bluuebunny/crossref_metadata_2025_split huggingface dataset:
RASEF is a Novel Diagnostic Biomarker and a Therapeutic Target for Lung Cancer
Authors: Oshita Hideto , Nishino Ryohei , Takano Atsushi , Fujitomo Takashi , Aragaki Masato , Kato Tatsuya , Akiyama Hirohiko , Tsuchiya Eiju , Kohno Nobuoki , Nakamura Yusuke , Daigo Yataro 
Published: May 2013

AbstractGenome-wide gene expression profiling revealed that the Ras and EF-hand domain containing (RASEF) transcript was significantly transactivated in the majority of lung cancers. Using lung cancer cells, transient expression of RASEF promoted cell growth, whereas RASEF knockdown not only reduced its expression but resulted in growth suppression of the cancer cells. Immunohistochemical staining using tumor tissue microarrays consisting of 341 archived non–small cell lung cancers (NSCLC) revealed the association of strong RASEF positivity with poor prognosis (P = 0.0034 by multivariate analysis). Mechanistically, RASEF interacted with extracellular signal-regulated kinase (ERK) 1/2 and enhanced ERK1/2 signaling. Importantly, inhibiting the interaction between RASEF and ERK1/2 using a cell-permeable peptide that corresponded to the ERK1/2-interacting site of RASEF, suppressed growth of lung cancer cells. This study demonstrates that elevated RASEF promoted cell growth via enhanced ERK signaling and is associated with poor prognosis of NSCLC.Implications: RASEF may play an important role in lung carcinogenesis and could serve as a vaiable prognostic biomarker and target for the development of new molecular therapies. Mol Cancer Res; 11(8); 937–51. ©2013 AACR.
Fer Protein-Tyrosine Kinase Promotes Lung Adenocarcinoma Cell Invasion and Tumor Metastasis
Authors: Ahn Joseph , Truesdell Peter , Meens Jalna , Kadish Carli , Yang Xiaolong , Boag Alexander H. , Craig Andrew W.B. 
Published: May 2013

Abstract
Epidermal growth factor receptor (EGFR) is frequently amplified or mutated in non–small cell lung cancer (NSCLC). Although Fer protein-tyrosine kinase signals downstream of EGFR, its role in NSCLC tumor progression has not been reported. Here, Fer kinase was elevated in NSCLC tumors compared to normal lung epithelium. EGFR signaling in NSCLC cells fosters rapid Fer activation and increased localization to lamellipodia. Stable silencing of Fer in H1299 lung adenocarcinoma cells (Fer KD) caused impaired EGFR-induced lamellipodia formation compared to control cells. Fer KD NSCLC cells showed reduced Vav2 tyrosine phosphorylation that was correlated with direct Fer-mediated phosphorylation of Vav2 on tyrosine-172, which was previously reported to increase the guanine nucleotide exchange factor activity of Vav2. Indeed, Fer KD cells displayed defects in Rac-GTP localization to lamellipodia, cell migration, and cell invasion in vitro. To test the role of Fer in NSCLC progression and metastasis, control and Fer KD cells were grown as subcutaneous tumors in mice. Although Fer was not required for tumor growth, Fer KD tumor-bearing mice had significantly fewer numbers of spontaneous metastases. Combined, these data demonstrate that Fer kinase is elevated in NSCLC tumors and is important for cellular invasion and metastasis.
Implications: Fer protein-tyrosine kinase is a potential therapeutic target in metastatic lung cancer. Mol Cancer Res; 11(8); 952–63. ©2013 AACR.
Characterization of Raloxifene Glucuronidation: Potential Role of UGT1A8 Genotype on Raloxifene Metabolism In Vivo
Authors: Sun Dongxiao , Jones Nathan R , Manni Andrea , Lazarus Philip 
Published: May 2013

