bluuebunny/crossref_metadata_2025 huggingface dataset:
Citrus junosTanaka Peel Extract Exerts Antidiabetic Effects via AMPK and PPAR-γbothIn VitroandIn Vivoin Mice Fed a High-Fat Diet
Authors: Kim Sung Hee , Hur Haeng Jeon , Yang Hye Jeong , Kim Hyun Jin , Kim Min Jung , Park Jae Ho , Sung Mi Jeong , Kim Myung Sunny , Kwon Dae Young , Hwang Jin-Taek
Published: May 2013

The antidiabetic effect of theCitrus junosTanaka (also known as yuja or yuzu) was examined. Ethanol extract of yuja peel (YPEE) significantly stimulated 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose (2-NBDG) uptake in C2C12 myotubes. However, ethanol extract of yuja pulp (YpEE) and water extract of yuja peel (YPWE) or pulp (YpWE) did not stimulate glucose uptake. In addition, peroxisome proliferator-activated receptor gamma (PPAR-γ) and AMP-activated protein kinase (AMPK) activities were increased by YPEE in a dose-dependent manner. Pretreatment of AMPK inhibitor decreased the glucose uptake stimulated by YPEE in C2C12 myotubes. We confirmed the anti-diabetic effect of YPEE in mice fed a high fat-diet (HFD). Compared with control mice on a normal diet (ND), these mice showed increased body weight, liver fat, insulin resistance, triacylglycerol (TG), and total cholesterol content. Addition of 5% YPEE significantly reduced the weight gain and rise in liver fat content, serum triacylglycerol (TG), total cholesterol, and insulin resistance found in mice fed a high-fat diet (HFD). Moreover, YPEE reduced the secretion of HFD-induced adipocytokines such as leptin and resistin. YPEE also resulted in increased phosphorylation of AMPK in muscle tissues. These results suggest that ethanol extract of yuja peel exerts anti-diabetic effects via AMPK and PPAR-γin both cell culture and mouse models.
The MET Oncogene in Glioblastoma Stem Cells: Implications as a Diagnostic Marker and a Therapeutic Target
Authors: Boccaccio Carla , Comoglio Paolo M.
Published: May 2013

The MET oncogene, a crucial regulator of the genetic program known as “invasive growth” or “epithelial–mesenchymal transition,” has recently emerged as a functional marker of glioblastoma stem cells. Here, we review findings that associate MET expression and activity with a specific, genetically defined glioblastoma stem cell subtype, and data showing how MET sustains the stem cell phenotype in glioblastoma and other tumors. Finally, we discuss issues related to identification of tumorigenic clones driven by MET in the context of genetically heterogeneous tumors and strategies aimed at eradicating cancer stem cells. Cancer Res; 73(11); 3193–9. ©2013 AACR.
Autophagy Plays a Critical Role in the Degradation of Active RHOA, the Control of Cell Cytokinesis, and Genomic Stability
Authors: Belaid Amine , Cerezo Michaël , Chargui Abderrahman , Corcelle–Termeau Elisabeth , Pedeutour Florence , Giuliano Sandy , Ilie Marius , Rubera Isabelle , Tauc Michel , Barale Sophie , Bertolotto Corinne , Brest Patrick , Vouret-Craviari Valérie , Klionsky Daniel J. , Carle Georges F. , Hofman Paul , Mograbi Baharia
Published: May 2013

Degradation of signaling proteins is one of the most powerful tumor-suppressive mechanisms by which a cell can control its own growth. Here, we identify RHOA as the molecular target by which autophagy maintains genomic stability. Specifically, inhibition of autophagosome degradation by the loss of the v-ATPase a3 (TCIRG1) subunit is sufficient to induce aneuploidy. Underlying this phenotype, active RHOA is sequestered via p62 (SQSTM1) within autolysosomes and fails to localize to the plasma membrane or to the spindle midbody. Conversely, inhibition of autophagosome formation by ATG5 shRNA dramatically increases localization of active RHOA at the midbody, followed by diffusion to the flanking zones. As a result, all of the approaches we examined that compromise autophagy (irrespective of the defect: autophagosome formation, sequestration, or degradation) drive cytokinesis failure, multinucleation, and aneuploidy, processes that directly have an impact upon cancer progression. Consistently, we report a positive correlation between autophagy defects and the higher expression of RHOA in human lung carcinoma. We therefore propose that autophagy may act, in part, as a safeguard mechanism that degrades and thereby maintains the appropriate level of active RHOA at the midbody for faithful completion of cytokinesis and genome inheritance. Cancer Res; 73(14); 4311–22. ©2013 AACR.
c-Src Modulates Estrogen-Induced Stress and Apoptosis in Estrogen-Deprived Breast Cancer Cells
Authors: Fan Ping , Griffith Obi L. , Agboke Fadeke A. , Anur Pavana , Zou Xiaojun , McDaniel Russell E. , Creswell Karen , Kim Sung Hoon , Katzenellenbogen John A. , Gray Joe W. , Jordan V. Craig
Published: May 2013

The emergence of anti-estrogen resistance in breast cancer is an important clinical phenomenon affecting long-term survival in this disease. Identifying factors that convey cell survival in this setting may guide improvements in treatment. Estrogen (E2) can induce apoptosis in breast cancer cells that have been selected for survival after E2 deprivation for long periods (MCF-7:5C cells), but the mechanisms underlying E2-induced stress in this setting have not been elucidated. Here, we report that the c-Src kinase functions as a key adapter protein for the estrogen receptor (ER, ESR1) in its activation of stress responses induced by E2 in MCF-7:5C cells. E2 elevated phosphorylation of c-Src, which was blocked by 4-hydroxytamoxifen (4-OHT), suggesting that E2 activated c-Src through the ER. We found that E2 activated the sensors of the unfolded protein response (UPR), IRE1α (ERN1) and PERK kinase (EIF2AK3), the latter of which phosphorylates eukaryotic translation initiation factor-2α (eIF2α). E2 also dramatically increased reactive oxygen species production and upregulated expression of heme oxygenase HO-1 (HMOX1), an indicator of oxidative stress, along with the central energy sensor kinase AMPK (PRKAA2). Pharmacologic or RNA interference–mediated inhibition of c-Src abolished the phosphorylation of eIF2α and AMPK, blocked E2-induced ROS production, and inhibited E2-induced apoptosis. Together, our results establish that c-Src kinase mediates stresses generated by E2 in long-term E2-deprived cells that trigger apoptosis. This work offers a mechanistic rationale for a new approach in the treatment of endocrine-resistant breast cancer. Cancer Res; 73(14); 4510–20. ©2013 AACR.
Declining Rates of High-Grade Cervical Lesions in Young Women in Connecticut, 2008–2011
Authors: Niccolai Linda M. , Julian Pamela J. , Meek James I. , McBride Vanessa , Hadler James L. , Sosa Lynn E.
Published: May 2013

