bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemical performance of stabilized/solidified zinc-contaminated soil
Authors: John U. E. , Jefferson I. , Boardman D. I. , Ghataora G. S. , Hills C. D.
Published: January 2014

Stabilization/solidification has been found to be a relatively sustainable and economical method for managing risks associated with contaminated land. The technology has been employed extensively over the last three decades, particularly for the containment of heavy metals. However, because contaminants are not removed, there is a need to validate the long-term effectiveness of the technique. This requires knowledge of the containment mechanisms, the kinetics of contaminant release (equilibrium and disequilibrium conditions), and identification of the reactive surfaces that induce containment. In the present study, cement-stabilized zinc-contaminated kaolin clay containing 1% humic acid was tested to evaluate chemical performance in the long term. Time-dependent (chemical kinetics) and pH-dependent (equilibrium conditions) and equilibrium porewater leaching were evaluated, using LeachXS and geochemical speciation modelling using ORCHESTRA (embedded in LeachXS). Results showed that zinc was effectively contained within the waste form matrix under the prevailing chemical conditions, with immobilization increasing with hydration. Presence of humic acid increased the availability of zinc at an early stage, but this decreased at later stages and was comparable with results for organic-free matrices.
Factors influencing unit weight and strength of lightweight cemented clay
Authors: Horpibulsuk Suksun , Wijitchot Apirat , Nerimitknornburee Anek , Shen S. L. , Suksiripattanapong Cherdsak
Published: January 2014

The use of lightweight cemented clay has wide applications in infrastructure rehabilitation and in the construction of new facilities. Effects of water content, cement content, air content and fly ash (FA) on the unit weight and strength of lightweight cemented clay are presented and analysed. FA decreases the liquid limit and the plasticity index of the lightweight cemented clay. Consequently, it improves the unit weight, strength and workability of the lightweight cemented clay. For the same generalized stress state,
w
/

w
L

(ratio of water content to the liquid limit), lightweight cemented clay with a higher replacement ratio has a higher strength for the same input of cement owing to a higher cement/clay-water ratio,
C
/
w
. The FA fixation point is a practical indicator to obtain a minimum FA replacement because it is simply obtained from an index test. The prediction of unit weight of the lightweight cemented clay for different water contents, air contents, FA replacement ratios and cement contents is performed and verified. From the critical analysis of test results, a mix design method to attain the target strength and unit weight is suggested. This method is useful from both engineering and economic viewpoints.
Sulphur springs of the Craven Basin, NW England: indicators of natural methane leakage?
Authors: Murphy Phillip J. , Bottrell Simon H. , Parker Kay
Published: January 2014

Sulphidic springs are a common feature of the Craven Basin and have long histories, indicating that they are natural phenomena, and not a result of recent anthropogenic contamination of groundwater. This study identified several extant sulphur springs and these were sampled and analysed for hydrochemistry and isotopic composition (δ
34
S of sulphate and sulphide, δ
18
O of sulphate and δ
13
C of total dissolved inorganic carbon (TDIC)). The springs are associated with limestone units and are located in anticlinal crests that are sometimes faulted. Sulphide concentrations at these ‘sulphur springs’ range from <0.5 to 96 mg l
−1
and light sulphide isotopic compositions indicate that sulphide originates by microbial sulphate reduction. One site, ‘Stinky Bottoms’, with high sulphide concentration (46 mg l
−1
) also has very low δ
13
C-TDIC (–25.3‰ V-PDB) characteristic of a significant component of TDIC generation via methane oxidation. Other sites have δ
13
C-TDIC more typical of shallow groundwaters (−14.2 to −16.3‰ V-PDB) and two sites with highest Cl concentration and elevated Sr:Ca have heavier δ
13
C-TDIC (−11.3 and −6.8‰ V-PDB), indicative of a more evolved, long residence-time brine component. At Stinky Bottoms a strong case can be made that generation of sulphidic groundwater is related to subsurface methane. At other sites, sulphide generation may also be related to hydrocarbon or methane seeps (in some cases associated with a brine component) but the δ
13
C-TDIC values are more equivocal.
Analytical method for stagnation point calculation: theoretical developments and application to a hydraulic barrier design (Sicily, Italy)
Authors: Colombo Loris , Francani Vincenzo
Published: January 2014

A stagnation point is any point in the aquifer where the fluid velocity is equal to zero. Stagnation points can occur where the flow encounters impermeable surfaces or where the potentiometric surface is nearly horizontal. The presence of stagnation points is useful to locate groundwater bodies characterized by a very long renewal time.
Groundwater conceptual models: implications for evaluating diffuse pollution mitigation measures
Authors: Allen D. J. , Darling W. G. , Davies J. , Newell A. J. , Gooddy D. C. , Collins A. L.
Published: January 2014

The EU Water Framework Directive (WFD) identifies diffuse pollution as a long-term threat to water quality. Farming contributes significantly to this pollution. There is a clear need for mitigation measures and assessment of their efficacy. Accordingly, Demonstration Test Catchments (DTCs) have been established in England to test the effect of changes in agricultural practice on river water quality and ecology. However, the presence of groundwater in these hydrological systems implies a wide range of travel times for pollutants from source to receptor. Unless flow routes are better characterized, it will be difficult to gauge the success of control measures in the short term. Using 3D modelling and supplementary hydrochemical information, this study considers the hydrogeology of several sub-catchments in the Avon DTC, southern England. Data suggest that groundwater ages >25 years exist in parts of the catchments; clearly, observations like these must be used to judge the likely effectiveness of targeted control measures. The revealed hydrogeological complexity of the Avon catchment is unlikely to be unique, so the techniques described here should be applicable to other lowland river systems with moderate to high baseflow indices (>0.5). To support the WFD, groundwater conceptual models should inform the design of effective measures for diffuse pollution mitigation.
Vascular endothelial growth factor-C: its unrevealed role in fibrogenesis
Authors: Zhao Tieqiang , Zhao Wenyuan , Meng Weixin , Liu Chang , Chen Yuanjian , Sun Yao
Published: January 2014

