bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic Aberrations Occurring in Subsets of Serrated Colorectal Lesions but not Conventional Adenomas
Authors: Burnett-Hartman Andrea N. , Newcomb Polly A. , Potter John D. , Passarelli Michael N. , Phipps Amanda I. , Wurscher Michelle A. , Grady William M. , Zhu Lee-Ching , Upton Melissa P. , Makar Karen W. 
Published: March 2013

Abstract
A subset of aggressive colorectal cancers exhibit BRAF mutation, MLH1 methylation, and a CpG island methylator phenotype (CIMP), but precursors are poorly established. In this study, we determined the status of these markers in colorectal polyps and evaluated associated risk factors. The study included 771 polyp cases and 1,027 controls who were ages 24 to 80 years, part of a group health program, received a colonoscopy from 1998 to 2007, and completed a structured questionnaire assessing risk factors. Following standard pathology review, polyps were assayed for BRAF mutation (V600E) and tested for MLH1 and CIMP methylation, the latter including the genes, CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1. Polytomous logistic regression was used to estimate ORs and 95% confidence intervals for the association between molecularly defined subsets of polyps and potential risk factors. There were 580 conventional adenomas and 419 serrated lesions successfully assayed. For adenomas, the prevalence of each marker was ≤1%. In contrast, 55% of serrated lesions harbored mutant BRAF, 26% were CIMP-high, and 5% had methylated MLH1. In these lesions, the highest prevalence of markers was in sessile-serrated polyps (SSP) of ≥10 mm that were in the right-side/cecal regions of the colon. Risk factors for CIMP-high–serrated lesions included Caucasian race, current smoking status, and a history of polyps, whereas for serrated lesions with mutant BRAF, the significant risk factors were male sex, current smoking status, obesity, and a history of polyps. Our results suggest that SSPs and other large, right-sided serrated lesions have a unique molecular profile that is similar to CIMP-high, BRAF-mutated colorectal cancers. Cancer Res; 73(9); 2863–72. ©2013 AACR.
Androgen Receptor-Independent Function of FoxA1 in Prostate Cancer Metastasis
Authors: Jin Hong-Jian , Zhao Jonathan C. , Ogden Irene , Bergan Raymond C. , Yu Jindan 
Published: March 2013

Abstract
FoxA1 (FOXA1) is a pioneering transcription factor of the androgen receptor (AR) that is indispensible for the lineage-specific gene expression of the prostate. To date, there have been conflicting reports on the role of FoxA1 in prostate cancer progression and prognosis. With recent discoveries of recurrent FoxA1 mutations in human prostate tumors, comprehensive understanding of FoxA1 function has become very important. Here, through genomic analysis, we reveal that FoxA1 regulates two distinct oncogenic processes via disparate mechanisms. FoxA1 induces cell growth requiring the AR pathway. On the other hand, FoxA1 inhibits cell motility and epithelial-to-mesenchymal transition (EMT) through AR-independent mechanism directly opposing the action of AR signaling. Using orthotopic mouse models, we further show that FoxA1 inhibits prostate tumor metastasis in vivo. Concordant with these contradictory effects on tumor progression, FoxA1 expression is slightly upregulated in localized prostate cancer wherein cell proliferation is the main feature, but is remarkably downregulated when the disease progresses to metastatic stage for which cell motility and EMT are essential. Importantly, recently identified FoxA1 mutants have drastically attenuated ability in suppressing cell motility. Taken together, our findings illustrate an AR-independent function of FoxA1 as a metastasis inhibitor and provide a mechanism by which recurrent FoxA1 mutations contribute to prostate cancer progression. Cancer Res; 73(12); 3725–36. ©2013 AACR.
Histone H3.3 Mutations Drive Pediatric Glioblastoma through Upregulation of MYCN
Authors: Bjerke Lynn , Mackay Alan , Nandhabalan Meera , Burford Anna , Jury Alexa , Popov Sergey , Bax Dorine A. , Carvalho Diana , Taylor Kathryn R. , Vinci Maria , Bajrami Ilirjana , McGonnell Imelda M. , Lord Christopher J. , Reis Rui M. , Hargrave Darren , Ashworth Alan , Workman Paul , Jones Chris 
Published: March 2013