Vaccines that prevent infection with human papillomavirus (HPV) types 16 and 18 that are known to cause cervical cancer have been available in the United States since 2006. High-grade cervical lesions are important for monitoring early vaccine impact because they are strong surrogates for cancer yet can develop within years after infection as opposed to decades. Trends in high-grade cervical lesions including cervical intraepithelial neoplasia grades 2, 2/3, and 3 and adenocarcinoma in situ among women ages 21 to 39 years old were examined using a statewide surveillance registry in Connecticut from 2008 to 2011. During this time period, HPV vaccine initiation increased among adolescent females from 45% to 61%. Analyses were stratified by age, according to census tract measures of proportion of population Black, Hispanic, living in poverty, and by urban/nonurban counties. The annual rate per 100,000 females ages 21 to 24 years declined from 834 in 2008 to 688 in 2011 (Ptrend < 0.001). No significant declines were observed among women ages 25 to 39 years. Significant declining trends also occurred in census tracts with lower proportions of the population being Black, Hispanic, or living below the federal poverty level. Declines in high-grade cervical lesions have occurred among young women during 2008 to 2011. This is the first report of declines in cervical neoplasia in the United States since HPV vaccines became available. Continued surveillance is needed to measure vaccine impact and monitor health disparities. Cancer Epidemiol Biomarkers Prev; 22(8); 1446–50. ©2013 AACR.
An Assessment of the Shared Allelic Architecture between Type II Diabetes and Prostate Cancer
Authors: Yu Oriana Hoi Yun , Foulkes William D. , Dastani Zari , Martin Richard M. , Eeles Rosalind ,   for the PRACTICAL Consortium and the CRUK GWAS Investigators, Richards J. Brent
Published: May 2013

Background: To determine whether the alleles that influence type II diabetes risk and glycemic traits also influence prostate cancer risk.

Methods: We used a multiple single-nucleotide polymorphisms (SNP) genotypic risk score to assess the average effect of alleles that increase type II diabetes risk or worsen glycemic traits on risk of prostate cancer in 19,662 prostate cancer cases and 19,715 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium and 5,504 prostate cancer cases and 5,834 controls from the Cancer Research UK (CRUK) prostate cancer study.

Results: Calculating the average additive effect of type II diabetes or glycemic trait risk alleles on prostate cancer risk using a logistic model revealed no evidence of a shared allelic architecture between type II diabetes, or worsened glycemic status, with prostate cancer risk [OR for type II diabetes alleles: 1.00 (P = 0.58), fasting glycemia alleles: 1.00 (P = 0.67), HbA1c alleles: 1.00 (P = 0.93), 2-hour OGTT alleles: 1.01 (P = 0.14), and HOMA-B alleles: 0.99 (P = 0.57)].

Conclusions: Using genetic data from large consortia, we found no evidence for a shared genetic etiology of type II diabetes or glycemic risk with prostate cancer.

Impact: Our results showed that alleles influencing type II diabetes and related glycemic traits were not found to be associated with the risk of prostate cancer. Cancer Epidemiol Biomarkers Prev; 22(8); 1473–5. ©2013 AACR.
Effectiveness of Advanced versus Conventional Wound Dressings on Healing of Chronic Wounds: Systematic Review and Meta-Analysis
Authors: Heyer K. , Augustin M. , Protz K. , Herberger K. , Spehr C. , Rustenbach S.J.
Published: May 2013

Background: Wound dressings are essential in the treatment of chronic wounds and should be selected on valid and recent evidence. Objective: Effectiveness of advanced compared to conventional dressings for chronic wound healing. Methods: Comprehensive literature search, systematic review and meta-analyses of the results of advanced dressing studies on chronic wound treatment. Comprehensiveness and coverage of all relevant studies is the most striking difference in relation to other meta-analyses and systematic reviews. Results: The mean odds ratio of complete healing was 1.52 favouring advanced over conventional dressings in 65 controlled trials. In 287 study conditions including uncontrolled studies, mean odds were 0.97 (advanced dressings/controlled studies), 0.77 (conventional/controlled) and 0.47 (advanced/uncontrolled). The overall healing rate was 33%. When causal treatment was applied, a reduced effect was observed. The consideration of all types of chronic wounds, advanced wound dressings and studies resulted in more study effects, more reliable estimates of mean effects and more statistical power. These differences in the design are likely to explain the differences in the meta-analytic results. Conclusion: A general superiority of advanced dressings on complete healing was shown. The generalizability of the results is limited by the methodological and report quality within studies identified, unexplained heterogeneity in study effects and possibly by publication bias.
Decreased Expression of miR-133a but Not of miR-1 is Associated with Signs of Heart Failure in Patients Undergoing Coronary Bypass Surgery
Authors: Danowski Nina , Manthey Iris , Jakob Heinz Günther , Siffert Winfried , Peters Jürgen , Frey Ulrich H.
Published: May 2013