Vascular endothelial growth factor (VEGF)-C is a key mediator of lymphangiogenesis. Our recent study shows that VEGF-C/VEGF receptors (VEGFR)-3 are significantly increased in the infarcted rat myocardium, where VEGFR-3 is expressed not only in lymph ducts but also in myofibroblasts, indicating that VEGF-C has an unrevealed role in fibrogenesis during cardiac repair. The current study is to explore the regulation and molecular mechanisms of VEGF-C in fibrogenesis. The potential regulation of VEGF-C on myofibroblast differentiation/growth/migration, collagen degradation/synthesis, and transforming growth factor (TGF)-β and ERK pathways was detected in cultured cardiac myofibroblasts. Our results showed that VEGF-C significantly increased myofibroblast proliferation, migration, and type I/III collagen production. Matrix metalloproteinase (MMP)-2 and -9 were significantly elevated in the medium of VEGF-C-treated cells, coincident with increased tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. Furthermore, VEGF-C activated the TGF-β1 pathway and ERK phosphorylation, which was significantly suppressed by TGF-β or ERK blockade. This is the first study indicating that in addition to lymphangiogenesis, VEGF-C is also involved in fibrogenesis through stimulation of myofibroblast proliferation, migration, and collagen synthesis, via activation of the TGF-β1 and ERK pathways.
Mechanism of reentry induction by a 9-V battery in rabbit ventricles
Authors: Bishop Martin J. , Burton Rebecca A. B. , Kalla Manish , Nanthakumar Kumaraswamy , Plank Gernot , Bub Gil , Vigmond Edward J.
Published: January 2014

Although the application of a 9-V battery to the epicardial surface is a simple method of ventricular fibrillation induction, the fundamental mechanisms underlying this process remain unstudied. We used a combined experimental and modelling approach to understand how the interaction of direct current (DC) from a battery may induce reentrant activity within rabbit ventricles and its dependence on battery application timing and duration. A rabbit ventricular computational model was used to simulate 9-V battery stimulation for different durations at varying onset times during sinus rhythm. Corresponding high-resolution optical mapping measurements were conducted on rabbit hearts with DC stimuli applied via a relay system. DC application to diastolic tissue induced anodal and cathodal make excitations in both simulations and experiments. Subsequently, similar static epicardial virtual electrode patterns were formed that interacted with sinus beats but did not induce reentry. Upon battery release during diastole, break excitations caused single ectopics, similar to application, before sinus rhythm resumed. Reentry induction was possible for short battery applications when break excitations were slowed and forced to take convoluted pathways upon interaction with refractory tissue from prior make excitations or sinus beats. Short-lived reentrant activity could be induced for battery release shortly after a sinus beat for longer battery applications. In conclusion, the application of a 9-V battery to the epicardial surface induces reentry through a complex interaction of break excitations after battery release with prior induced make excitations or sinus beats.
Enhanced large conductance K+channel activity contributes to the impaired myogenic response in the cerebral vasculature of Fawn Hooded Hypertensive rats
Authors: Pabbidi Mallikarjuna R. , Mazur Olga , Fan Fan , Farley Jerry M. , Gebremedhin Debebe , Harder David R. , Roman Richard J.
Published: January 2014

Recent studies have indicated that the myogenic response (MR) in cerebral arteries is impaired in Fawn Hooded Hypertensive (FHH) rats and that transfer of a 2.4 megabase pair region of chromosome 1 (RNO1) containing 15 genes from the Brown Norway rat into the FHH genetic background restores MR in a FHH.1BNcongenic strain. However, the mechanisms involved remain to be determined. The present study examined the role of the large conductance calcium-activated potassium (BK) channel in impairing the MR in FHH rats. Whole-cell patch-clamp studies of cerebral vascular smooth muscle cells (VSMCs) revealed that iberiotoxin (IBTX; BK inhibitor)-sensitive outward potassium (K+) channel current densities are four- to fivefold greater in FHH than in FHH.1BNcongenic strain. Inside-out patches indicated that the BK channel open probability ( NPo) is 10-fold higher and IBTX reduced NPoto a greater extent in VSMCs isolated from FHH than in FHH.1BNrats. Voltage sensitivity of the BK channel is enhanced in FHH as compared with FHH.1BNrats. The frequency and amplitude of spontaneous transient outward currents are significantly greater in VSMCs isolated from FHH than in FHH.1BNrats. However, the expression of the BK-α and -β-subunit proteins in cerebral vessels as determined by Western blot is similar between the two groups. Middle cerebral arteries (MCAs) isolated from FHH rats exhibited an impaired MR, and administration of IBTX restored this response. These results indicate that there is a gene on RNO1 that impairs MR in the MCAs of FHH rats by enhancing BK channel activity.
Cardiac contraction, calcium transients, and myofilament calcium sensitivity fluctuate with the estrous cycle in young adult female mice
Authors: MacDonald Jennifer K. , Pyle W. Glen , Reitz Cristine J. , Howlett Susan E.
Published: January 2014