Abstract
Children and young adults with glioblastoma (GBM) have a median survival rate of only 12 to 15 months, and these GBMs are clinically and biologically distinct from histologically similar cancers in older adults. They are defined by highly specific mutations in the gene encoding the histone H3.3 variant H3F3A, occurring either at or close to key residues marked by methylation for regulation of transcription—K27 and G34. Here, we show that the cerebral hemisphere-specific G34 mutation drives a distinct expression signature through differential genomic binding of the K36 trimethylation mark (H3K36me3). The transcriptional program induced recapitulates that of the developing forebrain, and involves numerous markers of stem-cell maintenance, cell-fate decisions, and self-renewal. Critically, H3F3A G34 mutations cause profound upregulation of MYCN, a potent oncogene that is causative of GBMs when expressed in the correct developmental context. This driving aberration is selectively targetable in this patient population through inhibiting kinases responsible for stabilization of the protein.
Significance: We provide the mechanistic explanation for how the first histone gene mutation in human disease biology acts to deliver MYCN, a potent tumorigenic initiator, into a stem-cell compartment of the developing forebrain, selectively giving rise to incurable cerebral hemispheric GBM. Using synthetic lethal approaches to these mutant tumor cells provides a rational way to develop novel and highly selective treatment strategies. Cancer Discov; 3(5); 512–19. ©2013 AACR.
See related commentary by Huang and Weiss, p. 484
This article is highlighted in the In This Issue feature, p. 471
Application of Infrared Laser to the Zebrafish Vascular System
Authors: Kimura Eiji , Deguchi Tomonori , Kamei Yasuhiro , Shoji Wataru , Yuba Shunsuke , Hitomi Jiro 
Published: March 2013

Objective—
Infrared laser–evoked gene operator is a new microscopic method optimized to heat cells in living organisms without causing photochemical damage. By combining the promoter system for the heat shock response, infrared laser–evoked gene operator enables laser-mediated gene induction in targeted cells. We applied this method to the vascular system in zebrafish embryos and demonstrated its usability to investigate mechanisms of vascular morphogenesis in vivo.

Approach and Results—

We used double-transgenic zebrafish with
fli1:nEGFP
to identify the endothelial cells, and with
hsp:mCherry
to carry out single-cell labeling. Optimizing the irradiation conditions, we finally succeeded in inducing the expression of the mCherry gene in single targeted endothelial cells, at a maximum efficiency rate of 60%. In addition, we indicated that this system could be used for laser ablation under certain conditions. To evaluate infrared laser–evoked gene operator, we applied this system to the endothelial cells of the first intersegmental arteries, and captured images of the connection between the vascular systems of the brain and spinal cord.

Conclusions—
Our results suggest that the infrared laser–evoked gene operator system will contribute to the elucidation of the mechanisms underlying vascular morphogenesis by controlling spatiotemporal gene activation in single endothelial cells, by labeling or deleting individual vessels in living embryos.
Photodynamic Therapy Using a Protease-Mediated Theranostic Agent Reduces Cathepsin-B Activity in Mouse Atheromata In Vivo
Authors: Shon Soo-Min , Choi Yongdoo , Kim Jeong-Yeon , Lee Dong Kun , Park Jin-Yong , Schellingerhout Dawid , Kim Dong-Eog 
Published: March 2013

Objective—
To investigate whether an intravenously injected cathepsin-B activatable theranostic agent (L-SR15) would be cleaved in and release a fluorescent agent (chlorin-e6) in mouse atheromata, allowing both the diagnostic visualization and therapeutic application of these fluorophores as photosensitizers during photodynamic therapy to attenuate plaque-destabilizing cathepsin-B activity by selectively eliminating macrophages.

Approach and Results—
Thirty-week-old apolipoprotein E knock-out mice (n=15) received intravenous injection of L-SR15 theranostic agent, control agent D-SR16, or saline 3× (D0, D7, D14). Twenty-four hours after each injection, the bilateral carotid arteries were exposed, and Cy5.5 near-infrared fluorescent imaging was performed. Fluorescent signal progressively accumulated in the atheromata of the L-SR15 group animals only, indicating that photosensitizers had been released from the theranostic agent and were accumulating in the plaque. After each imaging session, photodynamic therapy was applied with a continuous-wave diode-laser. Additional near-infrared fluorescent imaging at a longer wavelength (Cy7) with a cathepsin-B–sensing activatable molecular imaging agent showed attenuation of cathepsin-B–related signal in the L-SR15 group. Histological studies demonstrated that L-SR15–based photodynamic therapy decreased macrophage infiltration by inducing apoptosis without significantly affecting plaque size or smooth muscle cell numbers. Toxicity studies (n=24) showed that marked erythematous skin lesion was generated in C57/BL6 mice at 24 hours after intravenous injection of free chlorin-e6 and ultraviolet light irradiation; however, L-SR15 or saline did not cause cutaneous phototoxicity beyond that expected of ultraviolet irradiation alone, neither did we observe systemic toxicity or neurobehavioral changes.