Objectives: Coronary artery disease (CAD)-associated ischemic heart failure is characterized by dysregulated gene expression which is partly mediated by microRNAs (miRNAs). While the muscle-specific miR-1 and miR-133 are involved in cardiac development and hypertrophy, their role in heart failure resulting from CAD is unknown. We, therefore, tested the hypothesis that cardiac miR-1 and miR-133 expression is associated with signs of heart failure in patients undergoing coronary artery bypass grafting. Methods: 83 patients were included in this prospective study. Cardiac index and vascular pressures were measured under general anesthesia and the miRNA expression was quantified (RNase protection assay and real-time PCR) from samples of the right atrial myocardium. Results: miR-133 expression decreased significantly with increased severity of heart failure, as indicated by a greater New York Heart Association (NYHA) functional class (p = 0.014) and increased pulmonary artery occlusion pressure (p = 0.045). Furthermore, patients with NT-proBNP concentrations >1,800 pg/ml showed a 25% decrease in miR-133 expression compared to patients with concentrations <300 pg/ml (p = 0.023). In contrast, no associations were detected for miR-1 expression. Conclusions: In surgical CAD patients, a decreased miR-133 expression is associated with variables characteristic of heart failure. This supports a role for miR-133 but not miR-1 in the adaption to and/or remodeling of the ischemic heart.
Effects of Interferon β-1a and Interferon β-1b Monotherapies on Selected Serum Cytokines and Nitrite Levels in Patients with Relapsing-Remitting Multiple Sclerosis: A 3-Year Longitudinal Study
Authors: Stępień Adam , Chalimoniuk Małgorzata , Lubina-Dąbrowska Natalia , Chrapusta Stanisław J. , Galbo Henrik , Langfort Józef
Published: May 2013

Objective: Interferon (IFN)β treatment is a mainstay of relapsing-remitting multiple sclerosis (RRMS) immunotherapy. Its efficacy is supposedly a consequence of impaired trafficking of inflammatory cells into the central nervous system and modification of the proinflammatory/antiinflammatory cytokine balance. However, the effects of long-term monotherapy using various IFNβ preparations on cytokine profiles and the relevance of these effects for the therapy outcome have not yet been elucidated. Methods: Changes were compared in serum levels of TNFα, IFNγ, interleukin (IL)-6, IL-10 and nitrite between RRMS patients given 3-year treatment with intramuscular IFNβ-1a (30 μg once a week) or subcutaneous IFNβ-1b (250 μg every other day). Only the data from patients who completed the 3-year study (n = 20 and n = 18, respectively) were analyzed. Results: Three-year IFNβ-1a or IFNβ-1b monotherapy reduced serum nitrite levels by 77 and 71%, respectively, lowered multiple sclerosis relapse annual rate by 70 and 71%, respectively, and significantly and similarly lowered Expanded Disability Status Scale scores in both study groups (by 0.9 on average). The two monotherapies showed little if any effect on cytokine levels and cytokine level ratios after the first year, but exerted diverging effects on these indices later on; the only exception was the IFNγ/IL-6 ratio that showed a monotonous rise in both study groups over the entire study period. Conclusion: During long-term IFNβ monotherapy, the levels of the studied cytokines show no relevance to the course of RRMS and neurological status of patients, whereas there seems to be a link between these clinical indices and the activity of nitric oxide-mediated pathways.
Normalisation of Angiogenic Imbalance after Intra-Uterine Transfusion for Mirror Syndrome Caused by Parvovirus B19
Authors: Goa Satoko , Mimura Kazuya , Kakigano Aiko , Tomimatsu Takuji , Kinugasa-Taniguchi Yukiko , Endo Masayuki , Kanagawa Takeshi , Kimura Tadashi
Published: May 2013

We report a case of mirror syndrome caused by parvovirus B19, which resolved after intra-uterine transfusion. Mirror syndrome is a rare condition characterised by a triad of foetal hydrops, generalized maternal oedema and placentomegaly. Although the mechanism underlying the onset of this syndrome is unknown, it probably shares a common pathophysiologic origin with pre-eclampsia. Our patient showed increased circulating levels of soluble fms-like tyrosine kinase 1 (sFlt-1) and decreased levels of placental growth factor (PlGF), which have also been reported in pre-eclampsia. The sFlt-1/PlGF ratio decreased immediately after intra-uterine transfusion, followed by resolution of both maternal and foetal symptoms. This suggests that the sFlt-1/PlGF ratio may help to predict the post-treatment course of mirror syndrome.
Left Ventricular Functional Changes after Adenosine Vasodilator Stress Evaluated by Gated Single-Photon Emission Computed Tomography
Authors: Zhang Ling , Tian Yue-Qin , Zhang Xiao-Li , Sun Xiao-Xin , Guo Feng , Wei Hong-Xing , Xu Yin-Ying , He Zuo-Xiang
Published: May 2013

Objectives: Gated single-photon emission computed tomography (SPECT) myocardial perfusion imaging is useful in assessing left ventricular (LV) myocardial perfusion and function. This study evaluated the LV functional changes after adenosine vasodilator stress, using gated SPECT. Methods: The study population consisted of 70 patients who underwent adenosine-mediated stress and rest SPECT. All patients underwent coronary angiography. Semi-quantitative assessment of perfusion was analyzed and produced the summed rest score (SRS), the summed stress score (SSS) and the summed difference score (SDS). The global LV function parameters [ejection fraction (EF), end-diastolic volume (EDV), end-systolic volume (ESV)] and regional LV function [the summed motion score (SMS) and the summed thickening score (STS)] were quantified by gated SPECT. Results: Patients were divided into 2 groups: group 1 comprised 16 patients with worsening of LVEF (LVEFrest-LVEFado ≥5%), and group 2 comprised the other 54 patients. Compared with group 2, patients in group 1 had a significantly higher SSS and SDS (9.1 ± 6.8 vs. 5.6 ± 4.5 and 6.6 ± 3.8 vs. 3.6 ± 4.0, respectively; p < 0.05) and the severity of coronary artery stenosis was more serious (p < 0.05). Conclusion: Worsening of LVEF after adenosine-induced vasodilator stress, as shown by 99mTc-MIBI gated SPECT, is a valuable nonperfusion marker of significant CAD.
Use of Allosteric Targets in the Discovery of Safer Drugs
Authors: Grover Ashok Kumar
Published: May 2013