This study established conditions to induce regular estrous cycles in female C57BL/6J mice and investigated the impact of the estrous cycle on contractions, Ca2+transients, and underlying cardiac excitation-contraction (EC)-coupling mechanisms. Daily vaginal smears from group-housed virgin female mice were stained to distinguish estrous stage (proestrus, estrus, metestrus, diestrus). Ventricular myocytes were isolated from anesthetized mice. Contractions and Ca2+transients were measured simultaneously (4 Hz, 37°C). Interestingly, mice did not exhibit regular cycles unless they were exposed to male pheromones in bedding added to their cages. Field-stimulated myocytes from mice in estrus had larger contractions (∼2-fold increase), larger Ca2+transients (∼1.11-fold increase), and longer action potentials (>2-fold increase) compared with other stages. Larger contractions and Ca2+transients were not observed in estrus myocytes voltage-clamped with shorter action potentials. Voltage-clamp experiments also demonstrated that estrous stage had no effect on Ca2+current, EC-coupling gain, diastolic Ca2+, sarcoplasmic reticulum (SR) Ca2+content, or fractional release. Although contractions were largest in estrus, myofilament Ca2+sensitivity was lowest (EC50values ∼1.15-fold higher) in conjunction with increased phosphorylation of myosin binding protein C in estrus. Contractions were enhanced in ventricular myocytes from mice in estrus because action potential prolongation increased SR Ca2+release. These findings demonstrate that cyclical changes in reproductive hormones associated with the estrous cycle can influence myocardial electrical and contractile function and modify Ca2+homeostasis. However, such changes are unlikely to occur in female mice housed in groups under conventional conditions, since these mice do not exhibit regular estrous cycles.
Interaction between respiration and right versus left ventricular volumes at rest and during exercise: a real-time cardiac magnetic resonance study
Authors: Claessen Guido , Claus Piet , Delcroix Marion , Bogaert Jan , Gerche Andre La , Heidbuchel Hein
Published: January 2014

Breathing-induced changes in intrathoracic pressures influence left ventricular (LV) and right ventricular (RV) volumes, the exact nature and extent of which have not previously been evaluated in humans. We sought to examine this “respiratory pump” using novel real-time cardiac magnetic resonance (CMR) imaging. Eight healthy subjects underwent serial multislice real-time CMR during normal breathing, breath holding, and the Valsalva maneuver. Subsequently, a separate cohort of nine subjects underwent real-time CMR at rest and during incremental exercise. LV and RV end-diastolic volume (EDV) and end-systolic volume (ESV) and diastolic and systolic eccentricity indexes were determined at peak inspiration and expiration. During normal breathing, inspiration resulted in an increase in RV volumes [RVEDV: +18 ± 8%, RVESV: +14 ± 12%, and RV stroke volume (SV): +21 ± 10%, P < 0.01] and an opposing decrease in LV volumes ( P < 0.0001 for interaction). During end-inspiratory breath holding, RV SV decreased by 9 ± 10% ( P = 0.046), whereas LV SV did not change. During the Valsalva maneuver, volumes decreased in both ventricles (RVEDV: −29 ± 11%, RVESV: −16 ± 14%, RV SV: −36 ± 14%, LVEDV: −22 ± 17%, and LV SV: −25 ± 17%, P < 0.01). The reciprocal effect of respiration on LV and RV volumes was maintained throughout exercise. The diastolic and systolic eccentricity indexes were greater during inspiration than during expiration, both at rest and during exercise ( P < 0.0001 for both). In conclusion, ventricular volumes oscillate with respiratory phase such that RV and LV volumes are maximal at peak inspiration and expiration, respectively. Thus, interpretation of RV versus LV volumes requires careful definition of the exact respiratory time point for proper interpretation, both at rest and during exercise.
Resveratrol promotes endothelial cell wound healing under laminar shear stress through an estrogen receptor-α-dependent pathway
Authors: Yurdagul Arif , Kleinedler James J. , McInnis Marshall C. , Khandelwal Alok R. , Spence Allyson L. , Orr A. Wayne , Dugas Tammy R.
Published: January 2014

Restenosis is an adverse outcome of angioplasty, characterized by vascular smooth muscle cell (VSMC) hyperplasia. However, therapies targeting VSMC proliferation delay reendothelialization, increasing the risk of thrombosis. Resveratrol (RESV) inhibits restenosis and promotes reendothelialization after arterial injury, but in vitro studies assessing RESV-mediated effects on endothelial cell growth contradict these findings. We thus hypothesized that fluid shear stress, mimicking physiological blood flow, would recapitulate RESV-dependent endothelial cell wound healing. Since RESV is an estrogen receptor (ER) agonist, we tested whether RESV promotes reendothelialization through an ER-α-dependent mechanism. Mice fed a high-fat diet or a diet supplemented with RESV were subjected to carotid artery injury. At 7 days after injury, RESV significantly accelerated reendothelialization compared with vehicle. In vitro wound healing assays demonstrated that RESV exhibits cell-type selectivity, inhibiting VSMC, but not endothelial cell growth. Under laminar shear stress (LSS), RESV dramatically enhanced endothelial cell wound healing and increased both the activation of extracellular signal-regulated kinase (ERK) and endothelial cell proliferation. Under LSS, small interfering RNA against ER-α, but not endothelial nitric oxide synthase, abolished RESV-induced ERK activation, endothelial cell proliferation, and wound healing. Thus these studies suggest that the EC phenotype induced by LSS better models the prohealing effects of RESV and that RESV and LSS interact to promote an ER-α-dependent mitogenic effect in endothelial cells.
Novel role of aminopeptidase-A in angiotensin-(1–7) metabolism post myocardial infarction
Authors: Alghamri Mahmoud S. , Morris Mariana , Meszaros J. Gary , Elased Khalid M. , Grobe Nadja
Published: January 2014

