bluuebunny/crossref_metadata_2025 huggingface dataset:
Loss of PPP2R2A Inhibits Homologous Recombination DNA Repair and Predicts Tumor Sensitivity to PARP Inhibition
Authors: Kalev Peter , Simicek Michal , Vazquez Iria , Munck Sebastian , Chen Liping , Soin Thomas , Danda Natasha , Chen Wen , Sablina Anna
Published: October 2012

Reversible phosphorylation plays a critical role in DNA repair. Here, we report the results of a loss-of-function screen that identifies the PP2A heterotrimeric serine/threonine phosphatases PPP2R2A, PPP2R2D, PPP2R5A, and PPP2R3C in double-strand break (DSB) repair. In particular, we found that PPP2R2A-containing complexes directly dephosphorylated ATM at S367, S1893, and S1981 to regulate its retention at DSB sites. Increased ATM phosphorylation triggered by PPP2R2A attenuation dramatically upregulated the activity of the downstream effector kinase CHK2, resulting in G1 to S-phase cell-cycle arrest and downregulation of BRCA1 and RAD51. In tumor cells, blocking PPP2R2A thereby impaired the high-fidelity homologous recombination repair pathway and sensitized cells to small-molecule inhibitors of PARP. We found that PPP2R2A was commonly downregulated in non–small cell lung carcinomas, suggesting that PPP2R2A status may serve as a marker to predict therapeutic efficacy to PARP inhibition. In summary, our results deepen understanding of the role of PP2A family phosphatases in DNA repair and suggest PPP2R2A as a marker for PARP inhibitor responses in clinic. Cancer Res; 72(24); 6414–24. ©2012 AACR.
Kinase Pathway Dependence in Primary Human Leukemias Determined by Rapid Inhibitor Screening
Authors: Tyner Jeffrey W. , Yang Wayne F. , Bankhead Armand , Fan Guang , Fletcher Luke B. , Bryant Jade , Glover Jason M. , Chang Bill H. , Spurgeon Stephen E. , Fleming William H. , Kovacsovics Tibor , Gotlib Jason R. , Oh Stephen T. , Deininger Michael W. , Zwaan Christian Michel , Den Boer Monique L. , van den Heuvel-Eibrink Marry M. , O'Hare Thomas , Druker Brian J. , Loriaux Marc M.
Published: October 2012

Kinases are dysregulated in most cancers, but the frequency of specific kinase mutations is low, indicating a complex etiology in kinase dysregulation. Here, we report a strategy to rapidly identify functionally important kinase targets, irrespective of the etiology of kinase pathway dysregulation, ultimately enabling a correlation of patient genetic profiles to clinically effective kinase inhibitors. Our methodology assessed the sensitivity of primary leukemia patient samples to a panel of 66 small-molecule kinase inhibitors over 3 days. Screening of 151 leukemia patient samples revealed a wide diversity of drug sensitivities, with 70% of the clinical specimens exhibiting hypersensitivity to one or more drugs. From this data set, we developed an algorithm to predict kinase pathway dependence based on analysis of inhibitor sensitivity patterns. Applying this algorithm correctly identified pathway dependence in proof-of-principle specimens with known oncogenes, including a rare FLT3 mutation outside regions covered by standard molecular diagnostic tests. Interrogation of all 151 patient specimens with this algorithm identified a diversity of kinase targets and signaling pathways that could aid prioritization of deep sequencing data sets, permitting a cumulative analysis to understand kinase pathway dependence within leukemia subsets. In a proof-of-principle case, we showed that in vitro drug sensitivity could predict both a clinical response and the development of drug resistance. Taken together, our results suggested that drug target scores derived from a comprehensive kinase inhibitor panel could predict pathway dependence in cancer cells while simultaneously identifying potential therapeutic options. Cancer Res; 73(1); 285–96. ©2012 AACR.
Development of Gene Expression–Based Score to Predict Sensitivity of Multiple Myeloma Cells to DNA Methylation Inhibitors
Authors: Moreaux Jérôme , Rème Thierry , Leonard Wim , Veyrune Jean-Luc , Requirand Guilhem , Goldschmidt Hartmut , Hose Dirk , Klein Bernard
Published: October 2012

Multiple myeloma is a plasma cell cancer with poor survival, characterized by the clonal expansion of multiple myeloma cells (MMC), primarily in the bone marrow. Novel compounds are currently tested in this disease, but partial or minor patients' responses are observed for most compounds used as a single agent. The design of predictors for drug efficacy could be most useful to better understand basic mechanisms targeted by these drugs and design clinical trials. In the current study, we report the building of a DNA methylation score (DM score) predicting the efficacy of decitabine, an inhibitor of DNA methyltransferase (DNMT), targeting methylation-regulated gene expression. DM score was built by identifying 47 genes regulated by decitabine in human myeloma cell lines and the expression of which in primary MMCs of previously untreated patients is predictive for overall survival. A high DM score predicts patients' poor survival, and, of major interest, high sensitivity of primary MMCs or human myeloma cell lines to decitabine in vitro. Thus, DM score could be useful to design novel treatments with DMNT inhibitor in multiple myeloma and has highlighted 47 genes, the gene products of which could be important for multiple myeloma disease development. Mol Cancer Ther; 11(12); 2685–92. ©2012 AACR.
The Novel miR-7515 Decreases the Proliferation and Migration of Human Lung Cancer Cells by Targeting c-Met
Authors: Lee Ji Min , Yoo Jung Ki , Yoo Hanna , Jung Ho Yong , Lee Dong Ryul , Jeong Hye Cheol , Oh Seoung Hun , Chung Hyung Min , Kim Jin Kyeoung
Published: October 2012