The need for drugs with fewer side effects cannot be overemphasized. Today, most drugs modify the actions of enzymes, receptors, transporters and other molecules by directly binding to their active (orthosteric) sites. However, orthosteric site configuration is similar in several proteins performing related functions and this leads to a lower specificity of a drug for the desired protein. Consequently, such drugs may have adverse side effects. A new basis of drug discovery is emerging based on the binding of the drug molecules to sites away (allosteric) from the orthosteric sites. It is possible to find allosteric sites which are unique and hence more specific as targets for drug discovery. Of many available examples, two are highlighted here. The first is caloxins - a new class of highly specific inhibitors of plasma membrane Ca2+ pumps. The second concerns the modulation of receptors for the neurotransmitter acetylcholine, which binds to 12 types of receptors. Exploitation of allosteric sites has led to the discovery of drugs which can selectively modulate the activation of only 1 (M1 muscarinic) out of the 12 different types of acetylcholine receptors. These drugs are being tested for schizophrenia treatment. It is anticipated that the drug discovery exploiting allosteric sites will lead to more effective therapeutic agents with fewer side effects.
Sex Chromosome Pairing and Extensive NOR Polymorphism in Wadicosa fidelis (Araneae: Lycosidae)
Authors: Forman M. , Nguyen P. , Hula V. , Král J.
Published: May 2013

In terms of cytogenetics, entelegyne araneomorphs are the best studied clade of spiders. The typical karyotype of entelegyne males consists of acrocentric chromosomes, including 2 non-homologous X chromosomes. The present study is focused on the karyotype, nucleolus organising regions (NORs) and sex chromosome behaviour during meiosis of the entelegyne Wadicosa fidelis (Lycosidae). Preparations stained by Giemsa were used to study karyotype and meiosis. NORs were visualised by silver staining and fluorescence in situ hybridisation with 18S rDNA probe. The male karyotype consists of 28 acrocentric elements, including 2 X chromosomes. In contrast to the majority of other spiders, the male sex chromosomes pair during the major part of meiosis. Following an initial period of parallel pairing, the attachment of male sex chromosomes is restricted to centromeric areas and continues until metaphase II. Our study revealed an enormous number of NORs in the population from Galilee and indicates a considerable variability of NOR numbers in this population. The distal regions of 9 or 10 autosomal pairs contain NORs. The obtained data indicate the rapid spread of NORs in the karyotype of W. fidelis, which was presumably caused by ectopic recombinations and subsequent hybridisations of individuals with different NOR genotypes that produced heterozygotes.
Clinical Benefit for Patients with Non-Small Cell Lung Cancer Enrolled in Phase I Trials
Authors: Levy Antonin , Gomez-Roca Carlos , Massard Christophe , Planchard David , Albiges Laurence , Bahleda Ratislav , Bourgier Céline , Deutsch Eric , Soria Jean Charles , Besse Benjamin
Published: May 2013

Aim: To analyze the clinical features and outcomes of advanced non-small cell lung cancer (NSCLC) patients treated in phase I trials. Patients and Methods: The clinical characteristics, efficacy and toxicity data of 70 pretreated NSCLC patients enrolled in 17 phase I trials between January 2005 and June 2010 were analyzed at our institution. Results: The histological types were: adenocarcinoma (79%), squamous cell carcinoma (13%), and others. Patients received a median number of 3 prior lines of treatment before inclusion. 1 complete response (CR), 11 (16%) partial responses (PRs), and 29 (41%) stable diseases (SDs) were observed (according to Response Evaluation Criteria in Solid Tumors (RECIST)). The median overall survival (OS) time was 18 months and the median progression-free survival (PFS) time was 4.1 months. The median PFS of these patients within their prior therapy line before phase I inclusion was 4.3 months. A performance status score of 0 and the number of prior lines of treatment were significant for OS and PFS in multivariate analysis, respectively. Grade 3/4 toxicities were observed in 20 (27%) patients, and there was 1 treatment-related death. Conclusion: Patients in good general condition and with limited pretreatment derived an improved benefit, suggesting that phase I studies may be a valid option for pretreated NSCLC patients.
The Clinical Utility of Plasma Neutrophil Gelatinase-Associated Lipocalin in Acute Kidney Injury
Authors: Pickering John W. , Endre Zoltan H.
Published: May 2013

Background and Aim: Neutrophil gelatinase-associated lipocalin (NGAL) is derived from the distal tubule and is both reabsorbed and filtered and also shed into the urine after tubular injury. Plasma NGAL is unique amongst the candidate biomarkers of acute kidney injury (AKI) since elevated concentrations may reflect either a change in renal glomerular function or in structural tubular injury or both. In this study, we compared the performance of plasma NGAL in the diagnosis of functional changes and in the diagnosis of structural injury. Methods: Plasma and urine samples from 528 patients were collected on entry to an intensive care unit (ICU) as well as 12 and 24 h later. Plasma NGAL diagnostic performance was independently assessed for Functional-AKI and Structural-AKI. Functional-AKI was defined by changes in plasma creatinine, whereas Structural-AKI was defined by elevations in urinary NGAL. Results: On ICU entry, the area under the curve (AUC) for the diagnosis of Functional-AKI was 0.74 (95% CI: 0.69-0.79), and for Structural-AKI it was 0.79 (0.74-0.83). Plasma NGAL also predicted the need for dialysis (0.79; 0.66-0.81), but not for death. A principal component analysis demonstrated that the maximum plasma NGAL in 24 h reflected structural injury marginally more than functional changes. Plasma NGAL added value to an AKI diagnostic model comprising plasma creatinine, sepsis, age, and APACHE II score (integrated discrimination improvement: 0.073; 0.034-0.12). Conclusion: Increased plasma NGAL reflects both decreased filtration and structural injury. For patients at a low calculated risk, the addition of NGAL reduced the risk, and for those at a higher risk, NGAL correctly assigned patients to even a higher risk.
Telmisartan Exerts Pleiotropic Effects in Endothelial Cells and Promotes Endothelial Cell Quiescence and Survival
Authors: Siragusa Mauro , Sessa William C.
Published: May 2013

Objective—

Telmisartan, an angiotensin II type 1 receptor blocker, and amlodipine, a calcium channel blocker, are antihypertensive agents clinically used as monotherapy or in combination. They exert beneficial cardiovascular effects independently of blood pressure lowering and classic mechanisms of action. In this study, we investigate molecular mechanisms responsible for the off-target effects of telmisartan and telmisartan–amlodipine in endothelial cells (ECs), using an unbiased genomic approach.