Abstract
Raloxifene is a second-generation selective estrogen receptor modulator used for the prevention and treatment of osteoporosis and the prevention of breast cancer in postmenopausal women. Raloxifene is extensively metabolized by glucuronidation to form raloxifene-6-glucuronide (ral-6-Gluc) and raloxifene-4′-glucuronide (ral-4′-Gluc). The goal of the present study was to determine whether functional polymorphisms in active UGTs could play a role in altered raloxifene glucuronidation in vivo. Using homogenates from HEK293 UGT-overexpressing cell lines, raloxifene was shown to be glucuronidated primarily by the hepatic UGTs 1A1 and 1A9 and the extra-hepatic UGTs 1A8 and 1A10; no detectable raloxifene glucuronidation activity was found for UGT2B enzymes. Functional UGT1A1 transcriptional promoter genotypes were significantly (Ptrend = 0.005) associated with ral-6-Gluc formation in human liver microsomes, and, consistent with the decreased raloxifene glucuronidation activities observed in vitro with cell lines overexpressing UGT1A8 variants, the UGT1A8*2 variant was significantly (P = 0.023) correlated with total raloxifene glucuronide formation in human jejunum homogenates. While ral-4′-Gluc exhibited 1:100th the anti-estrogenic activity of raloxifene itself as measured by binding to the estrogen receptor, raloxifene glucuronides comprised about 99% of the circulating raloxifene dose in raloxifene-treated subjects, with ral-4′-Gluc comprising ∼70% of raloxifene glucuronides. Plasma ral-6-Gluc (Ptrend = 0.0025), ral-4′-Gluc (Ptrend = 0.001), and total raloxifene glucuronides (Ptrend = 0.001) were increased in raloxifene-treated subjects who were predicted slow metabolizers [UGT1A8 (*1/*3)] versus intermediate metabolizers [UGT1A8 (*1/*1) or UGT1A8 (*1/*2)] versus fast metabolizers [UGT1A8 (*2/*2). These data suggest that raloxifene metabolism may be dependent on UGT1A8 genotype and that UGT1A8 genotype may play an important role in overall response to raloxifene. Cancer Prev Res; 6(7); 719–30. ©2013 AACR.
Metabolic Syndrome and Mammographic Density in Mexican Women
Authors: Rice Megan S. , Biessy Carine , Lajous Martin , Bertrand Kimberly A. , Tamimi Rulla M. , Torres-Mejía Gabriela , López-Ridaura Ruy , Romieu Isabelle 
Published: May 2013

AbstractMetabolic syndrome has been associated with an increased risk of breast cancer; however, little is known about the association between metabolic syndrome and percent mammographic density, a strong predictor of breast cancer. We analyzed cross-sectional data from 789 premenopausal and 322 postmenopausal women in the Mexican Teacher's Cohort (ESMaestras). Metabolic syndrome was defined according to the harmonized definition. We measured percent density on mammograms using a computer-assisted thresholding method. Multivariable linear regression was used to estimate the association between density and metabolic syndrome, as well as its components by state (Jalisco, Veracruz) and menopausal status (premenopausal, postmenopausal). Among premenopausal women in Jalisco, women with metabolic syndrome had higher percent density than those without after adjusting for potential confounders including BMI [difference = 4.76; 95% confidence interval (CI), 1.72–7.81]. Among the metabolic syndrome components, only low high-density lipoprotein levels (&lt;50 mg/dL) were associated with significantly higher percent density among premenopausal women in Jalisco (difference = 4.62; 95% CI, 1.73–7.52). Metabolic syndrome was not associated with percent density among premenopausal women in Veracruz (difference = −2.91; 95% CI, −7.19 to 1.38), nor among postmenopausal women in either state. Metabolic syndrome was associated with higher percent density among premenopausal women in Jalisco, Mexico, but was not associated with percent density among premenopausal women in Veracruz, Mexico, or among postmenopausal women in either Jalisco or Veracruz. These findings provide some support for a possible role of metabolic syndrome in mammographic density among premenopausal women; however, results were inconsistent across states and require further confirmation in larger studies. Cancer Prev Res; 6(7); 701–10. ©2013 AACR.
Identification of Putative Immunologic Targets for Colon Cancer Prevention Based on Conserved Gene Upregulation from Preinvasive to Malignant Lesions
Authors: Broussard Elizabeth K. , Kim Rachel , Wiley Jesse C. , Marquez Juan Pablo , Annis James E. , Pritchard David , Disis Mary L. 
Published: May 2013