MicroRNAs (miRNA) are small noncoding RNAs that regulate gene expression in human diseases, including lung cancer. miRNAs have oncogenic and nononcogenic functions in lung cancer. In this study, we report the identification of a novel miRNA, miR-7515, from lung cancer cells. The novel miR-7515 was characterized using various predictive programs and experimental methods. miR-7515 was able to forming a stem-loop structure and its sequence was conserved in mammals. The expression level of miR-7515 in lung cancer cells and tissues was profiled using TaqMan miRNA assays. miR-7515 was downregulated in lung cancer compared with normal human lung cells and tissues. The target of miR-7515 was determined using a dual luciferase reporter assay. Expression of the target gene was determined by quantitative RT-PCR and Western blot analysis after transfection with miR-7515. miR-7515 directly suppressed human mesenchymal–epithelial transition factor (c-Met) by binding to the 3′ untranslated region (UTR). Overexpression of miR-7515 significantly decreased cell-cycle–related proteins downstream of c-Met through c-Met inhibition. Cell proliferation and migration were examined using the XTT proliferation assay and the Transwell migration assay. miR-7515 led to decreased cell proliferation, migration and invasion in a lung cancer cell line. These results suggest that miR-7515 plays an important role in the proliferation and migration of lung cancer cells through c-Met regulation. Mol Cancer Res; 11(1); 43–53. ©2012 AACR.
Characterizing the Molecular Spatial and Temporal Field of Injury in Early-Stage Smoker Non–Small Cell Lung Cancer Patients after Definitive Surgery by Expression Profiling
Authors: Kadara Humam , Shen Li , Fujimoto Junya , Saintigny Pierre , Chow Chi-Wan , Lang Wenhua , Chu Zuoming , Garcia Melinda , Kabbout Mohamed , Fan You-Hong , Behrens Carmen , Liu Diane A. , Mao Li , Lee J. Jack , Gold Kathryn A. , Wang Jing , Coombes Kevin R. , Kim Edward S. , Hong Waun Ki , Wistuba Ignacio I.
Published: October 2012

Gene expression alterations in response to cigarette smoke have been characterized in normal-appearing bronchial epithelium of healthy smokers, and it has been suggested that adjacent histologically normal tissue displays tumor-associated molecular abnormalities. We sought to delineate the spatial and temporal molecular lung field of injury in smoker patients with early-stage non–small cell lung cancer (NSCLC; n = 19) who were accrued into a surveillance clinical trial for annual follow-up and bronchoscopies within 1 year after definitive surgery. Bronchial brushings and biopsies were obtained from six different sites in the lung at the time of inclusion in the study and at 12, 24, and 36 months after the first time point. Affymetrix Human Gene 1.0 ST arrays were used for whole-transcript expression profiling of airways (n = 391). Microarray analysis identified gene features (n = 1,165) that were nonuniform by site and differentially expressed between airways adjacent to tumors relative to more distant samples as well as those (n = 1,395) that were significantly altered with time up to 3 years. In addition, gene interaction networks mediated by phosphoinositide 3-kinase (PI3K) and extracellular signal–regulated kinase (ERK)1/2 were modulated in adjacent compared with contralateral airways and the latter network with time. Furthermore, phosphorylated AKT and ERK1/2 immunohistochemical expression were significantly increased with time (nuclear pAKT, P = 0.03; cytoplasmic pAKT, P < 0.0001; pERK1/2, P = 0.02) and elevated in adjacent compared with more distant airways (nuclear pAKT, P = 0.04; pERK1/2, P = 0.03). This study highlights spatial and temporal cancer–associated expression alterations in the molecular field of injury of patients with early-stage NSCLCs after definitive surgery that warrant further validation in independent studies. Cancer Prev Res; 6(1); 8–17. ©2012 AACR.
Thrombospondin-1 Regulates Blood Flow via CD47 Receptor–Mediated Activation of NADPH Oxidase 1
Authors: Csányi Gábor , Yao Mingyi , Rodríguez Andrés I. , Ghouleh Imad Al , Sharifi-Sanjani Maryam , Frazziano Giovanna , Huang Xiaojun , Kelley Eric E. , Isenberg Jeffrey S. , Pagano Patrick J.
Published: October 2012

Objective—

Although the matricellular protein thrombospondin-1 (TSP1) is highly expressed in the vessel wall in response to injury, its pathophysiological role in the development of vascular disease is poorly understood. This study was designed to test the hypothesis that TSP1 stimulates reactive oxygen species production in vascular smooth muscle cells and induces vascular dysfunction by promoting oxidative stress.

Methods and Results—

Nanomolar concentrations of TSP1 found in human vascular disease robustly stimulated superoxide (O
2
•−
) levels in vascular smooth muscle cells at both cellular and tissue level as measured by cytochrome
c
and electron paramagnetic resonance. A peptide mimicking the C terminus of TSP1 known to specifically bind CD47 recapitulated this response. Transcriptional knockdown of CD47 and a monoclonal inhibitory CD47 antibody abrogated TSP1-triggered O
2
•−
in vitro and ex vivo. TSP1 treatment of vascular smooth muscle cells activated phospholipase C and protein kinase C, resulting in phosphorylation of the NADPH oxidase organizer subunit p47

phox

and subsequent Nox1 activation, leading to impairment of arterial vasodilatation ex vivo. Further, we observed that blockade of CD47 and NADPH oxidase 1 gene silencing in vivo in rats improves TSP1-induced impairment of tissue blood flow after ischemia reperfusion.

