bluuebunny/crossref_metadata_2025 huggingface dataset:
Precocious Albion: A New Interpretation of the British Industrial Revolution
Authors: Kelly Morgan , Mokyr Joel , Gráda Cormac Ó
Published: March 2014

Many explanations have been offered for the British Industrial Revolution. This article points to the importance of human capital (broadly defined) and the quality of the British labor force on the eve of the Industrial Revolution. It shows that in terms of both physical quality and mechanical skills, British workers around 1750 were at a much higher level than their continental counterparts. As a result, new inventions—no matter where they originated—were adopted earlier, faster, and on a larger scale in Britain than elsewhere. The gap in labor quality is consistent with the higher wages paid in eighteenth-century Britain. The causes for the higher labor quality are explored and found to be associated with a higher level of nutrition and better institutions, especially England’s Poor Law and the superior functioning of its apprenticeship system.
Disclosure: Psychology Changes Everything
Authors: Loewenstein George , Sunstein Cass R. , Golman Russell
Published: March 2014

We review literature examining the effects of laws and regulations that require public disclosure of information. These requirements are most sensibly imposed in situations characterized by misaligned incentives and asymmetric information between, for example, a buyer and seller or an advisor and advisee. We review the economic literature relevant to such disclosure and then discuss how different psychological factors complicate, and in some cases radically change, the economic predictions. For example, limited attention, motivated attention, and biased assessments of probability on the part of information recipients can significantly diminish, or even reverse, the intended effects of disclosure requirements. In many cases, disclosure does not much affect the recipients of the information but does significantly affect the behavior of the providers, sometimes for the better and sometimes for the worse. We review research suggesting that simplified disclosure, standardized disclosure, vivid disclosure, and social comparison information can all be used to enhance the effectiveness of disclosure policies.
Social Isolation in America
Authors: Parigi Paolo , Henson Warner
Published: March 2014

We offer a new measure for social isolation for contemporary society, where opportunities for making connections with others have become ubiquitous. We develop this measure after reviewing previous research on social isolation that we segment into two perspectives. On the one side, isolation has been studied as a negative outcome of processes related to modernization; on the other side, isolation has been studied as a structural position potentially capable of delivering positive returns. Although academic interest in isolation is long-standing, recent years have seen an explosion of research on the topic. We explore the connection between this explosion and new social media and highlight a division within the literature between researchers who see new social media as creating more feelings of isolation and others who think that the jury is still out. In the final section of the article, we offer our novel conceptual framework for studying isolation.
Aromatase transgenic upregulation modulates basal cardiac performance and the response to ischemic stress in male mice
Authors: Bell James R. , Bernasochi Gabriel B. , Varma Upasna , Boon Wah Chin , Ellem Stuart J. , Risbridger Gail P. , Delbridge Lea M. D.
Published: March 2014

Estrogen in females is conventionally considered a cardioprotective influence, but a role for estrogen in male cardioprotection has yet to be defined. Estrogen biosynthesis from testosterone is regulated by aromatase. Aromatase has recently been shown to be expressed in the adult heart, although little is known about its involvement in the regulation of myocardial function and stress responses. The goal of this study was to determine whether upregulation of tissue aromatase expression could improve ischemic resilience in male hearts. Isolated hearts from male transgenic aromatase-overexpressing (AROM+; high estrogen, low testosterone) mice and wild-type (WT) mice (12 wk) were Langendorff perfused and subjected to ischemia-reperfusion (25 min ischemia and 60 min of reperfusion). Basal systolic function was lower in AROM+hearts (dP/d tmax: 4,121 ± 255 vs. 4,992 ± 283 mmHg/s, P < 0.05) and associated with augmented Akt phosphorylation, consistent with a suppressor action of estrogen on contractility. Ischemic contracture was attenuated in AROM+hearts (43 ± 3 vs. 55 ± 4 mmHg, P < 0.05), yet AROM+hearts were more arrhythmic in early reperfusion. At the end of 60 min of reperfusion, AROM+systolic functional recovery was lower (left ventricular developed pressure: 39 ± 6 vs. 56 ± 5 %basal, P < 0.05) and diastolic dysfunction was accentuated (36 ± 4 vs. 24 ± 2 mmHg, P < 0.05). This is the first study to show that in vivo aromatase upregulation modulates basal cardiac performance and the response to ischemic stress. These data suggest that while chronic exposure to enhanced estrogenic influence may have benefits in limiting ischemic contracture severity, acute functional recovery in reperfusion is compromised. A temporally targeted, tissue-specific intervention combining aromatase treatment with inotropic support may offer therapeutic potential for men and women.
Adverse perinatal environment contributes to altered cardiac development and function
Authors: Velten Markus , Gorr Matthew W. , Youtz Dane J. , Velten Christina , Rogers Lynette K. , Wold Loren E.
Published: March 2014

