bluuebunny/crossref_metadata_2025 huggingface dataset:
TIGAR Has a Dual Role in Cancer Cell Survival through Regulating Apoptosis and Autophagy
Authors: Xie Jia-Ming , Li Bin , Yu Hong-Pei , Gao Quan-Geng , Li Wei , Wu Hao-Rong , Qin Zheng-Hong
Published: August 2014

The p53-induced glycolysis and apoptosis regulator (TIGAR) inhibits glycolysis, resulting in higher intracellular NADPH, lower reactive oxygen species (ROS) and autophagy activity. In this study, we investigated whether TIGAR might exert dual impacts on cancer cell survival based on its ability to inhibit both apoptosis and autophagy. In liver or lung cancer cells treated with the anticancer drug epirubicin, TIGAR levels increased in a dose- and time-dependent manner. TIGAR silencing enhanced epirubicin-induced elevations in ROS levels and apoptosis rates, in a manner that was blocked by ectopic addition of NADPH or N-acetyl cysteine. These findings were correlated with reduced tumorigenicity and increased chemosensitivity in mouse xenograft tumor assays. In parallel, TIGAR silencing also enhanced the epirubicin-induced activation of autophagy, in a manner that was also blocked by ectopic addition of NADPH. Notably, TIGAR silencing also licensed epirubicin-mediated inactivation of the mTOR pathway, suggesting TIGAR also exerted a negative impact on autophagy. However, genetic or pharmacologic inhibition of autophagy increased epirubicin-induced apoptosis in TIGAR-silenced cells. Overall, our results revealed that TIGAR inhibits both apoptosis and autophagy, resulting in a dual impact on tumor cell survival in response to tumor chemotherapy. Cancer Res; 74(18); 5127–38. ©2014 AACR.
A Novel Wnt Regulatory Axis in Endometrioid Endometrial Cancer
Authors: Zhao Yu , Yang Yihua , Trovik Jone , Sun Kun , Zhou Liang , Jiang Peiyong , Lau Tat-San , Hoivik Erling A. , Salvesen Helga B. , Sun Hao , Wang Huating
Published: August 2014

The Protocadherin 10 (PCDH10) is inactivated often by promoter hypermethylation in various human tumors, but its possible functional role as a tumor suppressor gene is not established. In this study, we identify PCDH10 as a novel Wnt pathway regulatory element in endometrioid endometrial carcinoma (EEC). PCDH10 was downregulated in EEC tumor cells by aberrant methylation of its promoter. Restoring PCDH10 levels suppressed cell growth and triggered apoptosis in EEC cells and tumor xenografts. Gene expression profiling revealed as part of the transcriptomic changes induced by PCDH10 a reduction in levels of MALAT1, a long noncoding RNA, that mediated tumor suppression functions of PCDH10 in EEC cells. We found that MALAT1 transcription was regulated by Wnt/β-catenin signaling via TCF promoter binding and PCDH10 decreased MALAT1 by modulating this pathway. Clinically, MALAT1 expression was associated with multiple parameters in patients with EEC. Taken together, our findings establish a novel PCDH10–Wnt/β-catenin–MALAT1 regulatory axis that contributes to EEC development. Cancer Res; 74(18); 5103–17. ©2014 AACR.
The SIRT1/HIF2α Axis Drives Reductive Glutamine Metabolism under Chronic Acidosis and Alters Tumor Response to Therapy
Authors: Corbet Cyril , Draoui Nihed , Polet Florence , Pinto Adan , Drozak Xavier , Riant Olivier , Feron Olivier
Published: August 2014

Extracellular tumor acidosis largely results from an exacerbated glycolytic flux in cancer and cancer-associated cells. Conversely, little is known about how tumor cells adapt their metabolism to acidosis. Here, we demonstrate that long-term exposure of cancer cells to acidic pH leads to a metabolic reprogramming toward glutamine metabolism. This switch is triggered by the need to reduce the production of protons from glycolysis and further maintained by the NAD+-dependent increase in SIRT1 deacetylase activity to ensure intracellular pH homeostasis. A consecutive increase in HIF2α activity promotes the expression of various transporters and enzymes supporting the reductive and oxidative glutamine metabolism, whereas a reduction in functional HIF1α expression consolidates the inhibition of glycolysis. Finally, in vitro and in vivo experiments document that acidosis accounts for a net increase in tumor sensitivity to inhibitors of SIRT1 and glutaminase GLS1. These findings highlight the influence that tumor acidosis and metabolism exert on each other. Cancer Res; 74(19); 5507–19. ©2014 AACR.
Intestinal Epithelial HuR Modulates Distinct Pathways of Proliferation and Apoptosis and Attenuates Small Intestinal and Colonic Tumor Development
Authors: Giammanco Antonina , Blanc Valerie , Montenegro Grace , Klos Coen , Xie Yan , Kennedy Susan , Luo Jianyang , Chang Sung-Hee , Hla Timothy , Nalbantoglu ILKe , Dharmarajan Sekhar , Davidson Nicholas O.
Published: August 2014

