bluuebunny/crossref_metadata_2025_split huggingface dataset:
Decreased Expression of Cyr61 Is Associated with Prostate Cancer Recurrence after Surgical Treatment
Authors: D'Antonio Katherine B. , Schultz Lucianna , Albadine Roula , Mondul Alison M. , Platz Elizabeth A. , Netto George J. , Getzenberg Robert H. 
Published: December 2010

Abstract
Purpose: Cysteine-rich angiogenic inducer 61 (Cyr61) is an extracellular matrix protein involved in the transduction of growth factor and hormone signaling. Previous studies have suggested that Cyr61 may be a marker for a more aggressive phenotype. In this study, we evaluated the association between Cyr61 staining intensity and subsequent recurrence after surgical treatment of clinically localized prostate cancer.
Experimental Design: A study of 229 men with recurrence and 229 controls matched on age, race, pathologic stage, and Gleason sum nested in a cohort of men who underwent radical prostatectomy for clinically localized prostate cancer, utilizing immunohistochemistry analysis of tissue microarray (TMA) sections, was conducted. Odds ratios (OR) of recurrence and 95% confidence intervals (CIs) were estimated using conditional logistic regression.
Results: Recurrence was identified in 12.2% of cases, and in 24.0% of controls that had at least 1 TMA spot containing cancer with a staining intensity of 3 (P = 0.001). Taking into account age, pathologic stage and grade, presurgery prostate-specific antigen concentration, and calendar of surgery as a measure of tissue block storage time, men with a Cyr61 staining intensity of 3 were 56% less likely to recur than men with a lower staining intensity (OR = 0.44, 95% CI = 0.22–0.90).
Conclusions: High Cyr61 staining intensity in adenocarcinoma was associated with a lower risk of recurrence after surgical treatment of prostate cancer independent of pathologic tumor characteristics. If validated in other sample sets, Cyr61 may serve as a tissue biomarker for stratifying men for risk of recurrence and thus could inform treatment decision making. Clin Cancer Res; 16(23); 5908–13. ©2010 AACR.
Personalizing Cancer Treatment in the Age of Global Genomic Analyses: PALB2 Gene Mutations and the Response to DNA Damaging Agents in Pancreatic Cancer
Authors: Villarroel Maria C. , Rajeshkumar N.V. , Garrido-Laguna Ignacio , De Jesus-Acosta Ana , Jones Siân , Maitra Anirban , Hruban Ralph H. , Eshleman James R. , Klein Alison , Laheru Daniel , Donehower Ross , Hidalgo Manuel 
Published: December 2010

Abstract
Metastasis and drug resistance are the major causes of mortality in patients with pancreatic cancer. Once developed, the progression of pancreatic cancer metastasis is virtually unstoppable with current therapies. Here, we report the remarkable clinical outcome of a patient with advanced, gemcitabine-resistant, pancreatic cancer who was later treated with DNA damaging agents, on the basis of the observation of significant activity of this class of drugs against a personalized xenograft generated from the patient's surgically resected tumor. Mitomycin C treatment, selected on the basis of its robust preclinical activity in a personalized xenograft generated from the patient's tumor, resulted in long-lasting (36+ months) tumor response. Global genomic sequencing revealed biallelic inactivation of the gene encoding PalB2 protein in this patient's cancer; the mutation is predicted to disrupt BRCA1 and BRCA2 interactions critical to DNA double-strand break repair. This work suggests that inactivation of the PALB2 gene is a determinant of response to DNA damage in pancreatic cancer and a new target for personalizing cancer treatment. Integrating personalized xenografts with unbiased exomic sequencing led to customized therapy, tailored to the genetic environment of the patient's tumor, and identification of a new biomarker of drug response in a lethal cancer. Mol Cancer Ther; 10(1); 3–8. ©2010 AACR. Mol Cancer Ther; 10(1); 3–8. ©2010 AACR.
AP-1 Regulates Cyclin D1 and c-MYC Transcription in an AKT-Dependent Manner in Response to mTOR Inhibition: Role of AIP4/Itch-Mediated JUNB Degradation
Authors: Vartanian Raffi , Masri Janine , Martin Jheralyn , Cloninger Cheri , Holmes Brent , Artinian Nicholas , Funk Alex , Ruegg Teresa , Gera Joseph 
Published: December 2010