Abstract
The length of time required for preinvasive adenoma to progress to carcinoma, the immunogenicity of colorectal cancer (CRC), and the identification of high-risk populations make development and testing of a prophylactic vaccine for the prevention of CRC possible. We hypothesized that genes upregulated in adenoma relative to normal tissue, which maintained increased expression in CRC, would encode proteins suitable as putative targets for immunoprevention. We evaluated existing adenoma and CRC microarray datasets and identified 160 genes that were ≥2-fold upregulated in both adenoma and CRC relative to normal colon tissue. We further identified 23 genes that showed protein overexpression in colon adenoma and CRC based on literature review. Silencing the most highly upregulated genes, CDH3, CLDN1, KRT23, and MMP7, in adenoma and CRC cell lines resulted in a significant decrease in viability (P &lt; 0.0001) and proliferation (P &lt; 0.0001) as compared to controls and an increase in cellular apoptosis (P &lt; 0.05 for CDH3, KRT23). Results were duplicated across cell lines representing microsatellite instability, CpG island methylator, and chromosomal instability phenotypes, suggesting immunologic elimination of cells expressing these proteins could impact the progression of all CRC phenotypes. To determine whether these proteins were immunogens, we interrogated sera from early stage CRC patients and controls and found significantly elevated CDH3 (P = 0.006), KRT23 (P = 0.0007), and MMP7 (P &lt; 0.0001) serum immunoglobulin G in cases as compared to controls. These data show a high throughput approach to the identification of biologically relevant putative immunologic targets for CRC and identified three candidates suitable for vaccine development. Cancer Prev Res; 6(7); 666–74. ©2013 AACR.
The Chemopreventive Efficacies of Nonsteroidal Anti-inflammatory Drugs: The Relationship of Short-term Biomarkers to Long-term Skin Tumor Outcome
Authors: Mikulec Carol D. , Rundhaug Joyce E. , Simper Melissa S. , Lubet Ronald A. , Fischer Susan M. 
Published: May 2013

Abstract
The ultraviolet B (UVB) component of sunlight, which causes DNA damage and inflammation, is the major cause of nonmelanoma skin cancer (NMSC), the most prevalent of all cancers. Nonsteroidal anti-inflammatory drugs (NSAID) and coxibs have been shown to be effective chemoprevention agents in multiple preclinical trials, including NMSC, colon, and urinary bladder cancer. NSAIDs, however, cause gastrointestinal irritation, which led to the recent development of nitric oxide (NO) derivatives that may partially ameliorate this toxicity. This study compared the efficacy of several NSAIDs and NO-NSAIDs on UV-induced NMSC in SKH-1 hairless mice and determined whether various short-term biomarkers were predictive of long-term tumor outcome with these agents. Naproxen at 100 (P = 0.05) and 400 ppm (P &lt; 0.01) in the diet reduced tumor multiplicity by 26% and 63%, respectively. The NO-naproxen at slightly lower molar doses shows similar activities. Aspirin at 60 or 750 ppm in the diet reduced tumor multiplicity by 19% and 50%, whereas the equivalent doses (108 and 1,350 ppm) were slightly less effective. Sulindac at 25 and 150 ppm in the diet, doses far below the human equivalent dose was the most potent NSAID with reductions of 50% and 94%, respectively. In testing short-term biomarkers, we found that agents that reduce UV-induced prostaglandin E2 synthesis and/or inhibit UV-induced keratinocyte proliferation yielded long-term tumor efficacy. Cancer Prev Res; 6(7); 675–85. ©2013 AACR.
Bone Marrow–Derived Kruppel-Like Factor 10 Controls Reendothelialization in Response to Arterial Injury
Authors: Wara Akm Khyrul , Manica Andre , Marchini Julio F. , Sun Xinghui , Icli Basak , Tesmenitsky Yevgenia , Croce Kevin , Feinberg Mark W. 
Published: May 2013

Objective—
The objective of this study was to investigate the role of Kruppel-like factor (KLF) 10, a zinc-finger transcription factor, in bone marrow (BM)–derived cell responses to arterial endothelial injury. Accumulating evidence indicates that BM-derived progenitors are recruited to sites of vascular injury and contribute to endothelial repair.

Approach and Results—

In response to carotid artery endothelial denudation, KLF10 mRNA expression was markedly increased in both BM and circulating lin
−
progenitor cells. To examine the specific role of KLF10 in arterial reendothelialization, we used 2 models of endothelial denudation (wire- and thermal-induced injury) of the carotid artery in wild-type (WT) and KLF10
−/−
mice. WT mice displayed higher areas of reendothelialization compared with KLF10
−/−
mice after endothelial injury using either method. BM transplant studies revealed that reconstitution of KLF10
−/−
mice with WT BM fully rescued the defect in reendothelialization and increased lin
−
CD34
+
kinase insert domain receptor
+
progenitors in the blood and injured carotid arteries. Conversely, reconstitution of WT mice with KLF10
−/−
BM recapitulated the defects in reendothelialization and peripheral cell progenitors. The media from cultured KLF10
–
/
–
BM progenitors was markedly inefficient in promoting endothelial cell growth and migration compared with the media from WT progenitors, indicative of defective paracrine trophic effects from KLF10
–
/
–
BM progenitors. Finally, BM-derived KLF10
−/−
lin
−
progenitors from reconstituted mice had reduced CXC-chemokine receptor 4 expression and impaired migratory responses.