HuR is a ubiquitous nucleocytoplasmic RNA-binding protein that exerts pleiotropic effects on cell growth and tumorigenesis. In this study, we explored the impact of conditional, tissue-specific genetic deletion of HuR on intestinal growth and tumorigenesis in mice. Mice lacking intestinal expression of HuR (Hur IKO mice) displayed reduced levels of cell proliferation in the small intestine and increased sensitivity to doxorubicin-induced acute intestinal injury, as evidenced by decreased villus height and a compensatory shift in proliferating cells. In the context of Apcmin/+ mice, a transgenic model of intestinal tumorigenesis, intestinal deletion of the HuR gene caused a three-fold decrease in tumor burden characterized by reduced proliferation, increased apoptosis, and decreased expression of transcripts encoding antiapoptotic HuR target RNAs. Similarly, HurIKO mice subjected to an inflammatory colon carcinogenesis protocol [azoxymethane and dextran sodium sulfate (AOM-DSS) administration] exhibited a two-fold decrease in tumor burden. HurIKO mice showed no change in ileal Asbt expression, fecal bile acid excretion, or enterohepatic pool size that might explain the phenotype. Moreover, none of the HuR targets identified in Apcmin/+HurIKO were altered in AOM-DSS–treated HurIKO mice, the latter of which exhibited increased apoptosis of colonic epithelial cells, where elevation of a unique set of HuR-targeted proapoptotic factors was documented. Taken together, our results promote the concept of epithelial HuR as a contextual modifier of proapoptotic gene expression in intestinal cancers, acting independently of bile acid metabolism to promote cancer. In the small intestine, epithelial HuR promotes expression of prosurvival transcripts that support Wnt-dependent tumorigenesis, whereas in the large intestine epithelial HuR indirectly downregulates certain proapoptotic RNAs to attenuate colitis-associated cancer. Cancer Res; 74(18); 5322–35. ©2014 AACR.
Methylation Status of Blood Leukocyte DNA and Risk of Gastric Cancer in a High-Risk Chinese Population
Authors: Zhang Yang , Su Hui-juan , Pan Kai-feng , Zhang Lian , Ma Jun-ling , Shen Lin , Li Ji-you , Liu Wei-dong , Oze Isao , Matsuo Keitaro , Yuasa Yasuhito , You Wei-cheng
Published: August 2014

Background: To evaluate the relationship between methylation status of blood leukocyte DNA and risk of gastric cancer, a population-based study was conducted in Linqu County.

Methods: Methylation levels of IGFII and N33 were determined by quantitative methylation-specific PCR. The temporal trend of methylation levels during gastric cancer development was investigated in 133 gastric cancer cases from two cohorts with pre– and/or post–gastric cancer samples. As the references of pre-GCs, 204 intestinal metaplasia (IM) or dysplasia (DYS) subjects who did not progress to gastric cancer during the follow-up period were selected. Meanwhile, 285 subjects with superficial gastritis/chronic atrophic gastritis (SG/CAG) were also selected as controls.

Results: IGFII median methylation level was significantly higher in gastric cancer cases than those with SG/CAG (61.47% vs. 49.73%; P < 0.001). IGFII and N33 methylation levels were elevated at least 5 years ahead of clinical gastric cancer diagnosis comparing with SG/CAG (63.38% vs. 49.73% for IGFII, 9.12% vs. 5.70% for N33; all P < 0.001). Furthermore, the frequency of hypermethylated IGFII was markedly increased in IM or DYS subjects who progressed to gastric cancer in contrast to those who remained with IM and DYS, and adjusted ORs were 12.52 [95% confidence interval (CI), 3.81–41.15] for IM and 10.12 (95% CI, 2.68–38.22) for DYS. Similar results were also found for N33 in subjects with IM (OR, 3.77; 95% CI, 1.20–11.86).

Conclusions: Our findings suggested that hypermethylated IGFII and N33 in blood leukocyte DNA were associated with risk of gastric cancer in a Chinese population.

Impact: IGFII and N33 methylation status may be related to gastric carcinogenesis. Cancer Epidemiol Biomarkers Prev; 23(10); 2019–26. ©2014 AACR.
Reproductive and Hormonal Risk Factors for Antinuclear Antibodies (ANA) in a Representative Sample of U.S. Women
Authors: Parks Christine G. , Miller Frederick W. , Satoh Minoru , Chan Edward K.L. , Andrushchenko Zhanna , Birnbaum Linda S. , Jusko Todd A. , Kissling Grace E. , Patel Mehul D. , Rose Kathryn M. , Weinberg Clarice , Zeldin Darryl C. , Sandler Dale P.
Published: August 2014

Background: Autoantibodies are of growing interest in cancer research as potential biomarkers; yet, the determinants of autoimmunity are not well understood. Antinuclear antibodies (ANA) are common in the general population and are more prevalent in women and older adults. Here, we examined the relationship of ANA with reproductive and hormonal factors in a representative sample of U.S. women.

Methods: We analyzed data on reproductive history and exogenous hormone use in relation to serum ANA in 2,037 females ages 12 years and older from the National Health and Nutrition Examination Survey (NHANES; 1999–2004). Estimated ANA prevalences were adjusted for sampling weights. Prevalence ORs (POR) and 95% confidence intervals (CI) were adjusted for age, race, and poverty–income ratio, and models were stratified by menopause status.

Results: In premenopausal women ages 20 years and older, ANA prevalence was associated with parity (P < 0.001; parous vs. nulliparous POR = 2.0; 95% CI, 1.2–3.4), but in parous women, ANA did not vary by number of births, age at first birth, years since last birth, or breastfeeding. In postmenopausal women, ANA prevalence was associated with an older age at menarche (P = 0.019; age 16–20 vs. 10–12 years POR = 3.0; 95% CI, 1.6–5.9), but not with parity. Oral contraceptives and estrogen therapy were not associated with a higher ANA prevalence.

Conclusions: Childbearing (having had one or more births) may explain age-associated elevations in ANA prevalence seen in premenopausal women.