Abstract
One mechanism by which AKT kinase-dependent hypersensitivity to mammalian target of rapamycin (mTOR) inhibitors is controlled is by the differential expression of cyclin D1 and c-MYC. Regulation of posttranscriptional processes has been demonstrated to be crucial in governing expression of these determinants in response to rapamycin. Our previous data suggested that cyclin D1 and c-MYC expression might additionally be coordinately regulated in an AKT-dependent manner at the level of transcription. Under conditions of relatively quiescent AKT activity, treatment of cells with rapamycin resulted in upregulation of cyclin D1 and c-MYC nascent transcription, whereas in cells containing active AKT, exposure repressed transcription. Promoter analysis identified AKT-dependent rapamycin responsive elements containing AP-1 transactivation sites. Phosphorylated c-JUN binding to these promoters correlated with activation of transcription whereas JUNB occupancy was associated with promoter repression. Forced overexpression of JunB or a conditionally active JunB-ER allele repressed cyclin D1 and c-MYC promoter activity in quiescent AKT-containing cells following rapamycin exposure. AIP4/Itch-dependent JUNB protein degradation was found to be markedly reduced in active AKT-containing cells compared with cells harboring quiescent AKT. Moreover, silencing AIP4/Itch expression or inhibiting JNK mediated AIP4 activity abrogated the rapamycin-induced effects on cyclin D1 and c-MYC promoter activities. Our findings support a role for the AKT-dependent regulation of AIP4/Itch activity in mediating the differential cyclin D1 and c-MYC transcriptional responses to rapamycin. Mol Cancer Res; 9(1); 115–30 ©2010 AACR.
Safety of edoxaban, an oral factor Xa inhibitor, in Asian patients with non-valvular atrial fibrillation
Authors: Jeon Hui-Kyung , Lien Li-Ming , Lai Wen-Ter , Tse Hung-Fat , Chung Wook-Sung , Lee Tsong-Hai , Chen Shih-Ann , Chung Namsik 
Published: December 2010

SummaryEdoxaban is an oral, reversible, direct factor Xa inhibitor in phase III clinical development for the prevention of stroke in atrial fibrillation (AF). A phase II study was undertaken to evaluate the safety and efficacy of edoxaban in Asian patients with non-valvular AF with CHADS2 score ≥1. In a multicentre, active-controlled, double-blind edoxaban and open-label warfarin, parallel-group study, a total of 235 patients from four Asian countries were randomly assigned to edoxaban 30 mg qd, 60 mg qd or warfarin dose adjusted to international normalised ratio of 2–3 for three months. The primary endpoint was the incidence of centrally adjudicated all bleeding events (major, clinically relevant non-major and minor). Secondary endpoints included thromboembolic events, biomarkers of thrombus formation and all adverse events (AEs). The incidence of all bleeding events (95% CI) was 20.3% (12.9, 30.4) for edoxaban 30 mg, 23.8% (15.8, 34.1) for edoxaban 60 mg, and 29.3% (20.2, 40.4) for warfarin. A subgroup analysis suggested low body weight (≤60 kg) may affect the incidence of bleeding events with edoxaban. The incidence of study drug-related AEs was 22% for edoxaban 30 mg, 29% for edoxaban 60 mg and 33% for warfarin. No thromboembolic events occurred in any treatment group. In conclusion, this phase II study found a trend for a reduction in the incidence of all bleeding events in Asian AF patients with edoxaban 30 mg and 60 mg compared with warfarin. Adverse events were similar between the edoxaban 60-mg and warfarin groups and were lower with the edoxaban 30-mg group.ClinicalTrials.gov number: NCT00806624
Cardiovascular risk assessment in haemophilia patients
Authors: Baarslag Manuel , Peters Marjolein , Kruip Marieke , Kraaijenhagen Roderik , Den Heijer Martin , Büller Harry , Kamphuisen Pieter , Biere-Rafi Sara 
Published: December 2010