Conclusion—

Our data suggest a highly regulated process of reactive oxygen species stimulation and blood flow regulation promoted through a direct TSP1/CD47-mediated activation of Nox1. This is the first report, to our knowledge, of a matricellular protein acting as a ligand for NADPH oxidase activation and through specific engagement of integrin-associated protein CD47.
A Systematic Approach to Multifactorial Cardiovascular Disease
Authors: Schwartz Stephen M. , Schwartz Hillel T. , Horvath Steven , Schadt Eric , Lee Su-In
Published: October 2012

The combination of systems biology and large data sets offers new approaches to the study of cardiovascular diseases. These new approaches are especially important for the common cardiovascular diseases that have long been described as multifactorial. This promise is undermined by biologists’ skepticism of the spider web–like network diagrams required to analyze these large data sets. Although these spider webs resemble composites of the familiar biochemical pathway diagrams, the complexity of the webs is overwhelming. As a result, biologists collaborate with data analysts whose mathematical methods seem much like those of experts using Ouija boards. To make matters worse, it is not evident how to design experiments when the network implies that many molecules must be part of the disease process. Our goal is to remove some of this mystery and suggest a simple experimental approach to the design of experiments appropriate for such analysis. We will attempt to explain how combinations of data sets that include all possible variables, graphical diagrams, complementation of different data sets, and Bayesian analyses now make it possible to determine the causes of multifactorial cardiovascular disease. We will describe this approach using the term causal analysis. Finally, we will describe how causal analysis is already being used to decipher the interactions among cytokines as causes of cardiovascular disease.
Blood Clots Are Rapidly Assembled Hemodynamic Sensors
Authors: Muthard Ryan W. , Diamond Scott L.
Published: October 2012

Objective—

Blood clots form under flow during intravascular thrombosis or vessel leakage. Prevailing hemodynamics influence thrombus structure and may regulate contraction processes. A microfluidic device capable of flowing human blood over a side channel plugged with collagen (±tissue factor) was used to measure thrombus permeability (κ) and contraction at controlled transthrombus pressure drops.

Methods and Results—

The collagen (κ
collagen
=1.98×10
−11
cm
2
) supported formation of a 20-µm thick platelet layer, which unexpectedly underwent massive platelet retraction on flow arrest. This contraction resulted in a 5.34-fold increase in permeability because of collagen restructuring. Without stopping flow, platelet deposits (no fibrin) had a permeability of κ
platelet
=5.45×10
−14
cm
2
and platelet-fibrin thrombi had κ
thrombus
=2.71×10
−14
cm
2
for ΔP=20.7 to 23.4 mm Hg, the first ever measurements for clots formed under arterial flow (1130 s
−1
wall shear rate). Platelet sensing of flow cessation triggered a 4.6- to 6.5-fold (n=3,
P
<0.05) increase in contraction rate, which was also observed in a rigid, impermeable parallel-plate microfluidic device. This triggered contraction was blocked by the myosin IIA inhibitor blebbistatin and by inhibitors of thromboxane A2 (TXA
2
) and ADP signaling. In addition, flow arrest triggered platelet intracellular calcium mobilization, which was blocked by TXA
2
/ADP inhibitors. As clots become occlusive or blood pools following vessel leakage, the flow diminishes, consequently allowing full platelet retraction.

Conclusion—

Flow dilution of ADP and thromboxane regulates platelet contractility with prevailing hemodynamics, a newly defined flow-sensing mechanism to regulate clot function.
No Shorter Telomeres in Subjects With a Family History of Cardiovascular Disease in the Asklepios Study
Authors: De Meyer Tim , Van daele Caroline M. , De Buyzere Marc L. , Denil Simon , De Bacquer Dirk , Segers Patrick , Cooman Luc , De Backer Guy G. , Gillebert Thierry C. , Bekaert Sofie , Rietzschel Ernst R.
Published: October 2012

Objective—

Shorter telomere length is associated with the occurrence of cardiovascular events, but the question of causality is complicated by the intertwined effects of inheritance, aging, and lifestyle factors on both telomere length and cardiovascular disease (CVD). Some studies indicated that healthy offspring of coronary artery disease patients exhibited shorter telomeres than subjects without a family history. Importantly, this result would imply that inheritance of shorter telomeres is a primary abnormality associated with an increased risk of CVD, the so-called Telomere Hypothesis of CVD. Therefore, we aimed at further validating the latter results in the large, population-representative Asklepios Study.

Methods and Results—

Peripheral blood leukocyte telomere length was measured using telomere restriction fragment analysis in the young to middle-aged (≈35–55 years old) Asklepios study population, free from overt CVD, and could be successfully combined with data from the Asklepios Family History Database for 2136 subjects. No shorter telomere length could be found in healthy subjects with a family history of CVD compared with those without.

Conclusion—

These findings cast serious doubt on the hypothesis that telomere length is shorter in families with an increased risk of CVD and do not support the Telomere Hypothesis of CVD.
Prospective Characterization of Catheter–Tissue Contact Force at Different Anatomic Sites During Antral Pulmonary Vein Isolation
Authors: Kumar Saurabh , Morton Joseph B. , Lee Justin , Halloran Karen , Spence Steven J. , Gorelik Alexandra , Hepworth Graham , Kistler Peter M. , Kalman Jonathan M.
Published: October 2012

Background—

Catheter–tissue contact is critical for effective lesion creation. We characterized the contact force (CF) at different anatomic sites during antral pulmonary vein (PV) isolation for atrial fibrillation.

