bluuebunny/crossref_metadata_2025 huggingface dataset:
OPTICAL AND MECHANICAL DESIGN OF THE CHARA ARRAY ADAPTIVE OPTICS
Authors: CHE X. , STURMANN L. , MONNIER J. D. , TEN BRUMMELAAR T. A. , STURMANN J. , RIDGWAY S. T. , IRELAND M. J. , TURNER N. H. , MCALISTER H. A.
Published: January 2014

The CHARA array is an optical/near infrared interferometer consisting of six 1-meter diameter telescopes with the longest baseline of 331 m. With high angular resolution, the CHARA array provides a unique and powerful way of studying nearby stellar systems. In 2011, the CHARA array was funded by NSF-ATI for an upgrade of adaptive optics systems to all six telescopes to improve the sensitivity by several magnitudes. The initial grant covers Phase I of the adaptive optics system, which includes an on-telescope Wavefront Sensor and fast tip/tilt correction. We are currently seeking funding for Phase II which will add fast deformable mirrors at the telescopes to close the loop. This paper will describe the design of the project, and show simulations of how much improvement the array will gain after the upgrade.
Task model-driven realization of interactive application functionality through services
Authors: Kritikos K. , Plexousakis D. , Paternò F.
Published: January 2014

The Service-Oriented Computing (SOC) paradigm is currently being adopted by many developers, as it promises the construction of applications through reuse of existing Web Services (WSs). However, current SOC tools produce applications that interact with users in a limited way. This limitation is overcome by model-based Human-Computer Interaction (HCI) approaches that support the development of applications whose functionality is realized with WSs and whose User Interface (UI) is adapted to the user's context. Typically, such approaches do not consider various functional issues, such as the applications' semantics and their syntactic robustness in terms of the WSs selected to implement their functionality and the automation of the service discovery and selection processes. To this end, we propose a model-driven design method for interactive service-based applications that is able to consider the functional issues and their implications for the UI. This method is realized by a semiautomatic environment that can be integrated into current model-based HCI tools to complete the development of interactive service front-ends. The proposed method takes as input an HCI task model, which includes the user's view of the interactive system, and produces a concrete service model that describes how existing services can be combined to realize the application's functionality. To achieve its goal, our method first transforms system tasks into semantic service queries by mapping the task objects onto domain ontology concepts; then it sends each resulting query to a semantic service engine so as to discover the corresponding services. In the end, only one service from those associated with a system task is selected, through the execution of a novel service concretization algorithm that ensures message compatibility between the selected services.
Joint virtual machine assignment and traffic engineering for green data center networks
Authors: Wang Lin , Zhang Fa , Vasilakos Athanasios V. , Hou Chenying , Liu Zhiyong
Published: January 2014

The popularization of cloud computing brings emergency concern to the energy consumption in big data centers. Besides the servers, the energy consumed by the network in a data center is also considerable. Existing works for improving the network energy efficiency are mainly focused on traffic engineering, i.e., consolidating flows and switching off unnecessary devices, which fails to comprehensively consider the unique features in data centers. In this paper, we advocate a joint optimization for achieving energy efficiency of data center networks by proposing a unified optimization framework. In this framework, we consider to take advantage of the application characteristics and topology features, and to integrate virtual machine assignment and traffic engineering. Under this framework, we then devise two efficient algorithms, TE VMA and TER, for assigning virtual machines and routing traffic flows respectively. Knowing the ncommunication patterns of the applications, the TE VMA algorithm is purposeful and can generate desirable traffic conditions for the next-step routing optimization. The TER algorithm makes full use of the hierarchical feature of the topology and is conducted on the multipath routing protocol. The performance of the overall framework is confirmed by both theoretical analysis and simulation results, where up to 50% total energy savings can be achieved, 20% more compared with traffic engineering only approaches.
NFAT transcription factor regulation by urocortin II in cardiac myocytes and heart failure
Authors: Walther Stefanie , Awad Sawsan , Lonchyna Vassyl A. , Blatter Lothar A.
Published: January 2014

Urocortin II (UcnII), a cardioactive peptide with beneficial effects in normal and failing hearts, is also arrhythmogenic and prohypertrophic. We demonstrated that cardiac effects are mediated by a phosphatidylinositol-3 kinase (PI3K)/Akt kinase (Akt)/endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) signaling pathways. Nuclear factor of activated T-cells (NFAT) transcription factors play a key role in the regulation of gene expression in cardiac development, maintenance of an adult differentiated cardiac phenotype, and remodeling processes in cardiac hypertrophy and heart failure (HF). We tested the hypothesis that UcnII differentially regulates NFAT activity in cardiac myocytes from both normal and failing hearts through the PI3K/Akt/eNOS/NO pathway. Isoforms NFATc1 and NFATc3 revealed different basal subcellular distribution in normal and HF rabbit ventricular myocytes with a nuclear NFATc1 and a cytosolic localization of NFATc3. However, in HF, the nuclear localization of NFATc1 was less pronounced, whereas the nuclear occupancy of NFATc3 was increased. In normal myocytes, UcnII induced nuclear export of NFATc1 and attenuated NFAT-dependent transcriptional activity but did not affect the distribution of NFATc3. In HF UcnII facilitated nuclear export of both isoforms and reduced transcriptional activity. NFAT regulation was mediated by a PI3K/Akt/eNOS/NO signaling cascade that converged on the activation of several kinases, including glycogen synthase kinase-3β (GSK3β), c-Jun NH2-terminal kinase (JNK), p38 mitogen-activated kinase (p38), and PKG, resulting in phosphorylation, deactivation, and nuclear export of NFAT. In conclusion, while NFATc1 and NFATc3 reveal distinct subcellular distribution patterns, both are regulated by the UcnII-PI3K/Akt/eNOS/NO pathway that converges on the activation of NFAT kinases and NFAT inactivation. The data reconcile cardioprotective and prohypertrophic UcnII effects mediated by different NFAT isoforms.
The relationship between longitudinal, lateral, and septal contribution to stroke volume in patients with pulmonary regurgitation and healthy volunteers
Authors: Stephensen Sigurdur , Steding-Ehrenborg Katarina , Munkhammar Peter , Heiberg Einar , Arheden Hakan , Carlsson Marcus
Published: January 2014

