bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Peripheral Circulating TH1 Cytokine Profile Is Inversely Associated with Prostate Cancer Risk in CLUE II
Authors: Bhavsar Nrupen A. , Bream Jay H. , Meeker Alan K. , Drake Charles G. , Peskoe Sarah B. , Dabitao Djeneba , De Marzo Angelo M. , Isaacs William B. , Platz Elizabeth A. 
Published: August 2014

Abstract
Background: TH1 cytokines, such as IFNγ and TNFα, and potentially innate cytokines, such as IL6, can potentiate the immune response to tumor. Cytokines, such as IL1β, IL8, and IL10, may suppress anticancer immunity. Thus, we prospectively evaluated the association between peripheral-cytokine concentrations and prostate cancer.
Methods: We conducted an age-race matched case–control study (268 pairs) of incident prostate cancer in CLUE-II. We measured plasma IFNγ, IL10, IL12p70, IL1β, IL6, IL8, and TNFα concentrations using an ultrasensitive multiplex kit. ORs and 95% confidence intervals (CI) were calculated using conditional logistic regression.
Results: The OR of prostate cancer decreased across quartiles of IFNγ (highest vs. lowest quartiles: OR, 0.49; 95% CI, 0.30–0.81; Ptrend = 0.006), TNFα (OR, 0.56; 95% CI, 0.33–0.96; Ptrend = 0.01), and IL6 (OR, 0.46; 95% CI, 0.26–0.79; Ptrend = 0.007). Higher TNFα (OR, 0.28; 95% CI, 0.09–0.85; Ptrend = 0.01) and IL6 (OR, 0.20; 95% CI, 0.06–0.67; Ptrend = 0.003) concentrations were associated with lower Gleason sum ≥7 disease risk. Other cytokines were not as clearly associated with risk.
Conclusions: Men with a prediagnostic circulating TH1 profile and higher IL6 may have a lower risk of prostate cancer, including aggressive disease. Whether this profile reflects (i) an intraprostatic immune environment in benign tissue that protects against prostate cancer, (ii) the immune milieu in response to a prostate adenocarcinoma that inhibits tumor growth and detectability, and/or (iii) a systemic immune profile that mediates the influence of modifiable factors on risk, warrants additional study.
Impact: Identifying specific inflammatory cytokines associated with prostate cancer may lead to improved prevention and treatment strategies. Cancer Epidemiol Biomarkers Prev; 23(11); 2561–7. ©2014 AACR.
Racial Differences in Adipose Tissue Distribution and Risk of Aggressive Prostate Cancer among Men Undergoing Radiotherapy
Authors: Allott Emma H. , Howard Lauren E. , Song Hai-Jun , Sourbeer Katharine N. , Koontz Bridget F. , Salama Joseph K. , Freedland Stephen J. 
Published: August 2014

Abstract
Background: Although elevated body mass index (BMI) has been associated with increased risk of aggressive prostate cancer, the importance of adipose tissue distribution is not well understood. We examined associations between overall and visceral obesity and aggressive prostate cancer risk. Moreover, given racial differences in adipose tissue distribution, we examined whether race modified these associations.
Methods: We conducted a cross-sectional analysis of 308 radiotherapy-treated patients with prostate cancer within the Durham VA from 2005 to 2011. Multivariable logistic regression examined the association between BMI categories and tertiles of waist circumference (WC), visceral fat area (VFA), and periprostatic adipose tissue area (PPAT) with high-grade prostate cancer risk (Gleason score ≥7 vs. ≤6). Models stratified by race examined whether these associations differed between black and nonblack men.
Results: Both elevated BMI (Ptrend = 0.054) and WC (Ptrend = 0.040) were associated with increased high-grade prostate cancer risk, with similar results between races, although the association with BMI was not statistically significant. In contrast, elevated VFA was associated with increased aggressive prostate cancer risk in black men (Ptrend = 0.002) but not nonblack men (Ptrend = 0.831), with a significant interaction between race and VFA (Pinteraction = 0.035). Though similar patterns were observed for PPAT, none was statistically significant.
Conclusions: Among men undergoing radiotherapy for prostate cancer, visceral obesity is associated with increased aggressive prostate cancer risk, particularly among black men. If confirmed in future studies, these results suggest that adipose tissue distribution differences may contribute to prostate cancer racial disparity.
Impact: These findings highlight the need to elucidate mechanisms contributing to racial differences in the association between visceral obesity and aggressive prostate cancer. Cancer Epidemiol Biomarkers Prev; 23(11); 2404–12. ©2014 AACR.
Development and Validation of a Gene Profile Predicting Benefit of Postmastectomy Radiotherapy in Patients with High-Risk Breast Cancer: A Study of Gene Expression in the DBCG82bc Cohort
Authors: Tramm Trine , Mohammed Hayat , Myhre Simen , Kyndi Marianne , Alsner Jan , Børresen-Dale Anne-Lise , Sørlie Therese , Frigessi Arnoldo , Overgaard Jens 
Published: August 2014