Aminopeptidase-A (APA) is a less well-studied enzyme of the renin-angiotensin system. We propose that it is involved in cardiac angiotensin (ANG) metabolism and its pathologies. ANG-(1–7) can ameliorate remodeling after myocardial injury. The aims of this study are to 1) develop mass spectrometric (MS) approaches for the assessment of ANG processing by APA within the myocardium; and 2) investigate the role of APA in cardiac ANG-(1–7) metabolism after myocardial infarction (MI) using sensitive MS techniques. MI was induced in C57Bl/6 male mice by ligating the left anterior descending (LAD) artery. Frozen mouse heart sections (in situ assay) or myocardial homogenates (in vitro assay) were incubated with the endogenous APA substrate, ANG II. Results showed concentration- and time-dependent cardiac formation of ANG III from ANG II, which was inhibited by the specific APA inhibitor, 4-amino-4-phosphonobutyric acid. Myocardial APA activity was significantly increased 24 h after LAD ligation (0.82 ± 0.02 vs. 0.32 ± 0.02 ρmol·min−1·μg−1, MI vs. sham, P < 0.01). Both MS enzyme assays identified the presence of a new peptide, ANG-(2–7), m/z 784, which accumulated in the MI (146.45 ± 6.4 vs. 72.96 ± 7.0%, MI vs. sham, P < 0.05). Use of recombinant APA enzyme revealed that APA is responsible for ANG-(2–7) formation from ANG-(1–7). APA exhibited similar substrate affinity for ANG-(1–7) compared with ANG II { Km(ANG II) = 14.67 ± 1.6 vs. Km[ANG-(1–7)] = 6.07 ± 1.12 μmol/l, P < 0.05}. Results demonstrate a novel role of APA in ANG-(1–7) metabolism and suggest that the upregulation of APA, which occurs after MI, may deprive the heart of cardioprotective ANG-(1–7). Thus APA may serve as a potentially novel therapeutic target for management of tissue remodeling after MI.
Transgelin as a therapeutic target to prevent hypoxic pulmonary hypertension
Authors: Zhang Ruifeng , Shi Liuhong , Zhou Lin , Zhang Gensheng , Wu Xiaohong , Shao Fangchun , Ma Guofeng , Ying Kejing
Published: January 2014

We previously observed that transgelin was preferentially expressed in human pulmonary arterial smooth muscle cells (PAMSCs) under hypoxia and that the upregulation of transgelin was independent of hypoxia-inducible factor 1α (HIF-1α). Reduced transgelin expression was accompanied by significantly impaired migration ability in vitro. However, the regulation mechanism of transgelin and its function in preventing hypoxic pulmonary hypertension (HPH) was unclear. In the present study, RNA interference with hypoxia-inducible factor 2α (HIF-2α) was employed in human PASMCs. Transgelin expression was diminished in HIF-2α-siRNA-treated cells at both the mRNA and protein levels under hypoxia. However, HIF-2α did not transactivate the transgelin promoter directly. TGF-β1concentration in human PASMCs culture medium was higher under hypoxia, and the accumulated TGF-β1under hypoxia was regulated by HIF-2α. Furthermore, luciferase and chromatin immunoprecipitation assays indicated that TGF-β1/Smad3 could bind to the transgelin promoter, resulting in increased transgelin expression. In addition to nonintact cellular migration, inhibition of transgelin expression resulted in impaired proliferation in vitro under hypoxia. A lentiviral vector used to inhibit transgelin expression was constructed and intratracheally instilled in rats 3 wk prior to hypoxia treatment. Our final results indicated that inhibition of transgelin expression locally could attenuate increased right ventricular systolic pressure and its associated cardiac and pulmonary vessel remodeling under hypoxia. Our findings indicate that HIF-2α upregulates transgelin indirectly and that accumulated TGF-β1is a mediator in the upregulation of transgelin by HIF-2α under hypoxia. Inhibition of transgelin expression locally could prevent HPH and pulmonary vascular remodeling in vivo.
Mechanisms of phagocytosis and host clearance ofPseudomonas aeruginosa
Authors: Lovewell Rustin R. , Patankar Yash R. , Berwin Brent
Published: January 2014

Pseudomonas aeruginosa is an opportunistic bacterial pathogen responsible for a high incidence of acute and chronic pulmonary infection. These infections are particularly prevalent in patients with chronic obstructive pulmonary disease and cystic fibrosis: much of the morbidity and pathophysiology associated with these diseases is due to a hypersusceptibility to bacterial infection. Innate immunity, primarily through inflammatory cytokine production, cellular recruitment, and phagocytic clearance by neutrophils and macrophages, is the key to endogenous control of P. aeruginosa infection. In this review, we highlight recent advances toward understanding the innate immune response to P. aeruginosa, with a focus on the role of phagocytes in control of P. aeruginosa infection. Specifically, we summarize the cellular and molecular mechanisms of phagocytic recognition and uptake of P. aeruginosa, and how current animal models of P. aeruginosa infection reflect clinical observations in the context of phagocytic clearance of the bacteria. Several notable phenotypic changes to the bacteria are consistently observed during chronic pulmonary infections, including changes to mucoidy and flagellar motility, that likely enable or reflect their ability to persist. These traits are likewise examined in the context of how the bacteria avoid phagocytic clearance, inflammation, and sterilizing immunity.
BRAF Inhibitor Resistance Mechanisms in Metastatic Melanoma: Spectrum and Clinical Impact
Authors: Rizos Helen , Menzies Alexander M. , Pupo Gulietta M. , Carlino Matteo S. , Fung Carina , Hyman Jessica , Haydu Lauren E. , Mijatov Branka , Becker Therese M. , Boyd Suzanah C. , Howle Julie , Saw Robyn , Thompson John F. , Kefford Richard F. , Scolyer Richard A. , Long Georgina V.
Published: January 2014

Purpose: Multiple BRAF inhibitor resistance mechanisms have been described, however, their relative frequency, clinical correlates, and effect on subsequent therapy have not been assessed in patients with metastatic melanoma.