SummaryHaemophilia patients have a reduced cardiovascular mortality, which may be the result of a lifelong deficiency of factor VIII or IX. On the other hand, the prevalence of risk factors may differ in these chronically ill patients compared to the general population. The prevalence of risk factors and expected risk of cardiovascular disease was compared in haemophilia patients and healthy controls. In adult haemophilia A and B patients, body mass index, blood pressure, cholesterol levels and fasting glucose levels were measured and compared to healthy age-matched males. The expected risk of mortality due to cardiovascular disease was calculated using a European risk prediction algorithm (SCORE). A total of 100 haemophilia A and B patients and 200 healthy controls were analysed. The mean age of the patients was 47 years (range 18–83). The number of haemophiliacs with hyperglycaemia (24%) and hypertension (51%) was higher than in the controls (p-values 0.001 and 0.03, respectively). The mean low-density lipoprotein (LDL) cholesterol level in cases was lower than the controls (3.02 mM (0.69–6.57) and 3.60 mM (1.68–5.95), respectively, p < 0.001). Fewer cases had increased LDL levels (p=0.045). No difference was found in the 10-year cardiovascular mortality risk >10% between cases and controls (12% and 7%, respectively, p = 0.18). The prevalence of risk factors and expected risk of cardiovascular disease in haemophilia patients is comparable to the general population. This strengthens the hypothesis that hypocoagulability may reduce cardiovascular mortality in haemophilia patients.
Epinephrine-mediated protein kinase C and Rap1b activation requires the co-stimulation of Gz-, Gq-, and Gi-coupled receptors
Authors: Canobbio Ilaria , Catricalà Silvia , Balduini Cesare , Lova Paolo , Guidetti Gianni Francesco , Torti Mauro 
Published: December 2010

SummaryWe have recently shown that ADP-induced activation of protein kinase C (PKC) requires the co-stimulation of both P2Y1 and P2Y12 receptors. In this work, we show that inhibition of ADP-mediated phosphorylation of pleckstrin, the main PKC substrate, caused by antagonists of the P2Y12 receptor can be reversed by stimulation of the α2-adrenergic receptor by epinephrine. However, we also observed that addition of epinephrine alone caused a marked phosphorylation of pleckstrin. This effect occurred in the absence of Gq stimulation, as it was not associated to intracellular Ca2+ release. Epinephrine-induced pleckstrin phosphorylation was time- and dose-dependent, and was inhibited by the α2-adrenergic antagonist yohimbin. Phosphorylation of pleckstrin did not occur when platelet stimulation with epinephrine was performed in the presence of the ADP scavenger apyrase, and was suppressed by antagonists of both P2Y1 and P2Y12 ADP receptors. Importantly, no release of dense granules was measured in epinephrine-treated platelets. Addition of epinephrine to platelets was also able to stimulate Rap1b activation. Similarly to pleckstrin phosphorylation, however, this effect was prevented in the presence of apyrase or upon pharmacologic blockade of either P2Y1 or P2Y12 receptors. These results indicate that sub-threshold amounts of ADP in the medium are essential to allow epinephrine stimulation of α2-adrenergic receptor to elicit platelet responses, and reveal a novel synergism among strong stimulation of Gz and sub-threshold stimulation of both Gq and Gi, able to dissociate PKC activation from intracellular Ca2+ mobilisation.
The effect of p22-PHOX (CYBA) polymorphisms on premature coronary artery disease (≤ 40 years of age)
Authors: Goliasch Georg , Grafl Andreas , Ponweiser Elisabeth , Blessberger Hermann , Tentzeris Ioannis , Wojta Johann , Schillinger Martin , Huber Kurt , Maurer Gerald , Mannhalter Christine , Sunder-Plaßmann Raute , Wiesbauer Franz 
Published: December 2010