AbstractPurpose: To identify genes predicting benefit of radiotherapy in patients with high-risk breast cancer treated with systemic therapy and randomized to receive or not receive postmastectomy radiotherapy (PMRT).Experimental Design: The study was based on the Danish Breast Cancer Cooperative Group (DBCG82bc) cohort. Gene-expression analysis was performed in a training set of frozen tumor tissue from 191 patients. Genes were identified through the Lasso method with the endpoint being locoregional recurrence (LRR). A weighted gene-expression index (DBCG-RT profile) was calculated and transferred to quantitative real-time PCR (qRT-PCR) in corresponding formalin-fixed, paraffin-embedded (FFPE) samples, before validation in FFPE from 112 additional patients.Results: Seven genes were identified, and the derived DBCG-RT profile divided the 191 patients into “high LRR risk” and “low LRR risk” groups. PMRT significantly reduced risk of LRR in “high LRR risk” patients, whereas “low LRR risk” patients showed no additional reduction in LRR rate. Technical transfer of the DBCG-RT profile to FFPE/qRT-PCR was successful, and the predictive impact was successfully validated in another 112 patients.Conclusions: A DBCG-RT gene profile was identified and validated, identifying patients with very low risk of LRR and no benefit from PMRT. The profile may provide a method to individualize treatment with PMRT. Clin Cancer Res; 20(20); 5272–80. ©2014 AACR.
CDK2 Transcriptional Repression Is an Essential Effector in p53-Dependent Cellular Senescence—Implications for Therapeutic Intervention
Authors: Zalzali Hasan , Nasr Bilal , Harajly Mohamad , Basma Hussein , Ghamloush Farah , Ghayad Sandra , Ghanem Noël , Evan Gerard I , Saab Raya 
Published: August 2014

Abstract
Cellular senescence, a form of cell-cycle arrest, is a tumor-suppressor mechanism triggered by multiple tumor-promoting insults, including oncogenic stress and DNA damage. The role of cyclin-dependent kinase 2 (CDK2) regulation has been evaluated in models of replicative senescence, but little is known regarding its role in other senescence settings. Using in vitro and in vivo models of DNA damage–and oncogene-induced cellular senescence, it was determined that activation of the tumor-suppressor protein p53 (TP53) resulted in repression of the CDK2 transcript that was dependent on intact RB. Ectopic CDK2 expression was sufficient to bypass p53-dependent senescence, and CDK2-specific inhibition, either pharmacologically (CVT313) or by use of a dominant-negative CDK2, was sufficient to induce early senescence. Pharmacologic inhibition of CDK2 in an in vivo model of pineal tumor decreased proliferation and promoted early senescence, and it also decreased tumor penetrance and prolonged time to tumor formation in animals lacking p53. In conclusion, for both oncogene- and DNA damage–induced cellular senescence, CDK2 transcript and protein are decreased in a p53- and RB-dependent manner, and this repression is necessary for cell-cycle exit during senescence.
Implications: These data show that CDK2 inhibition may be useful for cancer prevention in premalignant hyperproliferative lesions, as well as established tumors. Mol Cancer Res; 13(1); 29–40. ©2014 AACR.
Shear Stress–Activated Wnt-Angiopoietin-2 Signaling Recapitulates Vascular Repair in Zebrafish Embryos
Authors: Li Rongsong , Beebe Tyler , Jen Nelson , Yu Fei , Takabe Wakako , Harrison Michael , Cao Hung , Lee Juhyun , Yang Hongbo , Han Peidong , Wang Kevin , Shimizu Hirohito , Chen Jaunian , Lien Ching-Ling , Chi Neil C. , Hsiai Tzung K. 
Published: August 2014