Experimental Design: Fifty-nine BRAFV600-mutant melanoma metastases from patients treated with dabrafenib or vemurafenib were analyzed. The genetic profile of resistance mechanisms and tumor signaling pathway activity was correlated with clinicopathologic features and therapeutic outcomes.

Results: Resistance mechanisms were identified in 58% progressing tumors and BRAF alterations were common. Gene expression analysis revealed that mitogen-activated protein kinase (MAPK) activity remained inhibited in 21% of resistant tumors, and the outcomes of patients with these tumors were poor. Resistance mechanisms also occurred in pretreatment biopsies and heterogeneity of resistance mechanisms occurred within patients and within tumors. There were no responses to subsequent targeted therapy, even when a progressing tumor had a resistance mechanism predicted to be responsive.

Conclusions: Selecting sequential drugs based on the molecular characteristics of a single progressing biopsy is unlikely to provide improved responses, and first-line therapies targeting multiple pathways will be required. Clin Cancer Res; 20(7); 1965–77. ©2014 AACR.
Activation of Peroxisome Proliferator-Activated Receptor-β/δ (PPAR-β/δ) Inhibits Human Breast Cancer Cell Line Tumorigenicity
Authors: Yao Pei-Li , Morales Jose L. , Zhu Bokai , Kang Boo-Hyon , Gonzalez Frank J. , Peters Jeffrey M.
Published: January 2014

The effect of activation and overexpression of the nuclear receptor PPAR-β/δ in human MDA-MB-231 (estrogen receptor–negative; ER−) and MCF7 (estrogen-receptor-positive; ER+) breast cancer cell lines was examined. Target gene induction by ligand activation of PPAR-β/δ was increased by overexpression of PPAR-β/δ compared with controls. Overexpression of PPAR-β/δ caused a decrease in cell proliferation in MCF7 and MDA-MB-231 cells compared with controls, whereas ligand activation of PPAR-β/δ further inhibited proliferation of MCF7 but not MDA-MB-231 cells. Overexpression and/or ligand activation of PPAR-β/δ in MDA-MB-231 or MCF7 cells had no effect on experimental apoptosis. Decreased clonogenicity was observed in both MDA-MB-231 and MCF7 overexpressing PPAR-β/δ in response to ligand activation of PPAR-β/δ as compared with controls. Ectopic xenografts developed from MDA-MB-231 and MCF7 cells overexpressing PPAR-β/δ were significantly smaller, and ligand activation of PPAR-β/δ caused an even greater reduction in tumor volume as compared with controls. Interestingly, the decrease in MDA-MB-231 tumor size after overexpressing PPAR-β/δ and ligand activation of PPAR-β/δ correlated with increased necrosis. These data show that ligand activation and/or overexpression of PPAR-β/δ in two human breast cancer cell lines inhibits relative breast cancer tumorigenicity and provide further support for the development of ligands for PPAR-β/δ to specifically inhibit breast carcinogenesis. These new cell-based models will be invaluable tools for delineating the role of PPAR-β/δ in breast cancer and evaluating the effects of PPAR-β/δ agonists. Mol Cancer Ther; 13(4); 1008–17. ©2014 AACR.
Fhit Regulates EMT Targets through an EGFR/Src/ERK/Slug Signaling Axis in Human Bronchial Cells
Authors: Joannes Audrey , Grelet Simon , Duca Laurent , Gilles Christine , Kileztky Claire , Dalstein Véronique , Birembaut Philippe , Polette Myriam , Nawrocki-Raby Béatrice
Published: January 2014

In many cancers, including lung carcinomas, Fragile histidine triad (Fhit) is frequently decreased or lost. Fhit status has recently been shown to be associated with elevated in vitro and in vivo invasiveness in lung cancer. Tumor cell invasion is facilitated by epithelial–mesenchymal transition (EMT), a process by which tumor cells lose their epithelial features to acquire a mesenchymal cell-like phenotype. In this study, the mechanism underlying Fhit-regulated EMT was deciphered. Using Slug knockdown, pharmacologic inhibitors PD98059, PP1, and gefitinib as well as an anti-EGFR antibody, it was demonstrated that Fhit silencing in bronchial cells induced overexpression of two primary EMT-associated targets, MMP-9 and vimentin, to regulate cell invasion dependent on an EGFR/Src/ERK/Slug signaling pathway. Moreover, ectopic expression of Fhit in Fhit-deficient lung cancer cells downregulated this pathway. Finally, an inverse correlation was observed between Fhit and phospho-EGFR levels in a cohort of human squamous cell lung carcinoma specimens. These results demonstrate a Fhit-dependent mechanism in the control of EMT-regulated EGFR signaling.

