bluuebunny/crossref_metadata_2025_split huggingface dataset:
microRNA-Associated Progression Pathways and Potential Therapeutic Targets Identified by Integrated mRNA and microRNA Expression Profiling in Breast Cancer
Authors: Buffa Francesca M. , Camps Carme , Winchester Laura , Snell Cameron E. , Gee Harriet E. , Sheldon Helen , Taylor Marian , Harris Adrian L. , Ragoussis Jiannis 
Published: July 2011

Abstract
microRNA expression profiling plays an emerging role in cancer classification and identification of therapeutic strategies. In this study, we have evaluated the benefits of a joint microRNA–mRNA analysis in breast cancer.
Matched mRNA and microRNA global expression profiling was conducted in a well-annotated cohort of 207 cases with complete 10-year follow-up. Penalized Cox regression including microRNA expression, mRNA expression, and clinical covariates was used to identify microRNAs associated with distant relapse-free survival (DRFS) that provide independent prognostic information, and are not simply surrogates of previously identified prognostic covariates. Penalized regression was chosen to prevent overfitting. Furthermore, microRNA–mRNA relationships were explored by global expression analysis, and exploited to validate results in several published cohorts (n = 592 with DRFS, n = 1,050 with recurrence-free survival).
Four microRNAs were independently associated with DRFS in estrogen receptor (ER)-positive (3 novel and 1 known; miR-128a) and 6 in ER-negative (5 novel and 1 known; miR-210) cases. Of the latter, miR-342, -27b, and -150 were prognostic also in triple receptor-negative tumors. Coordinated expression of predicted target genes and prognostic microRNAs strengthened these results, most significantly for miR-210, -128a, and -27b, whose targets were prognostic in meta-analysis of several cohorts. In addition, miR-210 and -128a showed coordinated expression with their cognate pri-microRNAs, which were themselves prognostic in independent cohorts.
Our integrated microRNA–mRNA global profiling approach has identified microRNAs independently associated with prognosis in breast cancer. Furthermore, it has validated known and predicted microRNA–target interactions, and elucidated their association with key pathways that could represent novel therapeutic targets. Cancer Res; 71(17); 5635–45. ©2011 AACR.
Phase II Trials Powered to Detect Tumor Subtypes
Authors: Roberts John D. , Ramakrishnan Viswanathan 
Published: July 2011

Abstract
Classical phase II trial designs, including “adaptive” designs, require the prospective characterization of tumors. We propose a 2-stage phase II design that allows for characterization of tumors and selection of a tumor subtype of interest at the conclusion of stage 1. The stage 2 objective is either a classical estimate of the response rate for either the tumor or a subtype, or a formal test of the hypothesis that the response rate for a subtype is greater than the overall response rate. Considering likely scenarios, stage 1 sample sizes approximately range from 20 to 100 with a usual size of 50. This compares with typical classical stage 1 sample sizes of 12 to 30. Total sample sizes range from sizes identical to classical designs (tens to scores) to large sizes typical of phase III trials in metastatic disease (hundreds). Our design is more efficient than previous adaptive designs because it allows for the selection of a tumor subtype of interest on the basis of results from stage 1. It complements classical phase II and phase III designs in which investigators compare different treatments in similar patients and tumors by positioning a treatment as fixed (control) and using tumor subtype as the variable of interest. Clin Cancer Res; 17(17); 5538–45. ©2011 AACR.
Antitumor Activity of YM155, a Selective Small-Molecule Survivin Suppressant, Alone and in Combination with Docetaxel in Human Malignant Melanoma Models
Authors: Yamanaka Kentaro , Nakahara Takahito , Yamauchi Tomohiro , Kita Aya , Takeuchi Masahiro , Kiyonaga Fumiko , Kaneko Naoki , Sasamata Masao 
Published: July 2011

