bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alcohol and Acetaldehyde in African Fermented Milk Mursik—A Possible Etiologic Factor for High Incidence of Esophageal Cancer in Western Kenya
Authors: Nieminen Mikko T. , Novak-Frazer Lily , Collins Rebecca , Dawsey Sonja P. , Dawsey Sanford M. , Abnet Christian C. , White Russell E. , Freedman Neal D. , Mwachiro Michael , Bowyer Paul , Salaspuro Mikko , Rautemaa Riina 
Published: November 2012

Abstract
Background: Esophageal cancer is unusually frequent in Western Kenya, despite the low prevalence of classical risk factors such as heavy drinking and tobacco smoking. Among Kenyans consumption of fermented milk is an old tradition. Our hypothesis is that alcohol and acetaldehyde are produced during the fermentation process and that their carcinogenic potential contributes to the high incidence of esophageal cancer.
Methods: Eight samples of mursik milk starter cultures were collected from different Kalenjin families in the Rift Valley province, Western Kenya. A protocol provided by the families was used for milk fermentation. Ethanol and acetaldehyde levels were measured by gas chromatography. The microbial flora in starter cultures was identified by 16S and 18S sequencing.
Results: 7/8 starter cultures produced mutagenic (&gt;100 μmol/L) levels of acetaldehyde and 4/8 starter cultures produced more than 1,000 μmol/L of acetaldehyde. The highest alcohol levels (mean 79.4 mmol/L) were detected in the four fermented milks with highest acetaldehyde production. The mean number of microbial species in the starter cultures was 5 (range 2–8). Yeasts were identified in all starter cultures (mean 1.5 species/milk) but their proportion of the total microbial count varied markedly (mean 35%, range 7%–90%). A combination of yeast and lactobacilli, especially Candida krusei with Lactobacillus kefiri, with the exclusion of other species, seemed to correlate with higher acetaldehyde and ethanol levels.
Conclusions: Significant levels of ethanol and acetaldehyde were produced during mursik fermentation.
Impact: When ingested several times daily the repeated exposure to carcinogenic levels of acetaldehyde may contribute to esophageal carcinogenesis. Cancer Epidemiol Biomarkers Prev; 22(1); 69–75. ©2012 AACR.
A Comparison of Human Papillomavirus Genotype-Specific DNA and E6/E7 mRNA Detection to Identify Anal Precancer among HIV-Infected Men Who Have Sex with Men
Authors: Castle Philip E. , Follansbee Stephen , Borgonovo Sylvia , Tokugawa Diane , Schwartz Lauren M. , Lorey Thomas S. , LaMere Brandon , Gage Julia C. , Fetterman Barbara , Darragh Teresa M. , Rodriguez Ana Cecilia , Wentzensen Nicolas 
Published: November 2012

Abstract
Background: Human papillomavirus (HPV) RNA detection is reportedly more specific for the detection of anogenital precancer than HPV DNA but it is unknown whether this is due to detection of RNA or due to HPV genotype restriction.
Methods: A total of 363 human immunodeficiency virus (HIV)–positive men who have sex with men had two anal cytology samples taken and were evaluated using high-resolution anoscopy and biopsies of visible lesions. Anal specimens were tested for E6/E7 RNA for five carcinogenic HPV genotypes (HPV16, 18, 31, 33, and 45) and tested for the DNA of 13 carcinogenic HPV genotypes.
Results: DNA testing was more likely to be positive than RNA testing (53% vs. 48%; P = 0.02) for the same five HPV genotypes in aggregate. When restricted to five HPV genotypes targeted by the RNA test, the sensitivity to detect anal precancer was the same for DNA and RNA (81%), whereas RNA was more specific than DNA (65% vs. 58%; P = 0.007). In comparison, DNA detection of all 13 carcinogenic HPV genotypes was more sensitive (96% vs. 81%; P = 0.001) but much less specific (65% vs. 33%; P &lt; 0.001) as compared with RNA detection of the five HPV genotypes.
Conclusion: After controlling for HPV genotypes, RNA was only slightly more specific than DNA detection for anal precancer.
Impact: DNA or RNA testing for a subset of the most carcinogenic HPV genotypes may be useful for distinguishing between those HPV-positive men at higher and lower risk of anal precancer and cancer. Cancer Epidemiol Biomarkers Prev; 22(1); 42–9. ©2012 AACR.
Regulation of CXCR4-Mediated Invasion by DARPP-32 in Gastric Cancer Cells
Authors: Zhu Shoumin , Hong Jun , Tripathi Manish K , Sehdev Vikas , Belkhiri Abbes , El-Rifai Wael 
Published: November 2012