Impact: These findings highlight the importance of considering reproductive history in studies of autoimmunity and cancer in women. Cancer Epidemiol Biomarkers Prev; 23(11); 2492–502. ©2014 AACR.
Restoration of Compact Golgi Morphology in Advanced Prostate Cancer Enhances Susceptibility to Galectin-1–Induced Apoptosis by Modifying Mucin O-Glycan Synthesis
Authors: Petrosyan Armen , Holzapfel Melissa S. , Muirhead David E. , Cheng Pi-Wan
Published: August 2014

Prostate cancer progression is associated with upregulation of sialyl-T antigen produced by β-galactoside α-2,3-sialyltransferase-1 (ST3Gal1) but not with core 2-associated polylactosamine despite expression of core 2 N-acetylglucosaminyltransferase-L (C2GnT-L/GCNT1). This property allows androgen-refractory prostate cancer cells to evade galectin-1 (LGALS1)–induced apoptosis, but the mechanism is not known. We have recently reported that Golgi targeting of glycosyltransferases is mediated by golgins: giantin (GOLGB1) for C2GnT-M (GCNT3) and GM130 (GOLGA2)-GRASP65 (GORASP1) or GM130-giantin for core 1 synthase. Here, we show that for Golgi targeting, C2GnT-L also uses giantin exclusively whereas ST3Gal1 uses either giantin or GM130-GRASP65. In addition, the compact Golgi morphology is detected in both androgen-sensitive prostate cancer and normal prostate cells, but fragmented Golgi and mislocalization of C2GnT-L are found in androgen-refractory cells as well as primary prostate tumors (Gleason grade 2–4). Furthermore, failure of giantin monomers to be phosphorylated and dimerized prevents Golgi from forming compact morphology and C2GnT-L from targeting the Golgi. On the other hand, ST3Gal1 reaches the Golgi by an alternate site, GM130-GRASP65. Interestingly, inhibition or knockdown of non-muscle myosin IIA (MYH9) motor protein frees up Rab6a GTPase to promote phosphorylation of giantin by polo-like kinase 3 (PLK3), which is followed by dimerization of giantin assisted by protein disulfide isomerase A3 (PDIA3), and restoration of compact Golgi morphology and targeting of C2GnT-L. Finally, the Golgi relocation of C2GnT-L in androgen-refractory cells results in their increased susceptibility to galectin-1–induced apoptosis by replacing sialyl-T antigen with polylactosamine.

Implications: This study demonstrates the importance of Golgi morphology and regulation of glycosylation and provides insight into how the Golgi influences cancer progression and metastasis. Mol Cancer Res; 12(12); 1704–16. ©2014 AACR.
Active CREB1 Promotes a Malignant TGFβ2 Autocrine Loop in Glioblastoma
Authors: Rodón Laura , Gonzàlez-Juncà Alba , del Mar Inda María , Sala-Hojman Ada , Martínez-Sáez Elena , Seoane Joan
Published: August 2014

In advanced cancer, including glioblastoma, the TGFβ pathway acts as an oncogenic factor. Some tumors exhibit aberrantly high TGFβ activity, and the mechanisms underlying this phenomenon are not well understood. We have observed that TGFβ can induce TGFβ2, generating an autocrine loop leading to aberrantly high levels of TGFβ2. We identified cAMP-responsive element–binding protein 1 (CREB1) as the critical mediator of the induction of TGFβ2 by TGFβ. CREB1 binds to the TGFB2 gene promoter in cooperation with SMAD3 and is required for TGFβ to activate transcription. Moreover, the PI3K–AKT and RSK pathways regulate the TGFβ2 autocrine loop through CREB1. The levels of CREB1 and active phosphorylated CREB1 correlate with TGFβ2 in glioblastoma. In addition, using patient-derived in vivo models of glioblastoma, we found that CREB1 levels determine the expression of TGFβ2. Our results show that CREB1 can be considered a biomarker to stratify patients for anti-TGFβ treatments and a therapeutic target in glioblastoma.

Significance: TGFβ is considered a promising therapeutic target, and several clinical trials using TGFβ inhibitors are generating encouraging results. Here, we discerned the molecular mechanisms responsible for the aberrantly high levels of TGFβ2 found in certain tumors, and we propose biomarkers to predict the clinical response to anti-TGFβ therapies. Cancer Discov; 4(10); 1230–41. ©2014 AACR.

See related commentary by Wotton, p. 1123

This article is highlighted in the In This Issue feature, p. 1103
Perioperative Beta Blockade in Noncardiac Surgery: A Systematic Review for the 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery
Authors: Wijeysundera Duminda N. , Duncan Dallas , Nkonde-Price Chileshe , Virani Salim S. , Washam Jeffrey B. , Fleischmann Kirsten E. , Fleisher Lee A.
Published: August 2014

Objective—

To review the literature systematically to determine whether initiation of beta blockade within 45 days prior to noncardiac surgery reduces 30-day cardiovascular morbidity and mortality rates.

Methods—

PubMed (up to April 2013), Embase (up to April 2013), Cochrane Central Register of Controlled Trials (up to March 2013), and conference abstracts (January 2011 to April 2013) were searched for randomized controlled trials (RCTs) and cohort studies comparing perioperative beta blockade with inactive control during noncardiac surgery. Pooled relative risks (RRs) were calculated under the random-effects model. We conducted subgroup analyses to assess how the DECREASE-I (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography), DECREASE-IV, and POISE-1 (Perioperative Ischemic Evaluation) trials influenced our conclusions.

Results—

We identified 17 studies, of which 16 were RCTs (12 043 participants) and 1 was a cohort study (348 participants). Aside from the DECREASE trials, all other RCTs initiated beta blockade within 1 day or less prior to surgery. Among RCTs, beta blockade decreased nonfatal myocardial infarction (MI) (RR: 0.69; 95% confidence interval [CI]: 0.58 to 0.82) but increased nonfatal stroke (RR: 1.76; 95% CI: 1.07 to 2.91), hypotension (RR: 1.47; 95% CI: 1.34 to 1.60), and bradycardia (RR: 2.61; 95% CI: 2.18 to 3.12). These findings were qualitatively unchanged after the DECREASE and POISE-1 trials were excluded. Effects on mortality rate differed significantly between the DECREASE trials and other trials. Beta blockers were associated with a trend toward reduced all-cause mortality rate in the DECREASE trials (RR: 0.42; 95% CI: 0.15 to 1.22) but with increased all-cause mortality rate in other trials (RR: 1.30; 95% CI: 1.03 to 1.64). Beta blockers reduced cardiovascular mortality rate in the DECREASE trials (RR: 0.17; 95% CI: 0.05 to 0.64) but were associated with trends toward increased cardiovascular mortality rate in other trials (RR: 1.25; 95% CI: 0.92 to 1.71). These differences were qualitatively unchanged after the POISE-1 trial was excluded.

