bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Small-Molecule Inhibitor Targeting the Mitotic Spindle Checkpoint Impairs the Growth of Uterine Leiomyosarcoma
Authors: Shan Weiwei , Akinfenwa Patricia Y. , Savannah Kari B. , Kolomeyevskaya Nonna , Laucirica Rudolfo , Thomas Dafydd G. , Odunsi Kunle , Creighton Chad J. , Lev Dina C. , Anderson Matthew L. 
Published: April 2012

Abstract
Purpose: Uterine leiomyosarcoma (ULMS) is a poorly understood cancer with few effective treatments. This study explores the molecular events involved in ULMS with the goal of developing novel therapeutic strategies.
Experimental Design: Genome-wide transcriptional profiling, Western blotting, and real-time PCR were used to compare specimens of myometrium, leiomyoma, and leiomyosarcoma. Aurora A kinase was targeted in cell lines derived from metastatic ULMS using siRNA or MK-5108, a highly specific small-molecule inhibitor. An orthotopic model was used to evaluate the ability of MK-5108 to inhibit ULMS growth in vivo.
Results: We found that 26 of 50 gene products most overexpressed in ULMS regulate mitotic centrosome and spindle functions. These include UBE2C, Aurora A and B kinase, TPX2, and Polo-like kinase 1 (PLK1). Targeting Aurora A inhibited proliferation and induced apoptosis in LEIO285, LEIO505, and SK-LMS1, regardless of whether siRNA or MK-5108 was used. In vitro, MK-5108 did not consistently synergize with gemcitabine or docetaxel. Gavage of an orthotopic ULMS model with MK-5108 at 30 or 60 mg/kg decreased the number and size of tumor implants compared with sham-fed controls. Oral MK-5108 also decreased the rate of proliferation, increased intratumoral apoptosis, and increased expression of phospho-histone H3 in ULMS xenografts.
Conclusions: Our results show that dysregulated centrosome function and spindle assembly are a robust feature of ULMS that can be targeted to slow its growth both in vitro and in vivo. These observations identify novel directions that can be potentially used to improve clinical outcomes for this disease. Clin Cancer Res; 18(12); 3352–65. ©2012 AACR.
Romidepsin for Cutaneous T-cell Lymphoma
Authors: Prince H. Miles , Dickinson Michael 
Published: April 2012

Abstract
Cutaneous T-cell lymphomas (CTCL) are relatively rare lymphomas with an annual incidence of approximately 0.2 to 0.8/100,000 and comprise a variety of clinical entities; mycosis fungoides or its leukemic variant Sezary syndrome account for the majority of cases. Advanced-stage disease is typically treated with bexarotene (a retinoid), interferon, or conventional chemotherapeutic agents, but relapses are inevitable. Histone deacetylase inhibitors, which modify the epigenome, are an attractive addition to the armamentarium. On the basis of 2 large phase II studies, the U.S. Food and Drug Administration approved intravenous romidepsin for patients with relapsed and/or refractory CTCL. Romidepsin provides a subset of patients with an opportunity for prolonged clinical responses with a tolerable side effect profile. Clin Cancer Res; 18(13); 3509–15. ©2012 AACR.
Distinguishing Clinicopathologic Features of Patients with V600E and V600K BRAF-Mutant Metastatic Melanoma
Authors: Menzies Alexander M. , Haydu Lauren E. , Visintin Lydia , Carlino Matteo S. , Howle Julie R. , Thompson John F. , Kefford Richard F. , Scolyer Richard A. , Long Georgina V. 
Published: April 2012

