bluuebunny/crossref_metadata_2025_split huggingface dataset:
RASSF1A Deficiency Enhances RAS-Driven Lung Tumorigenesis
Authors: Schmidt M. Lee , Hobbing Katharine R. , Donninger Howard , Clark Geoffrey J. 
Published: May 2018

AbstractMutant K-RAS has been shown to have both tumor-promoting and -suppressing functions, and growing evidence suggests that the RASSF family of tumor suppressors can act as RAS apoptosis and senescence effectors. It has been hypothesized that inactivation of the RASSF1A tumor suppressor facilitates K-RAS–mediated transformation by uncoupling it from apoptotic pathways such as the Hippo pathway. In human lung tumors, combined activation of K-RAS and inactivation of RASSF1A is closely associated with the development of the most aggressive and worst prognosis tumors. Here, we describe the first transgenic mouse model for activation of K-RAS in the lung in a RASSF1A-defective background. RASSF1A deficiency profoundly enhanced the development of K-RAS–driven lung tumors in vivo. Analysis of these tumors showed loss of RASSF1A-uncoupled RAS from the proapoptotic Hippo pathway as expected. We also observed an upregulation of AKT and RALGEF signaling in the RASSF1A− tumors. Heterozygosity of RASSF1A alone mimicked many of the effects of RAS activation on mitogenic signaling in lung tissue, yet no tumors developed, indicating that nonstandard Ras signaling pathways may be playing a key role in tumor formation in vivo. In addition, we observed a marked increase in inflammation and IL6 production in RASSF1A-deficient tumors. Thus, RASSF1A loss profoundly affects RAS-driven lung tumorigenesis and mitogenic signaling in vivo. Deregulation of inflammatory pathways due to loss of RASSF1A may be essential for RAS-mediated tumorigenesis. These results may have considerable ramifications for future targeted therapy against RAS+/RASSF1A− tumors.Significance: A transgenic mouse model shows that suppression of RASSF1A dramatically enhances Ras-driven tumorigenesis and alters Ras signaling pathway activity.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/10/2614/F1.large.jpg. Cancer Res; 78(10); 2614–23. ©2018 AACR.
Circulating Exosomal miR-27a and miR-130a Act as Novel Diagnostic and Prognostic Biomarkers of Colorectal Cancer
Authors: Liu Xiangxiang , Pan Bei , Sun Li , Chen Xiaoxiang , Zeng Kaixuan , Hu Xiuxiu , Xu Tao , Xu Mu , Wang Shukui 
Published: May 2018

Abstract
Background: Colorectal cancer is one of the most common cancers worldwide usually is associated with poor prognosis due to the advanced stage when diagnosed. This study aimed to investigate whether specific circulating exosomal miRNAs could act as biomarkers for early diagnosis of colorectal cancer.
Methods: A total of 369 peripheral blood samples were included in this study. In the discovery phase, circulating exosomal miR-27a and miR-130a were selected after synthetical analysis of two GEO datasets and TCGA database. The differential expression and diagnostic utility of miR-27a and miR-130a panel were validated using qRT-PCR and ROC curve analysis in subsequent training phase, validation phase, and external validation phase. The prognosis of circulating exosomal miR-27a and miR-130a were investigated using the Kaplan–Meier method.
Results: The expression of exosomal miR-27a and miR-130a in plasma significantly increased in colorectal cancer. The area under ROC curves (AUC) of miR-27a (miR-130a) were 0.773 (0.742) in the training phase, 0.82 (0.787) in the validation phase, and 0.746 (0.697) in the external validation phase. The combination of two miRNAs presented higher diagnostic utility for colorectal cancer (AUCs = 0.846, 0.898, and 0.801 for the training, validation, and external validation phases, respectively). Patients with colorectal cancer with high expression of circulating exosomal miR-27a or miR-130a underwent poorer prognosis.
Conclusions: We identified a circulating exosomal miRNAs panel for the detection of colorectal cancer.
Impact: The exosomal miR-27a and miR-130a panel in plasma may act as a noninvasive biomarker for early detection and predicting prognosis of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 27(7); 746–54. ©2018 AACR.
Refugiados sírios em Campinas/SP e um Aladdin sem a lâmpada mágica
Authors: Begeres Bisneto Victor 
Published: May 2018