Implications: This study adds new insight into the regulatory mechanism of EMT, a process known to increase resistance to conventional and targeted therapies in lung cancer. Mol Cancer Res; 12(5); 775–83. ©2014 AACR.
CAF-Secreted Annexin A1 Induces Prostate Cancer Cells to Gain Stem Cell–like Features
Authors: Geary Lauren A. , Nash Kevin A. , Adisetiyo Helty , Liang Mengmeng , Liao Chun-Peng , Jeong Joseph H. , Zandi Ebrahim , Roy-Burman Pradip
Published: January 2014

Annexin A1 (AnxA1), a phospholipid-binding protein and regulator of glucocorticoid-induced inflammatory signaling, has implications in cancer. Here, a role for AnxA1 in prostate adenocarcinoma was determined using primary cultures and a tumor cell line (cE1), all derived from the conditional Pten deletion mouse model of prostate cancer. AnxA1 secretion by prostate-derived cancer-associated fibroblasts (CAF) was significantly higher than by normal prostate fibroblasts (NPF). Prostate tumor cells were sorted to enrich for epithelial subpopulations based on nonhematopoietic lineage, high SCA-1, and high or medium levels of CD49f. Compared with controls, AnxA1 enhanced stem cell–like properties in high- and medium-expression subpopulations of sorted cE1 and primary cells, in vitro, through formation of greater number of spheroids with increased complexity, and in vivo, through generation of more, larger, and histologically complex glandular structures, along with increased expression of p63, a basal/progenitor marker. The differentiated medium-expression subpopulations from cE1 and primary cells were most susceptible to gain stem cell–like properties as shown by increased spheroid and glandular formation. Further supporting this increased plasticity, AnxA1 was shown to regulate epithelial-to-mesenchymal transition in cE1 cells. These results suggest that CAF-secreted AnxA1 contributes to tumor stem cell dynamics via two separate but complementary pathways: induction of a dedifferentiation process leading to generation of stem-like cells from a subpopulation of cancer epithelial cells and stimulation of proliferation and differentiation of the cancer stem-like cells.

Implications: AnxA1 participates in a paradigm in which malignant prostate epithelial cells that are not cancer stem cells are induced to gain cancer stem cell–like properties. Mol Cancer Res; 12(4); 607–21. ©2014 AACR.
FAK Inhibition Abrogates the Malignant Phenotype in Aggressive Pediatric Renal Tumors
Authors: Megison Michael L. , Gillory Lauren A. , Stewart Jerry E. , Nabers Hugh C. , Mrozcek-Musulman Elizabeth , Beierle Elizabeth A.
Published: January 2014

Despite the tremendous advances in the treatment of childhood kidney tumors, there remain subsets of pediatric renal tumors that continue to pose a therapeutic challenge, mainly malignant rhabdoid kidney tumors and nonosseous renal Ewing sarcoma. Children with advanced, metastatic, or relapsed disease have a poor disease-free survival rate. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is important in many facets of tumor development and progression. FAK has been found in other pediatric solid tumors and in adult renal cellular carcinoma, leading to the hypothesis that FAK contributes to pediatric kidney tumors and would affect cellular survival. In the current study, FAK was present and phosphorylated in pediatric kidney tumor specimens. Moreover, the effects of FAK inhibition upon G401 and SK-NEP-1 cell lines were examined using a number of parallel approaches to block FAK, including RNA interference and small-molecule FAK inhibitors. FAK inhibition resulted in decreased cellular survival, invasion and migration, and increased apoptosis. Furthermore, small-molecule inhibition of FAK led to decreased SK-NEP-1 xenograft growth in vivo. These data deepen the knowledge of the tumorigenic process in pediatric renal tumors, and provide desperately needed therapeutic strategies and targets for these rare, but difficult to treat, malignancies.

Implications: This study provides a fundamental understanding of tumorigenesis in difficult to treat renal tumors and provides an impetus for new avenues of research and potential for novel, targeted therapies. Mol Cancer Res; 12(4); 514–26. ©2014 AACR.
Targeting Estrogen Receptor-β for the Prevention of Nonmelanoma Skin Cancer
Authors: Yao Pei-Li , Gonzalez Frank J. , Peters Jeffrey M.
Published: January 2014

The potential for targeting estrogen receptor (ER)-β in various cancer models has been gaining considerable attention in recent years. In this issue of the journal, Chaudhary and colleagues demonstrate markedly decreased ultraviolet B (UVB)-induced skin cancer in a mouse model using a highly specific ER-β agonist, ERB-041. The mechanisms that underlie this strong inhibitory effect are mediated by inhibition of proinflammatory signaling and epithelial–mesenchymal transition (EMT). The changes in EMT were due in part to modulation of WNT/β-catenin signaling. Collectively, the results from these studies provide important new insights into the mechanisms by which the ER-β agonist ERB-041 inhibits UVB-induced skin cancer and opens the door for future studies that could examine combinatorial approaches for UVB-dependent skin cancer chemoprevention. Cancer Prev Res; 7(2); 182–5. ©2014 AACR.
Double-Stranded RNA–Dependent Protein Kinase Deficiency Protects the Heart From Systolic Overload-Induced Congestive Heart Failure
Authors: Wang Huan , Xu Xin , Fassett John , Kwak Dongmin , Liu Xiaoyu , Hu Xinli , Falls Therasa J. , Bell John C. , Li Hongliang , Bitterman Peter , Bache Robert J. , Chen Yingjie
Published: January 2014

Background—

Double-stranded RNA–dependent protein kinase (PKR) is a eukaryotic initiation factor 2α kinase that inhibits mRNA translation under stress conditions. PKR also mediates inflammatory and apoptotic signaling independently of translational regulation. Congestive heart failure is associated with cardiomyocyte hypertrophy, inflammation, and apoptosis, but the role of PKR in left ventricular hypertrophy and the development of congestive heart failure has not been examined.