Abstract
Purpose: Certain clinicopathologic features correlate with BRAF mutation status in melanoma including younger age and primary subtype. This study sought to determine the BRAF mutation status by age-decade and whether BRAF-mutant genotypes correlated with clinicopathologic features and outcome in patients with metastatic melanoma.
Methods: A prospectively assembled cohort of Australian patients were followed from diagnosis of metastatic melanoma (N = 308). Clinicopathologic variables were correlated with BRAF mutational status, genotype, and survival.
Results: Forty-six percent of patients had a BRAF mutation; 73% V600E, 19% V600K, and 8% other genotypes. An inverse relationship existed between BRAF mutation prevalence and age-decade (P &lt; 0.001). All patients &lt;30 years and only 25% ≥70 years had BRAF-mutant melanoma. Amongst BRAF-mutant melanoma, the frequency of non-V600E genotypes (including V600K) increased with increasing age. Non-V600E genotypes comprised &lt;20% in patients &lt;50 years and &gt;40% in those ≥70 years. A higher degree of cumulative sun-induced damage correlated with V600K but not V600E melanoma (P = 0.002). The disease-free interval from diagnosis of primary melanoma to first distant metastasis was shorter for patients with V600K compared with V600E melanoma (17.4 vs. 39.2 months, P = 0.048), with no difference in survival thereafter. In patients BRAF tested at diagnosis of metastatic melanoma, one year survival from diagnosis of metastasis was significantly longer for patients with BRAF-mutant melanoma treated with an inhibitor (83%), than those not treated with an inhibitor (29%, P &lt; 0.001), or patients with BRAF wild-type melanoma (37%, P &lt; 0.001).
Conclusion: Different genotypes exist within BRAF-mutant metastatic melanoma, representing biologically and clinically discrete subtypes, suggesting distinct etiology and behavior. Clin Cancer Res; 18(12); 3242–9. ©2012 AACR.
Predictors of thromboxane levels in patients with non-ST-elevation acute coronary syndromes on chronic aspirin therapy
Authors: Giubilato Simona , Leo Andrea , Cosentino Nicola , Fracassi Francesco , Cataneo Leonardo , Porto Italo , Leone Antonio , Burzotta Francesco , Trani Carlo , Biasucci Luigi , Narducci Maria , Pulcinelli Fabio , Crea Filippo , Niccoli Giampaolo 
Published: April 2012

SummaryHigh levels of thromboxane A2 (TxA2), a key mediator of platelet activation and aggregation, are associated with an increased risk of cardiovascular events. We aimed at assessing the predictors of higher plasma levels of TxB2, the stable metabolite of TxA2, in consecutive patients presenting with non-ST-elevation acute coronary syndrome (NSTE-ACS) on previous aspirin (ASA) treatment undergoing coronary angiography. Ninety-eight consecutive patients (age 61 ± 11, 75% males) with NSTE-ACS, on previous chronic ASA treatment, were prospectively enrolled in this study. Coronary disease extent was assessed by angiography according to the Bogaty score. In all patients, admission plasma levels of TxB2 (pg/ml) were measured by enzyme-linked immunosorbent assay, and patients showing TxB2 levels in the fourth quartile were compared to patients showing TxB2 levels in the lower quartiles. Multivariable logistic regression analysis showed that platelet count (odds ratio [OR] 1.18, 95% confidence interval [CI] 1.02–1.63, p=0.04), multivessel coronary disease (OR 1.37, 95% CI 1.13–3.67, p=0.03), and coronary atherosclerosis extent index (OR 1.91, 95% CI 1.45–6.79, p=0.001) were independent predictors of TxB2 level upper quartile. Of note, C-reactive protein serum levels were similar in patients with TxB2 levels in the upper quartile as compared to those in the lower quartiles (p=0.49). In conclusion, NSTE-ACS patients with severe coronary atherosclerosis may have incomplete suppression of TxA2 production despite chronic ASA therapy. This finding suggests that additional efforts should be made to lower TxA2 levels in patients with widespread coronary artery disease.
The HAS-BLED score predicts bleedings during bridging of chronic oral anticoagulation
Authors: Omran Heyder , Bauersachs Rupert , Rübenacker Siegfried , Goss Franz , Hammerstingl Christoph 
Published: April 2012