Abstract
Purpose: Aggressive cell growth and chemoresistance are notorious obstacles in melanoma therapy. Accumulating evidence suggests that survivin is preferentially expressed in cancer cells and plays a crucial role in cell division and apoptosis dysfunction. Here, we evaluated the therapeutic potential of YM155, a selective survivin suppressant, alone and in combination with docetaxel using human melanoma models.
Experimental Design: A375 and SK-MEL-5 human malignant melanoma cells were treated with siRNA, YM155, and/or docetaxel, and cell viability, mRNA and protein expression levels, cell-cycle distribution, and immunohistochemical staining were then evaluated. Furthermore, the efficacy of YM155 combined with docetaxel was further examined in established xenograft models.
Results: Survivin suppression was sufficient to induce spontaneous apoptosis of melanoma cells. YM155 showed nanomolar antiproliferative effects and induced tumor regression in established melanoma xenograft models. Docetaxel showed antitumor activity against melanoma cells, although it also induced survivin upregulation and G2/M mitotic arrest; however, cotreatment with YM155 decreased survivin expression below basal levels. Combination treatment of YM155 and docetaxel induced a greater rate of apoptosis than the sum of the single-treatment rates and promoted tumor regression without enhanced body weight loss in the melanoma xenograft models.
Conclusions: Survivin is responsible for the inherent low levels of spontaneous apoptosis in melanoma cells. The concomitant combination of YM155 with docetaxel diminished the accumulation of survivin in G2/M mitotic arrest, and induced more intense apoptosis compared with each single treatment. YM155 in combination with docetaxel is well tolerated and shows greater efficacy than either agent alone in mouse xenograft models. Clin Cancer Res; 17(16); 5423–31. ©2011 AACR.
Membranous Expression of Ectodomain Isoforms of the Epidermal Growth Factor Receptor Predicts Outcome after Chemoradiotherapy of Lymph Node–Negative Cervical Cancer
Authors: Halle Cathinka , Lando Malin , Svendsrud Debbie Hege , Clancy Trevor , Holden Marit , Sundfør Kolbein , Kristensen Gunnar B. , Holm Ruth , Lyng Heidi 
Published: July 2011

Abstract
Purpose: We compared the prognostic significance of ectodomain isoforms of the epidermal growth factor receptor (EGFR), which lack the tyrosine kinase (TK) domain, with that of the full-length receptor and its autophosphorylation status in cervical cancers treated with conventional chemoradiotherapy.
Experimental Design: Expression of EGFR isoforms was assessed by immunohistochemistry in a prospectively collected cohort of 178 patients with squamous cell cervical carcinoma, and their detection was confirmed with Western blotting and reverse transcriptase PCR. A proximity ligation immunohistochemistry assay was used to assess EGFR-specific autophosphorylation. Pathways associated with the expression of ectodomain isoforms were studied by gene expression analysis with Illumina beadarrays in 110 patients and validated in an independent cohort of 41 patients.
Results: Membranous expression of ectodomain isoforms alone, without the coexpression of the full-length receptor, showed correlations to poor clinical outcome that were highly significant for lymph node–negative patients (locoregional control, P = 0.0002; progression-free survival, P &lt; 0.0001; disease-specific survival, P = 0.005 in the log-rank test) and independent of clinical variables. The ectodomain isoforms were primarily 60-kD products of alternative EGFR transcripts. Their membranous expression correlated with transcriptional regulation of oncogenic pathways including activation of MYC and MAX, which was significantly associated with poor outcome. This aggressive phenotype of ectodomain EGFR expressing tumors was confirmed in the independent cohort. Neither total nor full-length EGFR protein level, or autophosphorylation status, showed prognostic significance.
Conclusion: Membranous expression of ectodomain EGFR isoforms, and not TK activation, predicts poor outcome after chemoradiotherapy for patients with lymph node–negative cervical cancer. Clin Cancer Res; 17(16); 5501–12. ©2011 AACR.
Long-Range Epigenetic Silencing Associates with Deregulation of Ikaros Targets in Colorectal Cancer Cells
Authors: Javierre Biola M. , Rodriguez-Ubreva Javier , Al-Shahrour Fatima , Corominas Marina , Graña Osvaldo , Ciudad Laura , Agirre Xabier , Pisano David G. , Valencia Alfonso , Roman-Gomez Jose , Calasanz Maria Jose , Prosper Felipe , Esteller Manel , Gonzalez-Sarmiento Rogelio , Ballestar Esteban 
Published: July 2011