Septal systolic motion is towards the left ventricle (LV) in healthy hearts. Patients with pulmonary regurgitation (PR) and right ventricular (RV) volume overload have systolic septal motion toward the RV. This may affect the longitudinal contribution from atrioventricular plane displacement (AVPD) and septal and lateral contribution to stroke volume (SV). The study aimed to quantify these contributions to SV in patients with PR. Cardiac magnetic resonance imaging was used for assessment of cardiac volumes. Patients ( n = 30; age 9–59 yr) with PR due to surgically corrected tetralogy of Fallot and 54 healthy controls (age 10–66 yr) were studied. Longitudinal contribution to RVSV was 47 ± 2% (means ± SE) in patients with PR and 79 ± 1% in controls ( P < 0.001). Lateral contribution to RVSV and LVSV was 40 ± 1 and 62 ± 2% in patients and 31 ± 1 and 36 ± 1% in controls ( P < 0.001 for both). Septal motion contributed to RVSV by 8 ± 1% in patients and by 7 ± 1% to LVSV in controls ( P < 0.001). PR patients have decreased longitudinal contribution to RVSV and increased lateral pumping, resulting in larger outer volume changes and septal motion towards the RV. The changes in RV pumping physiology may be explained by RV remodeling resulting in lower systolic inflow of blood into the right atrium in relation to SV. This avoids the development of pendulum volume between the caval veins and right atrium, which would occur in PR patients if longitudinal contribution to SV was preserved. Decreased AVPD suggests that tricuspid annular excursion, a marker of RV function, is less valid in these patients.
Postconditioning leads to an increase in protein S-nitrosylation
Authors: Tong Guang , Aponte Angel M. , Kohr Mark J. , Steenbergen Charles , Murphy Elizabeth , Sun Junhui
Published: January 2014

Previous studies have shown a role for nitric oxide and S-nitrosylation (SNO) in postconditioning (PostC), but specific SNO proteins and sites have not been identified in the myocardium after PostC. In this study, we examined SNO signaling in PostC using a Langendorff-perfused mouse heart model. After 20 min of equilibrium perfusion and 25 min of global ischemia, PostC was applied at the beginning of reperfusion with six cycles of 10 s of reperfusion and 10 s of ischemia. The total period of reperfusion was 90 min. Compared with the ischemia-reperfusion (I/R) control, PostC significantly reduced postischemic contractile dysfunction and infarct size. PostC-induced protection was blocked by treatment with NG-nitro-l-arginine methyl ester (l-NAME) (10 μmol/l; a constitutive NO synthase inhibitor), but not by either ODQ (10 μmol/l, a highly selective soluble guanylyl cyclase inhibitor) or KT5823 (1 μmol/l, a specific protein kinase G inhibitor). Two biotin switch based methods, two dimensional CyDye-maleimide difference gel electrophoresis (2D CyDye-maleimide DIGE) and SNO-resin-assisted capture (SNO-RAC), were utilized to identify SNO-modified proteins and sites. Using 2D CyDye-maleimide DIGE analysis, PostC was found to cause a 25% or greater increase in SNO of a number of proteins, which was blocked by treatment with l-NAME in parallel with the loss of protection. Using SNO-RAC, we identified 77 unique proteins with SNO sites after PostC. These results suggest that NO-mediated SNO signaling is involved in PostC-induced cardioprotection and these data provide the first set of candidate SNO proteins in PostC hearts.
Cleavage of IκBα by calpain induces myocardial NF-κB activation, TNF-α expression, and cardiac dysfunction in septic mice
Authors: Li Xiaoping , Luo Rong , Chen Ruizhen , Song Li , Zhang Shu , Hua Wei , Chen Haozhu
Published: January 2014

Recent studies in septic models have shown that myocardial calpain activity and TNF-α expression increase during sepsis and that inhibition of calpain activation downregulates myocardial TNF-α expression and improves cardiac dysfunction. However, the mechanism underlying this pathological process is unclear. Thus, in the present study, we aimed to explore whether IκBα/NF-κB signaling linked myocardial calpain activity and TNF-α expression in septic mice. Adult male mice were injected with LPS (4 mg/kg ip) to induce sepsis. Myocardial calpain activity, IκBα/NF-κB signaling activity, and TNF-α expression were assessed, and myocardial function was evaluated using the Langendorff system. In septic mice, myocardial calpain activity and TNF-α expression were increased and IκBα protein was degraded. Furthermore, NF-κB was activated, as indicated by increased NF-κB p65 phosphorylation, cleavage of p105 into p50, and its nuclear translocation. Administration of the calpain inhibitors calpain inhibitor Ш and PD-150606 prevented the LPS-induced degradation of myocardial IκBα, NF-κB activation, and TNF-α expression and ultimately improved myocardial function. In calpastatin transgenic mice, an endogenous calpain inhibitor and cultured neonatal mouse cardiomyocytes overexpressing calpastatin also inhibited calpain activity, IκBα protein degradation, and NF-κB activation after LPS treatment. In conclusion, myocardial calpain activity was increased in septic mice. Calpain induced myocardial NF-κB activation, TNF-α expression, and myocardial dysfunction in septic mice through IκBα protein cleavage.
Let-7d microRNA affects mesenchymal phenotypic properties of lung fibroblasts
Authors: Huleihel Luai , Ben-Yehudah Ahmi , Milosevic Jadranka , Yu Guoying , Pandit Kusum , Sakamoto Koji , Yousef Hanadie , LeJeune Megan , Coon Tiffany A. , Redinger Carrie J. , Chensny Lara , Manor Ester , Schatten Gerald , Kaminski Naftali
Published: January 2014