Conclusions—

Perioperative beta blockade started within 1 day or less before noncardiac surgery prevents nonfatal MI but increases risks of stroke, death, hypotension, and bradycardia. Without the controversial DECREASE studies, there are insufficient data on beta blockade started 2 or more days prior to surgery. Multicenter RCTs are needed to address this knowledge gap.
Common and Rare Variants in
SCN10A
Modulate the Risk of Atrial Fibrillation
Authors: Jabbari Javad , Olesen Morten S. , Yuan Lei , Nielsen Jonas B. , Liang Bo , Macri Vincenzo , Christophersen Ingrid E. , Nielsen Nikolaj , Sajadieh Ahmad , Ellinor Patrick T. , Grunnet Morten , Haunsø Stig ,   on behalf of LuCamp, Holst Anders G. , Svendsen Jesper H. , Jespersen Thomas
Published: August 2014

Background—

Genome-wide association studies have shown that the common single nucleotide polymorphism rs6800541 located in
SCN10A
, encoding the voltage-gated Na
v
1.8 sodium channel, is associated with PR-interval prolongation and atrial fibrillation (AF). Single nucleotide polymorphism rs6800541 is in high linkage disequilibrium with the nonsynonymous variant in
SCN10A
, rs6795970 (V1073A,
r
2
=0.933). We therefore sought to determine whether common and rare
SCN10A
variants are associated with early onset AF.

Methods and Results—

SCN10A
was sequenced in 225 AF patients in whom there was no evidence of other cardiovascular disease or dysfunction (lone AF). In an association study of the rs6795970 single nucleotide polymorphism variant, we included 515 AF patients and 2 control cohorts of 730 individuals free of AF and 6161 randomly sampled individuals. Functional characterization of
SCN10A
variants was performed by whole-cell patch-clamping. In the lone AF cohort, 9 rare missense variants and 1 splice site donor variant were detected. Interestingly, AF patients were found to have higher G allele frequency of rs6795970, which encodes the alanine variant at position 1073 (described from here on as A1073, odds ratio =1.35 [1.16−1.54];
P
=2.3×10
−5
). Both of the common variants, A1073 and P1092, induced a gain-of-channel function, whereas the rare missense variants, V94G and R1588Q, resulted in a loss-of-channel function.

Conclusions—

The common variant A1073 is associated with increased susceptibility to AF. Both rare and common variants have effect on the function of the channel, indicating that these variants influence susceptibility to AF. Hence, our study suggests that
SCN10A
variations are involved in the genesis of AF.
A Common Polymorphism in Extracellular Superoxide Dismutase Affects Cardiopulmonary Disease Risk by Altering Protein Distribution
Authors: Hartney John M. , Stidham Timothy , Goldstrohm David A. , Oberley-Deegan Rebecca E. , Weaver Michael R. , Valnickova-Hansen Zuzana , Scavenius Carsten , Benninger Richard K.P. , Leahy Katelyn F. , Johnson Richard , Gally Fabienne , Kosmider Beata , Zimmermann Angela K. , Enghild Jan J. , Nozik-Grayck Eva , Bowler Russell P.
Published: August 2014

Background—

The enzyme extracellular superoxide dismutase (EC-SOD;
SOD3
) is a major antioxidant defense in lung and vasculature. A nonsynonomous single-nucleotide polymorphism in EC-SOD (rs1799895) leads to an arginine to glycine amino acid substitution at position 213 (R213G) in the heparin-binding domain. In recent human genetic association studies, this single-nucleotide polymorphism attenuates the risk of lung disease, yet paradoxically increases the risk of cardiovascular disease.

Methods and Results—

Capitalizing on the complete sequence homology between human and mouse in the heparin-binding domain, we created an analogous R213G single-nucleotide polymorphism knockin mouse. The R213G single-nucleotide polymorphism did not change enzyme activity, but shifted the distribution of EC-SOD from lung and vascular tissue to extracellular fluid (eg, bronchoalveolar lavage fluid and plasma). This shift reduces susceptibility to lung disease (lipopolysaccharide-induced lung injury) and increases susceptibility to cardiopulmonary disease (chronic hypoxic pulmonary hypertension).

Conclusions—

We conclude that EC-SOD provides optimal protection when localized to the compartment subjected to extracellular oxidative stress: thus, the redistribution of EC-SOD from the lung and pulmonary circulation to the extracellular fluids is beneficial in alveolar lung disease but detrimental in pulmonary vascular disease. These findings account for the discrepant risk associated with R213G in humans with lung diseases compared with cardiovascular diseases.
Infarct Characterization and Quantification by Delayed Enhancement Cardiac Magnetic Resonance Imaging Is a Powerful Independent and Incremental Predictor of Mortality in Patients With Advanced Ischemic Cardiomyopathy
Authors: Kwon Deborah H. , Asamoto Lisa , Popovic Zoran B. , Kusunose Kenya , Robinson Monique , Desai Milind , Marwick Thomas H. , Flamm Scott D.
Published: August 2014

Background—

Infarct heterogeneity has been shown to be independently associated with adverse outcomes in previous smaller studies. However, it is unknown whether infarct characterization is an independent predictor of all-cause mortality in patients with advanced ischemic cardiomyopathy, after adjusting for clinical risk factors, severity of ischemic mitral regurgitation, incomplete revascularization, and device therapy.