Methods and Results—

We observed increased myocardial PKR expression and translocation of PKR into the nucleus in humans and mice with congestive heart failure. To determine the impact of PKR on the development of congestive heart failure, PKR knockout and wild-type mice were exposed to pressure overload produced by transverse aortic constriction. Although heart size increased similarly in wild-type and PKR knockout mice after transverse aortic constriction, PKR knockout mice exhibited very little pulmonary congestion, well-preserved left ventricular ejection fraction and contractility, and significantly less myocardial fibrosis compared with wild-type mice. Bone marrow–derived cells from wild-type mice did not abolish the cardiac protective effect observed in PKR knockout mice, whereas bone marrow–derived cells from PKR knockout mice had no cardiac protective effect in wild-type mice. Mechanistically, PKR knockout attenuated transverse aortic constriction–induced tumor necrosis factor-α expression and leukocyte infiltration and lowered cardiac expression of proapoptotic factors (Bax and caspase-3), so that PKR knockout hearts were more resistant to transverse aortic constriction–induced cardiomyocyte apoptosis. PKR depletion in isolated cardiomyocytes also conferred protection against tumor necrosis factor-α– or lipopolysaccharide-induced apoptosis.

Conclusion—

PKR is a maladaptive factor upregulated in hemodynamic overload that contributes to myocardial inflammation, cardiomyocyte apoptosis, and the development of congestive heart failure.
Dominant Frequency Increase Rate Predicts Transition from Paroxysmal to Long-Term Persistent Atrial Fibrillation
Authors: Martins Raphael P. , Kaur Kuljeet , Hwang Elliot , Ramirez Rafael J. , Willis B. Cicero , Filgueiras-Rama David , Ennis Steven R. , Takemoto Yoshio , Ponce-Balbuena Daniela , Zarzoso Manuel , O’Connell Ryan P. , Musa Hassan , Guerrero-Serna Guadalupe , Avula Uma Mahesh R. , Swartz Michael F. , Bhushal Sandesh , Deo Makarand , Pandit Sandeep V. , Berenfeld Omer , Jalife José
Published: January 2014

Background—

Little is known about the mechanisms underlying the transition from paroxysmal to persistent atrial fibrillation (AF). In an ovine model of long-standing persistent AF we tested the hypothesis that the rate of electric and structural remodeling, assessed by dominant frequency (DF) changes, determines the time at which AF becomes persistent.

Methods and Results—

Self-sustained AF was induced by atrial tachypacing. Seven sheep were euthanized 11.5±2.3 days after the transition to persistent AF and without reversal to sinus rhythm; 7 sheep were euthanized after 341.3±16.7 days of long-standing persistent AF. Seven sham-operated animals were in sinus rhythm for 1 year. DF was monitored continuously in each group. Real-time polymerase chain reaction, Western blotting, patch clamping, and histological analyses were used to determine the changes in functional ion channel expression and structural remodeling. Atrial dilatation, mitral valve regurgitation, myocyte hypertrophy, and atrial fibrosis occurred progressively and became statistically significant after the transition to persistent AF, with no evidence for left ventricular dysfunction. DF increased progressively during the paroxysmal-to-persistent AF transition and stabilized when AF became persistent. Importantly, the rate of DF increase correlated strongly with the time to persistent AF. Significant action potential duration abbreviation, secondary to functional ion channel protein expression changes (Ca
V
1.2, Na
V
1.5, and K
V
4.2 decrease; Kir2.3 increase), was already present at the transition and persisted for 1 year of follow up.

Conclusions—

In the sheep model of long-standing persistent AF, the rate of DF increase predicts the time at which AF stabilizes and becomes persistent, reflecting changes in action potential duration and densities of sodium, L-type calcium, and inward rectifier currents.
Variations in Cause and Management of Atrial Fibrillation in a Prospective Registry of 15 400 Emergency Department Patients in 46 Countries
Authors: Oldgren Jonas , Healey Jeff S. , Ezekowitz Michael , Commerford Patrick , Avezum Alvaro , Pais Prem , Zhu Jun , Jansky Petr , Sigamani Alben , Morillo Carlos A. , Liu Lisheng , Damasceno Albertino , Grinvalds Alex , Nakamya Juliet , Reilly Paul A. , Keltai Katalin , Van Gelder Isabelle C. , Yusufali Afzal Hussein , Watanabe Eiichi , Wallentin Lars , Connolly Stuart J. , Yusuf Salim
Published: January 2014

Background—

Atrial fibrillation (AF) is the most common sustained arrhythmia; however, little is known about patients in a primary care setting from high-, middle-, and low-income countries.

Methods and Results—

This prospective registry enrolled patients presenting to an emergency department with AF at 164 sites in 46 countries representing all inhabited continents. Patient characteristics were compared among 9 major geographic regions. Between September 2008 and April 2011, 15 400 patients were enrolled. The average age was 65.9, standard deviation 14.8 years, ranging from 57.2, standard deviation 18.8 years in Africa, to 70.1, standard deviation 13.4 years in North America,
P
<0.001. Hypertension was globally the most common risk factor for AF, ranging in prevalence from 41.6% in India to 80.7% in Eastern Europe,
P
<0.001. Rheumatic heart disease was present in only 2.2% of North American patients, in comparison with 21.5% in Africa and 31.5% in India,
P
<0.001. The use of oral anticoagulation among patients with a CHADS
2
score of ≥2 was greatest in North America (65.7%) but was only 11.2% in China,
P
<0.001. The mean time in the therapeutic range was 62.4% in Western Europe, 50.9% in North America, but only between 32% and 40% in India, China, Southeast Asia, and Africa,
P
<0.001.