MicroRNAs are small noncoding RNAs that inhibit protein expression. We have previously shown that the inhibition of the microRNA let-7d in epithelial cells caused changes consistent with epithelial-to-mesenchymal transition (EMT) both in vitro and in vivo. The aim of this study was to determine whether the introduction of let-7d into fibroblasts alters their mesenchymal properties. Transfection of primary fibroblasts with let-7d caused a decrease in expression of the mesenchymal markers α-smooth muscle actin, N-cadherin, fibroblast-specific protein-1, and fibronectin, as well as an increase in the epithelial markers tight junction protein-1 and keratin 19. Phenotypic changes were also present, including a delay in wound healing, reduced motility, and proliferation of fibroblasts following transfection. In addition, we examined the effects of transfection on fibroblast responsiveness to TGF-β, an important factor in many fibrotic processes such as lung fibrosis and found that let-7d transfection significantly attenuated high-mobility group-A2 protein induction by TGF-β. Our results indicate that administration of the epithelial microRNA let-7d can significantly alter the phenotype of primary fibroblasts.
Glutathione attenuates ethanol-induced alveolar macrophage oxidative stress and dysfunction by downregulating NADPH oxidases
Authors: Yeligar Samantha M. , Harris Frank L. , Hart C. Michael , Brown Lou Ann S.
Published: January 2014

Chronic alcohol abuse increases lung oxidative stress and susceptibility to respiratory infections by impairing alveolar macrophage (AM) function. NADPH oxidases (Nox) are major sources of reactive oxygen species in AMs. We hypothesized that treatment with the critical antioxidant glutathione (GSH) attenuates chronic alcohol-induced oxidative stress by downregulating Noxes and restores AM phagocytic function. Bronchoalveolar lavage (BAL) fluid and AMs were isolated from male C57BL/6J mice (8–10 wk) treated ± ethanol in drinking water (20% wt/vol, 12 wk) ± orally gavaged GSH in methylcellulose vehicle (300 mg·kg−1·day−1, during week 12). MH-S cells, a mouse AM cell line, were treated ± ethanol (0.08%, 3 days) ± GSH (500 μM, 3 days or last 1 day of ethanol). BAL and AMs were also isolated from ethanol-fed and control mice ± inoculated airway Klebsiella pneumoniae (200 colony-forming units, 28 h) ± orally gavaged GSH (300 mg/kg, 24 h). GSH levels (HPLC), Nox mRNA (quantitative RT-PCR) and protein levels (Western blot and immunostaining), oxidative stress (2′,7′-dichlorofluorescein-diacetate and Amplex Red), and phagocytosis ( Staphylococcus aureus internalization) were measured. Chronic alcohol decreased GSH levels, increased Nox expression and activity, enhanced oxidative stress, impaired phagocytic function in AMs in vivo and in vitro, and exacerbated K. pneumonia-induced oxidative stress. Although how oral GSH restored GSH pools in ethanol-fed mice is unknown, oral GSH treatments abrogated the detrimental effects of chronic alcohol exposure and improved AM function. These studies provide GSH as a novel therapeutic approach for attenuating alcohol-induced derangements in AM Nox expression, oxidative stress, dysfunction, and risk for pneumonia.
Loss of caveolin-1 and adiponectin induces severe inflammatory lung injury following LPS challenge through excessive oxidative/nitrative stress
Authors: Cai Lei , Yi Fan , Dai Zhiyu , Huang Xiaojia , Zhao Yidan D. , Mirza Muhammad K. , Xu Jingsong , Vogel Stephen M. , Zhao You-Yang
Published: January 2014

Excessive reactive oxygen/nitrogen species have been associated with the onset, progression, and outcome of sepsis, both in preclinical and clinical studies. However, the signaling pathways regulating oxidative/nitrative stress in the pathogenesis of sepsis-induced acute lung injury and acute respiratory distress syndrome are not fully understood. Employing the novel mouse model with genetic deletions of both caveolin-1 ( Cav1) and adiponectin ( ADPN) [double knockout (DKO) mice], we have demonstrated the critical role of Cav1 and ADPN signaling cross talk in regulating oxidative/nitrative stress and resulting inflammatory lung injury following LPS challenge. In contrast to the inhibited inflammatory lung injury in Cav1 −/− mice, we observed severe lung inflammation and markedly increased lung vascular permeability in DKO mice in response to LPS challenge. Accordingly, the DKO mice exhibited an 80% mortality rate following a sublethal dose of LPS challenge. At basal state, loss of Cav1 and ADPN resulted in a drastic increase of oxidative stress and resultant nitrative stress in DKO lungs. Scavenging of superoxide by pretreating the DKO mice with MnTMPYP (a superoxide dismutase mimetic) restored the inflammatory responses to LPS challenge including reduced lung myeloperoxidase activity and vascular permeability. Thus oxidative/nitrative stress collectively modulated by Cav1 and ADPN signalings is a critical determinant of inflammatory lung injury in response to LPS challenge.
KCNQ (Kv7) potassium channel activators as bronchodilators: combination with a β2-adrenergic agonist enhances relaxation of rat airways
Authors: Brueggemann Lioubov I. , Haick Jennifer M. , Neuburg Samantha , Tate Shawn , Randhawa Devjit , Cribbs Leanne L. , Byron Kenneth L.
Published: January 2014

