bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ceramide–Antiestrogen Nanoliposomal Combinations—Novel Impact of Hormonal Therapy in Hormone-Insensitive Breast Cancer
Authors: Morad Samy A.F. , Levin Jonathan C. , Shanmugavelandy Sriram S. , Kester Mark , Fabrias Gemma , Bedia Carmen , Cabot Myles C. 
Published: September 2012

Abstract
Although the sphingolipid ceramide exhibits potent tumor suppressor effects, efforts to harness this have been hampered by poor solubility, uptake, bioavailability, and metabolic conversion. Therefore, identification of avenues to improve efficacy is necessary for development of ceramide-based therapies. In this study, we used mutant p53, triple-negative breast cancer (TNBC) cells, a type of breast cancer highly refractory to treatment, and cell-permeable nanoliposomal C6-ceramide in conjunction with the antiestrogen tamoxifen, which has been shown to be an effective modulator of ceramide metabolism. We show for the first time that nanoliposomal tamoxifen enhances nanoliposomal C6-ceramide cytotoxicity in cultured TNBC cells, a response that was accompanied by induction of cell-cycle arrest at G1 and G2, caspase-dependent induction of DNA fragmentation, and enhanced mitochondrial and lysosomal membrane permeability at 18 and 2 hours, respectively. Tamoxifen metabolites were also effective. Only tamoxifen promoted lysosomal membrane permeability. In addition, we show for the first time that tamoxifen inhibits acid ceramidase, as measured in intact cell assays; this effect was irreversible. Together, our findings show that tamoxifen magnifies the antiproliferative effects of C6-ceramide via combined targeting of cell-cycle traverse and lysosomal and mitochondrial integrity. We adduce that C6-ceramide–induced apoptosis is amplified by tamoxifen's impact on lysosomes and perhaps accompanying inhibition of acid ceramidase, which could result in decreased levels of sphingosine 1-phosphate. This drug regimen could serve as a promising therapy for chemoresistant and triple-negative types of breast cancer, and thus represents an indication for tamoxifen, irrespective of estrogen receptor status. Mol Cancer Ther; 11(11); 2352–61. ©2012 AACR.
Aberrant Methylation of RASGRF1 Is Associated with an Epigenetic Field Defect and Increased Risk of Gastric Cancer
Authors: Takamaru Hiroyuki , Yamamoto Eiichiro , Suzuki Hiromu , Nojima Masanori , Maruyama Reo , Yamano Hiro-o , Yoshikawa Kenjiro , Kimura Tomoaki , Harada Taku , Ashida Masami , Suzuki Ryo , Yamamoto Hiroyuki , Kai Masahiro , Tokino Takashi , Sugai Tamotsu , Imai Kohzoh , Toyota Minoru , Shinomura Yasuhisa 
Published: September 2012

Abstract
Aberrant DNA methylation is implicated in the epigenetic field defect seen in gastric cancer. Our aim in this study was to identify predictive biomarkers by screening for DNA methylation in noncancerous background gastric mucosa from patients with gastric cancer. Using methylated-CpG island amplification coupled with CpG island microarray (MCAM) analysis, we identified 224 genes that were methylated in the noncancerous gastric mucosa of patients with gastric cancer. Among them, RASGRF1 methylation was significantly elevated in gastric mucosa from patients with either intestinal or diffuse type gastric cancer, as compared with mucosa from healthy individuals (8.3% vs. 22.4%, P &lt; 0.001; 8.3% vs. 19.4%, P &lt; 0.001). RASGRF1 methylation was independent of mucosal atrophy and could be used to distinguish both serum pepsinogen test-positive [sensitivity, 70.0%; specificity, 86.7%; area under the receiver operator characteristic (ROC) curve, AUC, 0.763] and -negative patients with gastric cancer (sensitivity, 72.2%; specificity, 87.0%; AUC, 0.844) from healthy individuals. Ectopic expression of RASGRF1 suppressed colony formation and Matrigel invasion by gastric cancer cells, suggesting it may be involved in gastric tumorigenesis. Collectively, our data suggest that RASGRF1 methylation is significantly involved in an epigenetic field defect in the stomach, and that it could be a useful biomarker to identify individuals at high risk for gastric cancer. Cancer Prev Res; 5(10); 1203–12. ©2012 AACR.
Intervening to Reduce the Future Burden of Occupational Cancer in Britain: What Could Work?
Authors: Hutchings Sally , Cherrie John W. , Van Tongeren Martie , Rushton Lesley 
Published: September 2012