Epidemiological observations report an association between intrauterine growth restriction (IUGR) and cardiovascular diseases. Systemic maternal inflammation is the most common stress during pregnancy, leading to IUGR. We hypothesized that perinatal inflammation and hyperoxygenation induce discernible alterations in cardiomyocyte contractility and calcium signaling, causing early cardiac dysfunction. Pregnant C3H/HeN mice were injected with LPS or saline on embryonic day 16. Newborn mice were placed in 85% O2or room air (RA) for 14 days. Pups born to LPS-injected dams had reduced birth weight. Echocardiographic measurements revealed that in vivo LV function was compromised in LPS/O2mice as early as 3 days of life. Isolated cardiomyocytes from LPS/O2mice at day 14 exhibited decreased sarcomere fractional shortening, along with decreased time-to-90% peak shortening. Calcium transient amplitude was greatest in LPS/O2mice. SERCA2a mRNA and protein levels were increased and phospholamban mRNA levels were decreased in LPS/O2mice. Phosphorylation of phospholamban was increased, along with Sorcin mRNA levels in LPS/O2mice. Combined exposure to perinatal inflammation and hyperoxia resulted in growth restriction, in vivo and in vitro cardiac dysfunction, coinciding with humans and animal models of cardiac dysfunction. Expression of calcium handling proteins during the neonatal period was similar to that observed during fetal stages of development. Our data suggest that perinatal inflammation and hyperoxia exposure alter fetal development, resulting in early cardiac dysfunction.
Aortic valve sclerosis in mice deficient in endothelial nitric oxide synthase
Authors: El Accaoui Ramzi N. , Gould Sarah T. , Hajj Georges P. , Chu Yi , Davis Melissa K. , Kraft Diane C. , Lund Donald D. , Brooks Robert M. , Doshi Hardik , Zimmerman Kathy A. , Kutschke William , Anseth Kristi S. , Heistad Donald D. , Weiss Robert M.
Published: March 2014

Risk factors for fibrocalcific aortic valve disease (FCAVD) are associated with systemic decreases in bioavailability of endothelium-derived nitric oxide (EDNO). In patients with bicuspid aortic valve (BAV), vascular expression of endothelial nitric oxide synthase (eNOS) is decreased, and eNOS−/−mice have increased prevalence of BAV. The goal of this study was to test the hypotheses that EDNO attenuates profibrotic actions of valve interstitial cells (VICs) in vitro and that EDNO deficiency accelerates development of FCAVD in vivo. As a result of the study, coculture of VICs with aortic valve endothelial cells (vlvECs) significantly decreased VIC activation, a critical early phase of FCAVD. Inhibition of VIC activation by vlvECs was attenuated by NG-nitro-l-arginine methyl ester or indomethacin. Coculture with vlvECs attenuated VIC expression of matrix metalloproteinase-9, which depended on stiffness of the culture matrix. Coculture with vlvECs preferentially inhibited collagen-3, compared with collagen-1, gene expression. BAV occurred in 30% of eNOS−/−mice. At age 6 mo, collagen was increased in both bicuspid and trileaflet eNOS−/−aortic valves, compared with wild-type valves. At 18 mo, total collagen was similar in eNOS−/−and wild-type mice, but collagen-3 was preferentially increased in eNOS−/−mice. Calcification and apoptosis were significantly increased in BAV of eNOS−/−mice at ages 6 and 18 mo. Remarkably, these histological changes were not accompanied by physiologically significant valve stenosis or regurgitation. In conclusion, coculture with vlvECs inhibits specific profibrotic VIC processes. In vivo, eNOS deficiency produces fibrosis in both trileaflet and BAVs but produces calcification only in BAVs.
Are SR Ca content fluctuations or SR refractoriness the key to atrial cardiac alternans?: insights from a human atrial model
Authors: Lugo Carlos A. , Cantalapiedra Inma R. , Peñaranda Angelina , Hove-Madsen Leif , Echebarria Blas
Published: March 2014

Despite the important role of electromechanical alternans in cardiac arrhythmogenesis, its molecular origin is not well understood. The appearance of calcium alternans has often been associated to fluctuations in the sarcoplasmic reticulum (SR) Ca loading. However, cytosolic calcium alternans observed without concurrent oscillations in the SR Ca content suggests an alternative mechanism related to a dysfunction in the dynamics of the ryanodine receptor (RyR2). We have investigated the effect of SR release refractoriness in the appearance of alternans, using a mathematical model of a single human atrial cell, based on the model by Nygren et al. ( 30 ), where we modified the dynamics of the RyR2 and of SR Ca release. The genesis of calcium alternans was studied stimulating the cell for different periods and values of the RyR2 recovery time from inactivation. At fast rates cytosolic calcium alternans were obtained without concurrent SR Ca content fluctuations. A transition from regular response to alternans was also observed, changing the recovery time from inactivation of the RyR2. This transition was found to be hysteretic, so for a given set of parameters different responses were observed. We then studied the relevance of RyR2 refractoriness for the generation of alternans, reproducing the same protocols as in recent experiments. In particular, restitution of Ca release during alternans was studied with a S1S2 protocol, obtaining a different response if the S2 stimulation was given after a long or a short release. We show that the experimental results can be explained by RyR2 refractoriness, arising from a slow RyR2 recovery from inactivation, stressing the role of the RyR2 in the genesis of alternans.
Rapid electrical stimulation causes alterations in cardiac intercellular junction proteins of cardiomyocytes
Authors: Nakashima Tadamitsu , Ohkusa Tomoko , Okamoto Yoko , Yoshida Masaaki , Lee Jong-Kook , Mizukami Yoichi , Yano Masafumi
Published: March 2014

The intercellular junctions contain two complexes, adhesion junctions (AJ) and connexin (Cx) gap junctions (GJs). GJs provide the pathway for intercellular current flow. AJs mediate normal mechanical coupling and play an important role in the stability of GJs. We investigated the effects of rapid electrical stimulation (RES) on cardiac intercellular junctions, especially β-catenin and Cx43 alterations. We also studied the effects of ANG II receptor blockade on intercellular junction remodeling. Neonatal rats were euthanized by decapitation, and cardiomyocytes were prepared, cultured, and subjected to RES. We used real-time PCR, western blot analysis, and immunohistochemical methods. Conduction properties were examined by an extracellular potential mapping system. Cx43 protein expression in cardiomyocytes was significantly increased after 60 min. β-Catenin expression in the total cell fraction was significantly increased after 30 min. The expression level of β-catenin in the nucleus, which functions as a T cell factor/lymphocyte enhancer binding factor transcriptional activator of Cx43 with its degradation regulated by glycogen synthase kinase-3β, was dramatically increased after 10 min. Conduction velocity was increased significantly by RES for 60 min. Olmesartan prevented most these effects of RES. We showed an increase of phosphorylated glycogen synthase kinase-3β, which is phosphorylated by activated MAPKs and inhibits β-catenin degradation, was attenuated by olmesartan. The changes in β-catenin precede Cx43 GJ remodeling and might play an important role in the formation and stability of GJs. Olmesartan might be a new upstream arrhythmia therapy by modulating intercellular junction remodeling through the β-catenin signaling pathway.
Sex differences in the pulmonary circulation: implications for pulmonary hypertension
Authors: Martin Yvette N. , Pabelick Christina M.
Published: March 2014