Methods and Results—

Two experienced operators performed PV isolation in 22 patients facilitated by a novel CF-sensing ablation catheter in a blinded fashion. Average CF and force-time integral data from 1602 lesions were analyzed. The left and right PV antra were divided into the following: carina, superior, inferior, anterior, and posterior quadrants for analysis. There was significant variability in CF within and between different PV quadrants (
P
<0.05). Lowest CF of all left PV sites was at the carina and anterior quadrant, whereas highest CF was at the superior and inferior quadrants (
P
<0.05). Lowest CF of all right PV sites was at the carina, whereas highest CF was at the anterior and inferior quadrants (
P
<0.05). When comparing similar PV quadrants on the left versus right (eg, left carina versus right carina), CF was always higher in the right PVs (
P
<0.05), except at the superior quadrant where CF was similar in the left and right PVs (
P
=0.19). There was no specific pattern of anatomic distribution of excess CF (
P
=0.39).

Conclusions—

Monitoring of catheter–tissue CF during PV isolation demonstrates significant variability in CF within and between different PV antral sites. Sites of lowest CF were the carina and anterior left PVs and the carina of the right PVs. This information may be important for improving ablation efficacy and clinical outcomes during PV isolation.
Prognostic Role of Pulmonary Arterial Capacitance in Advanced Heart Failure
Authors: Dupont Matthias , Mullens Wilfried , Skouri Hadi N. , Abrahams Zuheir , Wu Yuping , Taylor David O. , Starling Randall C. , Tang W. H. Wilson
Published: October 2012

Background—

Right ventricular (RV) dysfunction frequently occurs and independently prognosticates in left-sided heart failure. It is not clear which RV afterload measure has the greatest impact on RV function and prognosis. We examined the determinants, prognostic role, and response to treatment of pulmonary arterial capacitance (PAC, ratio of stroke volume over pulmonary pulse pressure), in relation to pulmonary vascular resistance (PVR) in heart failure.

Methods and Results—

We reviewed 724 consecutive patients with heart failure who underwent right heart catheterization between 2000 and 2005. Changes in PAC were explored in an independent cohort of 75 subjects treated for acute decompensated heart failure. PAC showed a strong inverse relation with PVR (
r
=−0.64) and wedge pressure (
r
=−0.73), and provides stronger prediction of significant RV failure than PVR (area under the curve ROC 0.74 versus 0.67, respectively,
P
=0.003). During a mean follow-up of 3.2±2.2 years, both lower PAC (
P
<0.0001) and higher PVR (
P
<0.0001) portend more adverse clinical events (all-cause mortality and cardiac transplantation). In multivariate analysis, PAC (but not PVR) remains an independent predictor (Hazard ratio=0.92 [95% CI: 0.84–1.0,
P
=0.037]). Treatment of heart failure resulted in a decrease in PVR (270±165 to 211±88 dynes·s
–1
·cm
–5
,
P
=0.002), a larger increase in PAC (1.65±0.64 to 2.61±1.42 mL/mm Hg,
P
<0.0001), leading to an increase in pulmonary arterial time constant (PVR×PAC) (0.29±0.12 to 0.37±0.15 second,
P
<0.0001).

Conclusions—

PAC bundles the effects of PVR and left-sided filling pressures on RV afterload, explaining its strong relation with RV dysfunction, poor long-term prognosis, and response to therapy.
The Angiogenic Factor Secretoneurin Induces Coronary Angiogenesis in a Model of Myocardial Infarction by Stimulation of Vascular Endothelial Growth Factor Signaling in Endothelial Cells
Authors: Albrecht-Schgoer Karin , Schgoer Wilfried , Holfeld Johannes , Theurl Markus , Wiedemann Dominik , Steger Christina , Gupta Rajesh , Semsroth Severin , Fischer-Colbrie Reiner , Beer Arno G.E. , Stanzl Ursula , Huber Eva , Misener Sol , Dejaco Daniel , Kishore Raj , Pachinger Otmar , Grimm Michael , Bonaros Nikolaos , Kirchmair Rudolf
Published: October 2012

Background—

Secretoneurin is a neuropeptide located in nerve fibers along blood vessels, is upregulated by hypoxia, and induces angiogenesis. We tested the hypothesis that secretoneurin gene therapy exerts beneficial effects in a rat model of myocardial infarction and evaluated the mechanism of action on coronary endothelial cells.

Methods and Results—

In vivo secretoneurin improved left ventricular function, inhibited remodeling, and reduced scar formation. In the infarct border zone, secretoneurin induced coronary angiogenesis, as shown by increased density of capillaries and arteries. In vitro secretoneurin induced capillary tubes, stimulated proliferation, inhibited apoptosis, and activated Akt and extracellular signal-regulated kinase in coronary endothelial cells. Effects were abrogated by a vascular endothelial growth factor (VEGF) antibody, and secretoneurin stimulated VEGF receptors in these cells. Secretoneurin furthermore increased binding of VEGF to endothelial cells, and binding was blocked by heparinase, indicating that secretoneurin stimulates binding of VEGF to heparan sulfate proteoglycan binding sites. Additionally, secretoneurin increased binding of VEGF to its coreceptor neuropilin-1. In endothelial cells, secretoneurin also stimulated fibroblast growth factor receptor-3 and insulin-like growth factor-1 receptor, and in coronary vascular smooth muscle cells, we observed stimulation of VEGF receptor-1 and fibroblast growth factor receptor-3. Exposure of cardiac myocytes to hypoxia and ischemic heart after myocardial infarction revealed increased secretoneurin messenger RNA and protein.