Abstract
Transcription factors are common targets of epigenetic inactivation in human cancer. Promoter hypermethylation and subsequent silencing of transcription factors can lead to further deregulation of their targets. In this study, we explored the potential epigenetic deregulation in cancer of Ikaros family genes, which code for essential transcription factors in cell differentiation and exhibit genetic defects in hematologic neoplasias. Unexpectedly, our analysis revealed that Ikaros undergoes very specific promoter hypermethylation in colorectal cancer, including in all the cell lines studied and around 64% of primary colorectal adenocarcinomas, with increasing proportions in advanced Duke's stages. Ikaros hypermethylation occurred in the context of a novel long-range epigenetic silencing (LRES) region. Reintroduction of Ikaros in colorectal cancer cells, ChIP-chip analysis, and validation in primary samples led us to identify a number of direct targets that are possibly related with colorectal cancer progression. Our results not only provide the first evidence that LRES can have functional specific effects in cancer but also identify several deregulated Ikaros targets that may contribute to progression in colorectal adenocarcinoma. Mol Cancer Res; 9(8); 1139–51. ©2011 AACR.
Rho-Associated Kinase Activity, Endothelial Function, and Cardiovascular Risk Factors
Authors: Soga Junko , Noma Kensuke , Hata Takaki , Hidaka Takayuki , Fujii Yuichi , Idei Naomi , Fujimura Noritaka , Mikami Shinsuke , Maruhashi Tatsuya , Kihara Yasuki , Chayama Kazuaki , Kato Hitoshi , Liao James K. , Higashi Yukihito 
Published: July 2011

Objective—
Cardiovascular diseases are associated with chronic activation of Rho-associated kinases (ROCKs) and endothelial dysfunction. Both increased ROCK activity and endothelial dysfunction are thought to be closely associated with conventional cardiovascular risk factors. The purpose of this study was to determine the relationships between ROCK activity, endothelial function, and cardiovascular risk factors.

Methods and Results—

We evaluated ROCK activity in peripheral leukocytes by Western blot analysis and flow-mediated vasodilation by ultrasonography in 242 men who had no cardiovascular or cerebrovascular diseases (mean age, 40±10 years; range, 20 to 73 years). ROCK activity was defined as the ratio of phospho myosin-binding subunit on myosin light chain phosphatase to total myosin-binding subunit. Univariate regression analysis revealed that leukocyte ROCK activity significantly correlated with body mass index (
r
=0.29,
P
=0.003); systolic blood pressure (
r
=0.25,
P
=0.01); low-density lipoprotein cholesterol level (
r
=0.21,
P
=0.04); and Framingham risk factor score, a cumulative cardiovascular risk index for heart attack (
r
=0.31,
P
<0.001), and that flow-mediated vasodilation significantly correlated with age (
r
=−0.23,
P
=0.02), body mass index (
r
=0.19,
P
=0.05), systolic blood pressure (
r
=−0.22,
P
=0.03), total cholesterol level (
r
=−0.21,
P
=0.04), low-density lipoprotein cholesterol level (
r
=−0.22,
P
=0.04), glucose level (
r
=−0.20,
P
=0.04), and Framingham risk factor score (
r
=−0.37,
P
<0.001). There was a significant correlation between leukocyte ROCK activity and flow-mediated vasodilation (
r
=−0.41,
P
<0.001). Multivariate analysis revealed that flow-mediated vasodilation was an independent predictor of leukocyte ROCK activity.

Conclusion—
These findings suggest that cumulative cardiovascular risk may enhance ROCK activity and endothelial dysfunction, leading to progression of cardiovascular diseases and outcomes.
Strain-Rate Imaging Predicts the Attenuation of Left Ventricular Remodeling Induced by Ischemic Postconditioning After Myocardial Infarction in Mice
Authors: Thibault Hélène , Gomez Ludovic , Bergerot Cyrille , Augeul Lionel , Scherrer-Crosbie Marielle , Ovize Michel , Derumeaux Geneviève 
Published: July 2011

Background—
Systolic strain rate (SR) has been shown to correlate with the transmural extent of myocardial infarction (MI). Ischemic postconditioning (PC) decreases MI size. We aimed to determine whether SR may predict the reduction of left ventricular (LV) remodeling induced by PC in a murine model of ischemia-reperfusion.

Methods and Results—

C57BL6 mice underwent 60 minutes of left coronary artery occlusion followed by reperfusion. PC consisted of 3 cycles of 1 minute of reperfusion and 1 minute of ischemia performed immediately after reperfusion. After 24 hours of reperfusion, a first subset of mice was euthanized for determination of infarct size. An additional subset of mice underwent 3 months of reperfusion. Echocardiography and SR were serially assessed at baseline, 3 days, and 1, 2, 3 months after reperfusion. PC decreased the infarct size and increased SR values within infarcted segments as soon as 24 hours after reperfusion as compared with controls (14±1 versus 6±1 s
−1
,
P
<0.001). Systolic SR was correlated with MI size assessed by the area of infarction/area at risk (
r
=−0.88,
P
<0.001). At 3 months, PC improved LV ejection fraction (55±4 versus 45±3%;
P
<0.05) and decreased LV dimensions as compared with controls. Strain rate at day 3 correlated with LV ejection fraction (0.75;
P
<0.001), end-systolic (
r
=−0.75;
P
=0.001), and end-diastolic volumes (
r
=−0.70;
P
<0.001) at month 3.