Conclusions—

There is a large global variation in age, risk factors, concomitant diseases, and treatment of AF among regions. Improving outcomes globally requires an understanding of this variation and the conduct of research focused on AF associated with different underlying conditions and treatment of AF and predisposing conditions in different socioeconomic settings.
Technologies for intentional learning: Beyond a cognitive perspective
Authors: Spector J Michael , Kim ChanMin
Published: January 2014

The concept of intentional learning is well established in the educational community. Intentional learning implies that there is a recognized learning goal and that those involved are rational agents who can make choices with regard to achieving that goal. There are typically two different kinds of people involved in a learning situation—learners and those supporting learners (teachers, tutors, trainers, intelligent pedagogical agents, etc.). It is important to recognize that the goals of learners and those who are designated to support them may differ. Optimal learning occurs when such differences are minimized. A second well-established concept in education is that of engagement. Educational research has established time-on-task as a significant predictor of learning—the more time that a student spends on a learning task, the more likely that student is to master that task. More recently, this concept has been expanded to include initiating and sustaining engagement along with motivation and volition. According to the widely accepted constructivist epistemology, a person creates internal representations (a cognitive activity) to make sense of things that the person experiences, especially things that are new or puzzling in some way. In this paper, we review the logical landscape of the cognitive perspective of intentional learning and argue that it is incomplete without also taking into consideration a more holistic account of human learning that includes noncognitive aspects involved in human experience, somewhat akin to embodied cognition. Our review provides reminders of research-based principles that can inform technology-enhanced efforts to support intentional learning and promote engagement. We conclude with a framework for integrating technologies that are likely to engage learners taking into account a variety of learning goals, situations, and learners. This review is preliminary and intended to suggest areas worth investigating to elaborate a more complete picture of how best to promote and support intentional learning and active learner engagement using available technologies.
Connected authentic learning: Reflection and intentional learning
Authors: Herrington Jan , Parker Jenni , Boase-Jelinek Daniel
Published: January 2014

Authentic learning pedagogy not only allows students to engage in realistic tasks using real-world resources and tools, but it also provides opportunities for students to learn with intention by thinking and acting like professionals as they address real problems. This paper describes a research conducted in a first year university course, where social media were used to support authentic and intentional learning. Principles of authentic learning guided the design of the course, and learning tasks and activities focused on the completion of realistic and complex tasks. Students’ mental effort was expended largely on the creation of polished and accomplished products, rather than on the completion of a series of decontextualised or step-by-step exercises. Importantly, opportunities for reflection were provided through the completion of a complex and collaborative task, a journal and a reflective examination. A qualitative study of two cohorts of students was conducted, as part of a larger design-based research agenda, over a period of two years. Findings showed that providing such course elements to facilitate reflection allowed students to reflect both in action as they participated in the course tasks and on action as they wrote about their learning experiences.
Intentional learning with technological proxies: Goal orientations and efficacy beliefs
Authors: Hanham José , Ullman Jacqueline , Orlando Joanne , McCormick John
Published: January 2014

Digital technologies serve as an important educational resource for tertiary students. A key feature of many current digital technologies available to students is that they can function as proxies in the learning process; that is, technology can be used to carry out some academic-related tasks on behalf of the user. For tertiary educators, the widespread availability of technological proxies raises a number of important pedagogical issues. In this article, we discuss technological proxy in the context of intentional learning. Drawing from the literature on learner motivation, we identify three key variables – learners’ achievement goal orientations, self-efficacy beliefs, and proxy efficacy beliefs – and advance a set of propositions about how relationships between these variables may shape students’ use of technology as intentional learners. A key goal of this article is to expand current thinking around the ways in which tertiary learners’ efficacy beliefs relate to working with digital technology and, ultimately, their learning and performance outcomes.
Intrinsic and extrinsic intentional learning: The difference made by self-determination
Authors: Hung Woei
Published: January 2014

Intentional learning occurs in formal and informal settings throughout an individual’s life time. Intentional learning can be deemed as an ideal learning process where all the necessary elements for achieving a goal of effective learning are in place and in order. Intentional learners take an active role in and responsibility for their own learning, and they self-plan, execute, monitor and regulate their learning processes as well as learning strategies. Most importantly, intentional learners are willing and committed to reaching the learning goal. At its occurrence, intentional learning could be triggered by an external suggestion or guidance (e.g. teacher’s explanation of the importance of the subject), or internal factors (e.g. intrinsic interests or personal needs through self-evaluation and self-determination). Thus, intentional learning could be further differentiated into intrinsic or extrinsic. While both intrinsic and extrinsic intentional learning are likely to result in similar learning outcomes, cultivating students’ disposition of intrinsic intentional learning may have more beneficial long term effects than extrinsic intentional learning as it is one of the keys that sustain an individual’s lifelong learning. Also, the technology that could facilitate intrinsic intentional learning will be discussed.
Intentional learning with educational games: A Deweyan reconstruction
Authors: Chee Yam San
Published: January 2014

Intentional learning has customarily been construed from a perspective that foregrounds cognitive engagement and mental life in meaning making. In this paper, I interrogate the said perspective. I argue that a theoretical positioning based on the dominant paradigm of human information processing psychology leads to incoherence because this paradigm results in “meaning-less cognition.” To get out of this conundrum, I offer a reconstruction of intentional learning from the perspective of Deweyan inquiry and the philosophy of pragmatism. I situate this reconstruction in the context of game-based learning.