Objective—
Fluid shear stress intimately regulates vasculogenesis and endothelial homeostasis. The canonical Wnt/β-catenin signaling pathways play an important role in differentiation and proliferation. In this study, we investigated whether shear stress activated angiopoietin-2 (Ang-2) via the canonical Wnt signaling pathway with an implication in vascular endothelial repair.

Approach and Results—

Oscillatory shear stress upregulated both TOPflash Wnt reporter activities and the expression of Ang-2 mRNA and protein in human aortic endothelial cells accompanied by an increase in nuclear β-catenin intensity. Oscillatory shear stress–induced Ang-2 and Axin-2 mRNA expression was downregulated in the presence of a Wnt inhibitor, IWR-1, but was upregulated in the presence of a Wnt agonist, LiCl. Ang-2 expression was further downregulated in response to a Wnt signaling inhibitor, DKK-1, but was upregulated by Wnt agonist Wnt3a. Both DKK-1 and Ang-2 siRNA inhibited endothelial cell migration and tube formation, which were rescued by human recombinant Ang-2. Both Ang-2 and Axin-2 mRNA downregulation was recapitulated in the heat-shock–inducible transgenic
Tg(hsp70l:dkk1-GFP
) zebrafish embryos at 72 hours post fertilization. Ang-2 morpholino injection of
Tg (kdrl:GFP
) fish impaired subintestinal vessel formation at 72 hours post fertilization, which was rescued by zebrafish Ang-2 mRNA coinjection. Inhibition of Wnt signaling with IWR-1 also downregulated Ang-2 and Axin-2 expression and impaired vascular repair after tail amputation, which was rescued by zebrafish Ang-2 mRNA injection.

Conclusions—
Shear stress activated Ang-2 via canonical Wnt signaling in vascular endothelial cells, and Wnt-Ang-2 signaling is recapitulated in zebrafish embryos with a translational implication in vascular development and repair.
Apolipoprotein A-I Increases Insulin Secretion and Production From Pancreatic β-Cells via a G-Protein-cAMP-PKA-FoxO1–Dependent Mechanism
Authors: Cochran Blake J. , Bisoendial Radjesh J. , Hou Liming , Glaros Elias N. , Rossy Jérémie , Thomas Shane R. , Barter Philip J. , Rye Kerry-Anne 
Published: August 2014

Objective—
Therapeutic interventions that increase plasma levels of high-density lipoproteins and apolipoprotein A-I (apoA-I) A-I, the major high-density lipoprotein apolipoprotein, improve glycemic control in people with type 2 diabetes mellitus. High-density lipoproteins and apoA-I also enhance insulin synthesis and secretion in isolated pancreatic islets and clonal β-cell lines. This study identifies the signaling pathways that mediate these effects.

Approach and Results—
Incubation with apoA-I increased cAMP accumulation in Ins-1E cells in a concentration-dependent manner. The increase in cAMP levels was inhibited by preincubating the cells with the cell-permeable, transmembrane adenylate cyclase inhibitor, 2′5′ dideoxyadenosine, but not with KH7, which inhibits soluble adenylyl cyclases. Incubation of Ins-1E cells with apoA-I resulted in colocalization of ATP-binding cassette transporter A1 with the Gαs subunit of a heterotrimeric G-protein and a Gαs subunit-dependent increase in insulin secretion. Incubation of Ins-1E cells with apoA-I also increased protein kinase A phosphorylation and reduced the nuclear localization of forkhead box protein O1 (FoxO1). Preincubation of Ins-1E cells with the protein kinase A–specific inhibitors, H89 and PKI amide, prevented apoA-I from increasing insulin secretion and mediating the nuclear exclusion of FoxO1. Transfection of Ins-1E cells with a mutated FoxO1 that is restricted to the nucleus confirmed the requirement for FoxO1 nuclear exclusion by blocking insulin secretion in apoA-I–treated Ins-1E cells. ApoA-I also increased Irs1, Irs2, Ins1, Ins2, and Pdx1 mRNA levels.