SummaryPatients who receive long-term oral anticoagulant (OAC) therapy often require interruption of OAC for an elective invasive procedure. Current guidelines allow bridging therapy with either unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). Apart from the risk of embolism, bleeding is an important complication in this setting and the optimal perioperative management of such patients is still under discussion. The aims of this prospective, observational, multicentre registry of patients treated by cardiologists were: 1) to evaluate current practice of perioperative management of OAC in a large outpatient cohort, 2) to document embolic and haemorrhagic events, and 3) to identify risk factors predicting adverse events. In the years 2009 and 2010, 1,000 invasive procedures (cardiac catheterisation n=533, pacemaker implantation n = 128, surgery n = 194, other n = 145) were performed in patients with OAC. Sixty- one (6.1%) of those patients did not receive bridging therapy during interruption of OAC, 937 (93.7%) patients were treated with LMWH, two patients (0.2%) received UFH. In 22 patients (2.2%) LMWHs were given in prophylactic dose, 727 patients (72.7%) were treated with halved therapeutic (i.e. weight-adapted) LMWH doses and 188 (18.8%) received full therapeutic LMWH doses. Four thromboembolic complications were observed during 30 days of follow-up (two retinal embolisms, one stroke, one myocardial infarction; 0.4%). One major bleeding (0.1%) and 35 clinically relevant bleedings (3.5%) occurred. Rehospitalisation after bleedings was necessary in 20 patients. Independent predictors for bleedings were history of mechanical heart valve replacement (MVR) (p=0.0002) and the HAS-BLED score (<0.0001), with a cut off value ≥3 being the most predictive variable for haemorrhage (hazard ratio 11.8, 95% confidence interval 5.6–24.9, p<0.0001). A total of 527 patients with atrial fibrillation and a CHADS2 score ≤2 received halved therapeutic or full therapeutic dosages of LMWH despite a low embolic risk, whereas 49 of the patients with heart valve replacement (51%) did not receive dosages of bridging therapy as recommended in guidelines. In conclusion, in this registry of patients treated by cardiologists, 94% of patients who required interruption of OAC before invasive procedures received LMWH as a bridging therapy, of whom 73% were treated with halved therapeutic LMWH-dosages. Guideline recommendations were followed in only 31% of cases. Importantly, 69% of patients with AF were over-treated while 51% of patients with heart valve replacement were under-treated with LMWHs. A HASB-BLED score ≥3 was highly predictive of bleeding events.
Coagulation activation and microparticle-associated coagulant activity in cancer patients
Authors: van Doormaal Frederiek , Berckmans René , Mackman Nigel , Manly David , Kamphuisen Pieter , Richel Dick , Büller Harry , Sturk Auguste , Nieuwland Rienk , Kleinjan Ankie 
Published: April 2012

SummaryCancer increases the risk of venous thromboembolism (VTE). Here, we investigated the contribution of microparticle (MP)-dependent procoagulant activity to the prothrombotic state in these patients. In 43 cancer patients without VTE at study entry and 22 healthy volunteers, markers of in vivo and MP-dependent coagulation were measured and patients were prospectively followed for six months for the development of VTE. Procoagulant activity of MPs was measured in vitro using a tissue factor (TF)-independent phospholipid dependent test, a factor Xa-generation assay with and without anti-TF, and a fibrin generation test (FGT) with and without anti-factor VII(a). Markers of in vivo coagulation activation and total number of MPs at baseline were significantly elevated in cancer patients compared to controls (F1+2 246 vs. 156 pM, thrombin-antithrombin complexes 4.1 vs. 3.0 mg/l, D-dimer 0.76 vs. 0.22 mg/l and 5.53 x 106 vs. 3.37 x 106 MPs/ml). Five patients (11.6%) developed VTE. Patients with VTE had comparable levels of coagulation activation markers and phospholipid-dependent MP pro-coagulant activity. However, median TF-mediated Xa-generation (0.82 vs. 0.21 pg/ml, p=0.016) and median VIIa-dependent FGT (13% vs. 0%, p=0.036) were higher in the VTE group compared with the non-VTE group. In this exploratory study the overall hypercoagulable state in cancer patients was not associated directly with the MP phospholipid-dependent procoagulant activity. However, in the patients who developed VTE within six months when compared to those who did not, an increased MP procoagulant activity was present already at baseline, suggesting this activity can be used to predict VTE.
Biological efficacy of a 600 mg loading dose of clopidogrel in ST-elevation myocardial infarction
Authors: Berbis Julie , Laine Marc , Armero Sébastien , Bessereau Jacques , Jacquin Laurent , Bonello Caroline , Camillieri Elise , Barragan Paul , Dignat-George Françoise , Paganelli Franck , Camoin-Jau Laurence , Bonello Laurent 
Published: April 2012

