bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nrf2-Dependent Suppression of Azoxymethane/Dextran Sulfate Sodium–Induced Colon Carcinogenesis by the Cinnamon-Derived Dietary Factor Cinnamaldehyde
Authors: Long Min , Tao Shasha , Rojo de la Vega Montserrat , Jiang Tao , Wen Qing , Park Sophia L. , Zhang Donna D. , Wondrak Georg T. 
Published: February 2015

Abstract
The progressive nature of colorectal cancer and poor prognosis associated with the metastatic phase of the disease create an urgent need for the development of more efficacious strategies targeting colorectal carcinogenesis. Cumulative evidence suggests that the redox-sensitive transcription factor Nrf2 (nuclear factor-E2–related factor 2), a master regulator of the cellular antioxidant defence, represents a promising molecular target for colorectal cancer chemoprevention. Recently, we have identified cinnamon, the ground bark of Cinnamomum aromaticum (cassia cinnamon) and Cinnamomum verum (Ceylon cinnamon), as a rich dietary source of the Nrf2 inducer cinnamaldehyde (CA) eliciting the Nrf2-regulated antioxidant response in human epithelial colon cells, conferring cytoprotection against electrophilic and genotoxic insult. Here, we have explored the molecular mechanism underlying CA-induced Nrf2 activation in colorectal epithelial cells and have examined the chemopreventive potential of CA in a murine colorectal cancer model comparing Nrf2+/+ with Nrf2−/− mice. In HCT116 cells, CA caused a Keap1-C151–dependent increase in Nrf2 protein half-life via blockage of ubiquitination with upregulation of cytoprotective Nrf2 target genes and elevation of cellular glutathione. After optimizing colorectal Nrf2 activation and target gene expression by dietary CA-supplementation regimens, we demonstrated that CA suppresses AOM/DSS-induced inflammatory colon carcinogenesis with modulation of molecular markers of colorectal carcinogenesis. Dietary suppression of colorectal cancer using CA supplementation was achieved in Nrf2+/+ but not in Nrf2−/− mice confirming the Nrf2 dependence of CA-induced chemopreventive effects. Taken together, our data suggest feasibility of colorectal cancer suppression by dietary CA, an FDA-approved food additive derived from the third most consumed spice in the world. Cancer Prev Res; 8(5); 444–54. ©2015 AACR.
CXCR4 Is a Novel Target of Cancer Chemopreventative Isothiocyanates in Prostate Cancer Cells
Authors: Sakao Kozue , Vyas Avani R. , Chinni Sreenivasa R. , Amjad Ali I. , Parikh Rahul , Singh Shivendra V. 
Published: February 2015

Abstract
Isothiocyanates (ITCs) derived from cruciferous vegetables, including phenethyl isothiocyanate (PEITC) and sulforaphane (SFN), exhibit in vivo activity against prostate cancer in a xenograft and transgenic mouse model, and thus are appealing for chemoprevention of this disease. Watercress constituent PEITC and SFN-rich broccoli sprout extract are under clinical investigations but the molecular mechanisms underlying their cancer chemopreventive effects are not fully understood. The present study demonstrates that chemokine receptor CXCR4 is a novel target of ITCs in prostate cancer cells. Exposure of prostate cancer cells (LNCaP, 22Rv1, C4-2, and PC-3) to pharmacologically applicable concentrations of PEITC, benzyl isothiocyanate (BITC), and SFN (2.5 and 5 μmol/L) resulted in downregulation of CXCR4 expression. None of the ITCs affected secretion of CXCR4 ligand (stromal-derived factor-1). In vivo inhibition of PC-3 xenograft growth upon PEITC treatment was associated with a significant decrease in CXCR4 protein level. A similar trend was discernible in the tumors from SFN-treated TRAMP mice compared with those of control mice, but the difference was not significant. Stable overexpression of CXCR4 in PC-3 cells conferred significant protection against wound healing, cell migration, and cell viability inhibition by ITCs. Inhibition of cell migration resulting from PEITC and BITC exposure was significantly augmented by RNAi of CXCR4. This study demonstrates, for the first time, that cancer chemopreventive ITCs suppress CXCR4 expression in prostate cancer cells in vitro as well as in vivo. These results suggest that CXCR4 downregulation may be an important pharmacodynamic biomarker of cancer chemopreventative ITCs in prostate adenocarcinoma. Cancer Prev Res; 8(5); 365–74. ©2015 AACR.
Fenretinide Perturbs Focal Adhesion Kinase in Premalignant and Malignant Human Oral Keratinocytes. Fenretinide's Chemopreventive Mechanisms Include ECM Interactions
Authors: Han Byungdo B. , Li Suyang , Tong Meng , Holpuch Andrew S. , Spinney Richard , Wang Daren , Border Michael B. , Liu Zhongfa , Sarode Sachin , Pei Ping , Schwendeman Steven P. , Mallery Susan R. 
Published: February 2015