Conclusions—
In this murine model of MI, SR accurately assessed the reduction in MI size induced by PC early after reperfusion and the subsequent reduction of LV remodeling.
Fasting-Induced Myocardial Lipid Accumulation in Long-Chain Acyl-CoA Dehydrogenase Knockout Mice Is Accompanied by Impaired Left Ventricular Function
Authors: Bakermans Adrianus J. , Geraedts Tom R. , van Weeghel Michel , Denis Simone , João Ferraz Maria , Aerts Johannes M.F.G. , Aten Jan , Nicolay Klaas , Houten Sander M. , Prompers Jeanine J. 
Published: July 2011

Background—
Lipotoxicity may be a key contributor to the pathogenesis of cardiac abnormalities in mitochondrial long-chain fatty acid β-oxidation (FAO) disorders. Few data are available on myocardial lipid levels and cardiac performance in FAO deficiencies. The purpose of this animal study is to assess fasting-induced changes in cardiac morphology, function, and triglyceride (TG) storage as a consequence of FAO deficiency in a noninvasive fashion.

Methods and Results—

MRI and proton magnetic resonance spectroscopy (
1
H-MRS) were applied in vivo in long-chain acyl-CoA dehydrogenase (LCAD) knockout (KO) mice and wild-type (WT) mice (n=8 per genotype). Fasting was used to increase the heart's dependency on FAO for maintenance of energy homeostasis. In vivo data were complemented with ex vivo measurements of myocardial lipids. Left ventricular (LV) mass was higher in LCAD KO mice compared with WT mice (
P
<0.05), indicating LV myocardial hypertrophy. Myocardial TG content was higher in LCAD KO mice at baseline (
P
<0.001) and further increased in fasted LCAD KO mice (
P
<0.05). Concomitantly, LV ejection fraction (
P
<0.01) and diastolic filling rate (
P
<0.01) decreased after fasting, whereas these functional parameters did not change in fasted WT mice. Myocardial ceramide content was higher in fasted LCAD KO mice compared with fasted WT mice (
P
<0.05).

Conclusions—
Using a noninvasive approach, this study reveals accumulation of myocardial TG in LCAD KO mice. Toxicity of accumulating lipid metabolites such as ceramides may be responsible for the fasting-induced impairment of cardiac function observed in the LCAD KO mouse.
Evaluation of the Left Atrial Appendage With Real-Time 3-Dimensional Transesophageal Echocardiography
Authors: Nucifora Gaetano , Faletra Francesco F. , Regoli François , Pasotti Elena , Pedrazzini Giovanni , Moccetti Tiziano , Auricchio Angelo 
Published: July 2011

Background—
Precise knowledge of left atrial appendage (LAA) orifice size is crucial for correct sizing of LAA closure devices. The aim of the present study was to determine the performance of real-time 3D transesophageal echocardiography (RT3DTEE) for LAA orifice size assessment, compared with 2D transesophageal echocardiography (2DTEE), and to investigate the impact of atrial fibrillation (AF) on LAA orifice size.

Methods and Results—

One hundred thirty-seven patients (38 control subjects, 31 with paroxysmal AF, 38 with persistent AF and 30 with permanent AF) underwent 2DTEE and RT3DTEE. Both techniques were used to measure LAA orifice area. Clinically-indicated 64-slice computed tomography (CT) was used as reference technique in 46 patients. Two-dimensional TEE underestimated LAA orifice area, compared with RT3DTEE (1.99±0.94 cm
2
versus 3.05±1.27 cm
2
;
P
<0.001). RT3DTEE showed higher correlation with CT for the assessment of LAA orifice area, compared with 2DTEE (
r
=0.92; 95% confidence interval, 0.85 to 0.95, versus
r
=0.72; 95% confidence interval, 0.54 to 0.83, respectively). At Bland–Altman analysis, RT3DTEE and 2DTEE underestimated LAA orifice area, compared with CT. However, RT3DTEE showed smaller bias (0.07 cm
2
versus 0.72 cm
2
) and narrower limits of agreement (−0.71 to 0.85 cm
2
versus −0.58 to 2.02 cm
2
) with CT, compared with 2DTEE. Among AF patients, a progressive increase in RT3DTEE-derived LAA orifice area was observed with increasing frequency of AF (
P
<0.001). At multivariate analysis, AF and left atrial volume index (
P
<0.001 for both) were independently associated with RT3DTEE-derived LAA orifice area.

