bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting MYCN in Neuroblastoma by BET Bromodomain Inhibition
Authors: Puissant Alexandre , Frumm Stacey M. , Alexe Gabriela , Bassil Christopher F. , Qi Jun , Chanthery Yvan H. , Nekritz Erin A. , Zeid Rhamy , Gustafson William Clay , Greninger Patricia , Garnett Matthew J. , McDermott Ultan , Benes Cyril H. , Kung Andrew L. , Weiss William A. , Bradner James E. , Stegmaier Kimberly 
Published: February 2013

Abstract
Bromodomain inhibition comprises a promising therapeutic strategy in cancer, particularly for hematologic malignancies. To date, however, genomic biomarkers to direct clinical translation have been lacking. We conducted a cell-based screen of genetically defined cancer cell lines using a prototypical inhibitor of BET bromodomains. Integration of genetic features with chemosensitivity data revealed a robust correlation between MYCN amplification and sensitivity to bromodomain inhibition. We characterized the mechanistic and translational significance of this finding in neuroblastoma, a childhood cancer with frequent amplification of MYCN. Genome-wide expression analysis showed downregulation of the MYCN transcriptional program accompanied by suppression of MYCN transcription. Functionally, bromodomain-mediated inhibition of MYCN impaired growth and induced apoptosis in neuroblastoma. BRD4 knockdown phenocopied these effects, establishing BET bromodomains as transcriptional regulators of MYCN. BET inhibition conferred a significant survival advantage in 3 in vivo neuroblastoma models, providing a compelling rationale for developing BET bromodomain inhibitors in patients with neuroblastoma.
Significance: Biomarkers of response to small-molecule inhibitors of BET bromodomains, a new compound class with promising anticancer activity, have been lacking. Here, we reveal MYCN amplification as a strong genetic predictor of sensitivity to BET bromodomain inhibitors, show a mechanistic rationale for this finding, and provide a translational framework for clinical trial development of BET bromodomain inhibitors for pediatric patients with MYCN-amplified neuroblastoma. Cancer Discov; 3(3); 308–23. ©2012 AACR.
See related commentary by Schnepp and Maris, p. 255
This article is highlighted in the In This Issue feature, p. 239
Neuroimmune Guidance Cue Semaphorin 3E Is Expressed in Atherosclerotic Plaques and Regulates Macrophage Retention
Authors: Wanschel Amarylis , Seibert Tara , Hewing Bernd , Ramkhelawon Bhama , Ray Tathagat D. , van Gils Janine M. , Rayner Katey J. , Feig Jonathan E. , O’Brien Edward R. , Fisher Edward A. , Moore Kathryn J. 
Published: February 2013

Objective—

The persistence of myeloid-derived cells in the artery wall is a characteristic of advanced atherosclerotic plaques. However, the mechanisms by which these cells are retained are poorly understood. Semaphorins, a class of neuronal guidance molecules, play a critical role in vascular patterning and development, and recent studies suggest that they may also have immunomodulatory functions. The present study evaluates the expression of Semaphorin 3E (
Sema3E
) in settings relevant to atherosclerosis and its contribution to macrophage accumulation in plaques.

Approach and Results—

Immunofluorescence staining of
Sema3E
, and its receptor PlexinD1, demonstrated their expression in macrophages of advanced atherosclerotic lesions of Apoe
–/–
mice. Notably, in 2 different mouse models of atherosclerosis regression,
Sema3E
mRNA was highly downregulated in plaque macrophages, coincident with a reduction in plaque macrophage content and an enrichment in markers of reparative M2 macrophages. In vitro,
Sema3E
mRNA was highly expressed in inflammatory M1 macrophages and in macrophages treated with physiological drivers of plaque progression and inflammation, such as oxidized low-density lipoprotein and hypoxia. To explore mechanistically how
Sema3E
affects macrophage behavior, we treated macrophages with recombinant protein in the presence/absence of chemokines, including CCL19, a chemokine implicated in the egress of macrophages from atherosclerotic plaques.
Sema3E
blocked actin polymerization and macrophage migration stimulated by the chemokines, suggesting that it may immobilize these cells in the plaque.

