bluuebunny/crossref_metadata_2025_split huggingface dataset:
microRNA Expression Profiles Identify Subtypes of Mantle Cell Lymphoma with Different Clinicobiological Characteristics
Authors: Navarro Alba , Clot Guillem , Prieto Miriam , Royo Cristina , Vegliante Maria Carmela , Amador Virginia , Hartmann Elena , Salaverria Itziar , Beà Sílvia , Martín-Subero Jose Ignacio , Rosenwald Andreas , Ott German , Wiestner Adrian , Wilson Wyndham H. , Campo Elías , Hernández Luis 
Published: May 2013

Abstract
Purpose: microRNAs (miRNA) are posttranscriptional gene regulators that may be useful as diagnostic and/or prognostic biomarkers. We aim to study the expression profiles of a high number of miRNAs and their relationship with clinicopathologic and biologic relevant features in leukemic mantle cell lymphomas (MCL).
Experimental Design: Expression profiling of 664 miRNAs was investigated using a high-throughput quantitative real-time PCR platform in 30 leukemic MCLs. Statistical and bioinformatic analyses were conducted to define miRNAs associated with different clinicopathologic parameters. Gene expression profiling was investigated by microarrays in 16 matching cases to study the potential genes and pathways targeted by selected miRNAs. The prognostic value of miR-34a was investigated in 2 independent series of 29 leukemic and 50 nodal MCLs.
Results: Robust consensus clustering defined 2 main MCL subgroups with significant differences in the immunoglobulin (IGHV) mutational status, SOX11 expression, genomic complexity, and nodal clinical presentation. Supervised analyses of IGHV and SOX11 categories identified 17 and 22 miRNAs differentially expressed, respectively. Enriched targets of these miRNAs corresponded to relevant pathways in MCL pathogenesis such as DNA stress response, CD40 signaling, and chromatin modification. In addition, we found 7 miRNAs showing prognostic significance independently of IGHV status and SOX11 expression. Among them, miR-34a was also associated with poor prognosis in 2 independent series of leukemic and nodal MCL, and in cooperation with high expression of the MYC oncogene.
Conclusion: We have identified miRNAs and target pathways related to clinical and biologic variants of leukemic MCL, and validated miR-34a as a prognostic marker in MCL. Clin Cancer Res; 19(12); 3121–9. ©2013 AACR.
CYP3A4*22 Genotype and Systemic Exposure Affect Paclitaxel-Induced Neurotoxicity
Authors: de Graan Anne-Joy M. , Elens Laure , Sprowl Jason A. , Sparreboom Alex , Friberg Lena E. , van der Holt Bronno , de Raaf Pleun J. , de Bruijn Peter , Engels Frederike K. , Eskens Ferry A.L.M. , Wiemer Erik A.C. , Verweij Jaap , Mathijssen Ron H.J. , van Schaik Ron H.N. 
Published: May 2013