SummaryAcute myocardial infarction at a young age is associated with high morbidity and long-term mortality. The NADPH oxidase system as a main source of reactive oxygen species in vascular cells has been implicated in development and progression of coronary artery disease (CAD). In our study, we investigated the effect of polymorphisms in the p22-PHOX (CYBA) gene on CAD in young patients (≤ 40 years). We prospectively recruited 302 subjects into our multi-centre case control study, including 102 young myocardial infarction patients (≤ 40 years) from two high-volume cardiac catheterisation hospitals and frequency-matched them on age, gender, and center to 200 hospital controls in an approximate 2:1 ratio per case patient. The homozygote c.-930A>G promoter polymorphism was significantly more prevalent in the controls than in the infarction patients. In the adjusted logistic regression analysis, we detected a protective effect of the c.-930A>G promoter polymorphism against premature myocardial infarction. Using a logadditive/per-allele model, we detected an unadjusted odds ratio (OR) of 0.63 (95% confidence interval [CI] 0.45–0.9, p-value 0.011). In the adjusted model the association was more pronounced with an OR of 0.5 (95% CI 0.3–0.81, p-value 0.005). The C242T polymorphism and the 640A>G polymorphism did not differ significantly between the study groups. Furthermore we could not detect a significant effect for these polymorphisms in the logistic regression analysis. The present study suggests a protective association between the c.-930A>G promoter polymorphism in the p22-PHOX (CYBA) gene and the development of myocardial infarction in young individuals (≤ 40 years).
γ’/total fibrinogen ratio is associated with short-term outcome in ischaemic stroke
Authors: Cheung Elim , de Lau Lonneke , den Hertog Heleen , Leebeek Frank , Dippel Diederik , Koudstaal Peter , de Maat Moniek , van den Herik Evita 
Published: December 2010

SummaryFibrinogen γ’ (γ’) is a natural isoform of fibrinogen, and alters the rate of formation and the properties of clots. It could therefore affect outcome after ischaemic stroke. The prognostic significance of γ’ fibrinogen levels is, however, still unclear. It was the objective of this study to assess levels of γ’ in ischaemic stroke, and its association with short-term outcome. We included 200 ischaemic stroke patients and 156 control persons. Total fibrinogen and γ’ levels were measured; outcome at discharge was assessed by means of the modified Rankin Scale score (defined as unfavourable when >2). We compared levels between patients and controls using multiple linear regression analysis, and logistic regression analysis was used to assess the relationship between levels and outcome. All analyses were adjusted for age and sex. Mean γ’ levels were significantly higher in patients with ischaemic stroke than in controls (0.37 vs. 0.32 g/l, p<0.001), and patients also had a higher γ’/total fibrinogen ratio (0.102 vs. 0.096, p=0.19). The γ’/total fibrinogen ratio is associated with unfavourable outcome in patients with ischaemic stroke (odds ratio per unit increase of γ’/total fibrinogen ratio 1.27, 95% confidence interval 1.09–1.47). Our study shows that patients with ischaemic stroke have increased levels of fibrinogen γ’ and suggests a trend towards an increased γ’/total fibrinogen ratio in ischaemic stroke. Increased fibrinogen γ’ relative to total fibrinogen levels are associated with unfavourable outcome in the early phase after stroke.
Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty
Authors: Lassen Michael Rud , Eriksson Bengt , Gent Michael , Berkowitz Scott , Misselwitz Frank , Bandel Tiemo , Homering Martin , Westermeier Torsten , Kakkar Ajay , Turpie Alexander 
Published: December 2010