Conclusions—

Our data show that secretoneurin acts as an endogenous stimulator of VEGF signaling in coronary endothelial cells by enhancing binding of VEGF to low-affinity binding sites and neuropilin-1 and stimulates further growth factor receptors like fibroblast growth factor receptor-3. Our in vivo findings indicate that secretoneurin may be a promising therapeutic tool in ischemic heart disease.
Leukocyte-Dependent Responses of the Microvasculature to Chronic Angiotensin II Exposure
Authors: Yildirim Alper , Russell Janice , Yan Li-Sue S. , Senchenkova Elena Y. , Granger D. Neil
Published: October 2012

Angiotensin II (Ang II) contributes to the pathogenesis of hypertension and other cardiovascular diseases. Ang II induces a pro-oxidative, proinflammatory, and prothrombogenic phenotype in vascular endothelial cells. Although the peptide promotes the recruitment of leukocytes and platelets and induces oxidative stress in the microvasculature, it remains unclear whether and how the blood cell recruitment is linked to the production of reactive oxygen species. In this study, we addressed the contributions of Ang II type 1 receptors (AT
1
r) and gp91
phox
to the recruitment of leukocytes and platelets and reactive oxygen species production in venules during chronic (2-week) infusion of Ang II in wild-type (WT) and mutant mice. Intravital video microscopy was used to measure the adhesion and emigration of leukocytes, the adhesion of fluorescently labeled platelets, and dihydrorhodamine oxidation (a measure of oxidative stress) in cremaster muscle postcapillary venules. In WT mice, Ang II infusion induced a time-dependent increase in the adhesion of leukocytes and platelets and enhanced reactive oxygen species production in venules. These changes in blood cell adhesion and reactive oxygen species production were not observed in AT
1
r
−/−
mice, AT
1
r
−/−
bone marrow chimeras (blood cells deficient in AT
1
r), gp91
phox−/−
mice, gp91
phox−/−
chimeras (blood cells or endothelial cells deficient in gp91
phox
), and in WT mice rendered granulocytopenic via intraperitoneal injection of antimouse granulocyte receptor 1 antibody. Thrombocytopenic WT mice (platelets depleted by intraperitoneal injection of rabbit antimouse thrombocyte antiserum) responded similar to WT mice. These findings implicate leukocyte-associated AT
1
r and gp91
phox
in the induction of the pro-oxidative, proinflammatory, and prothrombogenic phenotype assumed by microvessels that is chronically exposed to elevated Ang II.
Evidence for a Strong Genetic Influence on Carotid Plaque Characteristics
Authors: Tarnoki Adam Domonkos , Baracchini Claudio , Tarnoki David Laszlo , Lucatelli Pierleone , Boatta Emanuele , Zini Chiara , Fanelli Fabrizio , Molnar Andrea Agnes , Meneghetti Giorgio , Stazi Maria Antonietta , Medda Emanuela , Cotichini Rodolfo , Nisticò Lorenza , Fagnani Corrado , Osztovits Janos , Jermendy Gyorgy , Preda Istvan , Kiss Robert Gabor , Metneki Julia , Horvath Tamas , Pucci Giacomo , Bata Pal , Karlinger Kinga , Littvay Levente , Berczi Viktor , Garami Zsolt , Schillaci Giuseppe
Published: October 2012

Background and Purpose—

Few family studies reported moderate genetic impact on the presence and scores of carotid plaques. However, the heritability of carotid plaque characteristics remains still unclear. Twin studies more reliably estimate the relative contribution of genes to these traits in contrast to family study design.

Methods—

One hundred ninety-two monozygotic and 83 dizygotic adult twin pairs (age 49±15 years) from Italy, Hungary, and the United States underwent B-mode and color Doppler ultrasound of bilateral common, internal, and external carotid arteries.

Results—

Age-, sex-, and country-adjusted heritability was 78% for the presence of carotid plaque (95% CI, 55%–90%), 74% for plaque echogenicity (hypoechoic, hyperechoic, or mixed; 95% CI, 38%–87%), 69% for plaque size (area in mm
2
in longitudinal plane; < or >50 percentile; 95% CI, 16%–86%), 74% for plaque sidedness (unilateral or bilateral; 95% CI, 25%–90%), 74% for plaque numerosity (95% CI, 26%–86%), 68% (95% CI, 40%–84%), and 66% (95% CI, 32%–90%) for the presence of plaque in carotid bulbs and proximal internal carotid arteries. No role of shared environmental factors was found. Unique environmental factors were responsible for the remaining variance (22%–34%). Controlling for relevant covariates did not change the results significantly.

Conclusions—

The heritability of ultrasound characteristics of carotid plaque is high. Unshared environmental effects account for a modest portion of the variance. Our findings should stimulate the search for genes responsible for these traits.
A Randomized Controlled Trial of Prophylactic Intra-aortic Balloon Counterpulsation in High-Risk Aneurysmal Subarachnoid Hemorrhage
Authors: Bulters Diederik Olivier , Birch Anthony A. , Hickey Edward , Tatlow Ian , Sumner Karen , Lamb Robert , Lang Dorothy
Published: October 2012

Background and Purpose—

To assess whether prophylactic postoperative intraaortic balloon counterpulsation (IABC) reduces the risk of poor outcome because of vasospasm following aneurysmal subarachnoid haemorrhage relative to conventional hypervolemic therapy (HT).