O drama dos refugiados sírios que buscam a Europa como solução para sobreviver à guerra em seu país que completa cinco anos, também se revela no Brasil. Baseando-se principalmente de relatos orais obtidos entre setembro e novembro de 2015, o presente artigo busca evidenciar as condições em que vivem os refugiados sírios na cidade de Campinas/SP (segunda no Estado em número de refugiados), a forma como o poder público municipal oferece suporte a essas pessoas e qual a visão desses imigrantes sobre o conflito na Síria, de modo a oferecer um ponto devista mais original e sem a intermediação dos grandes veículos de comunicação.
ERV1/ChemR23 Signaling Protects Against Atherosclerosis by Modifying Oxidized Low-Density Lipoprotein Uptake and Phagocytosis in Macrophages
Authors: Laguna-Fernandez Andres , Checa Antonio , Carracedo Miguel , Artiach Gonzalo , Petri Marcelo H. , Baumgartner Roland , Forteza Maria J. , Jiang Xintong , Andonova Teodora , Walker Mary E. , Dalli Jesmond , Arnardottir Hildur , Gisterå Anton , Thul Silke , Wheelock Craig E. , Paulsson-Berne Gabrielle , Ketelhuth Daniel F.J. , Hansson Göran K. , Bäck Magnus 
Published: May 2018

Background:
In addition to enhanced proinflammatory signaling, impaired resolution of vascular inflammation plays a key role in atherosclerosis. Proresolving lipid mediators formed through the 12/15 lipoxygenase pathways exert protective effects against murine atherosclerosis. n-3 Polyunsaturated fatty acids, including eicosapentaenoic acid (EPA), serve as the substrate for the formation of lipid mediators, which transduce potent anti-inflammatory and proresolving actions through their cognate G-protein–coupled receptors. The aim of this study was to identify signaling pathways associated with EPA supplementation and lipid mediator formation that mediate atherosclerotic disease progression.

Methods:

Lipidomic plasma analysis were performed after EPA supplementation in
Apoe
−/−
mice.
Erv1/Chemr23
−/−
xApoe
−/−
mice were generated for the evaluation of atherosclerosis, phagocytosis, and oxidized low-density lipoprotein uptake. Histological and mRNA analyses were done on human atherosclerotic lesions.

Results:

Here, we show that EPA supplementation significantly attenuated atherosclerotic lesion growth induced by Western diet in
Apoe
−/−
mice and was associated with local cardiovascular n-3 enrichment and altered lipoprotein metabolism. Our systematic plasma lipidomic analysis identified the resolvin E1 precursor 18-monohydroxy EPA as a central molecule formed during EPA supplementation. Targeted deletion of the resolvin E1 receptor
Erv1/Chemr23
in 2 independent hyperlipidemic murine models was associated with proatherogenic signaling in macrophages, increased oxidized low-density lipoprotein uptake, reduced phagocytosis, and increased atherosclerotic plaque size and necrotic core formation. We also demonstrate that in macrophages the resolvin E1–mediated effects in oxidized low-density lipoprotein uptake and phagocytosis were dependent on
Erv1/Chemr23.
When analyzing human atherosclerotic specimens, we identified ERV1/ChemR23 expression in a population of macrophages located in the proximity of the necrotic core and demonstrated augmented ERV1/ChemR23 mRNA levels in plaques derived from statin users.

Conclusions:
This study identifies 18-monohydroxy EPA as a major plasma marker after EPA supplementation and demonstrates that the ERV1/ChemR23 receptor for its downstream mediator resolvin E1 transduces protective effects in atherosclerosis. ERV1/ChemR23 signaling may represent a previously unrecognized therapeutic pathway to reduce atherosclerotic cardiovascular disease.
Effect of an siRNA Therapeutic Targeting PCSK9 on Atherogenic Lipoproteins
Authors: Ray Kausik K. , Stoekenbroek Robert M. , Kallend David , Leiter Lawrence A. , Landmesser Ulf , Wright R. Scott , Wijngaard Peter , Kastelein John J.P. 
Published: May 2018

Background:
The ORION-1 trial (Trial to Evaluate the Effect of ALN-PCSSC Treatment on Low Density Lipoprotein Cholesterol [LDL-C]) demonstrated that inclisiran, an siRNA therapeutic that targets protease proprotein convertase subtilisin/kexin type 9 mRNA within hepatocytes, produces significant low-density lipoprotein cholesterol reduction. The effects of inclisiran on other lipids are less well described.