KCNQ (Kv7 family) potassium (K+) channels were recently found in airway smooth muscle cells (ASMCs) from rodent and human bronchioles. In the present study, we evaluated expression of KCNQ channels and their role in constriction/relaxation of rat airways. Real-time RT-PCR analysis revealed expression of KCNQ4 > KCNQ5 > KCNQ1 > KCNQ2 > KCNQ3, and patch-clamp electrophysiology detected KCNQ currents in rat ASMCs. In precision-cut lung slices, the KCNQ channel activator retigabine induced a concentration-dependent relaxation of small bronchioles preconstricted with methacholine (MeCh; EC50 = 3.6 ± 0.3 μM). Bronchoconstriction was also attenuated in the presence of two other structurally unrelated KCNQ channel activators: zinc pyrithione (ZnPyr; 1 μM; 22 ± 7%) and 2,5-dimethylcelecoxib (10 μM; 24 ± 8%). The same three KCNQ channel activators increased KCNQ currents in ASMCs by two- to threefold. The bronchorelaxant effects of retigabine and ZnPyr were prevented by inclusion of the KCNQ channel blocker XE991. A long-acting β2-adrenergic receptor agonist, formoterol (10 nM), did not increase KCNQ current amplitude in ASMCs, but formoterol (1–1,000 nM) did induce a time- and concentration-dependent relaxation of rat airways, with a notable desensitization during a 30-min treatment or with repetitive treatments. Coadministration of retigabine (10 μM) with formoterol produced a greater peak and sustained reduction of MeCh-induced bronchoconstriction and reduced the apparent desensitization observed with formoterol alone. Our findings support a role for KCNQ K+ channels in the regulation of airway diameter. A combination of a β2-adrenergic receptor agonist with a KCNQ channel activator may improve bronchodilator therapy.
TNF-α induces cytosolic phospholipase A2expression via Jak2/PDGFR-dependent Elk-1/p300 activation in human lung epithelial cells
Authors: Yang Chuen-Mao , Lee I-Ta , Chi Pei-Ling , Cheng Shin-Ei , Hsiao Li-Der , Hsu Chih-Kai
Published: January 2014

Cytosolic phospholipase A2(cPLA2) plays a pivotal role in mediating agonist-induced arachidonic acid release for prostaglandin (PG) synthesis during inflammation triggered by tumor necrosis factor-α (TNF-α). However, the mechanisms underlying TNF-α-induced cPLA2expression in human lung epithelial cells (HPAEpiCs) were not completely understood. Here, we demonstrated that TNF-α induced cPLA2mRNA and protein expression, promoter activity, and PGE2secretion in HPAEpiCs. These responses induced by TNF-α were inhibited by pretreatment with the inhibitor of Jak2 (AG490), platelet-derived growth factor receptor (PDGFR) (AG1296), phosphoinositide 3 kinase (PI3K) (LY294002), or MEK1/2 (PD98059) and transfection with siRNA of Jak2, PDGFR, Akt, or p42. We showed that TNF-α markedly stimulated Jak2, PDGFR, Akt, and p42/p44 MAPK phosphorylation, which were attenuated by their respective inhibitors. Moreover, TNF-α stimulated Akt activation via a Jak2/PDGFR pathway in HPAEpiCs. In addition, TNF-α-induced p42/p44 MAPK phosphorylation was reduced by AG1296 or LY294002. On the other hand, TNF-α could induce Akt and p42/p44 MAPK translocation from the cytosol into the nucleus, which was inhibited by AG490, AG1296, or LY294002. Finally, we showed that TNF-α stimulated Elk-1 phosphorylation, which was reduced by LY294002 or PD98059. We also observed that TNF-α time dependently induced p300/Elk-1 and p300/Akt complex formation in HPAEpiCs, which was reduced by AG490, AG1296, or LY294002. The activity of cPLA2protein upregulated by TNF-α was reflected on the PGE2release, which was reduced by AG490, AG1296, LY294002 , or PD98059. Taken together, these results demonstrated that TNF-α-induced cPLA2expression and PGE2release were mediated through a Jak2/PDGFR/PI3K/Akt/p42/p44 MAPK/Elk-1 pathway in HPAEpiCs.
Oxidative Balance Score, Colorectal Adenoma, and Markers of Oxidative Stress and Inflammation
Authors: Kong So Yeon J. , Bostick Roberd M. , Flanders W. Dana , McClellan William M. , Thyagarajan Bharat , Gross Myron D. , Judd Suzanne , Goodman Michael
Published: January 2014

Background: An oxidative balance score (OBS) that combines pro- and antioxidant exposures was previously reported to be associated with incident sporadic colorectal adenoma. We extend the previous analyses by assessing associations of the OBS and colorectal adenoma with circulating biomarkers of oxidative stress [F2-isoprostanes (FIP) and fluorescent oxidation products (FOP)], and inflammation [C-reactive protein (CRP)].

Methods: Using pooled data from two previously conducted colonoscopy-based case–control studies of incident, sporadic colorectal adenoma (n = 365), the OBS was constructed and divided into three approximately equal intervals, with the lowest interval used as the reference. Biomarker levels were dichotomized as “high” versus “low” based on the median values among controls. Multivariable logistic regression was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs).

Results: For the OBS–adenoma association, the ORs (95% CIs) for the middle and highest (relative to the lowest) score intervals were 0.81 (0.46–1.43) and 0.39 (0.17–0.89), respectively. The corresponding OBS category-specific ORs (95% CIs) were 0.50 (0.25–1.01) and 0.25 (0.10–0.65) for FIP, 2.01 (1.13–3.75) and 3.48 (1.51–8.02) for FOP, and 0.57 (0.31–1.04) and 0.21 (0.09–0.49) for CRP. The ORs (95% CIs) reflecting associations of adenoma with high levels of FIP, FOP, and CRP were 1.89 (1.08–3.30), 1.82 (1.11–2.99), and 1.45 (0.88–2.40), respectively.