Methods and Results—

A total of 362 patients with ischemic cardiomyopathy (left ventricular dysfunction with >70% stenosis in ≥1 epicardial coronary artery) underwent delayed hyperenhancement-magnetic resonance imaging and coronary angiography between 2002 and 2006. Total myocardial scar and peri-infarct (PI) area were measured using various threshold techniques. Multivariate survival analysis (primary end point of all-cause mortality) was conducted. One hundred fifty-seven deaths occurred during a mean 5.4-year follow-up (mean left ventricular ejection fraction, 23±9%; mean end-systolic volume index, 113±48 mL; mean total myocardial scar %, 25.5±16.0%; mean PI%, 5.7±2.9%). PI% (β=2.07;
P
<0.001) was an independent predictor of survival, independent of age, end-systolic volume, sex, mitral regurgitation, diabetes mellitus, dyslipidemia, coronary artery disease severity, implantable cardioverter defibrillator, and incomplete revascularization. PI% using 2 to 3 SD technique yielded the highest incremental prognostic power (χ
2
score 149).

Conclusions—

In advanced ischemic cardiomyopathy, PI% is a powerful independent and incremental predictor of all-cause mortality. Infarct heterogeneity offers substantial further risk stratification when compared with quantification of total myocardial scar % alone even after adjusting for clinical risk factors, end-systolic volume index, mitral regurgitation, incomplete revascularization, and implantable cardioverter defibrillator implantation.
Ca
V
3.2 Channels and the Induction of Negative Feedback in Cerebral Arteries
Authors: Harraz Osama F. , Abd El-Rahman Rasha R. , Bigdely-Shamloo Kamran , Wilson Sean M. , Brett Suzanne E. , Romero Monica , Gonzales Albert L. , Earley Scott , Vigmond Edward J. , Nygren Anders , Menon Bijoy K. , Mufti Rania E. , Watson Tim , Starreveld Yves , Furstenhaupt Tobias , Muellerleile Philip R. , Kurjiaka David T. , Kyle Barry D. , Braun Andrew P. , Welsh Donald G.
Published: August 2014

Rationale:

T-type (Ca
V
3.1/Ca
V
3.2) Ca
2+
channels are expressed in rat cerebral arterial smooth muscle. Although present, their functional significance remains uncertain with findings pointing to a variety of roles.

Objective:

This study tested whether Ca
V
3.2 channels mediate a negative feedback response by triggering Ca
2+
sparks, discrete events that initiate arterial hyperpolarization by activating large-conductance Ca
2+
-activated K
+
channels.

Methods and Results:

Micromolar Ni
2+
, an agent that selectively blocks Ca
V
3.2 but not Ca
V
1.2/Ca
V
3.1, was first shown to depolarize/constrict pressurized rat cerebral arteries; no effect was observed in Ca
V
3.2
−/−
arteries. Structural analysis using 3-dimensional tomography, immunolabeling, and a proximity ligation assay next revealed the existence of microdomains in cerebral arterial smooth muscle which comprised sarcoplasmic reticulum and caveolae. Within these discrete structures, Ca
V
3.2 and ryanodine receptor resided in close apposition to one another. Computational modeling revealed that Ca
2+
influx through Ca
V
3.2 could repetitively activate ryanodine receptor, inducing discrete Ca
2+
-induced Ca
2+
release events in a voltage-dependent manner. In keeping with theoretical observations, rapid Ca
2+
imaging and perforated patch clamp electrophysiology demonstrated that Ni
2+
suppressed Ca
2+
sparks and consequently spontaneous transient outward K
+
currents, large-conductance Ca
2+
-activated K
+
channel mediated events. Additional functional work on pressurized arteries noted that paxilline, a large-conductance Ca
2+
-activated K
+
channel inhibitor, elicited arterial constriction equivalent, and not additive, to Ni
2+
. Key experiments on human cerebral arteries indicate that Ca
V
3.2 is present and drives a comparable response to moderate constriction.

Conclusions:

These findings indicate for the first time that Ca
V
3.2 channels localize to discrete microdomains and drive ryanodine receptor–mediated Ca
2+
sparks, enabling large-conductance Ca
2+
-activated K
+
channel activation, hyperpolarization, and attenuation of cerebral arterial constriction.
Inhibition of 14q32 MicroRNAs miR-329, miR-487b, miR-494, and miR-495 Increases Neovascularization and Blood Flow Recovery After Ischemia
Authors: Welten Sabine M.J. , Bastiaansen Antonius J.N.M. , de Jong Rob C.M. , de Vries Margreet R. , Peters Erna A.B. , Boonstra Martin C. , Sheikh Søren P. , La Monica Nicola , Kandimalla Ekambar R. , Quax Paul H.A. , Nossent A. Yaël
Published: August 2014

Rationale:

Effective neovascularization is crucial for recovery after cardiovascular events.

Objective:

Because microRNAs regulate expression of up to several hundred target genes, we set out to identify microRNAs that target genes in all pathways of the multifactorial neovascularization process. Using
www.targetscan.org
, we performed a reverse target prediction analysis on a set of 197 genes involved in neovascularization. We found enrichment of binding sites for 27 microRNAs in a single microRNA gene cluster. Microarray analyses showed upregulation of 14q32 microRNAs during neovascularization in mice after single femoral artery ligation.

Methods and Results:

Gene silencing oligonucleotides (GSOs) were used to inhibit 4 14q32 microRNAs, miR-329, miR-487b, miR-494, and miR-495, 1 day before double femoral artery ligation. Blood flow recovery was followed by laser Doppler perfusion imaging. All 4 GSOs clearly improved blood flow recovery after ischemia. Mice treated with GSO-495 or GSO-329 showed increased perfusion already after 3 days (30% perfusion versus 15% in control), and those treated with GSO-329 showed a full recovery of perfusion after 7 days (versus 60% in control). Increased collateral artery diameters (arteriogenesis) were observed in adductor muscles of GSO-treated mice, as well as increased capillary densities (angiogenesis) in the ischemic soleus muscle. In vitro, treatment with GSOs led to increased sprout formation and increased arterial endothelial cell proliferation, as well as to increased arterial myofibroblast proliferation.