Conclusions—
Sema3E is upregulated in macrophages of advanced plaques, is dynamically regulated by multiple atherosclerosis-relevant factors, and acts as a negative regulator of macrophage migration, which may promote macrophage retention and chronic inflammation in vivo.
Increased Serum Cholesterol Esterification Rates Predict Coronary Heart Disease and Sudden Death in a General Population
Authors: Tanaka Shin-ichiro , Yasuda Tomoyuki , Ishida Tatsuro , Fujioka Yoshio , Tsujino Takeshi , Miki Tetsuo , Hirata Ken-ichi 
Published: February 2013

Objective—
Lecithin:cholesterol acyltransferase (LCAT) is thought to be important in reverse cholesterol transport. However, its association with coronary heart disease (CHD) and sudden death is controversial.

Approach and Results—

We prospectively studied 1927 individuals from the general population. Serum concentrations of apolipoprotein A-I, A-II, B, C-II, C-III, E, and LCAT activity measured as a serum cholesterol esterification rate were evaluated. We documented 61 events of CHD and sudden death during 10.9 years of follow-up. After adjustment for age and sex, LCAT activity was significantly associated with the risk of CHD and sudden death (hazard ratio, 3.02; 95% confidence interval, 1.49−6.12;
P
=0.002). In multivariate analysis adjusted for age, sex, current smoking status, history of diabetes mellitus, body mass index, systolic blood pressure, serum total cholesterol, and serum high-density lipoprotein cholesterol concentrations, the hazard ratio of LCAT activity for the risk of CHD and sudden death remained significant (hazard ratio, 3.07; 95% confidence interval, 1.35−7.01;
P
=0.008). However, when it was analyzed for men and women separately, this association remained significant only in women.

Conclusions—
Increased LCAT activity measured as a serum cholesterol esterification rate was a risk for CHD and sudden death in a Japanese general population.
Diagnosing Present and Future Permafrost from Climate Models
Authors: Slater Andrew G. , Lawrence David M. 
Published: February 2013

Abstract
Permafrost is a characteristic aspect of the terrestrial Arctic and the fate of near-surface permafrost over the next century is likely to exert strong controls on Arctic hydrology and biogeochemistry. Using output from the fifth phase of the Coupled Model Intercomparison Project (CMIP5), the authors assess its ability to simulate present-day and future permafrost. Permafrost extent diagnosed directly from each climate model's soil temperature is a function of the modeled surface climate as well as the ability of the land surface model to represent permafrost physics. For each CMIP5 model these two effects are separated by using indirect estimators of permafrost driven by climatic indices and compared to permafrost extent directly diagnosed via soil temperatures. Several robust conclusions can be drawn from this analysis. Significant air temperature and snow depth biases exist in some model's climates, which degrade both directly and indirectly diagnosed permafrost conditions. The range of directly calculated present-day (1986–2005) permafrost area is extremely large (~4–25 × 106 km2). Several land models contain structural weaknesses that limit their skill in simulating cold region subsurface processes. The sensitivity of future permafrost extent to temperature change over the present-day observed permafrost region averages (1.67 ± 0.7) × 106 km2 °C−1 but is a function of the spatial and temporal distribution of climate change. Because of sizable differences in future climates for the representative concentration pathway (RCP) emission scenarios, a wide variety of future permafrost states is predicted by 2100. Conservatively, the models suggest that for RCP4.5, permafrost will retreat from the present-day discontinuous zone. Under RCP8.5, sustainable permafrost will be most probable only in the Canadian Archipelago, Russian Arctic coast, and east Siberian uplands.
A Study of Response of the Equatorial Pacific SST to Doubled-CO2 Forcing in the Coupled CAM–1.5-Layer Reduced-Gravity Ocean Model
Authors: Jia Fan , Wu Lixin 
Published: February 2013