Abstract
Purpose: Paclitaxel is used for the treatment of several solid tumors and displays a high interindividual variation in exposure and toxicity. Neurotoxicity is one of the most prominent side effects of paclitaxel. This study explores potential predictive pharmacokinetic and pharmacogenetic determinants for the onset and severity of neurotoxicity.
Experimental Design: In an exploratory cohort of patients (n = 261) treated with paclitaxel, neurotoxicity incidence, and severity, pharmacokinetic parameters and pharmacogenetic variants were determined. Paclitaxel plasma concentrations were measured by high-performance liquid chromatography or liquid chromatography/tandem mass spectrometry, and individual pharmacokinetic parameters were estimated from previously developed population pharmacokinetic models by nonlinear mixed effects modeling. Genetic variants of paclitaxel pharmacokinetics tested were CYP3A4*22, CYP2C8*3, CYP2C8*4, and ABCB1 3435 C&gt;T. The association between CYP3A4*22 and neurotoxicity observed in the exploratory cohort was validated in an independent patient cohort (n = 239).
Results: Exposure to paclitaxel (logAUC) was correlated with severity of neurotoxicity (P &lt; 0.00001). Female CYP3A4*22 carriers were at increased risk of developing neurotoxicity (P = 0.043) in the exploratory cohort. CYP3A4*22 carrier status itself was not associated with pharmacokinetic parameters (CL, AUC, Cmax, or T&gt;0.05) of paclitaxel in males or females. Other genetic variants displayed no association with neurotoxicity. In the subsequent independent validation cohort, CYP3A4*22 carriers were at risk of developing grade 3 neurotoxicity (OR = 19.1; P = 0.001).
Conclusions: Paclitaxel exposure showed a relationship with the severity of paclitaxel-induced neurotoxicity. In this study, female CYP3A4*22 carriers had increased risk of developing severe neurotoxicity during paclitaxel therapy. These observations may guide future individualization of paclitaxel treatment. Clin Cancer Res; 19(12); 3316–24. ©2013 AACR.
Grape Seed Extract Efficacy against Azoxymethane-Induced Colon Tumorigenesis in A/J Mice: Interlinking miRNA with Cytokine Signaling and Inflammation
Authors: Derry Molly M. , Raina Komal , Balaiya Velmurugan , Jain Anil K. , Shrotriya Sangeeta , Huber Kendra M. , Serkova Natalie J. , Agarwal Rajesh , Agarwal Chapla 
Published: May 2013

AbstractColorectal cancer (CRC) is the second leading cause of cancer-associated deaths, suggesting that additional strategies are needed to prevent/control this malignancy. As CRC growth and progression involve a large window (10–15 years), chemopreventive intervention could be a practical/translational strategy. Azoxymethane (AOM)-induced colon tumorigenesis in mice resembles human CRC in terms of progression of ACF to polyps, adenoma, and carcinomas and associated molecular mechanisms. Accordingly, herein we investigated grape seed extract (GSE) efficacy against AOM-induced colon tumorigenesis in A/J mice. GSE was fed in diet at 0.25% or 0.5% (w/w) dose starting 2 weeks after last AOM injection for 18 or 28 weeks. Our results showed that GSE feeding significantly decreases colon tumor multiplicity and overall tumor size. In biomarker analysis, GSE showed significant antiproliferative and pro-apoptotic activities. Detailed mechanistic studies highlighted that GSE strongly modulates cytokines/interleukins and miRNA expression profiles as well as miRNA processing machinery associated with alterations in NF-κB, β-catenin, and mitogen-activated protein kinase (MAPK) signaling. Additional studies using immunohistochemical analyses found that indeed GSE inhibits NF-κB activation and decreases the expression of its downstream targets (COX-2, iNOS, VEGF) related to inflammatory signaling, downregulates β-catenin signaling and decreases its target gene c-myc, and reduces phosphorylated extracellular signal—regulated kinase (ERK)1/2 levels. Together, these finding suggested that inflammation, proliferation, and apoptosis are targeted by GSE to prevent CRC. In summary, this study for the first time shows alterations in the expression of miRNAs and cytokines by GSE in its efficacy against AOM-induced colon tumorigenesis in A/J mouse sporadic CRC model, supporting its translational potential in CRC chemoprevention. Cancer Prev Res; 6(7); 625–33. ©2013 AACR.
p21 Activated Kinase Signaling Coordinates Glycoprotein Receptor VI–Mediated Platelet Aggregation, Lamellipodia Formation, and Aggregate Stability Under Shear
Authors: Aslan Joseph E. , Itakura Asako , Haley Kristina M. , Tormoen Garth W. , Loren Cassandra P. , Baker Sandra M. , Pang Jiaqing , Chernoff Jonathan , McCarty Owen J.T. 
Published: May 2013

Objective—
Rho GTPase proteins play a central role in regulating the dynamics of the platelet actin cytoskeleton. Yet, little is known regarding how Rho GTPase activation coordinates platelet activation and function. In this study, we aimed to characterize the role of the Rho GTPase effector, p21 activated kinase (PAK), in platelet activation, lamellipodia formation, and aggregate formation under shear.