Methods—

This was a single-center, parallel group randomized controlled trial. Patients suffering a subarachnoid hemorrhage at high risk of vasospasm were eligible. Patients were randomly allocated to receive prophylactic IABC (n=35) or HT (n=36). The primary end point was Glasgow Outcome and SF-36 scores assessed at 6 months by a blinded and independent observer and analyzed by intention to treat. Secondary analysis of physiological parameters was by treatment performed.

Results—

Twenty-seven patients in each arm had a good outcome (
P
=0.55). There was no statistical difference in mean SF-36 score (t=0.39,
P
=0.70). There were no long-term complications secondary to IABC. There were no differences in preload (pulmonary artery wedge pressure,
P
=0.97) or afterload (mean arterial pressure,
P
=0.97). IABC was associated with a lower cardiac output (
P
=0.002) and higher systemic vascular resistance (
P
=0.005), although for both groups mean cardiac output was >6 L/min. Cerebral blood flow was not different between groups: HT=41.5 (SD 7.2), IABP=44.9 (SD 8.6) mL/100 g/min (
P
=0.14).

Conclusions—

In this study, prophylactic IABC did not improve perfusion indices or confer any clinical benefit following subarachnoid haemorrhage in patients with normal cardiac function. The study was small, however, and cannot be extrapolated to patients with cardiac failure and medically refractory symptomatic cerebral vasospasm.

Clinical Trial Registration—

This trial was not registered because enrolment began prior to July 1, 2005.
Registry Report on Kinetics of Rescue Antiplatelet Treatment to Abolish Cerebral Microemboli After Carotid Endarterectomy
Authors: Saedon Mahmud , Singer Donald R.J. , Pang Raymand , Tiivas Carl , Hutchinson Charles E. , Imray Christopher H.E.
Published: October 2012

Background and Purpose—

Cerebral microemboli signals (MES) are associated with increased risk of acute stroke syndromes. We compared the effects on cerebral microemboli after carotid endarterectomy of tirofiban with dextran-40.

Methods—

We used transcranial Doppler ultrasound to study transient MES acutely after carotid endarterectomy between August 2000 and December 2010 in 128 subjects refractory to preoperative antiplatelet treatment. Antithrombotic treatment was given for MES ≥50 hour
−1
(tirofiban: 40 patients [age 74 ± 1 {SEM}, males 27, and white 38]; dextran-40: 34 patients [age 69 ± 2, males 22, white 30]). In 54 patients with MES <50 hour
−1
(age 71 ± 1, male 36, white 52), MES were monitored during their spontaneous resolution (controls). Data are median (interquartile range).

Results—

The time to 50% reduction in MES (tirofiban 23 minutes [15–28]; dextran-56 [43–83]; controls 30 [22–38];
P
<0.001, Kruskal-Wallis analysis) and for complete MES resolution (tirofiban 68 minutes [53–94]; dextran-113 [79–146]; controls 53 [49–68];
P
<0.001, Kruskal-Wallis analysis) were shorter with tirofiban. The early cardiovascular event rate was similar with tirofiban compared with controls but increased in patients who received dextran.

Conclusions—

These findings suggest that transcranial Doppler-directed tirofiban therapy is more effective than dextran-40 in suppression of cerebral microemboli after carotid endarterectomy.
The Electoral Origins of Polarized Politics
Authors: Jacobson Gary C.
Published: October 2012

Data from the 2010 Cooperative Congressional Election Study are examined to determine the extent to which partisan polarization is a popular as well as an elite phenomenon. The evidence indicates that ordinary Americans as well as political elites divide consistently along party lines over a broad range of issues and legislative preferences. Partisan ideological divisions are not confined to the political class; they extend downward into the citizenry to the degree that people are actively involved in politics. The coincidence of partisan differences across issues results in a bimodal distribution of aggregate preferences among voters, showing that partisan sorting can by itself polarize the electorate even if sorted partisans do not adopt extreme positions on individual issues. The distribution of partisan preferences is even more sharply bimodal and polarized when the electoral constituencies of the congressional parties are compared, so the electoral process sustains elite polarization. Primary electoral constituencies tend to be even more extreme, particularly on the Republican side, deterring departures from party orthodoxy and thus movement toward the median voter.
Forget the Good of the Game
Authors: Wolf Michael R. , Strachan J. Cherie , Shea Daniel M.
Published: October 2012

The growing literature on American party polarization has focused on growing differences in partisan vote outcomes, political values, and policy position. We argue that a second layer of party polarization has developed that goes far beyond simply issue and ideological differences. A growing unwillingness to want politicians to compromise with the other side and a determination to blame growing political incivility solely on the other party characterizes this additional division. This second layer is important to gauge because an electorate with a significant portion of voters deeply separated on policy questions but open to compromise is appreciably different from an electorate deeply divided on policy and unwilling to budge based on policy and emotion. Our findings show that a solid percentage of the electorate holds strong partisan preferences and wants their party leaders to stand firm on principle rather than compromise with the other side. Furthermore, this strong partisan mood is not simply driven by the particular conditions of the 2010 midterm election, such as the Tea Party or in particular regions. Rather, this stark divisive partisan atmosphere existed generally and was not concentrated in electorally competitive areas.
Presidential “Going Bipartisan” and the Consequences for Institutional Approval
Authors: Rottinghaus Brandon , Tedin Kent L.
Published: October 2012