Approach and Results—

In human umbilical vein ECs, microarray analysis of gene expression followed by pathway enrichment analysis and quantitative polymerase chain reaction validation revealed that telmisartan modulates the expression of key genes responsible for cell cycle progression and apoptosis. Amlodipine’s effect was similar to control. ECs exposed to telmisartan, but not amlodipine, losartan, or valsartan, exhibited a dose-dependent impairment of cell growth and failed to enter the S-phase of the cell cycle. Similarly, telmisartan inhibited proliferation in COS-7 cells lacking the angiotensin II type 1 receptor. In telmisartan-treated ECs, phosphorylation and activation of Akt, as well as MDM2, were reduced, leading to accumulation of p53 in the nucleus, where it represses the transcription of cell cycle–promoting genes. Phosphorylation of glycogen synthase kinase-3β was also reduced, resulting in rapid proteolytic turnover of CyclinD1. Telmisartan induced downregulation of proapoptotic genes and protected ECs from serum starvation–induced and 7-ketocholesterol–induced apoptosis.

Conclusions—

Telmisartan exerts antiproliferative and antiapoptotic effects in ECs. This may account for the improved endothelial dysfunction observed in the clinical setting.
Plasmin Promotes Foam Cell Formation by Increasing Macrophage Catabolism of Aggregated Low-Density Lipoprotein
Authors: Haka Abigail S. , Grosheva Inna , Singh Rajesh K. , Maxfield Frederick R.
Published: May 2013

Objective—

The plasmin/plasminogen system is involved in atherosclerosis. However, the mechanisms by which it stimulates disease are not fully defined. A key event in atherogenesis is the deposition of low-density lipoprotein (LDL) on arterial walls where it is modified, aggregated, and retained. Macrophages are recruited to clear the lipoproteins, and they become foam cells. The goal of this study was to assess the role of plasmin in macrophage uptake of aggregated LDL and foam cell formation.

Approach and Results—

Plasminogen treatment of macrophages catabolizing aggregated LDL significantly accelerated foam cell formation. Macrophage interaction with aggregated LDL increased the surface expression of urokinase-type plasminogen activator receptor and plasminogen activator activity, resulting in increased ability to generate plasmin at the cell surface. The high local level of plasmin cleaves cell-associated aggregated LDL, allowing a portion of the aggregate to become sequestered in a nearly sealed, yet extracellular, acidic compartment. The low pH in the plasmin-induced compartment allows lysosomal enzymes, delivered via lysosome exocytosis, greater activity, resulting in more efficient cholesteryl ester hydrolysis and delivery of a large cholesterol load to the macrophage, thereby promoting foam cell formation.

Conclusions—

These findings highlight a critical role for plasmin in the catabolism of aggregated LDL by macrophages and provide a new context for considering the atherogenic role of plasmin.
Proteomic Analysis of Intraluminal Thrombus Highlights Complement Activation in Human Abdominal Aortic Aneurysms
Authors: Martinez-Pinna Roxana , Madrigal-Matute Julio , Tarin Carlos , Burillo Elena , Esteban-Salan Margarita , Pastor-Vargas Carlos , Lindholt Jes S. , Lopez Juan A. , Calvo Enrique , de Ceniga Melina Vega , Meilhac Olivier , Egido Jesus , Blanco-Colio Luis M. , Michel Jean-Baptiste , Martin-Ventura Jose L.
Published: May 2013

Objective—

To identify proteins related to intraluminal thrombus biological activities that could help to find novel pathological mechanisms and therapeutic targets for human abdominal aortic aneurysm (AAA).

Approach and Results—

Tissue-conditioned media from patients with AAA were analyzed by a mass spectrometry–based strategy using liquid chromatography coupled to tandem mass spectrometry. Global pathway analysis by Ingenuity software highlighted the presence of several circulating proteins, among them were proteins from the complement system. Complement C3 concentration and activation were assessed in plasma from AAA patients (small AAA, AAA diameter=3–5 cm and large AAA, AAA diameter >5 cm), showing decreased C3 levels and activation in large AAA patients. No association of a combination of single-nucleotide polymorphisms in complement genes between large and small AAA patients was observed. Intense extracellular C3 inmunostaining, along with C9, was observed in AAA thrombus. Analysis of C3 in AAA tissue homogenates and tissue-conditioned media showed increased levels of C3 in AAA thrombus, as well as proteolytic fragments (C3a/C3c/C3dg), suggesting its local deposition and activation. Finally, the functional role of local complement activation in polymorphonuclear (PMN) cell activation was tested, showing that C3 blockade by anti-C3 antibody was able to decrease thrombus-induced neutrophil chemotaxis and reactive oxygen species production.

Conclusions—

A decrease of systemic C3 concentration and activity in the later stages of AAA associated with local complement retention, consumption, and proteolysis in the thrombus could induce PMN chemotaxis and activation, playing a detrimental role in AAA progression.
Stent Placement Versus Balloon Angioplasty for the Treatment of Obstructive Lesions of the Popliteal Artery
Authors: Rastan Aljoscha , Krankenberg Hans , Baumgartner Iris , Blessing Erwin , Müller-Hülsbeck Stefan , Pilger Ernst , Scheinert Dierk , Lammer Johannes , Gißler Martin , Noory Elias , Neumann Franz-Josef , Zeller Thomas
Published: May 2013

Background—

Stenting has been shown to improve patency after femoral artery revascularization compared with balloon angioplasty. Limited data are available evaluating endovascular treatment for obstructive lesions of the popliteal artery.