Abstract
The membrane-associated protein, focal adhesion kinase (FAK), modulates cell–extracellular matrix interactions and also conveys prosurvival and proliferative signals. Notably, increased intraepithelial FAK levels accompany transformation of premalignant oral intraepithelial neoplasia (OIN) to oral squamous cell carcinoma (OSCC). OIN chemoprevention is a patient-centric, optimal strategy to prevent OSCC's comorbidities and mortality. The cancer chemopreventive and synthetic vitamin A derivative, fenretinide, has demonstrated protein-binding capacities, for example, mTOR- and retinol-binding protein interactions. These studies used a continuum of human oral keratinocytes (normal-HPV E6/E7-transduced-OSCC) to assess potential fenretinide–FAK drug protein interactions and functional consequences on cellular growth regulation and motility. Molecular modeling studies demonstrated that fenretinide has approximately 200-fold greater binding affinity relative to the natural ligand (ATP) at FAK's kinase domain. Fenretinide also shows intermediate binding at FAK's FERM domain and interacts at the ATP-binding site of the closest FAK analogue, PYK2. Fenretinide significantly suppressed proliferation via induction of apoptosis and G2–M cell-cycle blockade. Fenretinide-treated cells also demonstrated F-actin disruption, significant inhibition of both directed migration and invasion of a synthetic basement membrane, and decreased phosphorylation of growth-promoting kinases. A commercially available FAK inhibitor did not suppress cell invasion. Notably, although FAK's FERM domain directs cell invasion, FAK inhibitors target the kinase domain. In addition, FAK-specific siRNA–treated cells showed an intermediate cell migration capacity; data which suggest cocontribution of the established migrating-enhancing PYK2. Our data imply that fenretinide is uniquely capable of disrupting FAK's and PYK2′s prosurvival and mobility-enhancing effects and further extend fenretinide's chemopreventive contributions beyond induction of apoptosis and differentiation. Cancer Prev Res; 8(5); 419–30. ©2015 AACR.
Subclinical atherosclerosis in patients with rheumatoid arthritis
Authors: Ambrosino Pasquale , Lupoli Roberta , Di Minno Alessandro , Tasso Marco , Peluso Rosario , Di Minno Matteo Nicola Dario 
Published: February 2015