Conclusions—
Collectively, these observations demonstrate a protective role for BM-derived KLF10 in paracrine and homing responses important for arterial endothelial injury and highlight KLF10 as a possible therapeutic target to promote endothelial repair in vascular disease states.
The Effect of Lacunar Infarcts on White Matter Tract Integrity
Authors: Reijmer Yael D. , Freeze Whitney M. , Leemans Alexander , Biessels Geert Jan 
Published: May 2013

Background and Purpose—
Lacunar infarcts may cause disturbances of the white matter (WM) structure remote from the primary lesion. Here, we used diffusion MRI and tractography to (1) spatially characterize microstructural abnormalities along WM tracts containing a lacunar infarct and (2) relate abnormalities in remote parts of the affected WM tract to cognitive outcome.

Methods—
In 17 participants with a lacunar infarct, we reconstructed the affected WM tract using fiber tractography. The corresponding nonlesioned tract in the contralateral hemisphere served as a control tract. Diffusion parameters (fractional anisotropy and mean diffusivity) were plotted along the tract and related to measures of memory, executive functioning and information processing speed.

Results—

Diffusion abnormalities remote from the lacune were present in the affected tract compared with the control tract up to 2 cm from the lacune (9% to 17% decrease in fractional anisotropy, 11% to 27% increase in mean diffusivity;
P
<0.05). The severity of these abnormalities attenuated with increasing distance to the primary lesion. Furthermore, the degree of remote WM disturbances was related to worse cognitive functioning on all 3 domains, independent of the size of the lacune (
r
=0.6–0.8;
P
<0.05).

Conclusions—
Lacunar infarcts are associated with abnormalities in the affected WM tract that extend centimeters beyond the lesion visible on conventional MRI. These secondary WM abnormalities may contribute to the cognitive deficits observed in patients with subcortical infarcts.
Influence of Chronic Ethanol Consumption on the Neurological Severity in Patients With Acute Cerebral Ischemia
Authors: Ducroquet Aude , Leys Didier , Saabi Alaa Al , Richard Florence , Cordonnier Charlotte , Girot Marie , Deplanque Dominique , Casolla Barbara , Allorge Delphine , Bordet Régis 
Published: May 2013

Background and Purpose—
We tested the hypothesis that excessive chronic ethanol consumption is associated with more severe ischemic strokes.

Methods—
We recruited patients with supratentorial cerebral ischemia within 48 hours of symptom onset. We defined heavy drinkers by a weekly consumption of ethanol of ≥300 g and severe strokes by a National Institutes of Health Stroke Scale score≥6.

Results—

Of 436 patients, 60 were heavy drinkers. Being a heavy drinker was independently associated with baseline National Institutes of Health Stroke Scale scores ≥6 (odds ratio, 2.35; 95% confidence interval, 1.12–5.26;
P
=0.023) at the logistic regression analysis. This result was not modified with the propensity analysis.

Conclusion—
An excessive chronic ethanol consumption is associated with higher baseline stroke severity.
Framingham Stroke Risk Score and Cognitive Impairment for Predicting First-Time Stroke in the Oldest Old
Authors: Sabayan Behnam , Gussekloo Jacobijn , de Ruijter Wouter , Westendorp Rudi G.J. , de Craen Anton J.M. 
Published: May 2013

Background and Purpose—
Predictive value of the conventional risk factors for stroke attenuates with age. Cognitive impairment has been implicated as a potential predictor for stroke in older subjects. Our aim was to compare the Framingham stroke risk score with cognitive functioning for predicting first-time stroke in a cohort of the oldest old individuals.

Methods—
We included 480 subjects, aged 85 years, from the Leiden 85-plus Study. At baseline, data on the Framingham stroke risk score and the Mini-Mental State Examination (MMSE) score were obtained. Risk of first-time stroke was estimated in tertiles of Framingham and MMSE scores. Receiver operating characteristic curves with corresponding areas under the curves (AUCs) and 95% confidence intervals (CIs) were constructed for both Framingham and MMSE scores.

Results—

Subjects with high Framingham risk score compared with those with low Framingham risk score did not have a higher risk of stroke (hazard ratio, 0.77; 95% CI, 0.39–1.54). Conversely, subjects with high levels of cognitive impairment compared with those with low levels of cognitive impairment had a higher risk of stroke (hazard ratio, 2.85; 95% CI, 1.48–5.51). In contrast to the Framingham risk score (AUCs, 0.48; 95% CI, 0.40–0.56), MMSE score had discriminative power to predict stroke (AUCs, 0.65; 95% CI, 0.57–0.72). There was a significant difference between AUCs for Framingham risk score and MMSE score (
P
=0.006).