Abstract
Although Dopamine and cAMP-regulated phosphoprotein, Mr 32000 (DARPP-32) is overexpressed in two-thirds of gastric cancers, its impact on molecular functions has not been fully characterized. In this study, we examined the role of DARPP-32 in gastric cancer cell invasion. Using matrigel-coated Boyden chamber invasion assay, DARPP-32-overexpressing AGS cells showed a three-fold increase in invasion relative to the vector control (P &lt; 0.01). We also tested the transendothelial cell invasion as a measure of cell aggressiveness using the impedance-based human umbilical vein endothelial cells invasion assay and obtained similar results (P &lt; 0.001). Western blot analysis indicated that overexpression of DARPP-32 mediated an increase in the membrane-type 1 matrix metalloproteinase (MT1-MMP) and CXCR4 protein levels. Consistent with the role of MT1-MMP in cleaving extracellular matrix proteins initiating the activation of soluble MMPs, we detected a robust increase in MMP-2 activity in DARPP-32-overexpressing cells. The knockdown of endogenous DARPP-32 in the MKN-45 cells reversed these signaling events and decreased cell invasive activity. We tested whether the invasive activity mediated by DARPP-32 might involve sustained signaling via CXCR4-dependent activation of the MT1-MMP/MMP-2 pathway. The small-molecule CXCR4 antagonist (AMD3100) and CXCR4-siRNA blocked DARPP-32-induced cell invasion. We further examined our hypothesis that DARPP-32 could interact with CXCR4 and stabilize its levels following stimulation with its ligand, CXCL12. Using reciprocal coimmunoprecipitation and immunofluorescence experiments, we found that DARPP-32 and CXCR4 coexist in the same protein complex. DARPP-32 prolonged the CXCR4 protein half-life and reduced ubiquitination of the CXCR4 protein, following treatment with its ligand, CXCL12. In conclusion, these findings show a novel mechanism by which DARPP-32 promotes cell invasion by regulating CXCR4-mediated activation of the MT1-MMP/MMP-2 pathway. Mol Cancer Res; 11(1); 86–94. ©2012 AACR.
Interleukin-33 Drives a Proinflammatory Endothelial Activation That Selectively Targets Nonquiescent Cells
Authors: Pollheimer Jürgen , Bodin Johanna , Sundnes Olav , Edelmann Reidunn J. , Skånland Sigrid S. , Sponheim Jon , Brox Mari Johanna , Sundlisæter Eirik , Loos Tamara , Vatn Morten , Kasprzycka Monika , Wang Junbai , Küchler Axel M. , Taskén Kjetil , Haraldsen Guttorm , Hol Johanna 
Published: November 2012

Objective—
Interleukin (IL)-33 is a nuclear protein that is released from stressed or damaged cells to act as an alarmin. We investigated the effects of IL-33 on endothelial cells, using the prototype IL-1 family member, IL-1β, as a reference.

Methods and Results—

Human umbilical vein endothelial cells were stimulated with IL-33 or IL-1β, showing highly similar phosphorylation of signaling molecules, induction of adhesion molecules, and transcription profiles. However, intradermally injected IL-33 elicited significantly less proinflammatory endothelial activation when compared with IL-1β and led us to observe that quiescent endothelial cells (ppRb
low
p27
high
) were strikingly resistant to IL-33. Accordingly, the IL-33 receptor was preferentially expressed in nonquiescent cells of low-density cultures, corresponding to selective induction of adhesion molecules and chemokines. Multiparameter phosphoflow cytometry confirmed that signaling driven by IL-33 was stronger in nonquiescent cells. Manipulation of nuclear IL-33 expression by siRNA or adenoviral transduction revealed no functional link between nuclear, endogenous IL-33, and exogenous IL-33 responsiveness.

Conclusion—
In contrast to other inflammatory cytokines, IL-33 selectively targets nonquiescent endothelial cells. By this novel concept, quiescent cells may remain nonresponsive to a proinflammatory stimulus that concomitantly triggers a powerful response in cells that have been released from contact inhibition.
Macrophage Activation by Heparanase Is Mediated by TLR-2 and TLR-4 and Associates With Plaque Progression
Authors: Blich Miry , Golan Amnon , Arvatz Gil , Sebbag Anat , Shafat Itay , Sabo Edmond , Cohen-Kaplan Victoria , Petcherski Sirouch , Avniel-Polak Shani , Eitan Amnon , Hammerman Haim , Aronson Doron , Axelman Elena , Ilan Neta , Nussbaum Gabriel , Vlodavsky Israel 
Published: November 2012

Objective—
Factors and mechanisms that activate macrophages in atherosclerotic plaques are incompletely understood. We examined the capacity of heparanase to activate macrophages.