SummaryWe performed a systematic review with meta-analysis and meta-regression of literature studies evaluating the impact of rheumatoid arthritis (RA) on common carotid artery intima-media thickness (CCAIMT) and on the prevalence of carotid plaques. Studies evaluating the relationship between RA and markers of cardiovascular (CV) risk (CCA-IMT and prevalence of carotid plaques) were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases. A total of 59 studies (4,317 RA patients and 3,606 controls) were included in the final analysis, 51 studies with data on CCA-IMT (52 data-sets on 3,600 RA patients and 3,020 controls) and 35 studies reporting on the prevalence of carotid plaques (2,859 RA patients and 2,303 controls). As compared to controls, RA patients showed a higher CCA-IMT (mean difference [MD]: 0.10 mm; 95 % confidence interval [CI]: 0.07, 0.12; p < 0.00001), and an increased prevalence of carotid plaques (odds ratio [OR]: 3.61; 95 %CI: 2.65, 4.93; p< 0.00001). Interestingly, when analysing studies on early RA, the difference in CCAIMT among RA patients and controls was even higher (MD: 0.21 mm; 95 %CI: 0.06, 0.35; p=0.006), and difference in the prevalence of carotid plaques was entirely confirmed (OR: 3.57; 95 %CI: 1.69, 7.51; p=0.0008). Meta-regression models showed that male gender and a more severe inflammatory status [as expressed by disease activity score in 28 joints (DAS28), C-reactive protein (CRP) levels, and erythrocyte sedimentation rate (ESR)] significantly impacted on CCA-IMT. In conclusion, RA appears significantly associated with subclinical atherosclerosis and CV risk. These findings can be useful to plan adequate prevention strategies and therapeutic approaches.
Role of High-Resolution Image Integration to Visualize Left Phrenic Nerve and Coronary Arteries During Epicardial Ventricular Tachycardia Ablation
Authors: Yamashita Seigo , Sacher Frédéric , Mahida Saagar , Berte Benjamin , Lim Han S. , Komatsu Yuki , Amraoui Sana , Denis Arnaud , Derval Nicolas , Laurent François , Montaudon Michel , Hocini Mélèze , Haïssaguerre Michel , Jaïs Pierre , Cochet Hubert 
Published: February 2015

Background—
Epicardial ventricular tachycardia (VT) ablation is associated with risks of coronary artery (CA) and phrenic nerve (PN) injury. We investigated the role of multidetector computed tomography in visualizing CA and PN during VT ablation.

Methods and Results—

Ninety-five consecutive patients (86 men; age, 57±15) with VT underwent cardiac multidetector computed tomography. The PN detection rate and anatomic variability were analyzed. In 49 patients undergoing epicardial mapping, real-time multidetector computed tomographic integration was used to display CAs/PN locations in 3-dimensional mapping systems. Elimination of local abnormal ventricular activities (LAVAs) was used as ablation end point. The distribution of CAs/PN with respect to LAVA was analyzed and compared between VT etiologies. Multidetector computed tomography detected PN in 81 patients (85%). Epicardial LAVAs were observed in 44 of 49 patients (15 ischemic cardiomyopathy, 15 nonischemic cardiomyopathy, and 14 arrhythmogenic right ventricular cardiomyopathy) with a mean of 35±37 LAVA points/patient. LAVAs were located within 1 cm from CAs and PN in 35 (80%) and 18 (37%) patients, respectively. The prevalence of LAVA adjacent to CAs was higher in nonischemic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy than in ischemic cardiomyopathy (100% versus 86% versus 53%;
P
<0.01). The prevalence of LAVAs adjacent to PN was higher in nonischemic cardiomyopathy than in ischemic cardiomyopathy (93% versus 27%;
P
<0.001). Epicardial ablation was performed in 37 patients (76%). Epicardial LAVAs could not be eliminated because of the proximity to CAs or PN in 8 patients (18%).

Conclusions—
The epicardial electrophysiological VT substrate is often close to CAs and PN in patients with nonischemic cardiomyopathy. High-resolution image integration is potentially useful to minimize risks of PN and CA injury during epicardial VT ablation.
Catheter-Based Renal Denervation Reduces Atrial Nerve Sprouting and Complexity of Atrial Fibrillation in Goats
Authors: Linz Dominik , van Hunnik Arne , Hohl Mathias , Mahfoud Felix , Wolf Milan , Neuberger Hans-Ruprecht , Casadei Barbara , Reilly Svetlana N. , Verheule Sander , Böhm Michael , Schotten Ulrich 
Published: February 2015

Background—
Atrial fibrillation (AF) leads to structural and neural remodeling in the atrium, which enhances AF complexity and perpetuation. Renal denervation (RDN) can reduce renal and whole-body sympathetic activity. Aim of this study was to determine the effect of sympathetic nervous system modulation by RDN on atrial arrhythmogenesis.