SummaryFour phase III studies compared oral rivaroxaban with subcutaneous enoxaparin for the prevention of venous thromboembolism (VTE) after total hip or knee arthroplasty (THA or TKA). A pooled analysis of these studies compared the effect of rivaroxaban with enoxaparin on symptomatic VTE plus all-cause mortality and bleeding events, and determined whether these effects were consistent in patient subgroups. Patients (N=12,729) aged ≥18 years and scheduled for elective THA or TKA received rivaroxaban 10 mg once daily or enoxaparin 40 mg once daily or 30 mg every 12 hours. The composite of symptomatic VTE and all-cause mortality, the prespecified primary efficacy endpoint and adjudicated bleeding events were analysed in the day 12 ± 2 active treatment pool. Subgroup analyses of these outcomes were performed over the total treatment period. In the day 12 ± 2 pool, the primary efficacy endpoint occurred in 29/6,183 patients receiving rivaroxaban (0.5%) versus 60/6,200 patients receiving enoxaparin (1.0%; p=0.001). Major bleeding occurred in 21 (0.3%) versus 13 (0.2%) patients, p=0.23; major plus non-major clinically relevant bleeding in 176 (2.8%) versus 152 (2.5%) patients, p=0.19; and any bleeding in 409 (6.6%) versus 384 (6.2%) patients, p=0.38, respectively. The reduction of symptomatic VTE plus all-cause mortality was consistent across prespecified subgroups (age, gender, body weight, creatinine clearance) in the total treatment period. Compared with enoxaparin regimens, rivaroxaban reduces the composite of symptomatic VTE and all-cause mortality after elective THA or TKA, with a small increase in bleeding, no signs of compromised liver safety and fewer serious adverse events.
Mechanisms Underlying the Lack of Effect of Implantable Cardioverter-Defibrillator Therapy on Mortality in High-Risk Patients With Recent Myocardial Infarction
Authors: Dorian Paul , Hohnloser Stefan H. , Thorpe Kevin E. , Roberts Robin S. , Kuck Karl-Heinz , Gent Michael , Connolly Stuart J. 
Published: December 2010

Background—
Although implantable cardioverter-defibrillators (ICDs) lower mortality in stable patients with low ejection fraction late after myocardial infarction, randomized trials of ICD versus control subjects implanted early after myocardial infarction do not show mortality benefit. Our objective was to investigate possible mechanisms underlying the lack of mortality benefit in the Defibrillation in Acute Myocardial Infarction Trial (DINAMIT).

Methods and Results—

This is a secondary analysis of the prospective randomized clinical trial. Outpatients with recent (6 to 40 days) acute myocardial infarction, left ventricular dysfunction (ejection fraction <35%), and low heart rate variability were randomized to ICD (n=311) or to standard medical therapy (n=342). In a competing-risks analysis, those factors that increased the risk of arrhythmic death also increased the risk of nonarrhythmic deaths. After adjustment for these factors, receiving an ICD was associated with a decreased risk of arrhythmic death (hazard ratio, 0.33; 95% confidence interval, 0.15 to 0.71) but an increase in nonarrhythmic death (hazard ratio, 1.70; 95% confidence interval, 1.00 to 2.80). In an adjusted time-dependent analysis, patients receiving an ICD and having appropriate ICD therapy had a 15.1% yearly hazard of mortality compared with 5.2% in ICD patients with no appropriate therapy (
P
<0.001). The reduction in sudden death in ICD patients was completely offset by increased nonarrhythmic deaths, which were greatest in patients receiving ICD shock therapy (hazard ratio, 6.0; 95% confidence interval, 2.8 to 12.7).

Conclusions—
In patients receiving ICDs early after myocardial infarction, those factors that are associated with arrhythmia requiring ICD therapy are also associated with a high risk of nonsudden death, negating the benefit of ICDs in this setting.
Autonomic Denervation With Magnetic Nanoparticles
Authors: Yu Lilei , Scherlag Benjamin J. , Dormer Kenneth , Nguyen Kytai T. , Pope Carey , Fung Kar-Ming , Po Sunny S. 
Published: December 2010

Background—
Prior studies indicated that ablation of the 4 major atrial ganglionated plexi (GP) suppressed atrial fibrillation.