Pulmonary arterial hypertension (PAH), a form of pulmonary hypertension, is a complex disease of multifactorial origin. While new developments regarding pathophysiological features and therapeutic options in PAH are being reported, one important fact has emerged over the years: there is a sex difference in the incidence of this disease such that while there is a higher incidence in females, disease outcomes are much worse in males. Accordingly, recent attention has been focused on understanding the features of sex differences in the pulmonary circulation and the contributory mechanisms, particularly sex hormones and their role in the pathological and pathophysiological features of PAH. However, to date, there is no clear consensus whether sex hormones (particularly female sex steroids) are beneficial or detrimental in PAH. In this review, we highlight some of the most recent evidence regarding the influence of sex hormones (estrogen, testosterone, progesterone, dehydroepiandrosterone) and estrogen metabolites on key pathophysiological features of PAH such as proliferation, vascular remodeling, vasodilation/constriction, and inflammation, thus setting the stage for research avenues to identify novel therapeutic target for PAH as well as potentially other forms of pulmonary hypertension.
Reduction of endoplasmic reticulum stress by 4-phenylbutyric acid prevents the development of hypoxia-induced pulmonary arterial hypertension
Authors: Koyama Masayuki , Furuhashi Masato , Ishimura Shutaro , Mita Tomohiro , Fuseya Takahiro , Okazaki Yusuke , Yoshida Hideaki , Tsuchihashi Kazufumi , Miura Tetsuji
Published: March 2014

Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and vascular remodeling of the pulmonary artery (PA). Recently, endoplasmic reticulum (ER) stress and inappropriate adaptation through the unfolded protein response (UPR) have been disclosed in various types of diseases. Here we examined whether ER stress is involved in the pathogenesis of PAH. Four weeks of chronic normobaric hypoxia increased right ventricular (RV) systolic pressure by 63% compared with that in normoxic controls and induced RV hypertrophy and medial thickening of the PA in C57BL/6J mice. Treatment with 4-phenylbutyric acid (4-PBA), a chemical chaperone, significantly reduced RV systolic pressure by 30%, attenuated RV hypertrophy and PA muscularization, and increased total running distance in a treadmill test by 70% in hypoxic mice. The beneficial effects of 4-PBA were associated with suppressed expression of inflammatory cytokines and ER stress markers, including Grp78 and Grp94 in the activating transcription factor-6 branch, sXbp1 and Pdi in the inositol-requiring enzyme-1 branch and Atf4 in the PKR-like ER kinase branch, and reduced phosphorylation of c-Jun NH2-terminal kinase and eukaryotic translation initiation factor-2α in the lung. The pattern of changes in ER stress and inflammatory markers by 4-PBA in the lung of the PAH model was reproduced in PA smooth muscle cells by chronic stimulation of platelet-derived growth factor-BB or hypoxia. Furthermore, knockdown of each UPR branch sensor activated other branches and promoted proliferation of PA smooth muscle cells. The findings indicate that activation of all branches of the UPR and accompanying inflammation play a major role in the pathogenesis of PAH, and that chemical chaperones are potentially therapeutic agents for PAH.
Cigarette smoke-induced mitochondrial fragmentation and dysfunction in human airway smooth muscle
Authors: Aravamudan Bharathi , Kiel Alexander , Freeman Michelle , Delmotte Philippe , Thompson Michael , Vassallo Robert , Sieck Gary C. , Pabelick Christina M. , Prakash Y. S.
Published: March 2014

The balance between mitochondrial fission and fusion is crucial for mitochondria to perform its normal cellular functions. We hypothesized that cigarette smoke (CS) disrupts this balance and enhances mitochondrial dysfunction in the airway. In nonasthmatic human airway smooth muscle (ASM) cells, CS extract (CSE) induced mitochondrial fragmentation and damages their networked morphology in a concentration-dependent fashion, via increased expression of mitochondrial fission protein dynamin-related protein 1 (Drp1) and decreased fusion protein mitofusin (Mfn) 2. CSE effects on Drp1 vs. Mfn2 and mitochondrial network morphology involved reactive oxygen species (ROS), activation of extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), protein kinase C (PKC) and proteasome pathways, as well as transcriptional regulation via factors such as NF-κB and nuclear erythroid 2-related factor 2. Inhibiting Drp1 prevented CSE effects on mitochondrial networks and ROS generation, whereas blocking Mfn2 had the opposite, detrimental effect. In ASM from asmatic patients, mitochondria exhibited substantial morphological defects at baseline and showed increased Drp1 but decreased Mfn2 expression, with exacerbating effects of CSE. Overall, these results highlight the importance of mitochondrial networks and their regulation in the context of cellular changes induced by insults such as inflammation (as in asthma) or CS. Altered mitochondrial fission/fusion proteins have a further potential to influence parameters such as ROS and cell proliferation and apoptosis relevant to airway diseases.
Surfactant protein D is a candidate biomarker for subclinical tobacco smoke-induced lung damage
Authors: Johansson Sofie L. , Tan Qihua , Holst René , Christiansen Lene , Hansen Niels C. G. , Hojland Allan T. , Wulf-Johansson Helle , Schlosser Anders , Titlestad Ingrid L. , Vestbo Jørgen , Holmskov Uffe , Kyvik Kirsten O. , Sorensen Grith L.
Published: March 2014