Conclusions—
This is the first study showing that macrophage-secreted cathepsin-B activity in atheromata could be attenuated by photodynamic therapy using a protease-mediated theranostic agent.
Nectin-Like Molecule-5 Regulates Intimal Thickening After Carotid Artery Ligation in Mice
Authors: Kureha Fumie , Satomi-Kobayashi Seimi , Kubo Yoshiki , Kinugasa Mitsuo , Ishida Tatsuro , Takai Yoshimi , Hirata Ken-ichi , Rikitake Yoshiyuki 
Published: March 2013

Objective—
Intimal thickening is considered to result from the dedifferentiation of medial smooth muscle cells (SMCs) from a contractile to a synthetic phenotype, and their subsequent migration and proliferation. It is unknown whether nectin-like molecule (Necl)-5, which is overexpressed in cancer cells, is involved in intimal thickening.

Approach and Results—
Necl-5 was upregulated in mouse carotid artery after ligation. Compared with wild-type mice, intimal thickening after carotid artery ligation was milder in Necl-5 knockout mice. In vitro, the expression levels of SMC differentiation markers were higher, whereas the expression level of an SMC dedifferentiation marker was lower, in Necl-5 knockout mouse aortic SMCs (MASMCs) compared with wild-type MASMCs. The migration, proliferation, and extracellular signal–regulated kinase activity in response to serum were decreased in Necl-5 knockout MASMCs compared with wild-type MASMCs. In wild-type MASMCs, inhibition of extracellular signal–regulated kinase activity increased the expression levels of SMC differentiation markers and decreased their migration and proliferation in response to serum.

Conclusions—
The present findings indicate that Necl-5 plays a role in the formation of intimal thickening after carotid artery ligation by regulating dedifferentiation, migration, and proliferation of SMCs in an extracellular signal–regulated kinase-dependent manner. Our results suggest that Necl-5 may represent a potential therapeutic target to limit intimal thickening after vascular injury.
Cocaine and Specific Cocaine Metabolites Induce von Willebrand Factor Release From Endothelial Cells in a Tissue-Specific Manner
Authors: Hobbs William E. , Moore Emily E. , Penkala Rebecca A. , Bolgiano Douglas D. , López José A. 
Published: March 2013

Objective—
Cocaine use is associated with arterial thrombosis, including myocardial infarction and stroke. Cocaine use results in increased plasma von Willebrand factor (VWF), accelerated atherosclerosis, and platelet-rich arterial thrombi, suggesting that cocaine activates the endothelium, promoting platelet–VWF interactions.

Approach and Results—
Human umbilical vein endothelial cells, brain microvasculature endothelial cells, or coronary artery endothelial cells were treated with cocaine or metabolites benzoylecgonine, cocaethylene, norcocaine, or ecgonine methylester. Supernatant VWF concentration and multimer structure were measured, and platelet–VWF strings formed on the endothelial surface under flow were quantified. Cocaine, benzoylecgonine, and cocaethylene induced endothelial VWF release, with the 2 metabolites being more potent than the parent molecule. Brain microvasculature endothelial cells were more sensitive to cocaine and metabolites than were human umbilical vein endothelial cells or coronary artery endothelial cells. Coronary artery endothelial cells released VWF into the supernatant but did not form VWF–platelet strings. Intracellular cAMP concentration was not increased after treatment with cocaine or its metabolites.

Conclusions—
Both cocaine and metabolites benzoylecgonine and cocaethylene induced endothelial VWF secretion, possibly explaining thrombotic risk after cocaine ingestion. VWF secretion is likely to vary between vascular beds, with brain endothelial cells being particularly sensitive. These results suggest that clinical management of cocaine-induced ischemia may benefit from therapies aimed at disrupting the VWF–platelet interaction.
Physiological Right Ventricular Adaptation in Elite Athletes of African and Afro-Caribbean Origin
Authors: Zaidi Abbas , Ghani Saqib , Sharma Rajan , Oxborough David , Panoulas Vasileios F. , Sheikh Nabeel , Gati Sabiha , Papadakis Michael , Sharma Sanjay 
Published: March 2013

Background—
Regular, intensive exercise results in physiological biventricular cardiac adaptation. Ethnicity is an established determinant of left ventricular remodeling; black athletes (BAs) exhibit more profound LV hypertrophy than white athletes (WAs). Right ventricular (RV) remodeling has not been characterized in BAs, although the issue is pertinent because BAs commonly exhibit ECG anomalies that resemble arrhythmogenic RV cardiomyopathy.