Conclusions:

The 14q32 microRNA gene cluster is highly involved in neovascularization. Inhibition of 14q32 microRNAs miR-329, miR-487b, miR-494, and miR-495 provides a promising tool for future therapeutic neovascularization.
FOXF1 Transcription Factor Is Required for Formation of Embryonic Vasculature by Regulating VEGF Signaling in Endothelial Cells
Authors: Ren Xiaomeng , Ustiyan Vladimir , Pradhan Arun , Cai Yuqi , Havrilak Jamie A. , Bolte Craig S. , Shannon John M. , Kalin Tanya V. , Kalinichenko Vladimir V.
Published: August 2014

Rationale:

Inactivating mutations in the Forkhead Box transcription factor F1 (
FOXF1
) gene locus are frequently found in patients with alveolar capillary dysplasia with misalignment of pulmonary veins, a lethal congenital disorder, which is characterized by severe abnormalities in the respiratory, cardiovascular, and gastrointestinal systems. In mice, haploinsufficiency of the
Foxf1
gene causes alveolar capillary dysplasia and developmental defects in lung, intestinal, and gall bladder morphogenesis.

Objective:

Although FOXF1 is expressed in multiple mesenchyme-derived cell types, cellular origins and molecular mechanisms of developmental abnormalities in FOXF1-deficient mice and patients with alveolar capillary dysplasia with misalignment of pulmonary veins remain uncharacterized because of lack of mouse models with cell-restricted inactivation of the
Foxf1
gene. In the present study, the role of FOXF1 in endothelial cells was examined using a conditional knockout approach.

Methods and Results:

A novel mouse line harboring
Foxf1
-floxed alleles was generated by homologous recombination.
Tie2-Cre
and
Pdgfb-CreER
transgenes were used to delete
Foxf1
from endothelial cells. FOXF1-deficient embryos exhibited embryonic lethality, growth retardation, polyhydramnios, cardiac ventricular hypoplasia, and vascular abnormalities in the lung, placenta, yolk sac, and retina. Deletion of FOXF1 from endothelial cells reduced endothelial proliferation, increased apoptosis, inhibited vascular endothelial growth factor signaling, and decreased expression of endothelial genes critical for vascular development, including vascular endothelial growth factor receptors Flt1 and Flk1, Pdgfb, Pecam1, CD34, integrin β3, ephrin B2, Tie2, and the noncoding RNA
Fendrr
. Chromatin immunoprecipitation assay demonstrated that Flt1, Flk1, Pdgfb, Pecam1, and Tie2 genes are direct transcriptional targets of FOXF1.

Conclusions:

FOXF1 is required for the formation of embryonic vasculature by regulating endothelial genes critical for vascular development and vascular endothelial growth factor signaling.
Cost-Effectiveness of Percutaneous Coronary Intervention With Drug-Eluting Stents Versus Bypass Surgery for Patients With 3-Vessel or Left Main Coronary Artery Disease
Authors: Cohen David J. , Osnabrugge Ruben L. , Magnuson Elizabeth A. , Wang Kaijun , Li Haiyan , Chinnakondepalli Khaja , Pinto Duane , Abdallah Mouin S. , Vilain Katherine A. , Morice Marie-Claude , Dawkins Keith D. , Kappetein A. Pieter , Mohr Friedrich W. , Serruys Patrick W.
Published: August 2014

Background—

The Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery (SYNTAX) trial demonstrated that in patients with 3-vessel or left main coronary artery disease, coronary artery bypass graft surgery (CABG) was associated with a lower rate of cardiovascular death, myocardial infarction, stroke, or repeat revascularization compared with percutaneous coronary revascularization with drug-eluting stents (DES-PCI)). The long-term cost-effectiveness of these strategies is unknown.

Methods and Results—

Between 2005 and 2007, 1800 patients with left main or 3-vessel coronary artery disease were randomized to CABG (n=897) or DES-PCI (n=903). Costs were assessed from a US perspective, and health state utilities were evaluated with the EuroQOL questionnaire. A patient-level microsimulation model based on the 5-year in-trial data was used to extrapolate costs, life expectancy, and quality-adjusted life expectancy over a lifetime horizon. Although initial procedural costs were $3415 per patient lower with CABG, total hospitalization costs were $10 036 per patient higher. Over the next 5 years, follow-up costs were higher with DES-PCI as a result of more frequent hospitalizations, revascularization procedures, and higher medication costs. Over a lifetime horizon, CABG remained more costly than DES-PCI, but the incremental cost-effectiveness ratio was favorable ($16 537 per quality-adjusted life-year gained) and remained <$20 000 per quality-adjusted life-year in most bootstrap replicates. Results were consistent across a wide range of assumptions about the long-term effect of CABG versus DES-PCI on events and costs. In patients with left main disease or a SYNTAX score ≤22, however, DES-PCI was economically dominant compared with CABG, although these findings were less certain.

Conclusions—

For most patients with 3-vessel or left main coronary artery disease, CABG is a clinically and economically attractive revascularization strategy compared with DES-PCI. However, among patients with less complex disease, DES-PCI may be preferred on both clinical and economic grounds.