Variation in surfactant protein D (SP-D) is associated with lung function in tobacco smoke-induced chronic respiratory disease. We hypothesized that the same association exists in the general population and could be used to identify individuals sensitive to smoke-induced lung damage. The association between serum SP-D (sSP-D) and expiratory lung function was assessed in a cross-sectional design in a Danish twin population ( n = 1,512, 18–72 yr old). The adjusted heritability estimates for expiratory lung function, associations between SP-D gene ( SFTPD) single-nucleotide polymorphisms or haplotypes, and expiratory lung function were assessed using twin study methodology and mixed-effects models. Significant inverse associations were evident between sSP-D and the forced expiratory volume in 1 s and forced vital capacity in the presence of current tobacco smoking but not in nonsmokers. The two SFTPD single-nucleotide polymorphisms, rs1923536 and rs721917, and haplotypes, including these single-nucleotide polymorphisms or rs2243539, were inversely associated with expiratory lung function in interaction with smoking. In conclusion, SP-D is phenotypically and genetically associated with lung function measures in interaction with tobacco smoking. The obtained data suggest sSP-D as a candidate biomarker in risk assessments for subclinical tobacco smoke-induced lung damage. The data and derived conclusion warrant confirmation in a longitudinal population following chronic obstructive pulmonary disease initiation and development.
Cachectic skeletal muscle response to a novel bout of low-frequency stimulation
Authors: Puppa Melissa J. , Murphy E. Angela , Fayad Raja , Hand Gregory A. , Carson James A.
Published: March 2014

While exercise benefits have been well documented in patients with chronic diseases, the mechanistic understanding of cachectic muscle's response to contraction is essentially unknown. We previously demonstrated that treadmill exercise training attenuates the initiation of cancer cachexia and the development of metabolic syndrome symptoms (Puppa MJ, White JP, Velazquez KT, Baltgalvis KA, Sato S, Baynes JW, Carson JA. J Cachexia Sarcopenia Muscle 3: 117–137, 2012). However, cachectic muscle's metabolic signaling response to a novel, acute bout of low-frequency contraction has not been determined. The purpose of this study was to determine whether severe cancer cachexia disrupts the acute contraction-induced response to low-frequency muscle contraction [low-frequency stimulation (LoFS)]. Metabolic gene expression and signaling was examined 3 h after a novel 30-min bout of contraction (10 Hz) in cachectic ApcMin/+(Min) and C57BL/6 (BL-6) mice. Pyrrolidine dithiocarbamate, a STAT/NF-κB inhibitor and free radical scavenger, was administered systemically to a subset of mice to determine whether this altered the muscle contraction response. Although glucose transporter-4 mRNA was decreased by cachexia, LoFS increased muscle glucose transporter-4 mRNA in both BL-6 and Min mice. LoFS also induced muscle peroxisome proliferator-activated receptor-γ and peroxisome proliferator-activated receptor-α coactivator-1 mRNA. However, in Min mice, LoFS was not able to induce muscle proliferator-activated receptor-α coactivator-1 targets nuclear respiratory factor-1 and mitochondrial transcription factor A mRNA. LoFS induced phosphorylated-S6 in BL-6 mice, but this induction was blocked by cachexia. Administration of pyrrolidine dithiocarbamate for 24 h rescued LoFS-induced phosphorylated-S6 in cachectic muscle. LoFS increased muscle phosphorylated-AMP-activated protein kinase and p38 in BL-6 and Min mice. These data demonstrate that cachexia alters the muscle metabolic response to acute LoFS, and combination therapies in concert with muscle contraction may be beneficial for improving muscle mass and function during cachexia.
Structural remodeling of the heart and its premotor cardioinhibitory vagal neurons following T5 spinal cord transection
Authors: Lujan Heidi L. , Janbaih Hussein , DiCarlo Stephen E.
Published: March 2014

Midthoracic spinal cord injury (SCI) is associated with enhanced cardiac sympathetic activity and reduced cardiac parasympathetic activity. The enhanced cardiac sympathetic activity is associated with sympathetic structural plasticity within the stellate ganglia, spinal cord segments T1–T4, and heart. However, changes to cardiac parasympathetic centers rostral to an experimental SCI are relatively unknown. Importantly, reduced vagal activity is a predictor of high mortality. Furthermore, this autonomic dysregulation promotes progressive left ventricular (LV) structural remodeling. Accordingly, we hypothesized that midthoracic spinal cord injury is associated with structural plasticity in premotor (preganglionic parasympathetic neurons) cardioinhibitory vagal neurons located within the nucleus ambiguus as well as LV structural remodeling. To test this hypothesis, dendritic arborization and morphology (cholera toxin B immunohistochemistry and Sholl analysis) of cardiac projecting premotor cardioinhibitory vagal neurons located within the nucleus ambiguus were determined in intact (sham transected) and thoracic level 5 transected (T5X) rats. In addition, LV chamber size, wall thickness, and collagen content (Masson trichrome stain and structural analysis) were determined. Midthoracic SCI was associated with structural changes within the nucleus ambiguus and heart. Specifically, following T5 spinal cord transection, there was a significant increase in cardiac parasympathetic preganglionic neuron dendritic arborization, soma area, maximum dendritic length, and number of intersections/animal. This parasympathetic structural remodeling was associated with a profound LV structural remodeling. Specifically, T5 spinal cord transection increased LV chamber area, reduced LV wall thickness, and increased collagen content. Accordingly, results document a dynamic interaction between the heart and its parasympathetic innervation.
Acute exercise increases brain region-specific expression of MCT1, MCT2, MCT4, GLUT1, and COX IV proteins
Authors: Takimoto Masaki , Hamada Taku
Published: March 2014