Methods and Result—

Eighteen goats were instrumented with an atrial endocardial pacemaker lead and a burst pacemaker. Percutaneous catheter-based RDN was performed in 8 goats (RDN-AF). Ten goats undergoing a sham procedure served as control (SHAM-AF). AF was induced and maintained by burst pacing for 6 weeks. High-resolution mapping was used to record epicardial conduction patterns of the right and left atrium. RDN reduced tyrosine hydroxylase-positive sympathetic nerve staining and resulted in lower transcardiac norepinephrine levels. This was associated with reduced expression of nerve growth factor-β, indicating less atrial nerve sprouting. Atrial endomysial fibrosis content was lower and myocyte diameter was smaller in RDN-AF. Median conduction velocity was higher (75±9 versus 65±10 cm/s,
P
=0.02), and AF cycle length was shorter in RDN-AF compared with SHAM-AF. Left atrial AF complexity (4.8±0.8 fibrillation waves/AF cycle length versus 8.5±0.8 waves/AF cycle length,
P
=0.001) and incidence of breakthroughs (2.0±0.3 versus 4.3±0.5 waves/AF cycle length,
P
=0.059) were lower in RDN-AF compared with SHAM-AF. Blood pressure was normal and not significantly different between the groups.

Conclusions—
RDN reduces atrial sympathetic nerve sprouting, structural alterations, and AF complexity in goats with persistent AF, independent of changes in blood pressure.
Epicardial Catheter Ablation of Ventricular Tachycardia in No Entry Left Ventricle
Authors: Soejima Kyoko , Nogami Akihiko , Sekiguchi Yukio , Harada Tomoo , Satomi Kazuhiro , Hirose Takeshi , Ueda Akiko , Miwa Yousuke , Sato Toshiaki , Nishio Satoru , Shirai Yasuhiro , Kowase Shinya , Murakoshi Nobuyuki , Kunugi Shinobu , Murata Hiroshige , Nitta Takashi , Aonuma Kazutaka , Yoshino Hideaki 
Published: February 2015

Background—
In patients with mechanical aortic and mitral valves and left ventricular tachycardia, catheter ablation may be prevented by limited access to the left ventricle.

Methods and Results—
In our series of 6 patients, 2 patients underwent direct surgical ablation and 4 underwent epicardial catheter ablation via a pericardial window. All patients had abnormal low voltage areas with fractionated or delayed isolated potentials on the apical epicardium. Most of the ventricular tachycardias were targeted by pace mapping. Sites with a good pace match or abnormal electrograms were ablated using an irrigated radiofrequency ablation catheter. A microscopic pathological evaluation of the resected tissue from 2 of the open-heart ablation patients revealed dense fibrosis on the epicardium compared with the endocardium, supporting the feasibility of an epicardial ablation for the ventricular tachycardia.

Conclusions—
Epicardial catheter ablation of ventricular tachycardia is a potentially useful therapy in patients who have mechanical aortic and mitral valves.
Quantification of the Transmural Dynamics of Atrial Fibrillation by Simultaneous Endocardial and Epicardial Optical Mapping in an Acute Sheep Model
Authors: Gutbrod Sarah R. , Walton Richard , Gilbert Stephen , Meillet Valentin , Jaïs Pierre , Hocini Mélèze , Haïssaguerre Michel , Dubois Rémi , Bernus Olivier , Efimov Igor R. 
Published: February 2015

Background—
Therapy strategies for atrial fibrillation based on electric characterization are becoming viable personalized medicine approaches to treat a notoriously difficult disease. In light of these approaches that rely on high-density surface mapping, this study aims to evaluate the presence of 3-dimensional electric substrate variations within the transmural wall during acute episodes of atrial fibrillation.

Methods and Results—
Optical signals were simultaneously acquired from the epicardial and endocardial tissue during acute fibrillation in ovine isolated left atria. Dominant frequency, regularity index, propagation angles, and phase dynamics were assessed and correlated across imaging planes to gauge the synchrony of the activation patterns compared with paced rhythms. Static frequency parameters were well correlated spatially between the endocardium and the epicardium (dominant frequency, 0.79±0.06 and regularity index, 0.93±0.009). However, dynamic tracking of propagation vectors and phase singularity trajectories revealed discordant activity across the transmural wall. The absolute value of the difference in the number, spatial stability, and temporal stability of phase singularities between the epicardial and the endocardial planes was significantly >0 with a median difference of 1.0, 9.27%, and 19.75%, respectively. The number of wavefronts with respect to time was significantly less correlated and the difference in propagation angle was significantly larger in fibrillation compared with paced rhythms.