Conclusions—
RT3DTEE is more accurate than 2DTEE for the assessment of LAA orifice size. A progressive increase in LAA orifice area is observed with increasing frequency of AF.
Atherosclerotic Plaque Vulnerability as an Explanation for the Increased Risk of Stroke in Elderly Undergoing Carotid Artery Stenting
Authors: van Lammeren Guus W. , Reichmann Boudewijn L. , Moll Frans L. , Bots Michiel L. , de Kleijn Dominique P.V. , de Vries Jean-Paul P.M. , Pasterkamp Gerard , de Borst Gert Jan 
Published: July 2011

Background and Purpose—
Recent randomized trials showed an increased periprocedural risk for stroke with increasing age in patients undergoing carotid artery stenting. Manipulation of atherosclerotic plaques during carotid artery stenting can result in plaque rupture with subsequent superimposed thrombus formation, embolization, and cerebrovascular events. We hypothesized that atherosclerotic plaques become more unstable with increasing age and thereby might provide insight into the age-related increased risk of cerebrovascular events during carotid artery stenting.

Methods—
Carotid atherosclerotic plaques were harvested from 1385 consecutive patients undergoing carotid endarterectomy between 2002 and 2010. Carotid plaques were quantitatively analyzed for macrophages, smooth muscle cells, and microvessels; and semiquantitatively analyzed for collagen, calcifications lipid cores, and intraplaque hemorrhages. Patients were divided in 4 groups by age: <60, 60 to 69, 70 to 79, and ≥80 years. Measures of association between age as a continuous variable and histological characteristics were also calculated.

Results—
Increasing age was associated with a decrease in the amount of smooth muscle cells in the carotid plaque. More plaques with large atheroma and heavy plaque calcifications were observed among elderly patients. After correction for baseline differences, risk factors, and medication use, age was independently associated with a more vulnerable carotid plaque composition.

Conclusion—
Plaque stability decreases gradually with age. Older patients with carotid stenosis have relatively unstable plaques with low smooth muscle cell content, a high amount of large lipid cores, and more calcified plaques as compared with younger patients. The underlying vulnerable plaque composition in the elderly might be an important contributing factor to the increased risk of stroke for older patients undergoing carotid artery stenting.
Statins Promote the Growth of Experimentally Induced Cerebral Aneurysms in Estrogen-Deficient Rats
Authors: Tada Yoshiteru , Kitazato Keiko T. , Yagi Kenji , Shimada Kenji , Matsushita Nobuhisa , Kinouchi Tomoya , Kanematsu Yasuhisa , Satomi Junichiro , Kageji Teruyoshi , Nagahiro Shinji 
Published: July 2011

Background and Purpose—
The pathogenesis of cerebral aneurysms is linked to inflammation, degradation of the extracellular matrix, and vascular wall apoptosis. Statins exert pleiotropic effects on the vasculature, independent of their cholesterol-lowering properties. To explore the detailed pathogenesis of cerebral aneurysms, we examined their progression in a rat model and studied whether statins prevent their initiation and growth.

Methods—
Cerebral aneurysms were induced in female rats subjected to hypertension, increased hemodynamic stress, and estrogen deficiency. The development of aneurysm was assessed morphologically on corrosion casts. The effects of pravastatin (5, 25, or 50 mg/kg per day) and of simvastatin (5 mg/kg per day) on their aneurysms were studied. Human brain endothelial cells were also used to determine the effects of pravastatin.

Results—
Pravastatin (5 mg/kg per day) reduced endothelial damage and inhibited aneurysm formation; there was an association with increased endothelial nitric oxide synthase (eNOS) levels and a decrease in human brain endothelial cell adhesion molecules. Unexpectedly, 25 mg/kg per day and 50 mg/kg per day pravastatin and 5 mg/kg per day simvastatin promoted aneurysmal growth, and high-dose pravastatin induced aneurysmal rupture. The deleterious effects exerted by these statins were associated with an increase in apoptotic caspase-3 levels and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, suggesting that statins exert bidirectional effects.

Conclusions—
Our results provide the first evidence that cerebral aneurysm growth is partly associated with apoptosis and issue a warning that statins exert bidirectional effects on cerebral aneurysms. Additional intensive research is necessary to understand better their mechanisms and to identify patients in whom the administration of statins may elicit deleterious effects.