Approach and Results—
Stimulation of platelets with the glycoprotein receptor VI agonist, collagen-related peptide, rapidly activated PAK in a time course preceding phosphorylation of PAK substrates, LIM domain kinase LIMK1 and the MAPK/ERK kinase MEK, and the subsequent activation of MAPKs and Akt. Pharmacological inhibitors of PAK blocked signaling events downstream of PAK and prevented platelet secretion as well as platelet aggregation in response to collagen-related peptide. PAK inhibitors also prevented PAK activation and platelet spreading on collagen surfaces. PAK was also required for the formation of platelet aggregates and to maintain aggregate stability under physiological shear flow conditions.

Conclusions—
These results suggest that PAK serves as an orchestrator of platelet functional responses after activation downstream of the platelet collagen receptor, glycoprotein receptor VI.
4-Hydroxy-2-Nonenal Enhances Tissue Factor Activity in Human Monocytic Cells via p38 Mitogen-Activated Protein Kinase Activation-Dependent Phosphatidylserine Exposure
Authors: Vatsyayan Rit , Kothari Hema , Pendurthi Usha R. , Rao L. Vijaya Mohan 
Published: May 2013

Objective—
4-hydroxy-2-nonenal (HNE) is one of the major aldehydes formed during lipid peroxidation and is believed to play a role in the pathogenesis of atherosclerosis. The objective of the present study is to investigate the effect of HNE on tissue factor (TF) procoagulant activity expressed on cell surfaces.

Approach and Results—
TF activity and antigen levels on intact cells were measured using factor Xa generation and TF monoclonal antibody binding assays, respectively. Exposure of phosphatidylserine on the cell surface was analyzed using thrombin generation assay or by binding of a fluorescent dye–conjugated annexin V. 2′,7′-dichlorodihydrofluorescein diacetate was used to detect the generation of reactive oxygen species. Our data showed that HNE increased the procoagulant activity of unperturbed THP-1 cells that express traces of TF antigen, but had no effect on unperturbed endothelial cells that express no measurable TF antigen. HNE increased TF procoagulant activity but not TF antigen of both activated monocytic and endothelial cells. HNE treatment generated reactive oxygen species, activated p38 mitogen-activated protein kinase, and increased the exposure of phosphatidylserine at the outer leaflet in THP-1 cells. Treatment of THP-1 cells with an antioxidant, N-acetyl cysteine, suppressed the above HNE-induced responses and negated the HNE-mediated increase in TF activity. Blockade of p38 mitogen-activated protein kinase activation inhibited HNE-induced phosphatidylserine exposure and increased TF activity.

Conclusions—
HNE increases TF coagulant activity in monocytic cells through a novel mechanism involving p38 mitogen-activated protein kinase activation that leads to enhanced phosphatidylserine exposure at the cell surface.
KRP-203, Sphingosine 1-Phosphate Receptor Type 1 Agonist, Ameliorates Atherosclerosis in LDL-R
−/−
Mice
Authors: Potì Francesco , Gualtieri Fabio , Sacchi Sandro , Weißen-Plenz Gabriele , Varga Georg , Brodde Martin , Weber Christian , Simoni Manuela , Nofer Jerzy-Roch 
Published: May 2013

Objective—
Sphingosine 1-phosphate (S1P) partly accounts for antiatherogenic properties of high-density lipoproteins. We previously demonstrated that FTY720, a synthetic S1P analog targeting all S1P receptors but S1P receptor type 2, inhibits murine atherosclerosis. Here, we addressed the identity of S1P receptor mediating atheroprotective effects of S1P.