Methods:
ORION-1 was a phase 2 trial assessing 6 different inclisiran dosing regimens versus placebo. Participants with elevated low-density lipoprotein cholesterol despite receiving maximally tolerated statin therapy received a single-dose (200, 300, or 500 mg) or 2-dose starting regimen (100, 200, or 300 mg on days 1 and 90) of inclisiran or placebo. This prespecified analysis reports the percentage reductions in non–high-density lipoprotein cholesterol (non–HDL-C), apolipoprotein (apo) B, very-low-density lipoprotein cholesterol, lipoprotein(a), triglycerides, HDL-C, and apo A1 at the primary efficacy time point (day 180) with mixed-effect models for repeated measures. Additional prespecified analyses report time course of changes from baseline at each visit to day 210, interindividual variation in response, and lipid goal attainment.

Results:

The mean age of the 501 participants was 63 years, 65% were male, 69% had atherosclerotic cardiovascular disease, 73% used statins, and mean low-density lipoprotein cholesterol was 128 mg/dL. A single dose of inclisiran reduced apo B, non–HDL-C, and very-low-density lipoprotein cholesterol over 210 days. A second dose of inclisiran provided additional lowering of these lipids. At day 180, non–HDL-C was lowered dose-dependently: by 25% from 148±43 to 110±45 mg/dL in the 200-mg single-dose group and by 46% from 161±58 to 91±58 mg/dL in the 2-dose 300-mg group. For the same dosing regimens, apo B was reduced by 23% from 101±23 to 78±29 mg/dL and by 41% from 106±31 to 65±33 mg/dL (
P
<0.001 for all groups versus placebo). In the 300-mg 2-dose group, all individuals experienced apo B and non–HDL-C reductions. There was larger interindividual variation in very-low-density lipoprotein cholesterol, triglycerides, and lipoprotein(a) reductions. In the 300-mg 2-dose group, the percentages of patients achieving guideline-recommended apo B goals for high- and very-high-risk patients at day 180 were 78% and 90%; 68% and 83% of participants achieved non–HDL-C <100 and <130 mg/dL.

Conclusions:
Inclisiran produces significant and prolonged reductions in atherogenic lipoproteins, suggesting that inhibiting the synthesis of protease proprotein convertase subtilisin/kexin type 9 through siRNA may be a viable alternative to other approaches that target protease proprotein convertase subtilisin/kexin type 9.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02597127.
Characteristics of Ethiopia Air Chemistry and Its Meteorological Context
Authors: Jury Mark R. 
Published: May 2018

Abstract
The concentration of trace gases and aerosols in Ethiopia is poorly characterized due to a limited history of surface measurements. Here, satellite measurements and model estimates of atmospheric composition are employed to understand space–time distributions in the period 2000–16. Methane (CH4) and carbon monoxide (CO) display high concentrations over the highlands and provide a focus for analysis of monthly and daily data. CH4 emissions from livestock peak at the beginning of the dry season, while CO from biomass burning rises at the end of the dry season. The seasonal cycle of dust, aerosol optical depth (AOD), and CO2 is inversely related with CH4, while CO closely follows sensible heat flux, thus linking drying and rural biomass burning. Stable easterly flow in the dry season accumulates local emissions, so near-surface concentrations of CO and CH4 are high then. The weather pattern underlying an episode of high nitrogen dioxide (NO2) concentrations was studied. In addition to a stable lapse rate and dry anticyclonic weather, midtropospheric subsidence was related to intrusion of the northern subtropical jet stream on 24–26 December 2010. The wind shadow was cast by the Rift Escarpment limited dispersion, particularly with the dry, stable weather conditions. A key outcome of this work is that CH4 concentrations over Ethiopia are high in global context and have increased &gt;0.1 ppm from 2002 to 2016; hence, there is a need to improve livestock management and production efficiency.
Modified NAM Microphysics for Forecasts of Deep Convective Storms
Authors: Aligo Eric A. , Ferrier Brad , Carley Jacob R. 
Published: May 2018