Abstract
In Britain, 14 carcinogenic agents and occupational circumstances currently account for 86% of estimated occupation attributable cancer. The future burden associated with these carcinogens has been forecast, using attributable fractions for forecast scenarios representing patterns of past and predicted future exposure, and exposure levels representing the introduction of new occupational exposure limits, increased levels of compliance with these limits and other reductions in worker exposure. Without intervention, occupational attributable cancers are forecast to remain at more than 10,000 by 2060. With modest intervention over 2,600, or with stricter interventions more than 8,200 cancers could be avoided by 2060 although because of long latency no impact will be seen until at least 10 years after intervention. Effective interventions assessed in this study include reducing workplace exposure limits and improving compliance with these limits. Cancers associated with asbestos, diesel engine exhaust, polycyclic aromatic hydrocarbons, work as a painter, radon, and solar radiation are forecast to continue, with construction remaining the prime industry of concern. Although exposure levels to the established carcinogens are falling, workers are remaining exposed at low levels at which there is still a cancer risk, although the aging population also contributes to rising cancer numbers, These forecasts can be used to assess the relative costs to society of different occupational carcinogenic agents, and the relative merits and savings associated with alternative intervention strategies. The methods are adaptable for different data circumstances, other types of interventions and could be extended to environmental carcinogens and other chronic diseases. Cancer Prev Res; 5(10); 1213–22. ©2012 AACR.
Metabolic Profiling, a Noninvasive Approach for the Detection of Experimental Colorectal Neoplasia
Authors: Montrose David C. , Zhou Xi Kathy , Kopelovich Levy , Yantiss Rhonda K. , Karoly Edward D. , Subbaramaiah Kotha , Dannenberg Andrew J. 
Published: September 2012

Abstract
Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Although noninvasive stool-based screening tests are used for the early detection of colorectal neoplasia, concerns have been raised about their sensitivity and specificity. A metabolomics-based approach provides a potential noninvasive strategy to identify biomarkers of colorectal carcinogenesis including premalignant adenomas. Our primary objective was to determine whether a distinct metabolic profile could be found in both feces and plasma during experimental colorectal carcinogenesis. Feces, plasma as well as tumor tissue and normal colorectal mucosa were obtained from A/J mice at several time points following administration of azoxymethane or saline. Ultra-performance liquid chromatography tandem mass spectroscopy and gas chromatography mass spectroscopy were used to quantify metabolites in each of these matrices. Here, we show that colorectal carcinogenesis was associated with significant metabolic alterations in both the feces and plasma, some of which overlap with metabolic changes in the tumor tissue. These consisted of 33 shared changes between feces and tumor, 14 shared changes between plasma and tumor, and 3 shared changes across all 3 matrices. For example, elevated levels of sarcosine were found in both tumor and feces whereas increased levels of 2-hydroxyglutarate were found in both tumor and plasma. Collectively, these results provide evidence that metabolomics can be used to detect changes in feces and plasma during azoxymethane-induced colorectal carcinogenesis and thus provide a strong rationale for future studies in humans. Cancer Prev Res; 5(12); 1358–67. ©2012 AACR.
Aspirin Use after a Prostate Cancer Diagnosis and Cancer Survival in a Prospective Cohort
Authors: Dhillon Preet K. , Kenfield Stacey A. , Stampfer Meir J. , Giovannucci Edward L. , Chan June M. 
Published: September 2012

Abstract
Experimental and clinical data suggest that aspirin and other nonsteroidal inflammatory drugs may delay the progression of prostate cancer through inhibition of the COX pathway and its effects on cellular proliferation, apoptosis, and angiogenesis. Epidemiologic data support a reduced risk of prostate cancer incidence with aspirin use, yet no evidence exists about whether aspirin after diagnosis influences progression or survival. We conducted a prospective study of 3,986 participants of the Health Professionals Follow-up Study, with a prostate cancer diagnosis between January 1, 1990, and December 31, 2005. We used Cox proportional hazards regression to evaluate the association between aspirin use after diagnosis and the development of metastases or fatal prostate cancer through January 31, 2008, adjusting for risk factors associated with incidence and mortality in this cohort, prediagnostic aspirin use, Gleason score, tumor–node–metastasis (TNM) stage, and primary treatment. In total, 265 men developed bony or other organ metastases or fatal prostate cancer during the 18 years of follow-up. We observed no association between updated aspirin use after diagnosis and lethal prostate cancer [tablets/week: &lt;2: HR, 1.12; 95% confidence interval (CI), 0.72–1.72; 2–5: HR, 1.05; 95% CI, 0.62–1.80; ≥ 6: HR, 1.08; 95% CI, 0.76–1.54; Ptrend = 0.99]. The results remained unchanged when we examined aspirin use at baseline only (Ptrend = 0.70) or frequency of use (d/wk; Ptrend = 0.35) or limited the outcome to fatal prostate cancer (Ptrend = 0.63). There was no association between aspirin use after a prostate cancer diagnosis and lethal disease in this cohort of prostate cancer survivors. Cancer Prev Res; 5(10); 1223–8. ©2012 AACR.
Reactivation of ERK Signaling Causes Resistance to EGFR Kinase Inhibitors
Authors: Ercan Dalia , Xu Chunxiao , Yanagita Masahiko , Monast Calixte S. , Pratilas Christine A. , Montero Joan , Butaney Mohit , Shimamura Takeshi , Sholl Lynette , Ivanova Elena V. , Tadi Madhavi , Rogers Andrew , Repellin Claire , Capelletti Marzia , Maertens Ophélia , Goetz Eva M. , Letai Anthony , Garraway Levi A. , Lazzara Matthew J. , Rosen Neal , Gray Nathanael S. , Wong Kwok-Kin , Jänne Pasi A. 
Published: September 2012