Methods and Results—

This prospective, randomized, multicenter trial compared primary nitinol stent placement to percutaneous transluminal balloon angioplasty in patients with peripheral artery disease Rutherford-Becker class 2 to 5 who had a de novo lesion in the popliteal artery. The primary study end point was 1-year primary patency, defined as freedom from target-lesion restenosis (luminal narrowing of ≥50%) as detected by duplex ultrasound. Secondary end points included target-lesion revascularization rate and changes in Rutherford-Becker class. Provisional stent placement was considered target-lesion revascularization and loss of primary patency. Two hundred forty-six patients were included in this trial. The mean target-lesion length was 42.3 mm. One hundred ninety-seven patients were available for the1-year follow-up. The 1-year primary patency rate was significantly higher in the group with primary nitinol stent placement (67.4%) than in the percutaneous transluminal balloon angioplasty group (44.9%,
P
=0.002). Target-lesion revascularization rates were 14.7% and 44.1%, respectively (
P
=0.0001); however, when provisional nitinol stent placement was not considered target-lesion revascularization and loss in patency, no significant differences prevailed between the study groups (67.4% versus 65.7%,
P
=0.92 for primary patency). Approximately 73% of patients in the percutaneous transluminal balloon angioplasty group and 77% in the nitinol stent group showed an improvement of ≥1 Rutherford-Becker class (
P
=0.31).

Conclusions—

Primary nitinol stent placement for obstructive lesions of the popliteal artery achieves superior acute technical success and higher 1-year primary patency only if provisional stenting is considered target-lesion revascularization. Provisional stenting as part of a percutaneous transluminal balloon angioplasty strategy has equivalent 1-year patency and should be preferred over primary stenting.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00712309.
Evidence That Acetylsalicylic Acid Attenuates Inflammation in the Walls of Human Cerebral Aneurysms: Preliminary Results
Authors: Hasan David M. , Chalouhi Nohra , Jabbour Pascal , Dumont Aaron S. , Kung David K. , Magnotta Vincent A. , Young William L. , Hashimoto Tomoki , Richard Winn H. , Heistad Donald
Published: May 2013

Background

Inflammatory cells and molecules may play a critical role in formation and rupture of cerebral aneurysms. Recently, an epidemiologic study reported that acetylsalicylic acid (
ASA
) decreases the risk of aneurysm rupture. The goal of this study was to determine the effects of
ASA
on inflammatory cells and molecules in the walls of human cerebral aneurysms, using radiographic and histological techniques.

Methods and Results

Eleven prospectively enrolled patients harboring unruptured intracranial aneurysms were randomized into an
ASA
‐treated (81 mg daily) group (n=6) and an untreated (control) group (n=5). Aneurysms were imaged at baseline using ferumoxytol‐enhanced
MRI
to estimate uptake by macrophages. After 3 months, patients were reimaged before undergoing microsurgical clipping. Aneurysm tissues were collected for immunostaining with monoclonal antibodies for cyclooxygenase‐1 (
COX
‐1), cyclooxygenase‐2 (
COX
‐2), microsomal prostaglandin E2 synthase‐1 (
mPGES
‐1), and macrophages. A decrease in signal intensity on ferumoxytol‐enhanced
MRI
was observed after 3 months of
ASA
treatment. Expression of
COX
‐2 (but not
COX
‐1),
mPGES
‐1, and macrophages was lower in the
ASA
group than in the control group.

Conclusions

This study provides preliminary radiographical and histological evidence that
ASA
may attenuate the inflammatory process in the walls of human cerebral aneurysms.

Clinical Trial Registration

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01710072.
Simple Risk Model Predicts Incidence of Atrial Fibrillation in a Racially and Geographically Diverse Population: the CHARGE‐AF Consortium
Authors: Alonso Alvaro , Krijthe Bouwe P. , Aspelund Thor , Stepas Katherine A. , Pencina Michael J. , Moser Carlee B. , Sinner Moritz F. , Sotoodehnia Nona , Fontes João D. , Janssens A. Cecile J. W. , Kronmal Richard A. , Magnani Jared W. , Witteman Jacqueline C. , Chamberlain Alanna M. , Lubitz Steven A. , Schnabel Renate B. , Agarwal Sunil K. , McManus David D. , Ellinor Patrick T. , Larson Martin G. , Burke Gregory L. , Launer Lenore J. , Hofman Albert , Levy Daniel , Gottdiener John S. , Kääb Stefan , Couper David , Harris Tamara B. , Soliman Elsayed Z. , Stricker Bruno H. C. , Gudnason Vilmundur , Heckbert Susan R. , Benjamin Emelia J.
Published: May 2013

Background

Tools for the prediction of atrial fibrillation (
AF
) may identify high‐risk individuals more likely to benefit from preventive interventions and serve as a benchmark to test novel putative risk factors.

Methods and Results

Individual‐level data from 3 large cohorts in the
U
nited
S
tates (Atherosclerosis Risk in Communities [
ARIC
] study, the Cardiovascular Health Study [
CHS
], and the Framingham Heart Study [
FHS
]), including 18 556 men and women aged 46 to 94 years (19%
A
frican
A
mericans, 81% whites) were pooled to derive predictive models for
AF
using clinical variables. Validation of the derived models was performed in 7672 participants from the Age, Gene and Environment—Reykjavik study (
AGES
) and the Rotterdam Study (
RS
). The analysis included 1186 incident
AF
cases in the derivation cohorts and 585 in the validation cohorts. A simple 5‐year predictive model including the variables age, race, height, weight, systolic and diastolic blood pressure, current smoking, use of antihypertensive medication, diabetes, and history of myocardial infarction and heart failure had good discrimination (C‐statistic, 0.765; 95%
CI
, 0.748 to 0.781). Addition of variables from the electrocardiogram did not improve the overall model discrimination (C‐statistic, 0.767; 95%
CI
, 0.750 to 0.783; categorical net reclassification improvement, −0.0032; 95%
CI
, −0.0178 to 0.0113). In the validation cohorts, discrimination was acceptable (
AGES
C‐statistic, 0.664; 95%
CI
, 0.632 to 0.697 and
RS
C‐statistic, 0.705; 95%
CI
, 0.664 to 0.747) and calibration was adequate.