Abstract
The Ferrier–Aligo (FA) microphysics scheme has been running operationally in the National Centers for Environmental Prediction (NCEP) North American Mesoscale Forecast System (NAM) since August 2014. It was developed to improve forecasts of deep convection in the NAM contiguous United States (CONUS) nest, and it replaces previous versions of the NAM microphysics. The FA scheme is the culmination of extensive microphysical scheme sensitivity experiments made over nearly a dozen warm- and cool-season severe weather cases, as well as an extensive real-time testing in a full, system-wide developmental version of the NAM. While the FA scheme advects each hydrometeor species separately, it was the mass-weighted rime factor (RF) that allowed rimed ice to be advected to very cold temperatures aloft and improved the vertical structure of deep convection. Rimed ice fall speeds were reduced in order to offset an increase in bias of heavy precipitation as a consequence of the mass-weighted RF advection. The FA scheme also incorporated findings from 3-km model runs using the Thompson scheme, including 1) improved closure assumptions for large precipitating ice that targeted the convective and anvil regions of storms, 2) a new diagnostic calculation of radar reflectivity from rimed ice in association with intense convection, and 3) a variable rain intercept parameter that reduced widespread spurious weak reflectivity from shallow boundary layer clouds and increased stratiform rainfall.
Augmentation strategies for clozapine refractory schizophrenia: A systematic review and meta-analysis
Authors: Siskind Dan J , Lee Michael , Ravindran Arul , Zhang Qichen , Ma Evelyn , Motamarri Balaji , Kisely Steve 
Published: May 2018

Background: Although clozapine is the most effective medication for treatment refractory schizophrenia, only 40% of people will meet response criteria. We therefore undertook a systematic review and meta-analysis of global literature on clozapine augmentation strategies. Methods: We systematically reviewed PubMed, PsycInfo, Embase, Cochrane Database, Chinese Biomedical Literature Service System and China Knowledge Resource Integrated Database for randomised control trials of augmentation strategies for clozapine resistant schizophrenia. We undertook pairwise meta-analyses of within-class interventions and, where possible, frequentist mixed treatment comparisons to differentiate treatment effectiveness Results: We identified 46 studies of 25 interventions. On pairwise meta-analyses, the most effective augmentation agents for total psychosis symptoms were aripiprazole (standardised mean difference: 0.48; 95% confidence interval: −0.89 to −0.07) fluoxetine (standardised mean difference: 0.73; 95% confidence interval: −0.97 to −0.50) and, sodium valproate (standardised mean difference: 2.36 95% confidence interval: −3.96 to −0.75). Memantine was effective for negative symptoms (standardised mean difference: −0.56 95% confidence interval: −0.93 to −0.20). However, many of these results included poor-quality studies. Single studies of certain antipsychotics (penfluridol), antidepressants (paroxetine, duloxetine), lithium and Ginkgo biloba showed potential, while electroconvulsive therapy was highly promising. Mixed treatment comparisons were only possible for antipsychotics, and these gave similar results to the pairwise meta-analyses. Conclusions: On the basis of the limited data available, the best evidence is for the use of aripiprazole, fluoxetine and sodium valproate as augmentation agents for total psychosis symptoms and memantine for negative symptoms. However, these conclusions are tempered by generally short follow-up periods and poor study quality.
The Cold War and Latin American Area Studies in the Former USSR: Reflections and Reminiscences
Authors: Bartley Russell H. 
Published: May 2018