AbstractThe clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors is limited by the development of drug resistance. The irreversible EGFR kinase inhibitor WZ4002 is effective against the most common mechanism of drug resistance mediated by the EGFR T790M mutation. Here, we show, in multiple complementary models, that resistance to WZ4002 develops through aberrant activation of extracellular signal-regulated kinase (ERK) signaling caused by either an amplification of mitogen-activated protein kinase 1 (MAPK1) or by downregulation of negative regulators of ERK signaling. Inhibition of MAP–ERK kinase (MEK) or ERK restores sensitivity to WZ4002 and prevents the emergence of drug resistance. We further identify MAPK1 amplification in an erlotinib-resistant EGFR-mutant non–small cell lung carcinoma patient. In addition, the WZ4002-resistant MAPK1-amplified cells also show an increase both in EGFR internalization and a decrease in sensitivity to cytotoxic chemotherapy. Our findings provide insights into mechanisms of drug resistance to EGFR kinase inhibitors and highlight rational combination therapies that should be evaluated in clinical trials.Significance: Our study identifies activated ERK signaling as a mediator of resistance to irreversible pyrimidine EGFR inhibitors in EGFR T790M-bearing cancers. We further provide a therapeutic strategy to both treat and prevent the emergence of this resistance mechanism. Cancer Discov; 2(10); 934–47. ©2012 AACR.Read the Commentary on this article by Blakely and Bivona, p. 872.This article is highlighted in the In This Issue feature, p. 857.
Macrophages Regulate Smooth Muscle Differentiation of Mesenchymal Stem Cells via a Prostaglandin F
2α
−Mediated Paracrine Mechanism
Authors: Lee Mi Jeong , Kim Min Young , Heo Soon Chul , Kwon Yang Woo , Kim Young Mi , Do Eun Kyoung , Park Ji Hye , Lee Jung Sub , Han Jin , Kim Jae Ho 
Published: September 2012

Objective—
Mesenchymal stem cells are useful for vascular regeneration of injured tissues. Macrophages are involved in acute or chronic inflammatory diseases, and interleukin-1β (IL-1β), a proinflammatory cytokine, plays a key role in the activation of macrophages within injured tissues. To explore the role of macrophages on mesenchymal stem cell–mediated vascular regeneration, we examined the effects of IL-1β–activated macrophages on differentiation of human adipose tissue–derived mesenchymal stem cells (hASCs) to smooth muscle cells (SMCs) and the vascular regenerative capacity of the differentiated SMCs in a hindlimb ischemia animal model.

Methods and Results—

We demonstrate that IL-1β–conditioned medium from RAW 264.7 macrophages induces differentiation of human adipose tissue–derived mesenchymal stem cells to α-smooth muscle actin–positive SMCs, and the differentiated SMCs exhibited increased contractility in response to KCl and carbachol treatment. Transplantation of the differentiated SMCs attenuated severe hindlimb ischemia and promoted vascular regeneration. IL-1β treatment stimulated secretion of prostaglandin F
2α
from RAW 264.7 cells. Small interfering RNA–mediated silencing of the prostaglandin F
2α
receptor completely abrogated IL-1β conditioned medium–stimulated α-smooth muscle actin expression. Moreover, prostaglandin F
2α
treatment stimulated expression of α-smooth muscle actin in human adipose tissue–derived mesenchymal stem cells.