Conclusion

A risk model including variables readily available in primary care settings adequately predicted
AF
in diverse populations from the
U
nited
S
tates and
E
urope.
Tissue‐ and Plasma‐Specific MicroRNA Signatures for Atherosclerotic Abdominal Aortic Aneurysm
Authors: Kin Keiwa , Miyagawa Shigeru , Fukushima Satsuki , Shirakawa Yukitoshi , Torikai Kei , Shimamura Kazuo , Daimon Takashi , Kawahara Yukio , Kuratani Toru , Sawa Yoshiki
Published: May 2013

Background

Atherosclerotic abdominal aortic aneurysm (
AAA
) is a progressive, gradual aortic rupture that results in death in the absence of surgical intervention. Key factors that regulate initiation and progression of
AAA
are unknown, making targeted interventions difficult. Micro
RNA
s play a fundamental role in atherosclerosis, and atherosclerotic coronary artery disease is characterized by tissue‐ and plasma‐specific micro
RNA
signatures. However, little is known about micro
RNA
s involved in
AAA
pathology. This study examined tissue and plasma micro
RNA
s specifically associated with
AAA
.

Methods and Results

AAA
and normal wall tissues were sampled from patients undergoing
AAA
repair (n=13; mean age, 68±6 years) and aortic valve replacement surgery (n=7; mean age, 66±4 years), respectively. Micro
RNA
expression was assessed by high‐throughput micro
RNA
arrays and validated by real‐time polymerase chain reaction for individual micro
RNA
s that showed significant expression differences in the initial screening. Micro
RNA
s related to fibrosis (miR‐29b), inflammation (miR‐124a, miR‐146a, miR‐155, and miR‐223), and endothelium (miR‐126, let‐7 family members, and miR‐21) were significantly upregulated in
AAA
tissue. Significant negative correlations were seen in expression levels of monocyte chemoattractant protein‐1 and miR‐124a, ‐146a, and ‐223; tumor necrosis factor‐α and miR‐126 and ‐223; and transforming growth factor‐β and miR‐146a. Expression of micro
RNA
s, such as miR‐29b, miR‐124a, miR‐155, and miR‐223, that were upregulated in
AAA
tissue was significantly reduced in plasma of patients with
AAA
(n=23; mean age, 72±9 years) compared to healthy controls (n=12; mean age, 51±11 years) and patients with coronary artery disease (n=17; mean age, 71±9 years).

Conclusions

The expression of some micro
RNA
s was specifically upregulated in
AAA
tissue, warranting further studies on the micro
RNA
function in
AAA
pathogenesis and on the possibility of using a micro
RNA
biomarker for
AAA
diagnosis.
Relationship of Plasma Galectin‐3 to Renal Function in Patients With Heart Failure: Effects of Clinical Status, Pathophysiology of Heart Failure, and Presence or Absence of Heart Failure
Authors: Gopal Deepa M. , Kommineni Maya , Ayalon Nir , Koelbl Christian , Ayalon Rivka , Biolo Andreia , Dember Laura M. , Downing Jill , Siwik Deborah A. , Liang Chang‐seng , Colucci Wilson S.
Published: May 2013

Background

Galectin‐3 (
GAL
‐3), a β‐galactoside–binding protein, is a new clinical biomarker believed to reflect cardiac remodeling/fibrosis in patients with heart failure (
HF
). Plasma
GAL
‐3 is inversely related to renal function. It is not known whether the relationship between renal function and
GAL
‐3 is influenced by clinical decompensation, type of
HF
, or the presence or absence of clinical
HF
.

Methods and Results

Patients were prospectively categorized as having acute decompensated
HF
or stable
HF
on the basis of clinical status and as having HF with reduced left ventricular ejection fraction or HF with preserved left ventricular ejection fraction. Plasma
GAL
‐3 was measured by enzyme‐linked immunosorbent assay in patients with
HF
(n=75), control patients without
HF
(n=32), and control patients without
HF
with moderate renal insufficiency (n=12). Compared to controls without
HF
(14±4 ng/mL),
GAL
‐3 was higher in patients with both acute decompensated
HF
(23±11 ng/mL) and stable
HF
(22±10 ng/mL) (
P
<0.001 versus controls for both) but did not differ between acute decompensated
HF
and stable
HF
(
P
=0.75). Likewise,
GAL
‐3 was elevated in both HF with preserved left ventricular ejection fraction (23±9 ng/mL) and HF with reduced left ventricular ejection fraction (22±11 ng/mL) (
P
<0.001 versus controls for both) but did not differ between HF with preserved ejection fraction and HF with reduced ejection fraction (
P
=0.37).
GAL
‐3 correlated strongly with estimated glomerular filtration rate, both in patients with
HF
(
r
=−0.75,
P
<0.001) and in patients without
HF
(
r
=−0.82,
P
<0.001), and this relationship was unaffected by the presence or absence of clinical
HF
.

Conclusions

Plasma
GAL
‐3 is inversely related to renal function in patients with and without clinical
HF
. Concentrations of plasma
GAL
‐3 do not seem to depend on the level of compensation or type of
HF
. Furthermore, the relationship between
GAL
‐3 and renal function seems to be affected little or not at all by the presence or absence of clinical
HF
.
Carotid Atherosclerotic Plaque Matrix Metalloproteinase‐12–Positive Macrophage Subpopulation Predicts Adverse Outcome After Endarterectomy
Authors: Scholtes Vincent P. W. , Johnson Jason L. , Jenkins Nicholas , Sala‐Newby Graciela B. , de Vries Jean‐Paul P. M. , de Borst Gert Jan , de Kleijn Dominique P. V. , Moll Frans L. , Pasterkamp Gerard , Newby Andrew C.
Published: May 2013

Background

Matrix metalloproteinase‐12 (
MMP
‐12) promotes atherosclerosis in animal models.
MMP
‐12 is expressed in only a subset of foam‐cell macrophages (
FCM
s) in human plaques. We investigated whether the prevalence of this
MMP
‐12–expressing subpopulation is a prognostic indicator of adverse outcome in patients after carotid endarterectomy (
CEA
).