Conclusions—
ApoA-I increases insulin synthesis and secretion via a heterotrimeric G-protein-cAMP-protein kinase A-FoxO1–dependent mechanism that involves transmembrane adenylyl cyclases and increased transcription of key insulin response and β-cell survival genes.
Implantable Defibrillators for Secondary Prevention of Sudden Cardiac Death in Cardiac Surgery Patients With Perioperative Ventricular Arrhythmias
Authors: Nageh Maged F. , Kim John J. , Chen Lie‐Hong , Yao Janis F. 
Published: August 2014

Background

Randomized studies of implantable cardioverter defibrillators (
ICD
) have excluded sudden cardiac death survivors who had revascularization
before
or
after
an arrhythmic event. To evaluate the role of
ICD
and the effects of clinical variables including degree of revascularization, we studied cardiac surgery patients who had an
ICD
implanted for sustained perioperative ventricular arrhythmias.

Methods and Results

The electronic database for Southern California Kaiser Foundation hospitals was searched for patients who had cardiac surgery between 1999 and 2005 and an
ICD
implanted within 3 months of surgery. One hundred sixty‐four patients were identified; 93/164 had an
ICD
for sustained pre‐ or postoperative ventricular tachycardia or fibrillation requiring resuscitation. Records were reviewed for the following: presenting arrhythmia, ejection fraction, and degree of revascularization. The primary end point was total mortality (
TM
) and/or appropriate
ICD
therapy (
ICD
‐T), and secondary end points are
TM
and
ICD
‐T. During the mean follow up of 49 months, the primary endpoint of
TM
+
ICD
‐T and individual end points of
TM
and
ICD
‐T were observed in 52 (56%), 35 (38%), and 28 (30%) patients, respectively, with 55% of
TM
, and 23% of
ICD
‐T occurring within 2 years of implant. In multivariate risk analysis, none of the following was associated with any of the end points: incomplete revascularization, presenting ventricular arrhythmia, and timing of arrhythmias.

Conclusion

Our data supports the recent guidelines for
ICD
in this cohort of patients, as the presence of irreversible substrate and triggers of ventricular arrhythmias, cannot be reliably excluded even with complete revascularization. Further studies are needed to understand this complex group of patients.
Automated Quantification of Myocardial Salvage in a Rat Model of Ischemia–Reperfusion Injury Using 3D High‐Resolution Magnetic Resonance Imaging (MRI)
Authors: Grieve Stuart M. , Mazhar Jawad , Callaghan Fraser , Kok Cindy Y. , Tandy Sarah , Bhindi Ravinay , Figtree Gemma A. 
Published: August 2014

Background

Quantification of myocardial “area at risk” (
AAR
) and myocardial infarction (
MI
) zone is critical for assessing novel therapies targeting myocardial ischemia–reperfusion (
IR
) injury. Current “gold‐standard” methods perfuse the heart with Evan's Blue and stain with triphenyl tetrazolium chloride (
TTC
), requiring manual slicing and analysis. We aimed to develop and validate a high‐resolution 3‐dimensional (3D) magnetic resonance imaging (MRI) method for quantifying
MI
and
AAR
.