The brain is capable of oxidizing lactate and ketone bodies through monocarboxylate transporters (MCTs). We examined the protein expression of MCT1, MCT2, MCT4, glucose transporter 1 (GLUT1), and cytochrome- c oxidase subunit IV (COX IV) in the rat brain within 24 h after a single exercise session. Brain samples were obtained from sedentary controls and treadmill-exercised rats (20 m/min, 8% grade). Acute exercise resulted in an increase in lactate in the cortex, hippocampus, and hypothalamus, but not the brainstem, and an increase in β-hydroxybutyrate in the cortex alone. After a 2-h exercise session MCT1 increased in the cortex and hippocampus 5 h postexercise, and the effect lasted in the cortex for 24 h postexercise. MCT2 increased in the cortex and hypothalamus 5–24 h postexercise, whereas MCT2 increased in the hippocampus immediately after exercise, and remained elevated for 10 h postexercise. Regional upregulation of MCT2 after exercise was associated with increases in brain-derived neurotrophic factor and tyrosine-related kinase B proteins, but not insulin-like growth factor 1. MCT4 increased 5–10 h postexercise only in the hypothalamus, and was associated with increased hypoxia-inducible factor-1α expression. However, none of the MCT isoforms in the brainstem was affected by exercise. Whereas GLUT 1 in the cortex increased only at 18 h postexercise, COX IV in the hippocampus increased 10 h after exercise and remained elevated for 24 h postexercise. These results suggest that acute prolonged exercise induces the brain region-specific upregulation of MCT1, MCT2, MCT4, GLUT1, and COX IV proteins.
JNK Signaling Mediates EPHA2-Dependent Tumor Cell Proliferation, Motility, and Cancer Stem Cell–like Properties in Non–Small Cell Lung Cancer
Authors: Song Wenqiang , Ma Yufang , Wang Jialiang , Brantley-Sieders Dana , Chen Jin
Published: March 2014

Recent genome-wide analyses in human lung cancer revealed that EPHA2 receptor tyrosine kinase is overexpressed in non–small cell lung cancer (NSCLC), and high levels of EPHA2 correlate with poor clinical outcome. However, the mechanistic basis for EPHA2-mediated tumor promotion in lung cancer remains poorly understood. Here, we show that the JNK/c-JUN signaling mediates EPHA2-dependent tumor cell proliferation and motility. A screen of phospho-kinase arrays revealed a decrease in phospho-c-JUN levels in EPHA2 knockdown cells. Knockdown of EPHA2 inhibited p-JNK and p-c-JUN levels in approximately 50% of NSCLC lines tested. Treatment of parental cells with SP600125, a c-JUN-NH2-kinase (JNK) inhibitor, recapitulated defects in EPHA2-deficient tumor cells, whereas constitutively activated JNK mutants were sufficient to rescue phenotypes. Knockdown of EPHA2 also inhibited tumor formation and progression in xenograft animal models in vivo. Furthermore, we investigated the role of EPHA2 in cancer stem–like cells (CSC). RNA interference-mediated depletion of EPHA2 in multiple NSCLC lines decreased the ALDH+ cancer stem–like population and tumor spheroid formation in suspension. Depletion of EPHA2 in sorted ALDH+ populations markedly inhibited tumorigenicity in nude mice. Furthermore, analysis of a human lung cancer tissue microarray revealed a significant, positive association between EPHA2 and ALDH expression, indicating an important role for EPHA2 in human lung CSCs. Collectively, these studies revealed a critical role of JNK signaling in EPHA2-dependent lung cancer cell proliferation and motility and a role for EPHA2 in CSC function, providing evidence for EPHA2 as a potential therapeutic target in NSCLC. Cancer Res; 74(9); 2444–54. ©2014 AACR.
Identification of miR-133b and RB1CC1 as Independent Predictors for Biochemical Recurrence and Potential Therapeutic Targets for Prostate Cancer
Authors: Li Xia , Wan Xuechao , Chen Hongbing , Yang Shu , Liu Yiyang , Mo Wenjuan , Meng Delong , Du Wenting , Huang Yan , Wu Hai , Wang Jingqiang , Li Tao , Li Yao
Published: March 2014

Objective: We aimed to investigate the contribution of microRNA-133b (miR-133b) in prostate cancer cell proliferation, cell cycle, and apoptosis. We also examined expression of miR-133b in prostate cancer tissues, and evaluated the prognostic significance of miR-133b, as well as its target gene RB1CC1 in patients with prostate cancer after radical prostatectomy.

Experimental Design: miR-133b mimics (miR-133bm) and anti–miR-133b were transfected into LNCaP and PC-3 cells. CCK-8 was used to look at cell proliferation, flow cytometric analysis was carried out to study cell cycle, and apoptosis was determined by caspase-3 activity. miR-133b expression was assessed by real-time reverse transcription PCR and in situ hybridization in prostatic cell lines and 178 prostate tissue samples, respectively. The protein level of RB1CC1 was examined by Western blot and immunohistochemistry in prostatic cell lines and prostate tissue samples, respectively.