SummaryOptimal platelet reactivity (PR) inhibition is critical to prevent thrombotic events in primary percutaneous coronary intervention (PCI). We aimed to determine the relationship between high on-treatment platelet reactivity (HTPR) and ST-elevation myocardial infarction (STEMI) following a 600 mg loading dose (LD) of clopidogrel. We performed a prospective monocentre study enrolling patients on clopidogrel undergoing PCI. The VASP index was used to assess PR inhibition after clopidogrel LD. HTPR was defined according to the consensus as a VASP index ≥50%. The present study included 833 patients undergoing PCI. Most patients had PCI for an acute coronary syndrome (58.7%). The mean VASP index was 50 ± 23% with a large inter-individual variability (range: 1–94%). Patients with a VASP index ≥50% were significantly older (p= 0.03), with a higher body mass index (BMI) (p<0.001), more often diabetic (p=0.03), taking omeprazole (p=0.03), admitted for an acute coronary syndrome (ACS) and with a high fibrinogen level compared to good responders (VASP <50%). In multivariate analysis BMI, omeprazole use, ACS and high fibrinogen level (p<0.001) remained significantly associated with HTPR. Of importance, in this analysis STEMI was independently associated with HTPR when compared with the other forms of ACS (NSTEMI and unstable angina) with an odd ratio of 2.14 (95% CI: 1.3 –3.5; p=0.003). In conclusion, STEMI is associated with high on-treatment platelet reactivity following 600 mg of clopidogrel. The present results suggest that 600 mg of clopidogrel may not be able to achieve an optimal PR inhibition in STEMI patients undergoing PCI and more potent drugs may be preferred.
Meta-Analysis of Bleeding Complications Associated With Cardiac Rhythm Device Implantation
Authors: Bernard Michael L. , Shotwell Matthew , Nietert Paul J. , Gold Michael R. 
Published: April 2012

Background—
Many patients receiving cardiac rhythm devices have conditions requiring antiplatelet (AP) and/or anticoagulant (AC) therapy. Current guidelines recommend a heparin-bridging strategy (HBS) for anticoagulated patients with moderate/high risk for thrombosis. Several studies reported lower bleeding risk with continued oral anticoagulation rather than HBS. The best strategy for perioperative management of patients on AP therapy is less clear. The present study was designed as a meta-analysis of device implantation-associated bleeding complications using different AC/AP therapies.

Methods and Results—
PubMed and Cochrane Database searches identified articles based on design, outcomes, and available data. Device recipients were grouped as follows: no therapy, aspirin only, AC held, AC continued, dual AP, and HBS. The primary outcome was defined as a bleeding complication including hematoma, transfusion, or prolonged hospital stay. Thirteen articles were identified for analysis including 5978 patients. The combined incidence of bleeding complications was 274 of 5978 (4.6%), ranging from 2.2% (no therapy) to 14.6% (HBS). The estimated odds of bleeding were increased by 8.3 (95% CI, 5.5–12.9) times in the HBS group, 5.0 (95% CI, 3.0–8.3) for dual AP therapy, 1.7 (95% CI, 1.0–3.1) for AC held, 1.6 (95% CI, 0.9–2.6) for AC continued, and 1.5 (95% CI, 0.9–2.3) for aspirin only relative to the no therapy group. HBS significantly increased bleeding events compared with holding or continuing AC. Continuing AC did not increase bleeding events compared with no therapy.