Approach and Results—

Low-density lipoprotein receptor–deficient mice on cholesterol-rich diet were given selective S1P receptor type 1 agonist KRP-203 (3.0 mg/kg per day; 6 and 16 weeks). KRP-203 substantially reduced atherosclerotic lesion formation without affecting plasma lipid concentrations. However, KRP-203 induced lymphopenia, reduced total (CD4
+
, CD8
+
) and activated (CD69
+
/CD8
+
, CD69
+
/CD4
+
) T cells in peripheral lymphoid organs, and interfered with lymphocyte function, as evidenced by decreased T-cell proliferation and interleukin-2 and interferon-γ production in activated splenocytes. Cyto- and chemokine (tumor necrosis factor-α, regulated and normal T cell expressed and secreted) levels in plasma and aortas were reduced by KRP-203 administration. Moreover, macrophages from KRP-203–treated mice showed reduced expression of activation marker MCH-II and poly(I:C)-elicited production of tumor necrosis factor-α, monocyte chemoattractant protein-1, and interleukin-6. In vitro studies demonstrated that KRP-203 reduced tumor necrosis factor-α, interleukin-6, and interferon-γ–induced protein-10 production; IκB and signal transducer and activator of transcription-1 phosphorylation; and nuclear factor κB and signal transducer and activator of transcription-1 activation in poly(I:C)-, lipopolysaccharide-, or interferon-γ–stimulated bone marrow macrophages, respectively.

Conclusions—
Present results demonstrate that activation of S1P signaling pathways inhibit atherosclerosis by modulating lymphocyte and macrophage function and suggest that S1P receptor type 1 at least partially mediates antiatherogenic effects of S1P.
Post-transcriptional Regulation of α-1-Antichymotrypsin by MicroRNA-137 in Chronic Heart Failure and Mechanical Support
Authors: Lok Sjoukje I. , van Mil Alain , Bovenschen Niels , van der Weide Petra , van Kuik Joyce , van Wichen Dick , Peeters Ton , Siera Erica , Winkens Bjorn , Sluijter Joost P.G. , Doevendans Pieter A. , da Costa Martins Paula A. , de Jonge Nicolaas , de Weger Roel A. 
Published: May 2013

Background—
Better understanding of the molecular mechanisms of remodeling has become a major objective of heart failure (HF) research to stop or reverse its progression. Left ventricular assist devices (LVADs) are being used in patients with HF, leading to partial reverse remodeling. In the present study, proteomics identified significant changes in α-1-antichymotrypsin (ACT) levels during LVAD support. Moreover, the potential role of ACT in reverse remodeling was studied in detail.

Methods and Results—

Expression of ACT mRNA (quantitative-polymerase chain reaction) decreased significantly in post-LVAD myocardial tissue compared with pre-LVAD tissue (n=15;
P
<0.01). Immunohistochemistry revealed that ACT expression and localization changed during LVAD support. Circulating ACT levels were elevated in HF patients (n=18) as compared with healthy controls (n=6;
P
=0.001) and normalized by 6 months of LVAD support. Because increasing evidence implicates that microRNAs (miRs) are involved in myocardial disease processes, we also investigated whether ACT is post-transcriptionally regulated by miRs. Bioinformatics analysis pointed miR-137 as a potential regulator of ACT. The miR-137 expression is inversely correlated with ACT mRNA in myocardial tissue. Luciferase activity assays confirmed ACT as a direct target for miR-137, and in situ hybridization indicated that ACT and miR-137 were mainly localized in cardiomyocytes and stromal cells.

Conclusions—
High ACT plasma levels in HF normalized during LVAD support, which coincides with decreased ACT mRNA in heart tissue, whereas miR-137 levels increased. MiR-137 directly targeted ACT, thereby indicating that ACT and miR-137 play a role in the pathophysiology of HF and reverse remodeling during mechanical support.
Efficacy and Safety of Apixaban Compared With Warfarin at Different Levels of Predicted International Normalized Ratio Control for Stroke Prevention in Atrial Fibrillation
Authors: Wallentin Lars , Lopes Renato D. , Hanna Michael , Thomas Laine , Hellkamp Anne , Nepal Sunil , Hylek Elaine M. , Al-Khatib Sana M. , Alexander John H. , Alings Marco , Amerena John , Ansell Jack , Aylward Philip , Bartunek Jozef , Commerford Patrick , De Caterina Raffaele , Erol Cetin , Harjola Veli-Pekka , Held Claes , Horowitz John D. , Huber Kurt , Husted Steen , Keltai Matyas , Lanas Fernando , Lisheng Liu , McMurray John J.V. , Oh Byung-Hee , Rosenqvist Mårten , Ruzyllo Witold , Steg Philippe Gabriel , Vinereanu Dragos , Xavier Denis , Granger Christopher B. 
Published: May 2013