Results: Overexpression of miR-133b in LNCaP cells boosted cell proliferation and cell-cycle progression, but inhibited apoptosis; in contrast, miR-133bm promoted cell apoptosis, but suppressed cell proliferation and cell-cycle progression in PC-3 cells. In LNCaP cells, silencing of RB1CC1, a target of miR-133b, inhibited cell apoptosis, and promoted cell-cycle progression. Moreover, miR-133b expression was significantly inversely correlated with RB1CC1 expression in prostate cancer tissues. Multivariate Cox analysis indicated that miR-133b and RB1CC1 might be two independent prognostic factors of biochemical recurrence.

Conclusions: miR-133b might enhance tumor-promoting properties in less aggressive LNCaP cells, whereas this miR may act as a tumor suppressor in more aggressive PC-3 cells. miR-133b and RB1CC1 were independent prognostic indicators for prostate cancer. Clin Cancer Res; 20(9); 2312–25. ©2014 AACR.
Selective JAK2 Inhibition Specifically Decreases Hodgkin Lymphoma and Mediastinal Large B-cell Lymphoma Growth In Vitro and In Vivo
Authors: Hao Yansheng , Chapuy Bjoern , Monti Stefano , Sun Heather H. , Rodig Scott J. , Shipp Margaret A.
Published: March 2014

Purpose: Classical Hodgkin lymphoma (cHL) and primary mediastinal large B-cell lymphoma (MLBCL) share similar histologic, clinical, and genetic features. In recent studies, we found that disease-specific chromosome 9p24.1/JAK2 amplification increased JAK2 expression and activity in both cHL and MLBCL. This prompted us to assess the activity of a clinical grade JAK2 selective inhibitor, fedratinib (SAR302503/TG101348), in in vitro and in vivo model systems of cHL and MLBCL with defined JAK2 copy numbers.

Experimental Design: We used functional and immunohistochemical analyses to investigate the preclinical activity of fedratinib and associated biomarkers in cell lines and murine xenograft models of cHL and MLBCL with known 9p24.1/JAK2 copy number.

Results: Chemical JAK2 inhibition decreased the cellular proliferation of cHL and MLBCL cell lines and induced their apoptosis. There was an inverse correlation between 9p24.1/JAK2 copy number and the EC50 of fedratinib. Chemical JAK2 inhibition decreased phosphorylation of JAK2, STAT1, STAT3, and STAT6 and reduced the expression of additional downstream targets, including PD-L1, in a copy number–dependent manner. In murine xenograft models of cHL and MLBCL with 9p24.1/JAK2 amplification, chemical JAK2 inhibition significantly decreased JAK2/STAT signaling and tumor growth and prolonged survival. In in vitro and in vivo studies, pSTAT3 was an excellent biomarker of baseline JAK2 activity and the efficacy of chemical JAK2 inhibition.

Conclusions: In in vitro and in vivo analyses, cHL and MLBCL with 9p24.1/JAK2 copy gain are sensitive to chemical JAK2 inhibition suggesting that clinical evaluation of JAK2 blockade is warranted. Clin Cancer Res; 20(10); 2674–83. ©2014 AACR.
Autophagy Is a Survival Mechanism of Acute Myelogenous Leukemia Precursors during Dual mTORC2/mTORC1 Targeting
Authors: Altman Jessica K. , Szilard Amy , Goussetis Dennis J. , Sassano Antonella , Colamonici Marco , Gounaris Elias , Frankfurt Olga , Giles Francis J. , Eklund Elizabeth A. , Beauchamp Elspeth M. , Platanias Leonidas C.
Published: March 2014

Purpose: To examine whether induction of autophagy is a mechanism of leukemic cell resistance to dual mTORC1/mTORC2 inhibitors in acute myelogenous leukemia (AML) leukemic progenitors.

Experimental Design: Combinations of different experimental approaches were used to assess induction of autophagy, including immunoblotting to detect effects on LC3II and p62/SQTM1 expression and on ULK1 phosphorylation, immunofluorescence, and electron microscopy. Functional responses were assessed using cell viability and apoptosis assays, and clonogenic leukemic progenitor assays in methylcellulose.

Results: We provide evidence that treatment of AML cells with catalytic mTOR inhibitors results in induction of autophagy, which acts as a regulatory mechanism to promote leukemic cell survival. Such induction of autophagy by dual mTORC1/mTORC2 inhibitors partially protects primitive leukemic precursors from the inhibitory effects of such agents and limits their activities. Simultaneous blockade of the autophagic process using chloroquine or by knockdown of ULK1 results in enhanced antileukemic responses.

Conclusions: Dual targeting of mTORC2 and mTORC1 results in induction of autophagy in AML cells. Combinations of catalytic mTOR targeting agents and autophagy inhibitors may provide a unique approach to target primitive leukemic precursors in AML. Clin Cancer Res; 20(9); 2400–9. ©2014 AACR.
Concordance of Genomic Alterations between Primary and Recurrent Breast Cancer
Authors: Meric-Bernstam Funda , Frampton Garrett M. , Ferrer-Lozano Jaime , Yelensky Roman , Pérez-Fidalgo Jose A. , Wang Ying , Palmer Gary A. , Ross Jeffrey S. , Miller Vincent A. , Su Xiaoping , Eroles Pilar , Barrera Juan Antonio , Burgues Octavio , Lluch Ana M. , Zheng Xiaofeng , Sahin Aysegul , Stephens Philip J. , Mills Gordon B. , Cronin Maureen T. , Gonzalez-Angulo Ana M.
Published: March 2014