Abstract
The response of the equatorial Pacific SST under CO2 doubling is investigated using Community Atmosphere Model, version 3.1 (CAM3.1)–1.5-layer reduced-gravity ocean (RGO) coupled model. A robust El Niño–like warming pattern is found in the equatorial Pacific. The surface heat budget analyses suggest the El Niño–like pattern results from a weakening of the Walker circulation. In the western equatorial Pacific, all the heat flux components are important to warm the ocean, with the vast majority canceled by entraiment cooling related to increased stratification. In the central-eastern Pacific, the oceanic horizontal advections along with longwave radiation and latent heat flux act to warm the ocean, with entrainment, shortwave radiation, and horizontal diffusion acting as damping terms. An enhanced annual cycle of SST in the equatorial Pacific is also found, which is driven by the ocean dynamical adjustments to changing winds in the eastern ocean.
Although the ocean model used here is a simple reduced-gravity model, the El Niño–like response supports the results of some full ocean–atmosphere general circulation models (GCMs) performed for the World Climate Research Programme (WCRP) Coupled Model Intercomparison Project (CMIP) phase-5, indicating that the CAM3.1–RGO model can be taken as a useful and efficient tool to study equatorial Pacific response under changing climate.
The Fate of Whistleblowers in Nonprofit Organizations
Authors: Rothschild Joyce 
Published: February 2013

What has come to be called ‘whistleblowing’ has grown enormously in the US over recent decades and it is spreading rapidly around the world. The research on which this paper is based develops a sample of whistleblowers from all walks of life and all regions of the US. This article focuses specifically on the treatment of whistleblowers in the non-profit sector. In examining the political meaning of the act of whistleblowing, the author describes whistleblowing as an act of parrhesia. In ancient Greece this was a citizen request to speak freely and frankly. In the case of the whistleblowers, they are moved to speak publicly and candidly, even without permission to do so, in defense of the substantive purposes of the organization that employs them. This study finds that there is little difference in how whistleblowers are treated in the three sectors of our economy. In the majority of cases in this sample, the organizational managers against whom the whistleblowers level claims of wrongdoing, seek quickly to discredit, defame and terminate them. The author’s research does find that most employees in non-profit organizations view their employer as reasonably open to their inputs. Nevertheless, these positive perceptions of the employer are destroyed among those employees who witness what they define as wrongful or illegal conduct on the part of their employer, and particularly where the employee brings their observations of corruption to “higher-ups” in the organization and sees no corrective action take place. The retaliation that too often follows their disclosures of corrupt practices leaves them with a magnified sense of their own integrity, a new political identity, and an indelible sense of distrust toward senior managers and hierarchal organizations in general. The paper concludes with some suggestions as to how non-profit organizations could respond in a more constructive way to dissenting viewpoints.
Proteinuria in membranous lupus nephritis: the pathology is in the podocyte
Authors: Desai N , Cimbaluk D , Lewis EJ , Whittier WL 
Published: February 2013

Background Patients with membranous lupus glomerulonephritis (MLN) can present with a broad range of urine protein excretion. The glomerular lesion underlying this functional abnormality has been presumed to be immune complexes which aggregate in the subepithelial area. However, the amount of proteinuria often fails to correlate with the quantity of immune deposits demonstrable on fluorescent and electron microscopy. The purpose of this study is to determine the correlation of alterations of the morphologic components of the glomerular capillary wall with the amount of proteinuria in MLN. Design We conducted a retrospective clinicopathologic study of patients with lupus nephritis ( n = 236). In those with pure MLN and proteinuria ( n = 20), the degree of immune aggregates in the capillary walls and mesangium was detailed using fluorescent and electron microscopy. The degree of foot process effacement (FPE) was detailed using electron microscopy. Result Eleven patients had nephrotic range proteinuria (≥3 g proteinuria/g creatinine (g/g)) and nine demonstrated subnephrotic range proteinuria (<3 g/g) (nephrotic, 8.3 ± 5.1 g/g vs. subnephrotic, 1.63 ± 0.83 g/g, p = 0.001). All patients demonstrated peripheral capillary wall granular deposits by immunofluorescence microscopy, and the degree of moderate (2 +) to severe (3 +) deposition was not different (nephrotic, 8/11, 73% vs. subnephrotic, 5/9, 55%, p = 0.64). By electron microscopy, FPE (88.6 ± 11% vs. 48.3 ± 36.1%, p = 0.002) and foot process width (1798 ± 736 nm vs. 1000 ± 333 nm, p = 0.008) was greater in the nephrotic group compared with subnephrotic. There were no other histopathologic differences between the groups. Conclusions In patients with MLN, a distinguishing morphologic feature of those with nephrotic range proteinuria is diffuse visceral epithelial cell FPE. We conclude that nephrotic range proteinuria in patients with MLN may be a manifestation of concomitant glomerular visceral epithelial cell dysfunction.
Aryl hydrocarbon receptor contributes to the MEK/ERK-dependent maintenance of the immature state of human dendritic cells
Authors: Aguilera-Montilla Noemí , Chamorro Sonia , Nieto Concha , Sánchez-Cabo Fátima , Dopazo Ana , Fernández-Salguero Pedro Maria , Rodríguez-Fernández Jose Luis , Pello Oscar M. , Andrés Vicente , Cuenda Ana , Alonso Bárbara , Domínguez-Soto Angeles , Sánchez-Ramón Silvia , Corbí Angel L. 
Published: February 2013