Background—
In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin reduced stroke and systemic embolism, major bleeding, and mortality. We evaluated treatment effects in relation to 2 predictions of time in therapeutic range (TTR).

Methods and Results—

The trial randomized 18 201 patients with atrial fibrillation to apixaban 5 mg twice daily or warfarin for at least 12 months. For each patient, a center average TTR was estimated with the use of a linear mixed model on the basis of the real TTRs in its warfarin-treated patients, with a fixed effect for country and random effect for center. For each patient, an individual TTR was also predicted with the use of a linear mixed effects model including patient characteristics as well. Median center average TTR was 66% (interquartile limits, 61% and 71%). Rates of stroke or systemic embolism, major bleeding, and mortality were consistently lower with apixaban than with warfarin across center average TTR and individual TTR quartiles. In the lowest and highest center average TTR quartiles, hazard ratios for stroke or systemic embolism were 0.73 (95% confidence interval [CI], 0.53–1.00) and 0.88 (95% CI, 0.57–1.35) (
P
interaction
=0.078), for mortality were 0.91 (95% CI, 0.74–1.13) and 0.91 (95% CI, 0.71–1.16) (
P
interaction
=0.34), and for major bleeding were 0.50 (95% CI, 0.36–0.70) and 0.75 (95% CI, 0.58–0.97) (
P
interaction
=0.095), respectively. Similar results were seen for quartiles of individual TTR.

Conclusions—
The benefits of apixaban compared with warfarin for stroke or systemic embolism, bleeding, and mortality appear similar across the range of centers’ and patients’ predicted quality of international normalized ratio control.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00412984.
Disparities in Evaluation at Certified Primary Stroke Centers
Authors: Mullen Michael T. , Judd Suzanne , Howard Virginia J. , Kasner Scott E. , Branas Charles C. , Albright Karen C. , Rhodes J. David , Kleindorfer Dawn O. , Carr Brendan G. 
Published: May 2013

Background and Purpose—
Evaluation at primary stroke centers (PSCs) has the potential to improve outcomes for patients with stroke. We looked for differences in evaluation at Joint Commission certified PSCs by race, education, income, and geography (urban versus nonurban; Southeastern Stroke Belt versus non-Stroke Belt).

Methods—
Community-dwelling, black and white participants from the national Reasons for Geographic And Racial Differences in Stroke (REGARDS) prospective population–based cohort were enrolled between January 2003 and October 2007. Participants were contacted at 6-month intervals for suspected stroke events. For suspected stroke events, it was determined whether the evaluating hospital was a certified PSC.

Results—

Of 1000 suspected strokes, 204 (20.4%) strokes were evaluated at a PSC. A smaller proportion of women than men (17.8% versus 23.0%;
P
=0.04), those with a previous stroke (15.1% versus 21.6%;
P
=0.04), those living in the Stroke Belt (14.7% versus 27.3%;
P
<0.001), and those in a nonurban area (9.1% versus 23.1%;
P
<0.001) were evaluated at a PSC. There were no differences by race, education, or income. In multivariable analysis, subjects were less likely to be evaluated at a PSC if they lived in a nonurban area (odds ratio, 0.39; 95% confidence interval, 0.22–0.67) or lived in the Stroke Belt (odds ratio, 0.54; 95% confidence interval, 0.38–0.77) or had a previous stroke (odds ratio, 0.46; 95% confidence interval, 0.27–0.78).