Methods and Results

Serial sections of culprit lesions from 236 patients who underwent
CEA
and had undergone 3 years of clinical follow‐up were stained immunocytochemically for
MMP
‐12 and for
CD
68, and the
MMP
‐12/
CD
68 ratio was used to quantify the
MMP
‐12–expressing subpopulation. A high
MMP
‐12/
CD
68 ratio correlated with a high content of lipid and total macrophages and a low content of vascular smooth muscle cells, as well as with
MMP
‐8 (
R
=0.211,
P
=0.001),
MMP
‐9 (
R
=0.251,
P
<0.001), and cleaved caspase‐3 (
R
=0.142,
P
=0.036) activity measured in a neighboring segment. Dual immunohistochemical examination confirmed the location of
MMP
‐12 in a subpopulation of
MMP
‐8– and
MMP
‐9–positive
FCM
s, whereas all apoptotic
FCM
s were
MMP
‐12 positive. Patients who yielded plaques within the highest quartile compared with the lowest quartile of
MMP
‐12/
CD
68 ratio had a 2.4‐fold (hazard ratio, 2.4; 95% CI, 1.1‐ to 5.1‐fold; adjusted
P
=0.027) increased risk of major adverse cardiovascular event and a 3.4‐fold (3.4; 1.2‐ to 9.6‐fold,
P
=0.024) increased risk for stroke.

Conclusions

The prevalence of an
MMP
‐12–positive subset of
FCM
s is a prognostic marker for adverse clinical outcome after CEA.
Hands‐On Defibrillation Has the Potential to Improve the Quality of Cardiopulmonary Resuscitation and Is Safe for Rescuers— A Preclinical Study
Authors: Neumann Tobias , Gruenewald Matthias , Lauenstein Christoph , Drews Tobias , Iden Timo , Meybohm Patrick
Published: May 2013

Background

Recently, it has been demonstrated that rescuers could safely provide a low, static downward force in direct contact with patients during elective cardioversion. The purpose of our experimental study was to investigate whether shock delivery during uninterrupted chest compressions may have an impact on cardiopulmonary resuscitation (
CPR
) quality and can be safely performed in a realistic animal model of
CPR
.

Methods and Results

Twenty anesthetized swine were subjected to 7 minutes of ventricular fibrillation followed by CPR according to the 2010
A
merican
H
eart
A
ssociation
G
uidelines. Pregelled self‐adhesive defibrillation electrodes were attached onto the torso in the ventrodorsal direction and connected to a biphasic defibrillator. Animals were randomized either to (1) hands‐on defibrillation, where rescuers wore 2 pairs of polyethylene gloves and shocks were delivered during ongoing chest compressions, or (2) hands‐off defibrillation, where hands were taken off during defibrillation.
CPR
was successful in 9 out of 10 animals in the hands‐on group (versus 8 out of 10 animals in the hands‐off group; not significant). In the hands‐on group, chest compressions were interrupted for 0.8% [0.6%; 1.4%] of the total
CPR
time (versus 8.2% [4.2%; 9.0%];
P
=0.0003), and coronary perfusion pressure was earlier restored to its pre‐interruption level (
P
=0.0205). Also, rescuers neither sensed any kind of electric stimulus nor did
H
olter
ECG
reveal any serious cardiac arrhythmia.

Conclusions

Hands‐on defibrillation may improve
CPR
quality and could be safely performed during uninterrupted chest compressions in our standardized porcine model.
Leptin Locally Synthesized in Carotid Atherosclerotic Plaques Could Be Associated With Lesion Instability and Cerebral Emboli
Authors: Schneiderman Jacob , Schaefer Katrin , Kolodgie Frank D. , Savion Naphtali , Kotev‐Emeth Shlomo , Dardik Rima , Simon Amos J. , Halak Moshe , Pariente Clara , Engelberg Isaac , Konstantinides Stavros , Virmani Renu
Published: May 2013

Background

Unstable carotid plaques cause cerebral emboli. Leptin promotes atherosclerosis and vessel wall remodeling. We hypothesized that carotid atherosclerotic lesion instability is associated with local leptin synthesis.

Methods and Results

Carotid endarterectomy plaques from symptomatic (n=40) and asymptomatic patients with progressive stenosis (n=38) were analyzed for local expression of leptin, tumor necrosis factor (
TNF
)‐α, and plasminogen activator inhibitor type 1. All lesions exhibited advanced atherosclerosis inclusive of thick‐ and thin‐cap fibroatheromas or lesion rupture. Symptomatic lesions exhibited more plaque ruptures and macrophage infiltration (
P
=0.001 and
P
=0.05, respectively). Symptomatic plaques showed preferential leptin,
TNF
‐α, and plasminogen activator inhibitor type 1 transcript (
P
=0.03,
P
=0.04, and
P=
0.05, respectively). Leptin
mRNA
and antigen in macrophages and smooth muscle cells were confirmed by in situ hybridization and immunohistochemistry. Plasma leptin levels were not significantly different between groups (
P
=1.0), whereas
TNF
‐α was significantly increased in symptomatic patients (
P
=0.006). Human aortic smooth muscle cell culture stimulated by
TNF
‐α, lipopolysaccharide, or lipoteichoic acid revealed 6‐, 6.7‐, and 6‐fold increased secreted leptin antigen, respectively, at 72 hours (
P
<0.05).

Conclusions

Neurologically symptomatic patients overexpress leptin
mRNA
and synthesize leptin protein in carotid plaque macrophages and smooth muscle cells. Local leptin induction, presumably by
TNF
‐α, could exert paracrine or autocrine effects, thereby contributing to the pathogenesis of lesion instability.

Clinical Trial Registration

URL:
www.Clinicaltrials.gov
. Unique identifier: NCT00449306.