Conclusions: As hypothesized, the OBS was inversely associated with colorectal adenoma and circulating FIP and CRP levels. The reason for the unexpected direct OBS–FOP association is unknown.

Impact: These data support the use of combined measures of pro- and antioxidant exposures in studies of colorectal neoplasia. Cancer Epidemiol Biomarkers Prev; 23(3); 545–54. ©2014 AACR.
The Prevalence of Colorectal Adenomas in Asymptomatic Korean Men and Women
Authors: Yang Moon Hee , Rampal Sanjay , Sung Jidong , Choi Yoon-Ho , Son Hee Jung , Lee Jun Haeng , Kim Young-Ho , Chang Dong Kyung , Rhee Poong-Lyul , Rhee Jong Chul , Guallar Eliseo , Cho Juhee
Published: January 2014

Background: Colorectal cancer incidence is rapidly rising in many Asian countries, with rates approaching those of Western countries. This study aimed to evaluate the prevalence and trends of colorectal adenomas by age, sex, and risk strata in asymptomatic Koreans.

Methods: Cross-sectional study of 19,372 consecutive participants aged 20 to 79 years undergoing screening colonoscopy at the Center for Health Promotion of the Samsung Medical Center in Korea from January 2006 to June 2009.

Results: Among participants at average risk, those without a history of colorectal polyps or a family history of colorectal cancer, the prevalence of colorectal adenomas and advanced adenomas were 34.5% and 3.1%, respectively, in men and 20.0% and 1.6%, respectively, in women. The prevalence of adenomas increased with age in both men and women, with a more marked increase for advanced adenoma. Participants with a family history of colorectal cancer or with a history of colorectal polyps had significantly higher prevalence of adenomas compared with participants of average risk (36.9% vs. 26.9%; age- and sex-adjusted prevalence ratio = 1.16; 95% confidence interval, 1.09–1.22). The prevalence of adenomas increased annually in both men and women.

Conclusions: In this large study of asymptomatic Korean men and women participating in a colonoscopy screening program, the prevalence of colorectal adenomas was comparable and possibly higher than previously reported in Western countries.

Impact: Cost-effectiveness studies investigating the optimal age for starting colonoscopy screening and etiological studies to identify the reasons for the increasing trend in colorectal adenomas in Koreans are needed. Cancer Epidemiol Biomarkers Prev; 23(3); 499–507. ©2014 AACR.
Lung Cancers with Concomitant EGFR Mutations and ALK Rearrangements: Diverse Responses to EGFR-TKI and Crizotinib in Relation to Diverse Receptors Phosphorylation
Authors: Yang Jin-Ji , Zhang Xu-Chao , Su Jian , Xu Chong-Rui , Zhou Qing , Tian Hong-Xia , Xie Zhi , Chen Hua-Jun , Huang Yi-Sheng , Jiang Ben-Yuan , Wang Zhen , Wang Bin-Chao , Yang Xue-Ning , Zhong Wen-Zhao , Nie Qiang , Liao Ri-Qiang , Mok Tony S. , Wu Yi-Long
Published: January 2014

Purpose: We investigated the incidence of concomitant epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements in Chinese patients with non–small cell lung cancer (NSCLC), and assessed responses to EGFR tyrosine kinase inhibitors (EGFR-TKIs) and crizotinib in such tumors.

Experimental Design: We screened 977 consecutive patients with NSCLC for the presence of concomitant EGFR mutations and ALK rearrangements by rapid amplification of cDNA ends-coupled PCR sequencing and FISH. Immunohistochemistry (IHC) and Western blotting were used to correlate the activation of EGFR, ALK, and downstream proteins with responses to EGFR-TKIs and crizotinib.

Results: The overall frequency of concomitant EGFR mutations and ALK rearrangements was 1.3% (13/977). EGFR/ALK co-alterations were found in 3.9% (13/336) EGFR-mutant and 18.6% (13/70) ALK-rearranged patients. Ten tumors were treated with first-line EGFR-TKIs, with a response rate of 80% (8/10). Two tumors with high phospho-ALK levels and low phospho-EGFR levels achieved stable and progressive disease, respectively. Median progression-free survival was 11.2 months. Coexpression of mutant EGFR and ALK fusion proteins in the same tumor cell populations was detected by IHC. Two cases with high phospho-ALK levels treated with crizotinib achieved partial responses; two cases with low phospho-ALK levels had progressive or stable disease.

Conclusion: ALK rearrangements and EGFR mutations could coexist in a small subgroup of NSCLC. Advanced pulmonary adenocarcinomas with such co-alterations could have diverse responses to EGFR-TKIs and crizotinib. Relative phospho-ALK and phospho-EGFR levels could predict the efficacy of EGFR-TKI and crizotinib. Clin Cancer Res; 20(5); 1383–92. ©2014 AACR.
Cotargeting the PI3K and RAS Pathways for the Treatment of Neuroendocrine Tumors
Authors: Valentino Joseph D. , Li Jing , Zaytseva Yekaterina Y. , Mustain W. Conan , Elliott Victoria A. , Kim Ji Tae , Harris Jennifer W. , Campbell Katherine , Weiss Heidi , Wang Chi , Song Jun , Anthony Lowell , Townsend Courtney M. , Evers B. Mark
Published: January 2014

Background: The precise involvement of the PI3K/mTOR and RAS/MEK pathways in carcinoid tumors is not well defined. Therefore, the purpose of our study was to evaluate the role these pathways play in carcinoid cell proliferation, apoptosis, and secretion and to determine the effects of combined treatment on carcinoid tumor inhibition.