Methods and Results—
Highly purified heparanase was added to mouse peritoneal macrophages and macrophage-like J774 cells, and the levels of tumor necrosis factor-α, matrix metalloproteinase-9, interlukin-1, and monocyte chemotactic protein-1 were evaluated by ELISA. Gene expression was determined by RT-PCR. Cells collected from Toll-like receptor-2 and Toll-like receptor-4 knockout mice were evaluated similarly. Heparanase levels in the plasma of patients with acute myocardial infarction, stable angina, and healthy subjects were determined by ELISA. Immunohistochemistry was applied to detect the expression of heparanase in control specimens and specimens of patients with stable angina or acute myocardial infarction. Addition or overexpression of heparanase variants resulted in marked increase in tumor necrosis factor-α, matrix metalloproteinase-9, interlukin-1, and monocyte chemotactic protein-1 levels. Mouse peritoneal macrophages harvested from Toll-like receptor-2 or Toll-like receptor-4 knockout mice were not activated by heparanase. Plasma heparanase level was higher in patients with acute myocardial infarction, compared with patients with stable angina and healthy subjects. Pathologic coronary specimens obtained from vulnerable plaques showed increased heparanase staining compared with specimens of stable plaque and controls.

Conclusion—
Heparanase activates macrophages, resulting in marked induction of cytokine expression associated with plaque progression toward vulnerability.
Aminotransferase Levels Are Associated With Cardiometabolic Risk Above and Beyond Visceral Fat and Insulin Resistance
Authors: Porter Stacy A. , Pedley Alison , Massaro Joseph M. , Vasan Ramachandran S. , Hoffmann Udo , Fox Caroline S. 
Published: November 2012

Objective—
We sought to characterize associations between aminotransferase levels and cardiometabolic risk after accounting for visceral adipose tissue and insulin resistance.

Methods and Results—

Participants (n=2621) from the Framingham Heart Study (mean age 51, 49.8% women) were included. Sex-specific linear and logistic regressions were used to evaluate associations between aminotransferase levels and cardiometabolic risk factors. In multivariable models, increased alanine aminotransferase levels were associated with elevated blood pressure, fasting plasma glucose, and triglycerides and lower high-density lipoprotein levels (all
P
≤0.007). Furthermore, each 1-SD increase in alanine aminotransferase corresponded to an increased odds of hypertension, diabetes mellitus, the metabolic syndrome, impaired fasting glucose, and insulin resistance estimated by the homeostasis model assessment of insulin resistance (odds ratio, 1.29–1.85, all
P
≤0.002). Associations with alanine aminotransferase persisted after additional adjustment for visceral adipose tissue, insulin resistance, and body mass index with the exception of high-density lipoprotein cholesterol in both sexes and blood pressure in women. Results were materially unchanged when moderate drinkers were excluded, when the sample was restricted to those with alanine aminotransferase <40 U/L, and when the sample was restricted to those without diabetes mellitus. Similar trends were observed for aspartate aminotransferase levels, but associations were more modest.

Conclusion—
Aminotransferase levels are correlated with multiple cardiometabolic risk factors above and beyond visceral adipose tissue and insulin resistance.
Cadherin-11 Regulates Cell–Cell Tension Necessary for Calcific Nodule Formation by Valvular Myofibroblasts
Authors: Hutcheson Joshua D. , Chen Joseph , Sewell-Loftin M.K. , Ryzhova Larisa M. , Fisher Charles I. , Su Yan Ru , Merryman W. David 
Published: November 2012

Objective—
Dystrophic calcific nodule formation in vitro involves differentiation of aortic valve interstitial cells (AVICs) into a myofibroblast phenotype. Interestingly, inhibition of the kinase MAPK Erk kinase (MEK)1/2 prevents calcific nodule formation despite leading to myofibroblast activation of AVICs, indicating the presence of an additional mechanotransductive component required for calcific nodule morphogenesis. In this study, we assess the role of transforming growth factor β1–induced cadherin-11 expression in calcific nodule formation.