Conclusions—
Continuing AC appears safer than HBS for device implantation. Dual AP therapy but not continuing AC carries a significant risk of bleeding.
Apolipoprotein E Genotype Predicts Hematoma Expansion in Lobar Intracerebral Hemorrhage
Authors: Brouwers H. Bart , Biffi Alessandro , Ayres Alison M. , Schwab Kristin , Cortellini Lynelle , Romero Javier M. , Rost Natalia S. , Viswanathan Anand , Greenberg Steven M. , Rosand Jonathan , Goldstein Joshua N. 
Published: April 2012

Background and Purpose—
Hematoma volume is the most potent predictor of outcome in spontaneous intracerebral hemorrhage (ICH), and hematoma expansion after hospital presentation occurs in up to 40% of individuals. Among patients with lobar ICH, the apolipoprotein E (APOE) ϵ2 allele predicts larger hematoma volumes at presentation. We investigated whether the ϵ2 allele also identifies individuals at increased risk of hematoma expansion.

Methods—
We analyzed 510 patients with primary ICH and genetic data available from an ongoing prospective cohort study. Baseline and follow-up CT scans were assessed for ICH location and volume using computer-assisted volumetric methods.

Results—

Individuals with lobar ICH who possessed APOE ϵ2 were at increased risk for hematoma expansion (OR, 2.72; 95% CI, 1.19–6.23;
P
=0.009). The highest odds of expansion were in patients who qualified for the diagnosis of cerebral amyloid angiopathy-related ICH and carried the APOE ϵ2 allele (OR, 6.02; 95% CI, 1.60–22.58;
P
=0.008). There was no effect of ϵ2 on hematoma expansion in deep ICH and APOE ϵ4 had no effect on hematoma expansion in lobar or deep ICH.

Conclusions—
Possession of APOE ϵ2 predisposes individuals with lobar ICH to hematoma expansion. This effect is even more pronounced in patients with amyloid angiopathy-related ICH, consistent with the ϵ2 allele's role in vascular amyloid deposition and vessel fragility.
Adverse Effect of Early Epileptic Seizures in Patients Receiving Endovascular Therapy for Acute Stroke
Authors: Jung Simon , Schindler Kaspar , Findling Oliver , Mono Marie-Luise , Fischer Urs , Gralla Jan , El-Koussy Marwan , Weck Anja , Galimanis Aekaterini , Brekenfeld Caspar , Schroth Gerhard , Mattle Heinrich P. , Arnold Marcel 
Published: April 2012

Background and Purpose—
The aim of this study was to analyze epileptic seizures and their impact on outcome in patients with stroke treated with endovascular therapy.

Methods—
From December 1992 to December 2010 we managed 805 patients with stroke with endovascular therapy. Epileptic seizures, bleeding complications, and 3-month outcomes were recorded prospectively. Outcomes of patients with early seizures (within 24 hours of stroke onset) and patients with late seizures (>24 hours after stroke) were compared with outcomes of seizure-free patients using uni- and multivariable statistics.

Results—

Forty-four of 805 patients (5.5%) had seizures between stroke onset and 3-month follow-up, 26 patients early and 18 late. Outcome of patients with late seizures and seizure-free patients was similar (
P
=0.144 and 0.807). Patients with early seizures had higher baseline National Institutes of Health Stroke Scale (
P
=0.023) and were younger (
P
=0.021) than seizure-free patients. Their mortality rate was 50% compared with 22.3% of the seizure free-patients (
P
=0.003), and less patients reached a favorable outcome (modified Rankin Scale 0–2): 15.4% and 46.8%, respectively (
P
=0.001). Early seizures independently predicted an unfavorable outcome (
P
=0.014; OR, 4.749; 95% CI, 0.376–3.914) and increased mortality (
P
=0.001; OR, 5.861; 95% CI, 0.770–2.947) in multiregression analysis. Patients with early seizures had a 1.6-fold higher risk for unfavorable outcome and a 2.2-fold higher risk for death compared with seizure-free patients.