Methods and Results—

Superparamagnetic nanoparticles (MNPs) made of Fe
3
O
4
(core), thermoresponsive polymeric hydrogel (shell), and neurotoxic agent (N-isopropylacrylamide monomer [NIPA-M]) were synthesized. In 23 dogs, a right thoracotomy exposed the anterior right GP (ARGP) and inferior right GP (IRGP). The sinus rate and ventricular rate slowing responses to high-frequency stimulation (20 Hz, 0.1 ms) were used as the surrogate for the ARGP and IRGP functions, respectively. In 6 dogs, MNPs carrying 0.4 mg NIPA-M were injected into the ARGP. In 4 other dogs, a cylindrical magnet (2600 G) was placed epicardially on the IRGP. MNPs carrying 0.8 mg NIPA-M were then infused into the circumflex artery supplying the IRGP. The hydrogel shell reliably contracted in vitro at temperatures ≥37°C, releasing NIPA-M. MNPs injected into the ARGP suppressed high-frequency stimulation–induced sinus rate slowing response (40±8% at baseline; 21±9% at 2 hours;
P
=0.006). The lowest voltage of ARGP high-frequency stimulation inducing atrial fibrillation was increased from 5.9±0.8 V (baseline) to 10.2±0.9 V (2 hours;
P
=0.009). Intracoronary infusion of MNPs suppressed the IRGP but not ARGP function (ventricular rate slowing: 57±8% at baseline, 20±8% at 2 hours;
P
=0.002; sinus rate slowing: 31±7% at baseline, 33±8% at 2 hours;
P
=0.604). Prussian Blue staining revealed MNP aggregates only in the IRGP, not the ARGP.

Conclusions—
Intravascularly administered MNPs carrying NIPA-M can be magnetically targeted to the IRGP and reduce GP activity presumably by the subsequent release of NIPA-M. This novel targeted drug delivery system can be used intravascularly for targeted autonomic denervation.
Aspirin Plus Clopidogrel Versus Aspirin Alone After Coronary Artery Bypass Grafting
Authors: Kulik Alexander , Le May Michel R. , Voisine Pierre , Tardif Jean-Claude , DeLarochelliere Robert , Naidoo Sarika , Wells George A. , Mesana Thierry G. , Ruel Marc 
Published: December 2010

Background—
Clopidogrel inhibits intimal hyperplasia in animal studies and therefore may reduce saphenous vein graft (SVG) intimal hyperplasia after coronary artery bypass grafting. The Clopidogrel After Surgery for Coronary Artery DiseasE (CASCADE) study was undertaken to evaluate whether the addition of clopidogrel to aspirin inhibits SVG disease after coronary artery bypass grafting, as assessed at 1 year by intravascular ultrasound.

Methods and Results—

In this double-blind phase II trial, 113 patients undergoing coronary artery bypass grafting with SVGs were randomized to receive aspirin 162 mg plus clopidogrel 75 mg daily or aspirin 162 mg plus placebo daily for 1 year. The primary outcome was SVG intimal hyperplasia (mean intimal area) as determined by intravascular ultrasound at 1 year. Secondary outcomes were graft patency, major adverse cardiovascular events, and major bleeding. One-year intravascular ultrasound and coronary angiography were performed in 92 patients (81.4%). At 1 year, SVG intimal area did not differ significantly between the 2 groups (4.1±2.0 versus 4.5±2.1 mm
2
, aspirin-clopidogrel versus aspirin-placebo,
P
=0.44). Overall 1-year graft patency was 95.2% in the aspirin-clopidogrel group compared with 95.5% in the aspirin-placebo group (
P
=0.90), and SVG patency was 94.3% in the aspirin-clopidogrel group versus 93.2% in the aspirin-placebo group (
P
=0.69). Freedom from major adverse cardiovascular events at 1 year was 92.9±3.4% in the aspirin-clopidogrel group and 91.1±3.8% in the aspirin-placebo group (
P
=0.76). The incidence of major bleeding at 1 year was similar for the 2 groups (1.8% versus 0%, aspirin-clopidogrel versus aspirin-placebo,
P
=0.50).

Conclusions—
Compared with aspirin monotherapy, the combination of aspirin plus clopidogrel did not significantly reduce the process of SVG intimal hyperplasia 1 year after coronary artery bypass grafting.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00228423.