Conclusions—
Atrial fibrillation substrates are dynamic 3-dimensional structures with a range of discordance between the epicardial and the endocardial tissue. The results of this study suggest that transmural propagation may play a role in atrial fibrillation maintenance mechanisms.
Three-Year Outcomes Associated With Embolic Protection in Saphenous Vein Graft Intervention
Authors: Brennan J. Matthew , Al-Hejily Wesam , Dai David , Shaw Richard E. , Trilesskaya Marina , Rao Sunil V. , Brilakis Emmanouil S. , Anstrom Kevin J. , Messenger John C. , Peterson Eric D. , Douglas Pamela S. , Sketch Michael H. 
Published: February 2015

Background—
Information is limited on contemporary use and outcomes of embolic protection devices (EPDs) in saphenous vein graft interventions.

Methods and Results—

We formed a longitudinal cohort (2005–2009; n=49 325) by linking National Cardiovascular Data Registry CathPCI Registry to Medicare claims to examine the association between EPD use and both procedural and long-term outcomes among seniors (65+ years), adjusting for clinical factors using propensity and instrumental variable methodologies. Prespecified high-risk subgroups included acute coronary syndrome and de novo or graft body lesions. EPDs were used in 21.2% of saphenous vein grafts (median age, 75; 23% women) and were more common in acute coronary syndrome (versus non–acute coronary syndrome; 22% versus 19%), de novo (versus restenotic; 22% versus 14%), and graft body lesions (versus aortic and distal anastomosis; 24% versus 20% versus 8%, respectively). EPDs were associated with a slightly higher incidence of procedural complications, including no reflow (3.9% versus 2.8%;
P
<0.001), vessel dissection (1.3% versus 1.1%;
P
=0.05), perforation (0.7% versus 0.4%;
P
=0.001), and periprocedural myocardial infarction (2.8% versus 1.8%;
P
<0.001). By 3 years, death, myocardial infarction, and repeat revascularization occurred in 25%, 15%, and 30% of cases, respectively. EPD use was associated with a similar adjusted risk of death (propensity score–matched hazard ratio, 0.96; 95% confidence interval, 0.91–1.02), myocardial infarction (propensity score–matched hazard ratio, 1.00; 95% confidence interval, 0.93–1.09), and repeat revascularization (propensity score–matched hazard ratio, 1.02; 95% confidence interval, 0.96–1.08) in the overall cohort and high-risk subgroups.

Conclusions—
In this contemporary cohort, EPDs were used more commonly among patients with high-risk clinical indications, yet there was no evidence of improved acute- or long-term outcomes. Further prospective studies are needed to support routine EPD use.
Doppler-Derived Intracoronary Physiology Indices Predict the Occurrence of Microvascular Injury and Microvascular Perfusion Deficits After Angiographically Successful Primary Percutaneous Coronary Intervention
Authors: Teunissen Paul F.A. , de Waard Guus A. , Hollander Maurits R. , Robbers Lourens F.H.J. , Danad Ibrahim , Biesbroek P. Stefan , Amier Raquel P. , Echavarría-Pinto Mauro , Quirós Alicia , Broyd Christopher , Heymans Martijn W. , Nijveldt Robin , Lammertsma Adriaan A. , Raijmakers Pieter G. , Allaart Cornelis P. , Lemkes Jorrit S. , Appelman Yolande E. , Marques Koen M. , Bronzwaer Jean G.F. , Horrevoets Anton J.G. , van Rossum Albert C. , Escaned Javier , Beek Aernout M. , Knaapen Paul , van Royen Niels 
Published: February 2015

Background—
A total of 40% to 50% of patients with ST-segment–elevation myocardial infarction develop microvascular injury (MVI) despite angiographically successful primary percutaneous coronary intervention (PCI). We investigated whether hyperemic microvascular resistance (HMR) immediately after angiographically successful PCI predicts MVI at cardiovascular magnetic resonance and reduced myocardial blood flow at positron emission tomography (PET).