Conclusions—
Seizures within 24 hours of stroke onset were associated with worse outcome in patients with stroke undergoing endovascular therapy. Our findings confirm a need for trials for prophylactic anticonvulsive treatment in patients receiving endovascular therapy for acute stroke.
Challenges in Assessing Hospital-Level Stroke Mortality as a Quality Measure
Authors: Xian Ying , Holloway Robert G. , Pan Wenqin , Peterson Eric D. 
Published: April 2012

Background and Purpose—
Public reporting efforts currently profile hospitals based on overall stroke mortality rates, yet the “mix” of hemorrhagic and ischemic stroke cases may impact this rate.

Methods—

Using the 2005 to 2006 New York state data, we examined the degree to which hospital stroke mortality rankings varied regarding ischemic versus hemorrhagic versus total stroke. Observed/expected ratio was calculated using the Agency for Healthcare Research and Quality Inpatient Quality Indicator software. The observed/expected ratio and outlier status based on stroke types across hospitals were examined using Pearson correlation coefficients (
r
) and weighted κ.

Results—

Overall 30-day stroke mortality rates were 15.2% and varied from 11.3% for ischemic stroke and 37.3% for intracerebral hemorrhage. Hospital risk-adjusted ischemic stroke observed/expected ratio was weakly correlated with its own intracerebral hemorrhage observed/expected ratio (
r
=0.38). When examining hospital performance group (mortality better, worse, or no different than average), disagreement was observed in 35 of 81 hospitals (κ=0.23). Total stroke mortality observed/expected ratio and rankings were correlated with intracerebral hemorrhage (
r
=0.61 and κ=0.36) and ischemic stroke (
r
=0.94 and κ=0.71), but many hospitals still switched classification depending on mortality metrics. However, hospitals treating a higher percent of hemorrhagic stroke did not have a statistically significant higher total stroke mortality rate relative to those treating fewer hemorrhagic strokes.

Conclusions—
Hospital stroke mortality ratings varied considerably depending on whether ischemic, hemorrhagic, or total stroke mortality rates were used. Public reporting of stroke mortality measures should consider providing risk-adjusted outcome on separate stroke types.
Age-Related Macular Degeneration and Long-Term Risk of Stroke Subtypes
Authors: Ikram M. Kamran , Mitchell Paul , Klein Ronald , Sharrett A. Rickey , Couper David J. , Wong Tien Y. 
Published: April 2012

Background and Purpose—
We examined the relationship of age-related macular degeneration (AMD) with incident stroke, including stroke subtypes of cerebral infarction and intracerebral hemorrhage.

Methods—
We included 12 216 participants with retinal photographs taken at the third examination visit (1993–1995) from the Atherosclerosis Risk in Communities (ARIC) Study, a population-based cohort study in middle-aged persons. Images were evaluated for AMD signs according to a standardized protocol. Incident events of stroke and its subtypes were identified and validated through case record review over time.

Results—
AMD was diagnosed in 591 participants, of whom 576 had early and 15 late AMD. After a mean follow-up of 13.0 years (SD, 3.3), 619 persons developed an incident stroke, including 548 cerebral infarction and 57 intracerebral hemorrhages. Participants with any AMD were at an increased risk of stroke (multivariable adjusted hazard ratio, 1.51; 95% CI, 1.11–2.06) with a stronger association for intracerebral hemorrhage (hazard ratio, 2.64; 95% CI, 1.18–5.87) than cerebral infarction (hazard ratio, 1.42; 95% CI, 1.01–1.99).

Conclusions—
Persons with AMD are at an increased risk of both cerebral infarction and intracerebral hemorrhage. These data provide further insight into common pathophysiological processes between AMD and stroke subtypes.