Conclusions—
In the oldest old, the Framingham stroke risk score is not predictive for first-time stroke. In contrast, cognitive impairment, as assessed by MMSE score, identifies subjects at higher risk for stroke.
Traditions within the Church of England and Psychological Type: A Study among the Clergy
Authors: Village Andrew 
Published: May 2013

Abstract
This study examines the relationship of psychological type preferences to membership of three different traditions within the Church of England: Anglo-catholic, broad church and evangelical. A sample of 1047 clergy recently ordained in the Church of England completed the Francis Psychological Type Scales and self-assigned measures of church tradition, conservatism and charismaticism. The majority of clergy preferred introversion over extraversion, but this preference was more marked among Anglo-catholics than among evangelicals. Anglo-catholics showed preference for intuition over sensing, while the reverse was true for evangelicals. Clergy of both sexes showed an overall preference for feeling over thinking, but this was reversed among evangelical clergymen. The sensing-intuition difference between traditions persisted after controlling for conservatism and charismaticism, suggesting it was linked to preferences for different styles of religious expression in worship. Conservatism was related to preferences for sensing over intuition (which may promote preference for traditional worship and parochial practices) and thinking over feeling (which for evangelicals may promote adherence to traditional theological principles and moral behaviour). Charismaticism was associated with preferences for extraversion over introversion, intuition over sensing, and feeling over thinking. Reasons for these associations are discussed in the light of known patterns of belief and practice across the various traditions of the Church of England.
Uncertainty and Predictability of Tropical Cyclone Rainfall Based on Ensemble Simulations of Typhoon Sinlaku (2008)
Authors: Wu Chun-Chieh , Chen Shin-Gan , Lin Shih-Chieh , Yen Tzu-Hsiung , Chen Ting-Chen 
Published: May 2013

Abstract
Using special data from the field campaign of 2008 and an ensemble Kalman filter–based vortex initialization method, this study explores the impact of different track clusters categorized under the ensemble simulations of Typhoon Sinlaku (2008) on the associated precipitation. In particular, the distinct pattern of cumulative frequencies in the 28 members is identified to correspond to three types of track clusters. The simulation integrated from the initial ensemble mean slightly underestimates the maximum amount of the observed rainfall in central Taiwan by about 30%. The quantitative evaluation based on the equitable threat score indicates that members with tracks close to the best track produce more consistent rainfall distribution in northern Taiwan although their cumulative frequencies are underestimated. For members with southwestward-biased tracks, although the cumulative frequencies are closer to the observation, the simulated rainfall pattern is less consistent with the observation in northern Taiwan and the maximum rainfall amount is overestimated. The comparison of rainfall simulation during landfall between two representative members shows that the distinct differences in the rainfall amount and distribution are primarily associated with the track differences on the windward side of the mountain. With a finer horizontal grid resolution, the rainfall accumulation becomes greater as a result of the enhancement of updraft from the better-resolved topography, yet the cumulative frequency stays nearly unchanged. Based on ensemble simulations, this study highlights that the uncertainties in rainfall patterns and amounts can be assessed from ensemble track variations, thus providing better insights into the rainfall predictability associated with typhoons near Taiwan.
The cognitive processing of candidates during reading tests: Evidence from eye-tracking
Authors: Bax Stephen 
Published: May 2013

The research described in this article investigates test takers’ cognitive processing while completing onscreen IELTS (International English Language Testing System) reading test items. The research aims, among other things, to contribute to our ability to evaluate the cognitive validity of reading test items (Glaser, 1991; Field, in press). The project focused on differences in reading behaviours of successful and unsuccessful candidates while completing IELTS test items. A group of Malaysian undergraduates ( n = 71) took an onscreen test consisting of two IELTS reading passages with 11 test items. Eye movements of a random sample of these participants ( n = 38) were tracked. Stimulated recall interview data was collected to assist in interpretation of the eye-tracking data. Findings demonstrated significant differences between successful and unsuccessful test takers on a number of dimensions, including their ability to read expeditiously (Khalifa & Weir, 2009), and their focus on particular aspects of the test items and texts, while no observable difference was noted in other items. This offers new insights into the cognitive processes of candidates during reading tests. Findings will be of value to examination boards preparing reading tests, to teachers and learners, and also to researchers interested in the cognitive processes of readers.