Methods: The human neuroendocrine cell lines BON (pancreatic carcinoid), NCI-H727 (lung carcinoid), and QGP-1 (somatostatinoma) were treated with either the pan-PI3K inhibitor, BKM120, or the dual PI3K–mTOR inhibitor, BEZ235, alone or in combination with the MEK inhibitor, PD0325901; proliferation, apoptosis, and protein expression were assessed. Peptide secretion was evaluated in BON and QGP-1 cells. The antiproliferative effect of BEZ235, alone or combined with PD0325901, was then tested in vivo.

Results: Both BKM120 and BEZ235 decreased proliferation and increased apoptosis; combination with PD0325901 significantly enhanced the antineoplastic effects of either treatment alone. In contrast, neurotensin peptide secretion was markedly stimulated with BKM120 treatment, but not BEZ235. The combination of BEZ235 + PD0325901 significantly inhibited the growth of BON xenografts without systemic toxicity.

Conclusions: Both BKM120 and BEZ235 effectively inhibited neuroendocrine tumor (NET) cell proliferation and stimulated apoptosis. However, inhibition of the PI3K pathway alone with BKM120 significantly stimulated neurotensin peptide secretion; this did not occur with the dual inhibition of both PI3K and mTOR using BEZ235 suggesting that this would be a more effective treatment regimen for NETs. Moreover, the combination of BEZ235 and the MEK inhibitor PD0325901 was a safe and more effective therapy in vivo compared with single agents alone. Clin Cancer Res; 20(5); 1212–22. ©2014 AACR.
Excess Weight Gain Accelerates 1-Methyl-1-Nitrosourea–Induced Mammary Carcinogenesis in a Rat Model of Premenopausal Breast Cancer
Authors: Matthews Shawna B. , Zhu Zongjian , Jiang Weiqin , McGinley John N. , Neil Elizabeth S. , Thompson Henry J.
Published: January 2014

In contrast to the null effects generally reported, high-risk premenopausal women (Gail score ≥1.66) enrolled in the Breast Cancer Prevention P-1 Trial were recently reported to be at increased risk for breast cancer when overweight (HR = 1.59) or obese (HR = 1.70). To investigate this clinical observation in a preclinical setting, ovary-intact female rats were intraperitoneally injected with 50 mg/kg 1-methyl-1-nitrosourea at 21 days of age to simulate premenopausal women with increased risk. Two commercially available strains of Sprague–Dawley rat (Taconic Farms) were used, which are dietary resistant (DR) or dietary susceptible (DS) to excess weight gain when fed a purified diet containing 32% kcal from fat, similar to levels consumed by the typical American woman. DS rats were approximately 15.5% heavier than DR rats at study termination and plasma leptin indicated a marked difference in adiposity. DS rats had higher incidence (26% increase), multiplicity (2.5-fold increase), and burden (5.4-fold increase) of mammary carcinomas with a concomitant reduction in cancer latency (16% earlier detection) compared with DR rats (P < 0.001 for all analyses), and displayed a higher proportion of hormone receptor negative tumors compared with DR rats [OR = 1.78; 95% confidence interval (CI), 0.83–3.81]. Circulating levels of several breast cancer–risk factors, including leptin, adiponectin:leptin ratio, insulin, insulin-like growth factor (IGF)-1, IGF-1:IGF-1 binding protein-3 ratio, and calculated insulin resistance (HOMA-IR) were negatively impacted in DS rats (P < 0.05 for all analyses). These findings support further investigation of the effects of excess weight in high-risk premenopausal women and demonstrate a useful preclinical model for rapid evaluation of mechanistic hypotheses. Cancer Prev Res; 7(3); 310–8. ©2014 AACR.
Requirement and Epigenetics Reprogramming of Nrf2 in Suppression of Tumor Promoter TPA-Induced Mouse Skin Cell Transformation by Sulforaphane
Authors: Su Zheng-Yuan , Zhang Chengyue , Lee Jong Hun , Shu Limin , Wu Tien-Yuan , Khor Tin Oo , Conney Allan H. , Lu Yao-Ping , Kong Ah-Ng Tony
Published: January 2014

Nrf2 is a transcription factor that plays critical roles in regulating the expression of cellular defensive antioxidants and detoxification enzymes. However, the role of Nrf2 and Nrf2's epigenetics reprogramming in skin tumor transformation is unknown. In this study, we investigated the inhibitory role and epigenetics of Nrf2 on tumor transformation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in mouse skin epidermal JB6 (JB6 P+) cells and the anticancer effect of sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables. After five days of treatment, SFN significantly inhibited TPA-induced JB6 cellular transformation and SFN enhanced the nuclear translocation of Nrf2 and increased the mRNA and protein levels of the Nrf2 target genes HO-1, NQO1 and UGT1A1. Knockdown of Nrf2 attenuated the induction of Nrf2, HO-1 and NQO1 by SFN, enhanced TPA-induced colony formation and dampened the inhibitory effect of SFN on TPA-induced JB6 transformation. Epigenetics investigation using bisulfite genomic sequencing showed that SFN decreased the methylation ratio of the first 15 CpGs of the Nrf2 gene promoter, which was corroborated by increased Nrf2 mRNA expression. Furthermore, SFN strongly reduced the protein expression of DNA methyltransferases (DNMT1, DNMT3a and DNMT3b). SFN also inhibited the total histone deacetylase (HDAC) activity and decreased the protein expression of HDAC1, HDAC2, HDAC3 and HDAC4. Collectively, these results suggest that the anti-cancer effect of SFN against TPA-induced neoplastic transformation of mouse skin could involve the epigenetic reprogramming of anti-cancer genes such as Nrf2, leading to the epigenetic reactivation of Nrf2 and the subsequent induction of downstream target genes involved in cellular protection. Cancer Prev Res; 7(3); 319–29. ©2014 AACR.
Adherence to Endocrine Therapy in Breast Cancer Adjuvant and Prevention Settings
Authors: Chlebowski Rowan T. , Kim Jisang , Haque Reina
Published: January 2014