Although scholars have described how legislative efforts to spur bipartisanship fare, we have little knowledge about how bipartisanship can affect political opinions with their rhetoric or the most impactful message for opponents to respond. Using President Obama’s bipartisan speech to the GOP House Issues Conference in 2010, we look at the effect of the one-sided message on President Obama’s favorability rating. We then pair this message with three competing messages of varying partisanship to determine the degree of change (if any). The results show that the President’s one-sided message is effective, but if met with a competitive bipartisan message from the opposition party, approval of the President by all partisan groups increases even more. However, if the President’s bipartisan message frame is met using a partisan message from the opposition party, the President’s approval declines among all partisans, and approval of the Republicans in Congress increases but only for Republican identifiers.
The Polarized American
Authors: Kaltenthaler Karl , Miller William J.
Published: October 2012

In recent years, many possible explanations have been offered for why America has become a more polarized country. In this article, we introduce a new variable to the discussion. Rather than focusing on specific policy beliefs or political attitudes, we instead suggest that social trust can be an important explanatory factor in predicting which Americans are most likely to be polarized. Through the analysis of ANES data, we find that individuals who are strong trusters of others are more likely to identify as Strong Democrats while those less likely to do so are more likely to self-identify as Strong Republicans. The article concludes by looking at how considering social trust as a predictor of polarization impacts our understanding of American politics.
We Can’t Win This on Our Own
Authors: Dixon Marc , Martin Andrew W.
Published: October 2012

To cope with steep losses in membership and eroding legal protections, some unions have begun to look outward for help. Scholars likewise point to broad-based coalitions as a potential route to labor’s revitalization. Yet surprisingly little is known about union coalition work, from when and why it occurs to what union allies typically bring to the table. We take up these issues with a unique dataset on strike events from the 1990s and 2000s, contributing to labor and social movement research. First, we show that despite considerable academic interest in union outreach to other social movements, this phenomenon remains fairly rare. Second, our findings demonstrate how the immediate threat to unions posed by employer intransigence matters not just for the mobilization of external allies, as the social movement literature would expect, but also for the assistance brought to bear by those allies, which has received relatively little attention from scholars. Third, although we find important distinctions in unions’ propensity for outreach, results suggest a more nuanced picture of union activity than previously conceived. In various ways during strike events, both social movement unions (typically highlighted in the literature) and declining industrial unions are turning to coalition partners.
Prescriptive Authority and Counseling Psychology
Authors: Rinaldi Anthony P.
Published: October 2012

The prescriptive authority for psychologists (RxP) movement is controversial in its notion that properly trained licensed psychologists should be granted the right to prescribe psychotropic medication. Since its inception, the RxP movement has been successful in engendering prescriptive authority for psychologists practicing at both federal and state levels. For the past20 years, the specialty of counseling psychology’s official position on prescriptive authority has been neutral. The author believes that renewed discourse is warranted. Therefore, the author will argue that counseling psychology practitioners should endorse the RxP movement, as prescriptive authority appeals to such unique facets of counseling psychology’s professional identity as holistic conceptualization of clients, a strengths-based approach to treatment, and a focus on social justice. The author also addresses concerns that may be preventing practitioners’ support, including the effectiveness of training programs for prescribing psychologists and the potential for prescriptive authority to dominate professional identity and practice.
Human Mesenchymal Stromal Cells are Mechanosensitive to Vibration Stimuli
Authors: Kim I.S. , Song Y.M. , Lee B. , Hwang S.J.
Published: October 2012

Low-magnitude high-frequency (LMHF) vibrations have the ability to stimulate bone formation and reduce bone loss. However, the anabolic mechanisms that are mediated by vibration in human bone cells at the cellular level remain unclear. We hypothesized that human mesenchymal stromal cells (hMSCs) display direct osteoblastic responses to LMHF vibration signals. Daily exposure to vibrations increased the proliferation of hMSCs, with the highest efficiency occurring at a peak acceleration of 0.3 g and vibrations at 30 to 40 Hz. Specifically, these conditions promoted osteoblast differentiation through an increase in alkaline phosphatase activity and in vitro matrix mineralization. The effect of vibration on the expression of osteogenesis-related factors differed depending on culture method. hMSCs that underwent vibration in a monolayer culture did not exhibit any changes in the expressions of these genes, while cells in three-dimensional culture showed increased expression of type I collagen, osteoprotegerin, or VEGF, and VEGF induction appeared in 2 different hMSC lines. These results are among the first to demonstrate a dose-response effect upon LMHF stimulation, thereby demonstrating that hMSCs are mechanosensitive to LMHF vibration signals such that they could facilitate the osteogenic process.
Stumbling toward a Democratic Theory of Incest
Authors: Seery John
Published: October 2012

Prompted by the prominence of incest themes in the U.S. literary canon, the author raises and explores the idea of a “democratic theory of incest.” To that end, the paper uncovers, tracks, and documents the interest in incest throughout the Western canon of political thought. It then presents and addresses a “standoff” in theoretical circles today: whereas many nonliberal political theorists have continued and developed the canonical interest in the politics of incest, contemporary liberals have largely dropped out of that extended discussion. By way of a re-reading of Freud’s Totem and Taboo along with an analysis of John Sayles’s 1996 film, Lone Star, the paper outlines a possible way out of a poststructuralist versus liberal theory impasse over incest, thus proposing movement in the direction of a democratic understanding of incest concerns.
Isaiah Berlin’s “Minimum of Common Moral Ground”
Authors: Riley Jonathan
Published: October 2012