Key PointsAryl hydrocarbon receptor (AhR) mediates the ERK-dependent maintenance of the immature state of monocyte-derived dendritic cells (MDDCs). MEK-ERK regulates antigen capture, lymph node homing, and the acquisition of maturation-associated genes in MDDCs.
Determinants of endothelial function in patients with COPD
Authors: Clarenbach Christian F. , Senn Oliver , Sievi Noriane A. , Camen Giovanni , van Gestel Arnoldus J.R. , Rossi Valentina A. , Puhan Milo A. , Thurnheer Robert , Russi Erich W. , Kohler Malcolm 
Published: February 2013

Chronic obstructive pulmonary disease (COPD) is associated with increased cardiovascular mortality. Endothelial dysfunction may underpin this association. This cross-sectional study aimed to determine the impact of airflow obstruction, systemic inflammation, oxidative stress, sympathetic activation, hypoxaemia and physical activity on endothelial function in COPD.In stable COPD patients, assessments of endothelial function by flow-mediated dilatation (FMD), cardiovascular risk (Pocock score), airflow obstruction (forced expiratory volume in 1 s (FEV1)), systemic inflammation (high-sensitivity C-reactive protein and interleukin-6), oxidative stress (malondialdehyde), sympathetic activation (baroreflex sensitivity), hypoxaemia (arterial oxygen tension), hypercapnia (arterial carbon dioxide tension (PaCO2)), physical activity (steps per day) and exercise capacity (6-min walking distance) were performed. Associations between FMD and potential determinants were assessed in univariate and multivariate analyses.106 patients (Global Initiative for Chronic Obstructive Lung Disease stage I/II 35%, stage III 25% and stage IV 40%) were included. In multivariate analysis FEV1was positively associated with FMD, independent of other significant FMD determinants from univariate analysis (sex, smoking, combined inhaled long-acting β-adrenergic and steroid medication, heart rate, baroreflex sensitivity andPaCO2) and adjusted for potential confounders (cardiovascular risk and age). In addition, the FMD and FEV1association was modified by physical activity.The findings of this study demonstrate that the severity of airflow obstruction is a significant determinant of endothelial function in patients with COPD. A high level of physical activity seems to have a favourable effect on this association.
Gastric non-secreting neuroendocrine tumor and hypochlorhydria-related hypergastrinemia: a case report
Authors: Biolato Marco , Alfieri Sergio , Ianiro Gianluca , Pizzoferrato Marco , Gasbarrini Giovanni 
Published: February 2013

Abstract

Introduction
Zollinger–Ellison syndrome is characterized by recurrent peptic ulcers and diarrhea that result from gastrin-secreting neuroendocrine tumors of the gastrointestinal tract; nevertheless, severe hypergastrinemia may also have alternative pathogenetic explanations.

Case presentation
A 61-year-old woman of Caucasian origin presented with a history of epigastric pain and early satiety, severe hypergastrinemia (approximately 2000 pg/mL) and a neuroendocrine polyp in the corpus of her stomach. Chronic atrophic gastritis and intestinal metaplasia was present, but she denied use of acid suppressant drugs and the results of tests for Helicobacter pylori as well as gastric parietal cell and intrinsic factor antibodies were negative. She underwent a radical gastric tangential resection. Six months later, serum gastrin was still elevated despite lack of recurrence of tumor.