Methods and Results—

Sixty patients with ST-segment–elevation myocardial infarction were included in this prospective study. Immediately after successful PCI, intracoronary pressure–flow measurements were performed and analyzed off-line to calculate HMR and indices derived from the pressure–velocity loops, including pressure at zero flow. Cardiovascular magnetic resonance and H
2
15
O PET imaging were performed 4 to 6 days after PCI. Using cardiovascular magnetic resonance, MVI was defined as a subendocardial recess of myocardium with low signal intensity within a gadolinium-enhanced area. Myocardial perfusion was quantified using H
2
15
O PET. Reference HMR values were obtained in 16 stable patients undergoing coronary angiography. Complete data sets were available in 48 patients of which 24 developed MVI. Adequate pressure–velocity loops were obtained in 29 patients. HMR in the culprit artery in patients with MVI was significantly higher than in patients without MVI (MVI, 3.33±1.50 mm Hg/cm per second versus no MVI, 2.41±1.26 mm Hg/cm per second;
P
=0.03). MVI was associated with higher pressure at zero flow (45.68±13.16 versus 32.01±14.98 mm Hg;
P
=0.015). Multivariable analysis showed HMR to independently predict MVI (
P
=0.04). The optimal cutoff value for HMR was 2.5 mm Hg/cm per second. High HMR was associated with decreased myocardial blood flow on PET (myocardial perfusion reserve <2.0, 3.18±1.42 mm Hg/cm per second versus myocardial perfusion reserve ≥2.0, 2.24±1.19 mm Hg/cm per second;
P
=0.04).

Conclusions—
Doppler-flow–derived physiological indices of coronary resistance (HMR) and extravascular compression (pressure at zero flow) obtained immediately after successful primary PCI predict MVI and decreased PET myocardial blood flow.

Clinical Trial Registration—

URL:
http://www.trialregister.nl
. Unique identifier: NTR3164.
Percutaneous Fetal Cardiac Catheterization Technique for Stenting the Foramen Ovale in a Midgestation Lamb Model
Authors: Edwards Andrew , Veldman Alex , Nitsos Ilias , Chan Yuen , Brew Nadine , Teoh Mark , Menahem Samuel , Schranz Dietmar , Wong Flora Y. 
Published: February 2015

Background—
Intact or highly restricted intra-atrial septum can be reliably diagnosed in the human fetus as early as 22 to 24 weeks of gestation. Fetal interventions targeting the atrial septum have used a direct approach through the atrial wall. Here, we report stenting of the foramen ovale with a large, open-cell stent via percutaneous access through the fetal hepatic vein in a sheep model.

Methods and Results—
In 5 fetal sheep of 109 to 111 days of gestation (term, 147 days), the fetal hepatic vein was punctured percutaneously under ultrasound guidance and a 13.3-cm 14-gauge intravenous catheter was inserted. After catheterization of the inferior vena cava, right atrium, foramen ovale, and left atrium with a guidewire and 1.8F to 2.6F tapered catheter, a self-expandable, 8×12-mm flexible open-cell stent was positioned in an unrestricted foramen ovale. Flow and fetal well-being were documented for 45 minutes after the procedure. Access to the left atrium was achieved in all 5 animals and all survived. In 4 animals, the stent was successfully positioned in the foramen ovale. One fetus was born at term and euthanized on day 3: postmortem examination confirmed the patency of the stent. The other 3 fetuses were well after being monitored by ultrasound for 45 minutes. In 1 animal, the stent dislodged immediately after release obstructing the mitral valve. This fetus developed ascites and was euthanized after 4 days.

Conclusions—
It is feasible to safely advance a large diameter, self-expandable, open-cell design stent into the fetal atrial septum via a percutaneous access route through the fetal hepatic vein.