Clinical Trial Registration—

URL:
www.clinicaltrials.gov
. Unique identifier: NCT00114972.
Paricalcitol and Endothelial Function in Chronic Kidney Disease Trial
Authors: Zoccali Carmine , Curatola Giuseppe , Panuccio Vincenzo , Tripepi Rocco , Pizzini Patrizia , Versace Marica , Bolignano Davide , Cutrupi Sebastiano , Politi Raffaele , Tripepi Giovanni , Ghiadoni Lorenzo , Thadhani Ravi , Mallamaci Francesca
Published: August 2014

Altered vitamin D metabolism and low levels of the active form of this vitamin, 1,25-dihydroxy-vitamin D, is a hallmark of chronic kidney disease (CKD), but there is still no randomized controlled trial testing the effect of active forms of vitamin D on vascular function in patients with CKD. Paricalcitol and ENdothelial fuNction in chronic kidneY disease (PENNY) is a double-blinded randomized controlled trial (ClinicalTrials.gov, NCT01680198) testing the effect of an active form of vitamin D, paricalcitol (2 μg/d×12 weeks) on endothelium-dependent and endothelium-independent vasodilatation in 88 patients with stage 3 to 4 CKD and parathormone >65 pg/mL (paricalcitol, n=44; placebo, n=44). Paricalcitol treatment reduced parathormone (−75 pg/mL; 95% confidence interval, –90 to –60), whereas parathormone showed a small rise during placebo (21 pg/mL; 95% confidence interval, 5–36). Blood pressure did not change in both study arms. Baseline flow-mediated dilation was identical in patients on paricalcitol (3.6±2.9%) and placebo (3.6±2.9%) groups. After 12 weeks of treatment, flow-mediated dilation rose in the paricalcitol but not in the placebo group, and the between-group difference in flow-mediated dilation changes (the primary end point, 1.8%; 95% confidence interval, 0.3–3.1%) was significant (
P
=0.016), and the mean proportional change in flow-mediated dilation was 61% higher in paricalcitol-treated patients than in placebo-treated patients. Such an effect was abolished 2 weeks after stopping the treatment. No effect of paricalcitol on endothelium-independent vasodilatation was registered. Paricalcitol improves endothelium-dependent vasodilatation in patients with stage 3 to 4 CKD. Findings in this study support the hypothesis that vitamin D may exert favorable effects on the cardiovascular system in patients with CKD.
Acute Effects of Intracoronary Tirofiban on No-Reflow Phenomena in Patients With ST-Segment Elevated Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention
Authors: Akpek Mahmut , Sahin Omer , Sarli Bahadir , Baktir Ahmet Oguz , Saglam Hayrettin , Urkmez Serkan , Ergin Ali , Oguzhan Abdurrahman , Arinc Huseyin , Kaya Mehmet G.
Published: August 2014

We evaluated the acute effect of intracoronary administration of tirofiban on no-reflow phenomenon in patients with ST-segment elevated myocardial infarction undergoing primary percutaneous coronary intervention. Consecutive patients (n = 162) were randomized into 2 groups based on whether intracoronary tirofiban was administered. After the administration of intracoronary tirofiban, thrombolysis in myocardial infarction (TIMI) flow grade significantly increased ( P < .001) and successful reperfusion was achieved in 26 (32%) patients. In the placebo group, however, after the administration of intracoronary placebo the TIMI flow grade did not change ( P = .070), and successful reperfusion was achieved only in 8 (10%) patients. In-hospital major adverse cardiac events (MACE) were significantly lower in the tirofiban group (36% vs 19%, P = .013). Intracoronary administration of tirofiban significantly improves TIMI flow grade and is associated with a lower in-hospital rate of MACE.
Towards a global environmental sociology? Legacies, trends and future directions
Authors: Lidskog Rolf , Mol Arthur PJ , Oosterveer Peter
Published: August 2014

A current debate on environmental sociology involves how the subdiscipline should conceptualise and investigate the environment and whether it should be prescriptive and deliver policy recommendations. Taking this debate as a point of departure this article discusses the current and future role of sociology in a globalised world. It discusses how environmental sociology in the US and Europe differ in their understandings of sociology’s contribution to the study of the environment. Particular stress is placed on how these two regions differ with respect to their use of the tradition of sociological thought, views on what constitutes the environment and ways of institutionalising environmental sociology as a sociological field. In conclusion, the question is raised of whether current versions of environmental sociology are appropriate for analysing a globalised world environment; or whether environmental sociology’s strong roots in European and US cultures make it less relevant when facing an increasingly globalised world. Finally, the article proposes some new rules for a global environmental sociology and describes some of their possible implications for the sociological study of climate change.
Beliefs about the causes of schizophrenia among Aymara and non-Aymara patients and their primary caregivers in the Central–Southern Andes
Authors: Caqueo-Urízar Alejandra , Breslau Joshua , Gilman Stephen E
Published: August 2014

Aim:

The aim of this study is to investigate differences in the beliefs about the causes of schizophrenia between Aymara and non-Aymara patients with schizophrenia and their primary caregivers. Ethnic background plays an important role in the formation of beliefs regarding the causes of schizophrenia, and there have been no prior studies on such beliefs among the Aymara, an indigenous community with a population of about 2 million people living in the Andes. We focused on three systems of beliefs distinguished in the literature: biological, psychosocial and magical–religious.

Methods:

The sample comprised 253 patients ( n = 117 Aymara, and n = 136 non-Aymara) of public mental health centers in Chile (33.6%), Peru (33.6%) and Bolivia (32.8%) with a diagnosis of schizophrenia, and each patient’s primary caregiver. We administered to patients and caregivers a questionnaire with scales assessing the perceived causes of schizophrenia. Linear regression models were fitted to compare differences in the levels of causal beliefs between Aymara and non-Aymara patients and caregivers, and to identify socio-demographic and clinical predictors of different types of beliefs about the causes of schizophrenia.

Results:

Adjusted for socio-demographic and clinical covariates, levels of psychosocial beliefs were significantly higher for Aymara caregivers (0.33, 95% confidence interval (CI) = 0.05, 0.62) than non-Aymara caregivers.