Isaiah Berlin’s political thought consistently combines tragic value pluralism with moral priority for a minimum sphere of individual liberty which is defined and protected by a core set of basic human rights. His fundamental concept of a common moral minimum includes multiple components, including the idea that there is a common moral world of plural and conflicting incommensurable objective values and the idea that humans share a common nucleus of needs and interests centered on the overriding goal of human survival. The basic human rights have priority over competing values because the rights are essential for human survival. They determine a common threshold of human decency: decent societies must respect the rights, which are in principle mutually harmonious under ordinary conditions, although emergencies can arise in which some of the rights must be sacrificed to respect others. Berlin’s focus is on decency, which he insists can be maintained without a commitment to political democracy.
The Lack of Power or the Power of Lack in Leadership as a Discursively Constructed Identity
Authors: Driver Michaela
Published: October 2012

The study uses a psychoanalytic framework to explore how leadership identities are constructed. It advances the idea that leadership identities are imaginary constructions that invariable fail, reiterating a lack of being. Empirical material consisting of interviews with 15 leaders is used to explore the productive role this lack plays. The study suggests that leadership identities are always already subverted by unconscious desire and therefore less powerful than we might think with regard to imposing structures on others, but also much more powerful than we might think as liberating struggles with leaders’ imaginary selves.
A semblance of identity
Authors: Widder Nathan
Published: October 2012

This article challenges the idea that individual and collective agency require centred, fixed identities to be efficacious and meaningful. In post-foundational political thought, this idea frequently underpins an understanding of the subject as something temporarily consolidated through constitutive exclusions and a claim that political and ethical thought must negotiate the necessity for and inevitable failure of these exclusions. Against this thesis, the article presents a reading of Nietzsche’s analysis of the drives and their relation to the ego, holding that for Nietzsche drives are synthesized into a complex but still dispersed assemblage that generates the illusion of unity in the form of an ego or ‘I’. For Nietzsche, the article argues, concrete agency is located in this assemblage of differences, the semblance of a centre being important in the coordination of these differences, but having no causal efficacy itself. The article concludes by examining whether Nietzsche falls into a variant of the ‘homunculus problem’ before turning to the doctrine of eternal return and showing how Nietzsche links his ethics to using the semblance of identity in order to overcome the need to link subjectivity to identity.
Kidney Injury Biomarkers in Hypertensive, Diabetic, and Nephropathy Rat Models Treated with Contrast Media
Authors: Rouse Rodney L. , Stewart Sharron R. , Thompson Karol L. , Zhang Jun
Published: October 2012

Contrast-induced nephropathy (CIN) refers to a decline in renal function following exposure to iodinated contrast media (CM). The present study was initiated to explore the role of known human risk factors (spontaneous hypertension, diabetes, protein-losing nephropathy) on CIN development in rodent models and to determine the effect of CM administration on kidney injury biomarkers in the face of preexisting kidney injury. Spontaneously hypertensive rats (hypertension), streptozotocin-treated Sprague Dawley rats (diabetes), and Dahl salt-sensitive rats (protein-losing nephropathy) were given single intravenous injections of the nonionic, low osmolar contrast medium, iohexol. Blood urea nitrogen (BUN), serum creatinine (sCr), and urinary biomarkers; albumin, lipocalin 2 (Lcn-2), osteopontin (Opn), kidney injury molecule 1 (Kim-1), renal papillary antigen 1 (Rpa-1), α-glutathione S-transferase (α-Gst), µ-glutathione S-transferase (µ-Gst), and beta-2 microglobulin (β2m) were measured in disease models and appropriate controls to determine the response of these biomarkers to CM administration. Each disease model produced elevated biomarkers of kidney injury without CM. Preexisting histopathology was exacerbated by CM but little or no significant increases in biomarkers were observed. When 1.5-fold or greater sCr increases from pre-CM were used to define true positives, receiver–operating characteristic curve analysis of biomarker performance showed sCr was the best predictor of CIN across disease models. β2m, Lcn-2, and BUN were the best predictors of histopathology defined kidney injury.
On-target and Off-target-based Toxicologic Effects
Authors: Rudmann Daniel G.
Published: October 2012

Adverse toxicologic effects are categorized as chemical-based, on-target, or off-target effects. Chemical-based toxicity is defined as toxicity that is related to the physicochemical characteristics of a compound and its effects on cellular organelles, membranes, and/or metabolic pathways. On-target refers to exaggerated and adverse pharmacologic effects at the target of interest in the test system. Off-target refers to adverse effects as a result of modulation of other targets; these may be related biologically or totally unrelated to the target of interest. Both the risk assessment and development strategies used for xenobiotics are influenced by the understanding of the mechanism of toxicity. It is imperative that the toxicologic pathologist use the toxicologic and biologic data at hand and literature information on the target to form testable hypotheses related to whether a toxicity is chemical-based, on-target, or off-target. The objective of this session at the 2012 Society of Toxicologic Pathologists Symposium in Boston, Massachusetts, was to discuss chemical-based, on-target, and off-target-based effects and the scientific approaches used to aid in their human risk assessment.