All bodies of scholarship reflect societal mindsets and ideologies. Academic fields of geopolitical area studies exemplify this fact, having developed historically in response to the global objectives and related policy requirements of major nation-states over the past century and a half. In the case of Latin American area studies, the field was given decisive impetus by the Cold War, as were the related fields of Soviet and United States studies in each of the two contending superpowers. Discussion of a representative selection of Latin Americanists in the former USSR, their varied statuses within the Soviet academic establishment, and their professional relations with their U.S counterparts and of the development of Soviet Latin American area studies from the post–World War II years down to the demise of the USSR in the early 1990s makes clear that both Soviet and American academic establishments were constrained by Cold War political imperatives and accompanying mindsets that hampered but did not preclude the pursuit and achievement of genuine scholarship. Todos los campos de estudio reflejan mentalidades e ideologías sociales. Los campos académicos de los estudios geopolíticos dan ejemplo de esto, dado que se desarrollaron en respuesta a los objetivos globales y requisitos políticos pertinentes de las principales naciones-estado durante el último siglo y medio. Los estudios sobre América Latina recibieron un impulso decisivo durante la Guerra Fría, junto con los estudios soviéticos y estadounidenses en cada una de las dos superpotencias contendientes. Un vistazo a una selección representativa de latinoamericanistas en la antigua URSS, sus variantes condiciones dentro del status quo académico soviético, y sus relaciones profesionales con sus contrapartes estadounidenses, así como al desarrollo de los estudios soviéticos sobre América Latina después la Segunda Guerra Mundial y hasta la desaparición de la URSS a principios de la década de 1990, dejan en claro que tanto los establecimientos académicos soviéticos como estadounidenses estaban constreñidos por los imperativos políticos de la Guerra Fría y la mentalidad acompañante. Esto obstaculizaba, pero no impedía, la búsqueda y el logro de auténtica investigación.
Whole‐Exome Sequencing of Sinonasal Small Cell Carcinoma Arising within a Papillary Schneiderian Carcinoma In Situ
Authors: Smith Joshua , Kulkarni Aditi , Birkeland Andrew C. , McHugh Jonathan B. , Brenner J. Chad 
Published: May 2018

ObjectiveThe pathogenetic underpinnings of extrapulmonary small cell carcinomas (EPSCCs) of the head and neck are poorly understood. We sought to describe the clinical case and whole‐exome DNA sequencing data of a patient with sinonasal Schneiderian carcinoma in situ whose tumor progressed to small cell carcinoma (SCC).Study DesignCase report and whole‐exome sequencing of tumor DNA.SettingAcademic medical center.Subjects and MethodsA 52‐year‐old man with sinonasal Schneiderian carcinoma in situ whose tumor progressed to small cell carcinoma. We performed whole‐exome genetic sequencing and copy‐number variation (CNV) analysis of tumor and normal DNA extracted from flash‐frozen, paraffin‐embedded (FFPE) samples.ResultsA total of 93 high‐confidence, nonsynonymous somatic mutation events were identified in sinonasal SCC, including loss‐of‐function mutations in TP53, MAML3, a transcriptional coactivator of the Notch pathway, and GAS6, an activating ligand of the TAM family of tyrosine kinase receptors. Focal amplifications of chromosomal regions 6p25‐11.1, containing SOX4 and VEGFA, and 14q32.1‐32.3, containing AKT1 and the Notch inhibitory ligand DLK1, were also seen. Further CNV analysis revealed deletions in the critical cell cycle regulators CDKN2A, RB1, RBL1, and RBL2 and the chromatin modifier EP300.ConclusionsSmall cell carcinoma may rarely arise from sinonasal Schneiderian carcinoma in situ and exhibits similar genomic aberrations (eg, SOX amplification, Notch pathway inactivation) to pulmonary small cell carcinoma.
Are ecstasy induced serotonergic alterations overestimated for the majority of users?
Authors: Szigeti Balázs , Winstock Adam R , Erritzoe David , Maier Larissa J 
Published: May 2018

Background: Neuroimaging studies imply that the regular use of ±3,4-methylenedioxymethamphetamine (MDMA), the major constituent of ecstasy pills, alters the brain’s serotonergic system in a dose-dependent manner. However, the relevance of these findings remains unclear due to limited knowledge about the ecstasy/MDMA use pattern of real-life users. Aims: We examined the representativeness of ecstasy users enrolled in neuroimaging studies by comparing their ecstasy use habits with the use patterns of a large, international sample. Methods: A systematic literature search revealed 10 imaging studies that compare serotonin transporter levels in recreational ecstasy users to matched controls. To characterize the ecstasy use patterns we relied on the Global Drug Survey, the world’s largest self-report database on drug use. The basis of the dose comparison were the Usual Amount (pills/session), Use Frequency (sessions/month) and Dose Intensity (pills/year) variables. Results: Both the average Usual Amount (pills/session) and Use Frequency (sessions/month) of neuroimaging study participants corresponded to the top 5–10% of the Global Drug Survey sample and imaging participants, on average, consumed 720% more pills over a year than the Global Drug Survey participants. Conclusions: Our findings suggest that the serotonin brain imaging literature has focused on unusually heavy ecstasy use and therefore the conclusions from these studies are likely to overestimate the extent of serotonergic alterations experienced by the majority of people who use ecstays.