Conclusion
The clinical picture was suggestive for a hypochlorhydria-related hypergastrinemia with subsequent development of a non-secreting carcinoid. We suggest a periodic endoscopic follow-up in patients with severe hypochlorhydria-related hypergastrinemia in order to earlier detect neuroendocrine polyps.
Functional analysis of a zebrafishmyd88mutant identifies key transcriptional components of the innate immune system
Authors: van der Vaart Michiel , van Soest Joost J. , Spaink Herman P. , Meijer Annemarie H. 
Published: February 2013

SummaryToll-like receptors (TLRs) are an important class of pattern recognition receptors (PRRs) that recognize microbial and danger signals. Their downstream signaling upon ligand binding is vital for initiation of the innate immune response. In human and mammalian models, myeloid differentiation factor 88 (MYD88) is known for its central role as an adaptor molecule in interleukin 1 receptor (IL-1R) and TLR signaling. The zebrafish is increasingly used as a complementary model system for disease research and drug screening. Here, we describe a zebrafish line with a truncated version of MyD88 as the first zebrafish mutant for a TLR signaling component. We show that this immune-compromised mutant has a lower survival rate under standard rearing conditions and is more susceptible to challenge with the acute bacterial pathogens Edwardsiella tarda and Salmonella typhimurium. Microarray and quantitative PCR analysis revealed that expression of genes for transcription factors central to innate immunity (including NF-κB and AP-1) and the pro-inflammatory cytokine Il1b, is dependent on MyD88 signaling during these bacterial infections. Nevertheless, expression of immune genes independent of MyD88 in the myd88 mutant line was sufficient to limit growth of an attenuated S. typhimurium strain. In the case of infection with the chronic bacterial pathogen Mycobacterium marinum, we show that MyD88 signaling has an important protective role during early pathogenesis. During mycobacterial infection, the myd88 mutant shows accelerated formation of granuloma-like aggregates and increased bacterial burden, with associated lower induction of genes central to innate immunity. This zebrafish myd88 mutant will be a valuable tool for further study of the role of IL1R and TLR signaling in the innate immunity processes underlying infectious diseases, inflammatory disorders and cancer.
Stereoscopic particle image velocimetry measurements of the three-dimensional flow field of a descending autorotating Mahogany seed (Swietenia macrophylla)
Authors: Salcedo Erick , Treviño Cesar , Vargas Rene O. , Martínez Lorenzo A. 
Published: February 2013

SummaryAn experimental investigation of near field aerodynamics of wind dispersed rotary seeds has been performed using stereoscopic digital particle image velocimetry (DPIV). The detailed three-dimensional (3D) flow structure of the leading-edge vortex (LEV) of autorotating Mahogany seeds (Swietenia macrophylla) in a low-speed vertical wind tunnel are revealed for the first time. The results confirm that the presence of strong spanwise flow and strain produced by centrifugal forces through a spiral vortex are responsible for the attachment and stability of the LEV, with its core forming a cone pattern with gradual increase in vortex size. The LEV appears at 25% of the wingspan, increases in size and strength outboard along the wing, and reaches its maximum stability and spanwise velocity at 75% of the wingspan. At a region between 90% and 100% of the wingspan, the strength and stability of the vortex core decreases and the LEV re-orientation/inflection with the tip vortex takes place. In this study, the instantaneous flow structure and the instantaneous velocity and vorticity fields measured in planes parallel to the free stream direction are presented as contour plots using an inertial and a non-inertial frame of reference. Results for the mean aerodynamic thrust coefficients as a function of the Reynolds number are presented to supplement the DPIV data.
Low Temperature B Activation in SOI Using Optimised Vacancy Engineering Implants
Authors: Smith A.J. , Colombeau B. , Bennett N. , Gwilliam R. , Cowern N. , Sealy B. 
Published: February 2013

AbstractIn this study 300keV and 1MeV Si vacancy engineering implants have been used to optimise the activation of a 2keV 1×1015cm-2 B implant into SOI. Although the two implants generate a similar areal density of excess vacancies in the SOI top layer, Hall Effect measurements show that low temperature activation is possible to a greater level with the 300keV Si co-implant than with the 1MeV implant. Hall and SIMS data are consistent with a high level of activation of the B at 700°C, with no significant diffusion at the metallurgical junction depth.