Conclusion—

These results suggest that IL-1β–activated macrophages promote differentiation of human adipose tissue–derived mesenchymal stem cells to SMCs through a prostaglandin F
2α
–mediated paracrine mechanism.
Endocardial Cushion Morphogenesis and Coronary Vessel Development Require Chicken Ovalbumin Upstream Promoter-Transcription Factor II
Authors: Lin Fu-Jung , You Li-Ru , Yu Cheng-Tai , Hsu Wen-Hsin , Tsai Ming-Jer , Tsai Sophia Y. 
Published: September 2012

Objective—
Septal defects and coronary vessel anomalies are common congenital heart defects, yet their ontogeny and the underlying genetic mechanisms are not well understood. Here, we investigated the role of chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII, NR2F2) in cardiac organogenesis.

Methods and Results—

We analyzed embryos deficient in
COUP-TFII
and observed a spectrum of cardiac defects, including atrioventricular septal defect, thin-walled myocardium, and abnormal coronary morphogenesis. We show by expression analysis that COUP-TFII is expressed in the endocardium and the epicardium but not in the myocardium of the ventricle. Using endothelial-specific
COUP-TFII
mutants and molecular approaches, we show that
COUP-TFII
deficiency resulted in endocardial cushion hypoplasia. This was attributed to the reduced growth and survival of atrioventricular cushion mesenchymal cells and defective epithelial-mesenchymal transformation (EMT) in the underlying endocardium. In addition, the endocardial EMT defect was accompanied by downregulation of
Snai1
, one of the master regulators of EMT, and upregulation of vascular endothelial-cadherin. Furthermore, we show that although COUP-TFII does not play a major role in the formation of epicardial cell cysts, it is critically important for the formation of epicardium. Ablation of COUP-TFII impairs epicardial EMT and coronary plexus formation.

Conclusion—
Our results reveal that COUP-TFII plays cell-autonomous roles in the endocardium and the epicardium for endocardial and epicardial EMT, which are required for proper valve and coronary vessel formation during heart development.
Serious Cardiac Arrhythmias After Stroke
Authors: Kallmünzer Bernd , Breuer Lorenz , Kahl Nicolas , Bobinger Tobias , Raaz-Schrauder Dorette , Huttner Hagen Bernhard , Schwab Stefan , Köhrmann Martin 
Published: September 2012

Background and Purpose—
Patients with acute cerebrovascular events are susceptible to serious cardiac arrhythmias, but data on the time course and the determinants of their onset are scarce.

Methods—
The prospective Stroke-Arrhythmia-Monitoring-Database (SAMBA) assessed cardiac arrhythmias with need for urgent evaluation and treatment in 501 acute neurovascular patients during the first 72 hours after admission to a monitored stroke unit. Arrhythmias were systematically detected by structured processing of telemetric data. Time of arrhythmia onset and predisposing factors were investigated.

Results—
Significant cardiac arrhythmias occurred in 25.1% of all patients. Incidence was highest during the first 24 hours after admission. Serious arrhythmic tachycardia (ventricular or supraventricular >130 beats/min) was more frequent than bradycardic arrhythmia (sinus-node dysfunction, bradyarrhythmia, or atrioventricular block °II and °III). Arrhythmias were independently associated with higher age and severer neurological deficits as measured by the National Institutes of Health Stroke Scale on admission.

Conclusions—
The risk for significant cardiac arrhythmia after an acute cerebrovascular event is highest during the first 24 hours of care and declines with time during the first 3 days. Along with established vascular risk factors, the National Institutes of Health Stroke Scale may be considered for a stratified allocation of monitoring capabilities.

Clinical Trial Registration—

URL:
www.clinicaltrials.gov
. Unique identifier: NCT01177748.
Antegrade Flow Across Incomplete Vessel Occlusions Can Be Distinguished From Retrograde Collateral Flow Using 4-Dimensional Computed Tomographic Angiography
Authors: Frölich Andreas M.J. , Psychogios Marios N. , Klotz Ernst , Schramm Ramona , Knauth Michael , Schramm Peter 
Published: September 2012

Background and Purpose—
In acute stroke patients with intracranial vessel occlusion, angiographic demonstration of antegrade contrast opacification distal to the occlusion site (termed the “clot outline sign”) has been associated with higher rates of vessel recanalization. We sought to determine whether antegrade flow can be demonstrated on timeresolved 4-dimensional computed tomographic angiography (4-dimensional CTA), whether it can be distinguished from retrograde collateral flow, and if it can be used to predict early recanalization.