There is growing interest in delivering genomically informed cancer therapy. Our aim was to determine the concordance of genomic alterations between primary and recurrent breast cancer. Targeted next-generation sequencing was performed on formalin-fixed paraffin-embedded (FFPE) samples, profiling 3,320 exons of 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer. Point mutations, indels, copy-number alterations (CNA), and select rearrangements were assessed in 74 tumors from 43 patients (36 primary and 38 recurrence/metastases). Alterations potentially targetable with established or investigational therapeutics were considered “actionable.” Alterations were detected in 55 genes (mean 3.95 alterations/sample, range 1–12), including mutations in PIK3CA, TP53, ARID1A, PTEN, AKT1, NF1, FBXW7, and FGFR3 and amplifications in MCL1, CCND1, FGFR1, MYC, IGF1R, MDM2, MDM4, AKT3, CDK4, and AKT2. In 33 matched primary and recurrent tumors, 97 of 112 (86.6%) somatic mutations were concordant. Of identified CNAs, 136 of 159 (85.5%) were concordant: 37 (23.3%) were concordant, but below the reporting threshold in one of the matched samples, and 23 (14.5%) discordant. There was an increased frequency of CDK4/MDM2 amplifications in recurrences, as well as gains and losses of other actionable alterations. Forty of 43 (93%) patients had actionable alterations that could inform targeted treatment options. In conclusion, deep genomic profiling of cancer-related genes reveals potentially actionable alterations in most patients with breast cancer. Overall there was high concordance between primary and recurrent tumors. Analysis of recurrent tumors before treatment may provide additional insights, as both gains and losses of targets are observed. Mol Cancer Ther; 13(5); 1382–9. ©2014 AACR.
Endocannabinoid-Hydrolysing Enzymes in the Post-Mortem Cerebellum of Humans Affected by Hereditary Autosomal Dominant Ataxias
Authors: Rodríguez-Cueto Carmen , Benito Cristina , Romero Julián , Hernández-Gálvez Mariluz , Gómez-Ruiz María , Fernández-Ruiz Javier
Published: March 2014

Objectives: Spinocerebellar ataxias (SCAs) are characterized by a loss of balance and motor coordination due to degeneration of the cerebellum and its afferent and efferent connections. We recently found important changes in cannabinoid CB1 and CB2 receptors in the post-mortem cerebellum of patients affected by different SCAs. Methods: We wanted to further explore this issue by analysing the two major endocannabinoid-hydrolysing enzymes, fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL), in the post-mortem cerebellum of SCA patients and control subjects. Results: Immunoreactivity for the FAAH and MAGL enzymes was found in the granular layer, in Purkinje cells, in neurons of the dentate nucleus and in areas of white matter in the cerebellum of patients at levels frequently notably higher than those in control subjects. Using double-labelling procedures, we found co-localization of FAAH and MAGL with calbindin, supporting the presence of these enzymes in Purkinje neurons. Conclusions: Degradative endocannabinoid enzymes are significantly increased in the cerebellum of SCA patients, which would presumably lead to reduced endocannabinoid levels. The identification of these enzymes in Purkinje neurons suggests a relationship with the pathogenesis of SCAs and suggests that the endocannabinoid system could provide potential therapeutic targets for the treatment of disease progression in SCAs.
High Birth Weight Is Associated With Obesity and Increased Carotid Wall Thickness in Young Adults
Authors: Skilton Michael R. , Siitonen Niina , Würtz Peter , Viikari Jorma S.A. , Juonala Markus , Seppälä Ilkka , Laitinen Tomi , Lehtimäki Terho , Taittonen Leena , Kähönen Mika , Celermajer David S. , Raitakari Olli T.
Published: March 2014

Objective—

There is some evidence that people born with high birth weight may be at increased risk of cardiovascular disease in adulthood. Details of the underlying mechanisms remain unknown. We sought to determine whether people born large for gestational age have poor arterial health, increased adiposity, and a poor cardiovascular risk factor profile.

Approach and Results—

Carotid intima-media thickness, brachial flow–mediated dilatation, and cardiovascular risk factors were compared between young adults (24–45 years) born at term who were large for gestational age (birth weight >90th percentile; n=171), and a control group with normal birth weight (50–75th percentile; n=525), in the Cardiovascular Risk in Young Finns Study. Those born large for gestational age had higher body mass index throughout childhood, adolescence, and as young adults (26.4 kg/m
2
[SD 4.9], versus normal birth weight 25.1 kg/m
2
[SD 4.6];
P
=0.002), and 2-fold greater risk of obesity. Other cardiovascular risk factors and arterial function did not differ; however, carotid intima-media thickness was increased in people born large for gestational age (0.60 mm [SD 0.09], versus normal birth weight 0.57 mm [SD 0.09];
P
=0.003), independent of cardiovascular risk factors (
P
=0.001 after adjustment). Both obesity and high birth weight were independently associated with carotid intima-media thickness in a graded and additive fashion.

Conclusions—

Young adults born large for gestational age are more likely to be obese, yet have an otherwise healthy cardiovascular risk profile. Nonetheless, they have increased carotid intima-media thickness, a marker of subclinical atherosclerosis, consistent with an increased risk of cardiovascular disease.
Relationship Between Connexin Expression and Gap–Junction Resistivity in Human Atrial Myocardium
Authors: Dhillon Paramdeep S. , Chowdhury Rasheda A. , Patel Pravina M. , Jabr Rita , Momin Aziz U. , Vecht Joshua , Gray Rosaire , Shipolini Alex , Fry Christopher H. , Peters Nicholas S.
Published: March 2014

Background—

The relative roles of the gap-junctional proteins connexin40 (Cx40) and connexin43 (Cx43) in determining human atrial myocardial resistivity is unknown. In addressing the hypothesis that changing relative expression of Cx40 and Cx43 underlies an increase in human atrial myocardial resistivity with age, this relationship was investigated by direct ex vivo measurement of gap-junctional resistivity and quantitative connexin immunoblotting and immunohistochemistry.