Conclusions:

Contrary to expectations, beliefs about the causes of schizophrenia among Aymara are not more magical–religious than those of their non-Aymara counterparts. It may be necessary for mental health staff members to evaluate beliefs about the disorder, especially in ethnic minorities, before applying a standard model of treatment.
Cognitive Existentialism and the Global Politics of State Survival: The Nigeria/Cameroun Bakassi Conflict
Authors: Ebohon Sylvanus Idahota
Published: August 2014

This paper attempts to situate Nigeria’s capitulation to Cameroun in the Bakassi boundary conflict between the two nations within the context and logic of global politics driven by global states such as the United States of America, Great Britain, France and Germany. It makes a case for why and how a sub-regional war was averted within the Gulf of Guinea. The paper argued that although the crisis was a sub-regional inter-state boundary dispute which threatened to escalate into a sub-regional war within the Gulf of Guinea, it acquired a global stature within the context of the operational security architecture of AFRICOM that seeks to globalize security in the incipient second wave of neo-global governance. The crisis provided ample opportunity for the operationalization of the new geography of power in global politics, founded and driven by the mirror image of ‘cognitive existentialism’. The paper concludes that Obasanjo’s lowering of the Nigerian flag in Bakassi in the context of the new security architecture was fuelled more by the fears of an escalated anti-federal militant upsurge in the Niger Delta; the official records showing Bakassi as an oil axis; America’s incorporation of Bakassi into the Gulf of Guinea; the painful remembrance of the ugly Nigerian civil war experience; and America’s refusal to supply Nigeria arms in the event of a war with Cameroun, than by a global environment characterized by the low politics of environmental recreation, humanitarian intervention and the politics of human rights.
Trait and State Authenticity Across Cultures
Authors: Slabu Letitia , Lenton Alison P. , Sedikides Constantine , Bruder Martin
Published: August 2014

We examined the role of culture in both trait and state authenticity, asking whether the search for and experience of the “true self” is a uniquely Western phenomenon or is relevant cross-culturally. We tested participants from the United States, China, India, and Singapore. U.S. participants reported higher average levels of trait authenticity than those from Eastern cultures (i.e., China, India, Singapore), but this effect was partially explained by cultural differences in self-construal and thinking style. Importantly, the experience of state authenticity, and especially state inauthenticity, was more similar than different across cultures. In all, people from different cultures do experience authenticity, even if they do not endorse the (Western) value of “independence.” The findings contribute to a more nuanced understanding of state authenticity.
Burglar Target Selection
Authors: Townsley Michael , Birks Daniel , Bernasco Wim , Ruiter Stijn , Johnson Shane D. , White Gentry , Baum Scott
Published: August 2014

Objectives:

This study builds on research undertaken by Bernasco and Nieuwbeerta and explores the generalizability of a theoretically derived offender target selection model in three cross-national study regions.

Methods:

Taking a discrete spatial choice approach, we estimate the impact of both environment- and offender-level factors on residential burglary placement in the Netherlands, the United Kingdom, and Australia. Combining cleared burglary data from all study regions in a single statistical model, we make statistical comparisons between environments.

Results:

In all three study regions, the likelihood an offender selects an area for burglary is positively influenced by proximity to their home, the proportion of easily accessible targets, and the total number of targets available. Furthermore, in two of the three study regions, juvenile offenders under the legal driving age are significantly more influenced by target proximity than adult offenders. Post hoc tests indicate the magnitudes of these impacts vary significantly between study regions.

Conclusions:

While burglary target selection strategies are consistent with opportunity-based explanations of offending, the impact of environmental context is significant. As such, the approach undertaken in combining observations from multiple study regions may aid criminology scholars in assessing the generalizability of observed findings across multiple environments.
Rotary jet-spinning of hematite fibers
Authors: Schabikowski Mateusz , Tomaszewska Justyna , Kata Dariusz , Graule Thomas
Published: August 2014

This work presents fabrication of purely ceramic submicron fibers by rotary jet-spinning – a recently developed method. An inertial force is used to form fibrous jets made of viscous dispersions, which then solidify during solvent evaporation. Precursor suspensions were prepared with the use of water as the only solvent, non-toxic Fe2O3 ceramic powder and poly(ethylene oxide) – a fiber-forming agent. The obtained fibers were in the range of 0.2–1.4 µm in diameter. This work presents a concept that utilizes ceramic fibers that could potentially be used for arsenic removal based on adsorption-enhanced filtration. We prove that ceramic fibers can be formed by simply adding non-agglomerated particles to a polymer solution. The nonwoven fiber-based approach will allow higher flow rates of the filtrate during purification and enable heat treatment for cleaning the filters. However, by changing the type of particles and/or preparing a mixture of them, the application range of the final product can be significantly broadened.
Research into the specifications of woven composites obtained from raffia fibers pretreated using the ecological method
Authors: Kocak Dilara , Merdan Nigar , Evren Oya Burcak
Published: August 2014

Studies on using cellulosic natural fibers as reinforcement for composites are rapidly growing. The aim of this study is using a raffia-based woven fabric as reinforcement for composites that are grown in the Mediterranean Zone of Turkey. These fabrics benefit from their mechanical performances, low density and their biodegradability. However, it is necessary for the fabrics to form adhesion in the matrix. Therefore, chemical processes should be applied onto the surface of the raffia-based woven fabrics. In this study, three different formulations (different concentrations of maleic anhydride, formic acid and acetic acid) were applied by using conventional and microwave energy on the raffia fabrics. At the end of the application, composite structures were formed by using the fabric as the reinforcement layer and isophtalic polyester as the matrix by the vacuum infusion method.

The composite structures were characterized by attenuated total reflectance scanning electron microscope analysis and their mechanical tests were performed through tensile testing.

Considering all results, the combination of acetic acid with the microwave process was found to modify the raffia fabric surfaces.