Methods and Results—

Between 2006 and 2012, 300 consecutive BAs (n=243 males) from 25 sporting disciplines were evaluated by use of ECG and echocardiography. Results were compared with 375 WAs and 153 sedentary control subjects (n=69 blacks). There were no ethnic differences between RV parameters in control subjects. Both BAs and WAs exhibited greater RV dimensions than control subjects. RV dimensions were marginally smaller in BAs than in WAs (proximal outflow tract, 30.9±5.5 versus 32.8±5.3 mm,
P
<0.001; longitudinal dimension, 86.6±9.5 versus 89.8±9.6 mm,
P
<0.001), although only 2.3% of variation was attributable to ethnicity. RV enlargement compatible with diagnostic criteria for arrhythmogenic RV cardiomyopathy was frequently observed (proximal outflow tract ≥32 mm; 45.0% of BAs, 58.5% of WAs). Anterior T-wave inversion was present in 14.3% of BAs versus 3.7% of WAs (
P
<0.001). Marked RV enlargement with concomitant anterior T-wave inversion was observed in 3.0% of BAs versus 0.3% of WAs (
P
=0.005). Further investigation did not diagnose arrhythmogenic RV cardiomyopathy in any athlete.

Conclusions—
Physiological RV enlargement is commonly observed in both black and white athletes. The impact of ethnicity is minimal, which obviates the need for race-specific RV reference values. However, in the context of frequent ECG repolarization anomalies in BAs, the potential for erroneous diagnosis of arrhythmogenic RV cardiomyopathy is considerably greater in this ethnic group.
The iScore Predicts Functional Outcome in Korean Patients With Ischemic Stroke
Authors: Park Tai Hwan , Saposnik Gustavo , Bae Hee-Joon , Lee Soo Joo , Lee Kyung Bok , Lee Jun , Park Jong-Moo , Choi Jay Chol , Kim Dong-Eog , Cho Yong-Jin , Kim Joon-Tae , Cha Jae-Kwan , Lee Juneyoung , Yu Kyung-Ho , Lee Byung-Chul , Yoon Byung-Woo 
Published: March 2013

Background and Purpose—
Several stroke risk scores for prediction of functional outcome have been developed, but rarely validated in Asian populations. We assessed the validity of the iScore, recently developed from Canadian stroke population, in an Asian stroke population from Korea.

Methods—
We applied the iScore to 4061 eligible participants with acute ischemic stroke in the nationwide multicenter stroke registry in Korea. The main outcome was poor functional outcome defined as having a modified Rankin Scale 3 to 6 at 3 months after stroke onset. The secondary outcome was death at 3 months. C-statistics were calculated to assess performance of the iScore.

Results—

Poor functional outcome was found in 1496 patients (36.8%), whereas death at 3 months occurred in 294 patients (7.2%). C-statistics were 0.819 (95% confidence interval, 0.805–0.833) for poor functional outcome and 0.861 (95% confidence interval, 0.840–0.883) for death. Overall, there was a high correlation between observed and expected outcomes for poor functional outcome (Pearson correlation coefficient,
r
=0.990) and for death (
r
=0.969) according to risk score.

Conclusions—
The iScore reliably predicts poor functional outcome or death at 3 months after stroke in Korean patients.
Early Perfusion Computerized Tomography Imaging as a Radiographic Surrogate for Delayed Cerebral Ischemia and Functional Outcome After Subarachnoid Hemorrhage
Authors: Etminan Nima , Beseoglu Kerim , Heiroth Hi-Jae , Turowski Bernd , Steiger Hans Jakob , Hänggi Daniel 
Published: March 2013

Background and Purpose—
To date, there is no immediate radiographic surrogate to quantify primary cerebral injury to identify patients at risk for delayed cerebral ischemia and poor clinical outcome after aneurysmal subarachnoid hemorrhage. Therefore, we investigated the relation of early cerebral perfusion–computerized tomography and clot volume with radiological events of delayed cerebral ischemia and clinical outcome in patients with aneurysmal subarachnoid hemorrhage.

Methods—
Data from 2 cohorts of patients (51 in main, 28 patients in control cohort) with aneurysmal subarachnoid hemorrhage, receiving computerized tomography and perfusion-computerized tomography scanning <12 hours after ictus, were included. A risk group model for functional outcome was developed on the basis of early mean transit time (MTT) and volumetric blood clot measurements. The relation of the risk group model with subsequent MTT, angiographic vasospasm, new cerebral infarction, and functional outcome was analyzed. Actual and predicted functional outcomes based on the risk group model were compared in the control cohort.