Methods and Results—

Oil-gap impedance measurements were performed to determine resistivity of the intracellular pathway (
R
i
), which correlated with total Cx40 quantification by Western blotting (r
s
=0.64,
P
<0.01, n=20). Specific gap-junctional resistivity (
R
j
) correlated not only with Western immunoquantification of Cx40 (r
s
=0.63,
P
=0.01, n=20), but also more specifically, with the Cx40 fraction localized to the intercalated disks on immunohistochemical quantification (r
s
=0.66,
P
=0.02, n=12). Although Cx43 expression showed no correlation with resistivity values, the proportional expression of the 2 connexins, (Cx40/[Cx40+Cx43]) correlated with
R
i
and
R
j
(r
s
=0.58,
P
<0.01 for
R
i
and r
s
=0.51,
P
=0.02 for
R

j

). Advancing age was associated with a rise in
R
i
(r
s
=0.77,
P
<0.0001),
R
j
(r
s
=0.65,
P
<0.001, n=23), Cx40 quantity (r
s
=0.54,
P
=0.01, n=20), and Cx40 gap–junction protein per unit area of en face disk (r
s
=0.61,
P
=0.02, n=12).

Conclusions—

Cx40 is associated with human right atrial gap-junctional resistivity such that increased total, gap-junctional, and proportional Cx40 expression increases gap-junctional resistivity. Accordingly, advancing age is associated with an increase in Cx40 expression and a corresponding increase in gap-junctional resistivity. These findings are the first to demonstrate this relationship and a mechanistic explanation for changing atrial conduction and age-related arrhythmic tendency.
Net Clinical Benefit of Warfarin Therapy in Elderly Chinese Patients With Atrial Fibrillation
Authors: Siu Chung-Wah , Tse Hung-Fat
Published: March 2014

Background—

Little is known about the net clinical benefit of warfarin therapy in elderly patients with atrial fibrillation.

Methods and Results—

We studied 2339 Chinese patients with nonvalvular atrial fibrillation aged ≥80 years: 1805 with no antithrombotic therapy and 534 on warfarin therapy. Patients were stratified according to their CHA
2
DS
2
-VASc and HAS-BLED score. The primary end point was a composite of hospital admission with ischemic stroke or death. After 2.2-year follow-up (5199 patient-years), a primary end point had occurred for 1861 patients (79.6%): 66.9% in patients on warfarin (66.9%) compared with 80.8% in patients with no antithrombotic therapy (80.8%; hazard ratio, 0.53; 95% confidence interval, 0.48–0.58;
P
<0.001). This was related to substantially better mortality rate (hazard ratio, 0.40; 95% confidence interval, 0.37–0.45;
P
<0.0001) and ischemic stroke rate (hazard ratio, 0.64; 95% confidence interval, 0.54–0.77;
P
<0.0001) among patients on warfarin. For the net clinical benefit, 510 ischemic strokes and 42 intracranial hemorrhage were recorded. The annual incidence of ischemic stroke and intracranial hemorrhage was 11.3%/y and 0.6%/y, respectively, in patients prescribed no antithrombotic therapy and 7.1%/y and 1.1%/y, respectively, in those prescribed warfarin. The adjusted net clinical benefit favored warfarin for all elderly patients, and the best net benefit from warfarin was in those with high stroke and intracranial hemorrhage risk. In these high-risk patients, warfarin therapy was associated with 7.2 to 8.0 fewer events per 100 patient-years compared with no antithrombotic therapy.

Conclusions—

In elderly patients with atrial fibrillation, warfarin therapy is associated with lower death and ischemic stroke and an overall net clinical benefit.
Comparison of the First and Second Cryoballoon
Authors: Straube Florian , Dorwarth Uwe , Schmidt Martin , Wankerl Michael , Ebersberger Ulrich , Hoffmann Ellen
Published: March 2014

Background—

Cryoballoon (CB) ablation results in >70% freedom from atrial fibrillation at 1 year. Single-center data of the first (CBG1) and second (CBG2) cryoballoon, recently introduced, were analyzed to compare safety and efficacy.

Methods and Results—

From March 2011 to December 2012, CB ablation with spiral mapping was performed consecutively in 484 patients with symptomatic atrial fibrillation. CBG1 was used in 364 of 484 (75%) and CBG2 in 120 of 484 (25%) patients. Periprocedural data were analyzed. Acute pulmonary vein (PV) isolation with CB only was achieved in 99.86% and 100% of veins with CBG1 and CBG2, respectively (
P
=0.43). Number of applications until PV isolation decreased significantly with CBG2 (1.45±0.81 versus 1.28±0.64;
P
=0.001). Procedural, left atrial, and fluoroscopy time were reduced by −5%, −11%, and −15% (
P
<0.05), respectively. Two balloons were used less frequently. Time to isolation decreased significantly with 23-mm (48 versus 33 seconds;
P
<0.0001) and 28-mm CBG2 (76 versus 52 seconds;
P
<0.0001). Early PV reconduction rarely occurred with CBG2 (2.6% versus 0.42%;
P
=0.0023). In-hospital atrial fibrillation recurrence rates were similar. Balloon temperatures were significantly warmer with 23-mm CBG2 and a trend for colder balloon temperature with 28-mm CBG2 were observed compared with their predecessors. Comparable low rates of phrenic nerve palsy were recorded (1.1% versus 1.7%;
P
=0.64). Esophageal temperatures were similar. Major complication rates were low (3.3% versus 3.33%;
P
=1.0).

Conclusions—

CBG2 attains high rates of acute PV isolation within a significant faster and less complex procedure. Time to isolation is shorter, and PV isolation is achieved with fewer applications using CBG2. These enhancements were not at the cost of complications. Long-term success rates remain to be demonstrated.