Methods and Results—
As shown previously, porcine AVICs treated with transforming growth factor β1 before cyclic strain exhibit increased myofibroblast activation and significant calcific nodule formation. In addition to an increase in contractile myofibroblast markers, transforming growth factor β1–treated AVICs exhibit significantly increased expression of cadherin-11. This expression is inhibited by the addition of U0126, a specific MEK1/2 inhibitor. The role of increased cadherin-11 is revealed through a wound assay, which demonstrates increased intercellular tension in transforming growth factor β1–treated AVICs possessing cadherin-11. Furthermore, when small interfering RNA is used to knockdown cadherin-11, calcific nodule formation is abrogated, indicating that robust cell–cell connections are necessary in generating tension for calcific nodule morphogenesis. Finally, we demonstrate enrichment of cadherin-11 in human calcified leaflets.

Conclusion—
These results indicate the necessity of cadherin-11 for dystrophic calcific nodule formation, which proceeds through an Erk1/2-dependent pathway.
Soluble CD14
Authors: Reiner Alex P. , Lange Ethan M. , Jenny Nancy S. , Chaves Paulo H.M. , Ellis Jaclyn , Li Jin , Walston Jeremy , Lange Leslie A. , Cushman Mary , Tracy Russell P. 
Published: November 2012

Objective—
CD14 is a glycosylphosphotidylinositol-anchored membrane glycoprotein expressed on neutrophils and monocytes/macrophages that also circulates as a soluble form (sCD14). Despite the well-recognized role of CD14 in inflammation, relatively little is known about the genetic determinants of sCD14 or the relationship of sCD14 to vascular- and aging-related phenotypes.

Methods and Results—

We measured baseline levels of sCD14 in >5000 European-American and black adults aged 65 years and older from the Cardiovascular Health Study, who were well characterized at baseline for atherosclerotic risk factors and subclinical cardiovascular disease, and who have been followed for clinical cardiovascular disease and mortality outcomes up to 20 years. At baseline, sCD14 generally showed strong positive correlations with traditional cardio-metabolic risk factors and with subclinical measures of vascular disease such as carotid wall thickness and ankle-brachial index (independently of traditional cardiovascular disease risk factors), and was also inversely correlated with body mass index. In genomewide association analyses of sCD14, we (1) confirmed the importance of the
CD14
locus on chromosome 5q21 in European-American; (2) identified a novel African ancestry-specific allele of
CD14
associated with lower sCD14 in blacks; and (3) identified a putative novel association in European-American of a nonsynonymous variant of
PIGC
, which encodes an enzyme required for the first step in glycosylphosphotidylinositol anchor biosynthesis. Finally, we show that, like other acute phase inflammatory biomarkers, sCD14 predicts incident cardiovascular disease, and strongly and independently predicts all-cause mortality in older adults.

Conclusion—
CD14 independently predicts risk mortality in older adults.
Heterodimerization With the Prostacyclin Receptor Triggers Thromboxane Receptor Relocation to Lipid Rafts
Authors: Ibrahim Salam , McCartney Ann , Markosyan Nune , Smyth Emer M. 
Published: November 2012

Objective—
Prostacyclin and thromboxane mediate opposing cardiovascular actions through receptors termed IP and TP, respectively. When dimerized with IP, the TP shifts to IP-like function. IP localizes to cholesterol-enriched membrane rafts, but TP and IPTP heterodimer localization is not defined. We examined these receptors’ membrane localization and the role of rafts in receptor function.

Methods and Results—
Microdomain distribution of IP, TP, and IPTP heterodimers was examined in COS-7 cells by measuring energy transfer from renilla luciferase-fused receptors to fluorescently labeled rafts. IP raft association was confirmed. TP was raft excluded, but redistributed to rafts upon dimerization with IP. Signaling of the IP and IPTP heterodimer, but not TP alone, was suppressed after raft disruption by cholesterol depletion. Cholesterol enrichment also selectively suppressed IP and IPTP function. Native IP and IPTP signaling in smooth muscle cells and macrophages were similarly sensitive to cholesterol manipulation, whereas macrophages from hypercholesterolemic mice displayed suppressed IP and IPTP function.