Results—
The risk group model correlated significantly with subsequent MTT measurements, cerebral infarction, and functional outcome. Odds for poor outcome were significantly higher in case of concomitant increase of early MTT and clot volumes, as opposed to exclusive early MTT or clot volume increase. For patients in the high- or low-risk groups, neurological outcome in the control cohort correlated significantly with predicted outcomes.

Conclusions—
Assessment of early cerebral perfusion and intracranial blood clot may serve as a radiographic surrogate for delayed cerebral ischemia and functional outcome in patients with aneurysmal subarachnoid hemorrhage using risk group modeling.
Role of SCH79797 in Maintaining Vascular Integrity in Rat Model of Subarachnoid Hemorrhage
Authors: Yan Junhao , Manaenko Anatol , Chen Sheng , Klebe Damon , Ma Qingyi , Caner Basak , Fujii Mutsumi , Zhou Changman , Zhang John H. 
Published: March 2013

Background and Purpose—
Plasma thrombin concentration is increased after subarachnoid hemorrhage (SAH). However, the role of thrombin receptor (protease-activated receptor-1 [PAR-1]) in endothelial barrier disruption has not been studied. The aims of this study were to investigate the role of PAR-1 in orchestrating vascular permeability and to assess the potential therapeutics of a PAR-1 antagonist, SCH79797, through maintaining vascular integrity.

Methods—
SCH79797 was injected intraperitoneally into male Sprauge-Dawley rats undergoing SAH by endovascular perforation. Assessment was conducted at 24 hours after SAH for brain water content, Evans blue content, and neurobehavioral testing. To explore the role of PAR-1 activation and the specific mechanism of SCH79797’s effect after SAH, Western blot, immunoprecipitation, and immunofluorescence of hippocampus tissue were performed. A p21-activated kinase-1 (PAK1) inhibitor, IPA-3, was used to explore the underlying protective mechanism of SCH79797.

Results—
At 24 hours after SAH, animals treated with SCH79797 demonstrated a reduction in brain water content, Evans blue content, and neurobehavioral deficits. SCH79797 also attenuated PAR-1 expression and maintained the level of vascular endothelial-cadherin, an important component of adherens junctions. Downstream to PAR-1, c-Src–dependent activation of p21-activated kinase-1 led to an increased serine/threonine phosphorylation of vascular endothelial-cadherin; immunoprecipitation results revealed an enhanced binding of phosphorylated vascular endothelial-cadherin with endocytosis orchestrator β-arrestin-2. These pathological states were suppressed after SCH79797 treatment.

Conclusions—
PAR-1 activation after SAH increases microvascular permeability, at least, partly through a PAR-1-c-Src-p21-activated kinase-1-vascular endothelial-cadherin phosphorylation pathway. Through suppressing PAR-1 activity, SCH79797 plays a protective role in maintaining microvascular integrity after SAH.
On Religiosity and Super-religiosity (I): Measures of Radical Religion
Authors: Aran Gideon 
Published: March 2013

Abstract
This essay submits a thesis on radical religion, discusses the measures of religion, and proposes the concept of “super-religiosity.” This will be followed by a second essay (in Numen vol. 60, issue 4, 2013) that presents a contemporary case to which the analytic model of super-religiosity is applied. Though the two essays systematically relate to each other and are complementary, they can be read independently of one another.
The theoretical core of the essay addresses the issue of the measurability of religiosity. It supports the recent claim that religion in general and religious extremism in particular, is not so much a matter of belief or experience but rather that it is essentially a matter of performance of the self and the group. It then argues that advancing our understanding of religious extremism requires turning the spotlight from an externally oriented performance towards a religion’s environment to an inward-facing religious performance. It further maintains that religious extremism’s center of gravity is the in-group dynamics of competition over religious excellence rather than (rational choice) competition over external resources. Finally, the paper proposes a measure of religiosity: that used by the practitioners of religion themselves.
The religious group that constitutes the empirical focus of the essay is the ultra-Orthodox Jews in contemporary Israel known as Haredim. More precisely, the essay describes and analyzes the hard core of the Haredi society that manifests religious extremism. It offers a comprehensive and methodic picture of Haredi society based on a critical survey of the literature, combined with an examination of updated data into which findings of an extensive field research are integrated. The discussion of the Haredi world is harnessed to the effort to deconstruct and reevaluate the prevalent concepts of tradition and fundamentalism, and suggests a new perspective on scaling religiosity and on high-scale religiosity.