Methods—
Fiftyseven acute stroke patients with intracranial anterior circulation vessel occlusion were retrospectively identified. All patients had received a multimodal computed tomography examination including thinsection 4-dimensional CTA and subsequent digital subtraction angiography as part of an endovascular procedure. Pretreatment 4-dimensional CTA and singlephase CTA were assessed for presence of antegrade contrast opacification distal to the occlusion site. Digital subtraction angiograms were reviewed for preintervention Thrombolysis in Cerebral Infarction grade, presence of the clot outline sign, as well as postintervention Thrombolysis in Cerebral Infarction grade.

Results—
On 4-dimensional CTA, evidence of antegrade flow was present in 11 of 57 cases (19.3%). Compared with angiography, 4-dimensional CTA predicted antegrade flow with 100% sensitivity and 97.9% specificity. Singlephase CTA offered 40% sensitivity and 87.2% specificity. Early recanalization occurred in 3 patients (6.5%) after intravenous thrombolysis (n=46); all demonstrated antegrade flow on 4-dimensional CTA.

Conclusions—
Using 4-dimensional CTA, it is possible to noninvasively distinguish antegrade flow across a cerebral artery occlusion from retrograde collateral flow. Presence of antegrade flow on 4-dimensional CTA is associated with an increased chance of early vessel recanalization.
Features of Acute Ischemic Stroke With Rheumatic Heart Disease in a Hospitalized Chinese Population
Authors: Wang Deren , Liu Ming , Hao Zilong , Tao Wendan , Lin Sen , Zhang Shihong , Wu Bo , Ma Zhenxing , Dong Wei 
Published: September 2012

Background and Purpose—
Rheumatic heart disease (RHD) is an important risk factor for ischemic stroke in developing countries. Observational data on its characteristics and influence on outcome or recurrence of ischemic stroke are scarce. We aimed to investigate proportions, characteristics, functional outcome, and recurrence of acute ischemic stroke patients with RHD in a hospitalized Chinese population.

Methods—
We prospectively enrolled consecutive patients with acute ischemic stroke who were admitted within 1 month of stroke onset from January 2003 to February 2007, into the analysis. Clinical characteristics such as age, gender, risk factors, and National Institutes of Health Stroke Scale on admission were investigated. Basic characteristics, functional outcomes, and recurrence were compared between RHD group and nonRHD group.

Results—

Of the 1638 cases included, RHD was present in 130 patients (7.9%). RHD patients, compared with those without RHD, were younger, more frequently female, and more often had experienced atrial fibrillation and higher National Institutes of Health Stroke Scale score on admission (all
P
<0.006). After adjustment for age, sex, and National Institutes of Health Stroke Scale on admission, the death risk in patients with RHD was 2.0-fold higher at 3 months, 6 months, and 1 year compared with patients without RHD (all
P
<0.013). Compared with patients without RHD, those with RHD showed a significantly higher cumulative recurrence rate (13.6% vs 6.0%;
P
=0.001, log rank test) by 1-year cumulative recurrent curves.

Conclusions—
Stroke attributable to RHD is still common in the Chinese population. RHD was associated with 2-fold increased risk of death and 1-fold increased risk of recurrence in stroke patients.
The Effect of Proximity, Tall Man Lettering, and Time Pressure on Accurate Visual Perception of Drug Names
Authors: Irwin Amy , Mearns Kathryn , Watson Margaret , Urquhart Jim 
Published: September 2012

Objective: The aim of this study is to assess the effect of proximity and time pressure on accurate and effective visual search during medication selection from a computer screen. Background: The presence of multiple similar objects in proximity to a target object increases the difficulty of a visual search. Visual similarity between drug names can also lead to selection error. The proximity of several similarly named drugs within a visual field could, therefore, adversely affect visual search. Method: In Study 1, 60 nonpharmacy participants selected a target drug name from an array of mock drug packets shown on a computer screen, where one or four similarly named nontargets might be present. Of the participants, 30 completed the task with a time constraint, and the remainder did not. In Study 2, the same experiment was repeated with 28 pharmacy staff. Results: In Study 1, the proximity of multiple similarly named nontargets within the specified visual field reduced selection accuracy and increased reaction times in the nonpharmacists. Time constraint also had an adverse effect. In Study 2, the pharmacy participants showed increased reaction times when multiple nontargets were present, but the time constraint had no effect. There was no effect of Tall Man lettering. Conclusion: The presence of multiple similarly named medications in close proximity to a target medication increases the difficulty of the visual search for the target. Tall Man lettering has no impact on this adverse effect. Application: The widespread use of the alphabetical system in medication storage increases the risk of proximity-based errors in drug selection.