Methods and Results

Forty‐eight hours after
IR
was induced, rats were anesthetized and gadopentetate dimeglumine was administered intravenously. After 10 minutes, the coronary artery was re‐ligated and a solution containing iron oxide microparticles and Evan's Blue was infused (for comparison). Hearts were harvested and transversally sectioned for
TTC
staining. Ex vivo
MR
images of slices were acquired on a 9.4‐T magnet. T2* data allowed visualization of
AAR
, with microparticle‐associated signal loss in perfused regions. T1 data demonstrated gadolinium retention in infarcted zones. Close correlation (
r
=0.92 to 0.94;
P
<0.05) of
MRI
and Evan's Blue/
TTC
measures for both
AAR
and
MI
was observed when the combined techniques were applied to the same heart slice. However, 3D
MRI
acquisition and analysis of whole heart reduced intra‐observer variability compared to assessment of isolated slices, and allowed automated segmentation and analysis, thus reducing interobserver variation. Anatomical resolution of 81 μm
3
was achieved (versus ≈2 mm with manual slicing).

Conclusions

This novel, yet simple,
MRI
technique allows precise assessment of infarct and
AAR
zones. It removes the need for tissue slicing and provides opportunity for 3D digital analysis at high anatomical resolution in a streamlined manner accessible for all laboratories already performing
IR
experiments.
Cardioprotection by Controlling Hyperamylinemia in a “Humanized” Diabetic Rat Model
Authors: Despa Sanda , Sharma Savita , Harris Todd R. , Dong Hua , Li Ning , Chiamvimonvat Nipavan , Taegtmeyer Heinrich , Margulies Kenneth B. , Hammock Bruce D. , Despa Florin 
Published: August 2014

Background
Chronic hypersecretion of the pancreatic hormone amylin is common in humans with obesity or prediabetic insulin resistance and induces amylin aggregation and proteotoxicity in the pancreas. We recently showed that hyperamylinemia also affects the cardiovascular system. Here, we investigated whether amylin aggregates interact directly with cardiac myocytes and whether controlling hyperamylinemia protects the heart.

Methods and Results

By Western blot, we found abundant amylin aggregates in lysates of cardiac myocytes from obese patients, but not in controls. Aggregated amylin was elevated in failing hearts, suggesting a role in myocyte injury. Using rats overexpressing human amylin in the pancreas (
HIP
rats) and control myocytes incubated with human amylin, we show that amylin aggregation at the sarcolemma induces oxidative stress and Ca
2+
dysregulation. In time,
HIP
rats developed cardiac hypertrophy and left‐ventricular dilation. We then tested whether metabolites with antiaggregation properties, such as eicosanoid acids, limit myocardial amylin deposition. Rats were treated with an inhibitor of soluble epoxide hydrolase, the enzyme that degrades endogenous eicosanoids. Treatment doubled the blood concentration of eicosanoids, which drastically reduced incorporation of aggregated amylin in cardiac myocytes and blood cells, without affecting pancreatic amylin secretion. Animals in the treated group showed reduced cardiac hypertrophy and left‐ventricular dilation. The cardioprotective mechanisms included the mitigation of amylin‐induced cardiac oxidative stress and Ca
2+
dysregulation.

Conclusions
The results suggest blood amylin as a novel therapeutic target in diabetic heart disease and elevating blood levels of antiaggregation metabolites as a pharmacological strategy to reduce amylin aggregation and amylin‐mediated cardiotoxicity.
Benefit of Clopidogrel Therapy in Patients With Myocardial Infarction and Chronic Kidney Disease—A Danish Nation‐Wide Cohort Study
Authors: Blicher Thalia Marie , Hommel Kristine , Kristensen Søren Lund , Torp‐Pedersen Christian , Madsen Mette , Kamper Anne‐Lise , Olesen Jonas Bjerring 
Published: August 2014

Background

The aim of the present study was to evaluate clopidogrel treatment after incident myocardial infarction (
MI
) in patients with and without chronic kidney disease (
CKD
).

Methods and Results

By linking nation‐wide registries, information about patients admitted with incident
MI
was found. Primary endpoints were all‐cause and cardiovascular (
CV
) mortality, a composite of all‐cause mortality and recurrent
MI
, and a composite of fatal and nonfatal bleedings. Effect of clopidogrel use versus clopidogrel nonuse was estimated using an adjusted Cox's regression model stratified according to percutaneous coronary intervention (
PCI
) treatment.