Adherence to oral endocrine therapy in adjuvant breast cancer settings is a substantial clinical problem. To provide current perspective on adherence to oral endocrine therapies, a comprehensive literature review was conducted. In adjuvant trials, endocrine therapy adherence is relatively high with greater adherence for aromatase inhibitors compared with tamoxifen. In contrast, adherence to adjuvant therapy in clinical practice is relatively poor, with only about 50% of women successfully completing 5-year therapy. Importantly, good adherence (>80% use) has been associated with lower recurrence risk. Endocrine therapy adherence in primary breast cancer prevention trials parallels that seen in adjuvant trials. Factors associated with nonadherence include low recurrence risk perception, side effects, age extremes, medication cost, suboptimal patient–physician communication, and lack of social support. Few prospective studies have evaluated interventions designed to improve adherence. Interventions currently proposed reflect inferences from clinical trial procedures in which clinical contacts are commonly greater than in usual practice settings. In conclusion, for optimal breast cancer outcome, adherence to endocrine therapy must improve. Although general recommendations likely to improve adherence can be made based on clinical trial results and preliminary prospective trial findings, research specifically targeting this issue is needed to establish effective intervention strategies. Cancer Prev Res; 7(4); 378–87. ©2014 AACR.
Radiogenomics: Using Genetics to Identify Cancer Patients at Risk for Development of Adverse Effects Following Radiotherapy
Authors: Kerns Sarah L. , Ostrer Harry , Rosenstein Barry S.
Published: January 2014

Normal-tissue adverse effects following radiotherapy are common and significantly affect quality of life. These effects cannot be accounted for by dosimetric, treatment, or demographic factors alone, and evidence suggests that common genetic variants are associated with radiotherapy adverse effects. The field of radiogenomics has evolved to identify such genetic risk factors. Radiogenomics has two goals: (i) to develop an assay to predict which patients with cancer are most likely to develop radiation injuries resulting from radiotherapy, and (ii) to obtain information about the molecular pathways responsible for radiation-induced normal-tissue toxicities. This review summarizes the history of the field and current research.

Significance: A single-nucleotide polymorphism–based predictive assay could be used, along with clinical and treatment factors, to estimate the risk that a patient with cancer will develop adverse effects from radiotherapy. Such an assay could be used to personalize therapy and improve quality of life for patients with cancer. Cancer Discov; 4(2); 155–65. ©2014 AACR.
Apoptosis-Regulated Low-Avidity Cancer-Specific CD8+ T Cells Can Be Rescued to Eliminate HER2/neu–Expressing Tumors by Costimulatory Agonists in Tolerized Mice
Authors: Black Chelsea M. , Armstrong Todd D. , Jaffee Elizabeth M.
Published: January 2014

A major barrier to vaccines in cancer treatment is their failure to activate and maintain a complete cancer-specific CD8+ effector T-cell repertoire. Low-avidity T cells are more likely to escape clonal deletion in the thymus when compared with high-avidity T cells, and therefore comprise the major population of effector T cells available for activation in patients with cancer. However, low-avidity T cells fail to traffic into the tumor microenvironment and function in eradicating tumor under optimal vaccination conditions as opposed to high-avidity T cells that escape clonal deletion and function in tumor killing. We used high- and low-avidity T-cell receptor transgenic CD8+ T cells specific for the immunodominant epitope HER2/neu (RNEU420–429) to identify signaling pathways responsible for the inferior activity of the low-avidity T cells. Adoptive transfer of these cells into tumor-bearing vaccinated mice identified the members of apoptosis pathways that are upregulated in low-avidity T cells. The increased expression of proapoptotic proteins by low-avidity T cells promoted their own cell death and also that of other tumor-specific CD8+ T cells within their local environment. Importantly, we show that this proapoptotic effect can be overcome by using a strong costimulatory signal that prevents the activation-induced cell death and enables the low-avidity T cells to traffic into the tumor and assist in tumor clearance. These findings identify new therapeutic opportunities for activating the most potent anticancer T-cell responses. Cancer Immunol Res; 2(4); 307–19. ©2014 AACR.
MEK Inhibition, Alone or in Combination with BRAF Inhibition, Affects Multiple Functions of Isolated Normal Human Lymphocytes and Dendritic Cells
Authors: Vella Laura J. , Pasam Anupama , Dimopoulos Nektaria , Andrews Miles , Knights Ashley , Puaux Anne-Laure , Louahed Jamila , Chen Weisan , Woods Katherine , Cebon Jonathan S.
Published: January 2014

Combination therapy with BRAF and MEK inhibition is currently in clinical development for the treatment of BRAF-mutated malignant melanoma. BRAF inhibitors are associated with enhanced antigen-specific T-lymphocyte recognition in vivo. Consequently, BRAF inhibition has been proposed as proimmunogenic and there has been considerable enthusiasm for combining BRAF inhibition with immunotherapy. MEK inhibitors inhibit ERK phosphorylation regardless of BRAF mutational status and have been reported to impair T-lymphocyte and modulate dendritic cell function. In this study, we investigate the effects on isolated T lymphocytes and monocyte-derived dendritic cells (moDC) of a MEK (trametinib) and BRAF (dabrafenib) inhibitor combination currently being evaluated in a randomized controlled clinical trial. The effects of dabrafenib and trametinib, alone and in combination, were studied on isolated normal T lymphocytes and moDCs. Lymphocyte viability, together with functional assays including proliferation, cytokine production, and antigen-specific expansion, were assessed. MoDC phenotype in response to lipopolysaccharide stimulation was evaluated by flow cytometry, as were effects on antigen cross-presentation. Dabrafenib did not have an impact on T lymphocytes or moDCs, whereas trametinib alone or in combination with dabrafenib suppressed T-lymphocyte proliferation, cytokine production, and antigen-specific expansion. However, no significant decrease in CD4+ or CD8+ T-lymphocyte viability was observed following kinase inhibition. MoDC cross-presentation was suppressed in association with enhanced maturation following combined inhibition of MEK and BRAF. The results of this study demonstrate that MEK inhibition, alone or in combination with BRAF inhibition, can modulate immune cell function, and further studies in vivo will be required to evaluate the potential clinical impact of these findings. Cancer Immunol Res; 2(4); 351–60. ©2014 AACR.
Outcomes of Patients With Peripartum Cardiomyopathy Who Received Mechanical Circulatory Support
Authors: Loyaga-Rendon Renzo Y. , Pamboukian Salpy V. , Tallaj Jose A. , Acharya Deepak , Cantor Ryan , Starling Randall C. , Naftel David , Kirklin James
Published: January 2014