Conclusions—
Disparities in evaluation by PSCs are predominately related to geographic factors but not to race, education, or low income. Despite an increased burden of cerebrovascular disease in the Stroke Belt, subjects there were less likely to be evaluated at certified hospitals.
Incidence and Predictors of Late Seizures in Intracerebral Hemorrhages
Authors: Rossi Costanza , De Herdt Veerle , Dequatre-Ponchelle Nelly , Hénon Hilde , Leys Didier , Cordonnier Charlotte 
Published: May 2013

Background and Purpose—
To identify incidence and predictors of late seizures (LS, occurring >1 week of stroke) in a cohort of patients with intracerebral hemorrhage (ICH).

Methods—
Prospective cohort of consecutive adults with spontaneous ICH. Incidence and predictors were identified with Cox regression. We included multivariate analyses on MRI biomarkers (global cortical atrophy, leukoaraiosis, brain microbleeds).

Results—

Our study population consisted of 325 patients: 54% men, median age 70 years (interquartile range, 58–79). During 778 person-years of follow-up, the incidence rate was 4 new cases/100 person-years (95% confidence interval, 3–6). The median delay between ICH and LS was 9 months (interquartile range, 3–23). The only factor independently associated with the occurrence of LS was a cortical involvement of the ICH (hazard ratio, 2.8; 95% confidence interval, 1.3–6.1). Concerning MRI biomarkers, multivariate analyses found lobar brain microbleeds to be associated with LS (hazard ratio, 2.4; 95% confidence interval, 1.1–5.4), especially if ≥3 (hazard ratio, 2.7; 95% confidence interval, 1.1–6.8). LS were associated with a worse functional outcome after 3 years of follow-up (
P
=0.009).

Conclusions—
LS frequently occur >9 months after ICH onset, imposing a long-term follow-up. The association of lobar brain microbleeds with the risk of LS might suggest a link with the underlying vasculopathy (cerebral amyloid angiopathy).
Influence of the Great East Japan Earthquake and Tsunami 2011 on Occurrence of Cerebrovascular Diseases in Iwate, Japan
Authors: Omama Shinichi , Yoshida Yuki , Ogasawara Kuniaki , Ogawa Akira , Ishibashi Yasuhiro , Nakamura Motoyuki , Tanno Kozo , Ohsawa Masaki , Onoda Toshiyuki , Itai Kazuyoshi , Sakata Kiyomi 
Published: May 2013

Background and Purpose—
Little information is available regarding the occurrence of cerebrovascular diseases after tsunamis. This study was performed to determine the influence of the tsunami damage caused by the Great East Japan earthquake on occurrence of cerebrovascular diseases.

Methods—
Subjects from the coastline and inland areas of Iwate Prefecture who developed cerebrovascular diseases before and after the disaster were included in the analysis. Standardized incidence ratios of 2011 against the previous 3 years were calculated in two 4-week periods before and four 4-week periods after the disaster, according to stroke subtype, sex, age group, and flood damage.

Results—
The standard incidence ratio for cerebrovascular diseases was 1.20 (1.00–1.40) in the first 4-week period after the disaster and was not significant in other periods. The standard incidence ratios in the first 4-week period for cerebral infarction, intracerebral hemorrhage, and subarachnoid hemorrhage were 1.22 (0.98–1.46), 1.15 (0.76–1.55), and 1.20 (0.52–1.88), respectively. These values were 1.51 (1.19–1.88) for men, 1.35 (1.06–1.64) for subjects aged ≥75 years, and 1.35 (1.06–1.64) for the high flooding areas. The standard incidence ratio of cerebral infarction in the first 4-week period for men aged ≥75 years in the high flooding areas was 2.34 (1.34–3.34).

Conclusions—
In the areas highly flooded by the tsunami caused by the Great East Japan earthquake, the occurrence of cerebral infarction among elderly men more than doubled in the first 4 weeks after the disaster.