A total of 69 082 incident
MI
patients in the period 2002–2011 were included. Clopidogrel treatment was associated with hazard ratios (
HR
s) for the combined endpoint of all‐cause mortality and recurrent
MI
in
PCI
‐treated patients of 0.90 (95% confidence interval [
CI
], 0.47 to 1.72) in renal replacement therapy (
RRT
) patients, 0.59 (95%
CI
: 0.40 to 0.88) in non‐end‐stage
CKD
patients and 0.69 (95%
CI
, 0.61 to 0.77) in patients without kidney disease (
P
for interaction=0.60). In patients not treated with
PCI
,
HR
s were 0.90 (95%
CI
, 0.68 to 1.21) in
RRT
patients, 0.86 (95%
CI
, 0.75 to 0.99) in non‐end‐stage
CKD
patients, and 0.91 (95%
CI
, 0.87 to 0.95) in patients without kidney disease (
P
for interaction=0.74). An increase in bleeding events (not significant) was noted for clopidogrel‐treated patients not undergoing
PCI
and for non‐end‐stage
CKD
patients undergoing
PCI
, whereas clopidogrel was associated with less bleedings in
PCI
‐treated
RRT
patients and patients without kidney disease.

Conclusions

During a 1‐year follow‐up, after
MI
, clopidogrel was associated with improved outcomes in patients with non‐end‐stage
CKD
. Even though no effect difference, compared to patients without
CKD
, was observed, the benefit associated with the use of clopidogrel after
MI
in patients requiring
RRT
is less clear.
Eligibility and Preference of New Oral Anticoagulants in Patients With Atrial Fibrillation
Authors: Yoon Chang Hyo , Park Yoon Kyung , Kim Suk Jae , Lee Mi-ji , Ryoo Sookyung , Kim Gyeong-Moon , Chung Chin-Sang , Lee Kwang Ho , Kim June Soo , Bang Oh Young 
Published: August 2014

Background and Purpose—
Recent randomized clinical trials (RCTs) have evaluated the benefit of new oral anticoagulants in reducing the risk of vascular events and bleeding complications in patients with atrial fibrillation (AF). However, abundant and strict enrollment criteria may limit the validity and applicability of results of RCTs to clinical practice. We estimated the eligibility for participation in RCTs of an unselected group of patients with AF. In addition, we compared features favoring new oral anticoagulant use between patients with versus without stroke. Randomized Evaluation of Long-Term Anticoagulation Therapy

Methods—
We applied enrollment criteria of 4 RCTs (RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE-AF-TIMI 48) to 695 patients with AF taking warfarin, prospectively and consecutively collected at a university medical center; 500 patients with and 195 patients without stroke. Time in therapeutic range and bleeding risk scheme (anticoagulation and risk factors in atrial fibrillation) were also measured.

Results—

The proportions of patients fulfilling the trial enrollment criteria varied, ranging from 39% to 72.8%, depending on the differences in indications/contraindications among studies and presence/absence of stroke. The main reasons for ineligibility for RCTs were hemorrhagic risk (anticoagulation and risk factors in atrial fibrillation [ATRIA] score) (10.8%–40.5%) and planned cardioversion (5.1%–7.7%) for nonstroke patients, and a low creatinine clearance (5.6%–9.2%) and higher risk of bleeding (15.2%–20.8%) for patients with stroke. When compared with nonstroke patients, patients with stroke showed a lower time in therapeutic range (54.4±42.8% versus 65.4±34.9%, especially with severe disability) and a high hemorrhagic risk (ATRIA score) (3.06±2.30 versus 2.18±2.16) (
P
<0.05 in both cases).

Conclusions—
Patients enrolled in RCTs are partly representative of patients with AF in clinical practice. When time in therapeutic range and bleeding tendency with warfarin use were considered, the use of new oral anticoagulants was preferred in patients with stroke than in nonstroke patients, but they were more likely to be excluded in RCTs.