Background—

We describe the characteristics and outcomes of peripartum cardiomyopathy (PPCMP) patients who received durable mechanical circulatory support and compared it with other etiologies of advanced heart failure.

Methods and Results—

We analyzed 1258 women who were registered in Interagency Registry for Mechanically Assisted Circulatory Support between June 2006 and March 2012. Baseline characteristics, implant strategies, hemodynamics, echocardiographic data, and outcomes were compared. Ninety-nine women had PPCMP and 1159 had non-PPCMP as primary diagnosis. PPCMP women were younger (
P
<0.001), more likely to be blacks, and had less comorbidities than non-PPCMP patients. PPCMP women had better survival than non-PPCMP women (
P
=0.01) with a 2-year survival of 83%. Multivariable risk factor adjustment analysis showed that the improved survival was likely because of younger age and fewer comorbidities. At 36 months, a proportion of 48% PPCMP received heart transplantation. Recovery occurred at a frequency of 6% and 2% in the PPCMP and non-PPCMP groups (
P
=0.1). Adverse event rates were similar in PPCMP and non-PPCMP patients except for higher cardiac arrhythmias and respiratory failure in the non-PPCMP in the first 3 months post implant.

Conclusions—

PPCMP women who receive durable mechanical circulatory support have a better survival than women with non-PPCPM. The improved survival observed in PPCMP is likely related to their fewer comorbidities and younger age. Myocardial recovery was uncommon and less than half of women with end-stage PPCPM received heart transplantation after 3 years of mechanical support.
Psilocybe chuxiongensis, a new bluing species from subtropical China
Authors: Ma Tao , FENG YING , LIN XIAO-FEI , KARUNARATHNA SAMANTHA C. , DING WEI-FENG , HYDE KEVIN D.
Published: January 2014

A new bluing species of Psilocybe in sect. Caerulescentes is described from subtropical China. It is closely related to P. cubensis but can be differentiated by the lack of an annulus and the buff-yellow to yellowish brown, hemispheric to hemispheric-convex pileus without an umbo or papilla. Phylogenetic analyses of ITS, nrLSU and combined rpb2-tef1-α datasets using maximum parsimony and Bayesian inference also indicate its uniqueness. The relationship with P. cubensis is well-supported by molecular data with high support values in all three datasets. Psilocybe chuxiongensis sp. nov. is presented here with a description, photographs, and line drawings.
Regional order and peaceful change: Security communities as a via media in international relations theory
Authors: Koschut Simon
Published: January 2014

The security community concept generally inhabits a rather small niche in the study of International Relations, as the logic of community fundamentally challenges the prevailing logic of anarchy. In this article, it is argued both on ontological and theoretical grounds that the concept’s intellectual heritage and depth transcends the boundaries of existing theories. In this sense, the concept of security community serves as a via media by linking different strands of International Relations theory together and by bridging various theoretical gaps. This argument will be developed in two steps. Firstly, it will be shown that the security community framework developed by Karl W Deutsch is deeply rooted in International Political Theory without belonging to one particular branch. By locating the concept in International Political Theory, an exercise that has been neglected by the security community literature; it will be secondly demonstrated that the concept of security community takes the middle ground between specific strands of International Relations theory, as these strands are ultimately based on concepts of moral philosophy.
Effects of Conversation on Situation Awareness and Working Memory in Simulated Driving
Authors: Heenan Adam , Herdman Chris M. , Brown Matthew S. , Robert Nicole
Published: January 2014

Objective:

In the present research, we investigated the hypothesis that working memory mediates conversation-induced impairment of situation awareness (SA) while driving.

Background:

Although there is empirical evidence that conversation impairs driving performance, the cognitive mechanisms that mediate this relationship remain underspecified. Researchers have reported that a phonological working memory task decreased drivers’ SA for vehicles located behind them whereas a visuospatial working memory task impaired SA for vehicles ahead. Conversation, therefore, might impair SA for vehicles behind the driver by preferentially taxing the phonological loop.

Method:

A 20-questions task was used as a proxy for natural conversation. In Experiment 1, driving performance was measured across three within-subjects conversation conditions (i.e., no conversation, driver asks questions, driver answers questions) with the use of a driving simulator. In Experiment 2, participants drove in the same simulator while either conversing (20-questions task) or not. Participants estimated the positions of other vehicles after the screens were blanked at the end of each trial.

Results:

Speed monitoring and responses to visual probes were impaired by the 20-questions conversation task (Experiment 1). As predicted, conversation impaired SA for the location of other vehicles more for vehicles located behind the driver than for those in front (Experiment 2).

Conclusion:

Conversation impairs drivers’ SA of vehicles behind them by taxing working memory’s phonological loop and impairs SA generally by taxing working memory’s central executive.

Application:

Provides a theoretical framework that links driver SA to working memory and a mechanism for understanding why conversation impairs driving performance.