Methods and Results—

Three hundred forty-nine patients (intent-to-treat population) not receiving endothelin receptor antagonist or phosphodiesterase type-5 inhibitor background therapy were randomized (treprostinil, n=233; placebo, n=116). The primary analysis population (modified intent-to-treat) included 228 patients (treprostinil, n=151; placebo, n=77) with access to 0.25-mg treprostinil tablets at randomization. The primary end point was change from baseline in 6-minute walk distance at week 12. Secondary end points included Borg dyspnea index, clinical worsening, and symptoms of PAH. The week 12 treatment effect for 6-minute walk distance (modified intent-to-treat population) was 23.0 m (
P
=0.0125). For the intent-to-treat population, 6-minute walk distance improvements were observed at peak (26.0 m;
P
=0.0001) and trough (17.0 m;
P
=0.0025) plasma study drug concentrations. Other than an improvement in the combined 6-minute walk distance/Borg dyspnea score, there were no significant changes in secondary end points. Oral treprostinil therapy was generally well tolerated; the most common adverse events (intent-to-treat) were headache (69%), nausea (39%), diarrhea (37%), and pain in jaw (25%).

Conclusions—
Oral treprostinil improves exercise capacity in PAH patients not receiving other treatment. Oral treprostinil could provide a convenient, first-line prostacyclin treatment option for PAH patients not requiring more intensive therapy.

Clinical Trial Registration:—

URL:
http://www.clinicaltrials.gov
. Unique identifier:
NCT00325403
.
Comparison of Ischemic Stroke Outcomes and Patient and Hospital Characteristics by Race/Ethnicity and Socioeconomic Status
Authors: Hanchate Amresh D. , Schwamm Lee H. , Huang Wei , Hylek Elaine M. 
Published: January 2013

Background and Purpose—
Current literature provides mixed evidence on disparities by race/ethnicity and socioeconomic status in discharge outcomes after hospitalization for acute ischemic stroke. Using comprehensive data from 8 states, we sought to compare inpatient mortality and length of stay by race/ethnicity and socioeconomic status.

Methods—
We examined all 2007 hospitalizations for acute ischemic stroke in all nonfederal acute care hospitals in Arizona, California, Florida, Maine, New Jersey, New York, Pennsylvania, and Texas. Population was stratified by race/ethnicity (non-Hispanic whites, non-Hispanic blacks, and Hispanics) and socioeconomic status, measured by median income of patient zip code. For each stratum, we estimated risk-adjusted rates of inpatient mortality and longer length of stay (greater than median length of stay). We also compared the hospitals where these subpopulations received care.

Results—

Hispanic and black patients accounted for 14% and 12% of all ischemic stroke admissions (N=147 780), respectively, and had lower crude inpatient mortality rates (Hispanic=4.5%, blacks=4.4%; all
P
<0.001) compared with white patients (5.8%). Hispanic and black patients were younger and fewer had any form of atrial fibrillation. Adjusted for patient risk, inpatient mortality was similar by race/ethnicity, but was significantly higher for low-income area patients than that for high-income area patients (odds ratio, 1.08; 95% confidence interval, 1.02–1.15). Risk-adjusted rates of longer length of stay were higher among minority and low-income area populations.

Conclusions—
Risk-adjusted inpatient mortality was similar among patients by race/ethnicity but higher among patients from lower income areas. However, this pattern was not evident in sensitivity analyses, including the use of mechanical ventilation as a partial surrogate for stroke severity.