Conclusion—
IP and TP function within distinct microdomains. Raft incorporation of TP in the IPTP heterodimer likely facilitates its signaling shift. We speculate that changes in IP and IPTP signaling after perturbation of membrane cholesterol may contribute to cardiovascular disease associated with hypercholesterolemia.
Atrioventricular Node Reentrant Tachycardia in Patients With Congenitally Corrected Transposition of the Great Arteries and Results of Radiofrequency Catheter Ablation
Authors: Liao Zili , Chang Yu , Ma Jian , Fang Pihua , Zhang Kuijun , Ren Xiaoqing , Yang Pingzhen , Yu Bo , Hu Jiqiang , Yang Qian , Ouyang Feifan , Zhang Shu 
Published: November 2012

Background—
We sought to investigate the feasibility of radiofrequency catheter ablation of atrioventricular node reentrant tachycardia and the ideal site for slow pathway (SP) ablation in congenitally corrected transposition of the great arteries.

Methods and Results—
Nine patients with congenitally corrected transposition of the great arteries referred for catheter ablation of atrioventricular node reentrant tachycardia were studied. A single His potential was recorded in 8 patients (89%, 6 {S,L,L} and 2 {I,D,D}). The earliest atrial activation during retrograde atrioventricular node conduction occurred at His bundle region (HBE; n=7) or shifting from HBE to coronary sinus ostium (n=1, {S,L,L}). Two anatomically separate His potentials were recorded in 1 patient (11%, {S,L,L}), one at the anteroseptum (HBE-1) and the other at the confluence of the pulmonary and mitral annulus (HBE-2). In 8 cases with a single His potential recorded, SP was abated at the posterior-midseptum, 2 ({S,L,L}) at the right posteroseptum, 1 ({S,L,L}) at the left posteroseptum, and 5 (3 {S,L,L} and 2 {I,D,D}) at the midseptum after failure of energy application at the posteroseptum. Junctional rhythm was observed during radiofrequency catheter ablation in all 8 of the cases. In the remaining patient with 2 anatomically separate His potentials recorded, SP was successfully ablated from the confluence of the pulmonary and mitral annulus, slightly below the HBE-2. Junctional rhythm was also induced during radiofrequency catheter ablation.

Conclusions—
In {S,L,L} or {I,D,D}, radiofrequency catheter ablation of atrioventricular node reentrant tachycardia is feasible. SP input region can mainly be found in the posterior midseptum, especially in patients with single penetrating atrioventricular nodes. SP could usually be successfully ablated in these regions.
Role of Transcytolemmal Water-Exchange in Magnetic Resonance Measurements of Diffuse Myocardial Fibrosis in Hypertensive Heart Disease
Authors: Coelho-Filho Otavio R. , Mongeon François-Pierre , Mitchell Richard , Moreno Heitor , Nadruz Wilson , Kwong Raymond , Jerosch-Herold Michael 
Published: November 2012

Background—
The myocardial extracellular volume fraction (MECVF) has been used to detect diffuse fibrosis. Estimation of MECVF relies on quantification of the T1 relaxation time after contrast enhancement, which can be sensitive to equilibrium transcytolemmal water-exchange. We hypothesized that MECVF, quantified with a parsimonious 2-space water-exchange model, correlates positively with the connective tissue volume fraction in a rodent model of hypertensive heart disease, whereas the widely used analysis based on assuming fast transcytolemmal water-exchange could result in a significant underestimate of MECVF.

Methods and Results—

Nω–nitro-L-arginine-methyl-ester (L-NAME) or placebo was administered to 22 and 15 wild-type mice, respectively. MECVF was measured at baseline and 7-week follow-up by pre- and postcontrast T1 cardiac magnetic resonance imaging at 4.7 T, using a 2-space water-exchange model. Connective tissue volume fraction was quantified, using Masson trichrome stain. L-NAME induced hypertrophy (weight-indexed left-ventricular mass 2.2±0.3 versus 4.1±0.4 μg/g,
P
<0.001), and increased connective tissue volume fraction (8.6%±1.5 versus 2.58%±0.6,
P
<0.001), were compared with controls. MECVF was higher in L-NAME-treated animals (0.43±0.09 versus 0.26±0.03,
P
<0.001), and correlated with connective tissue volume fraction and weight-indexed left-ventricular mass (
r
=0.842 and
r
=0.737, respectively, both
P
<0.0001). Neglecting transcytolemmal water-exchange caused a significant underestimate of MECVF changes. Ten patients with history of hypertension had significantly higher MECVF (0.446±0.063) compared with healthy controls (0.307±0.030,
P
<0.001).

Conclusions—
Cardiac magnetic resonance allowed detection of myocardial extracellular matrix expansion in a mouse model and in patients with a history of hypertension. Accounting for the effects of transcytolemmal water-exchange can result in a substantial difference of MECVF, compared with assuming fast transcytolemmal water-exchange.