bluuebunny/crossref_metadata_2025_split huggingface dataset:
Snail Recruits Ring1B to Mediate Transcriptional Repression and Cell Migration in Pancreatic Cancer Cells
Authors: Chen Jiangzhi , Xu Hong , Zou Xiuqun , Wang Jiamin , Zhu Yi , Chen Hao , Shen Baiyong , Deng Xiaxing , Zhou Aiwu , Chin Y. Eugene , Rauscher Frank J. , Peng Chenghong , Hou Zhaoyuan 
Published: June 2014

Abstract
Transcriptional repressor Snail is a master regulator of epithelial–mesenchymal transition (EMT), yet the epigenetic mechanism governing Snail to induce EMT is not well understood. Here, we report that in pancreatic ductal adenocarcinoma (PDAC), elevated levels of the ubiquitin E3 ligase Ring1B and Snail, along with elevated monoubiquitination of H2A at K119 (H2AK119Ub1), are highly correlated with poor survival. Mechanistic investigations identified Ring1B as a Snail-interacting protein and showed that the carboxyl zinc fingers of Snail recruit Ring1B and its paralog Ring1A to repress its target promoters. Simultaneous depletion of Ring1A and Ring1B in pancreatic cancer cells decreased Snail binding to the target chromatin, abolished H2AK119Ub1 modification, and thereby compromised Snail-mediated transcriptional repression and cell migration. We found that Ring1B and the SNAG-associated chromatin modifier EZH2 formed distinct protein complexes with Snail and that EZH2 was required for Snail-Ring1A/B recruitment to the target promoter. Collectively, our results unravel an epigenetic mechanism underlying transcriptional repression by Snail, suggest Ring1A/B as a candidate therapeutic target, and identify H2AK119Ub1 as a potential biomarker for PDAC diagnosis and prognosis. Cancer Res; 74(16); 4353–63. ©2014 AACR.
Aumento na expressão de telomerase por fibroblastos ocorre precocemente à expressão de alfa-actina de músculo liso por miofibroblastos no processo de remodelamento da pneumonia intersticial usual
Authors: Waisberg Daniel Reis , Silva Osmar Bianchi da , Atanazio Marcelo Junqueira , Parra Edwin Roger , Barbas Filho João Valente , Capelozzi Vera Luiza 
Published: June 2014

Objetivo: Identificar potenciais marcadores associados à expressão de telomerase em fibroblastos e de α-actina de músculo liso (α-AMS) em miofibroblastos de pulmões de pacientes com fibrose pulmonar idiopática/pneumonia intersticial usual (FPI/PIU). Métodos: Utilizamos cortes histológicos de 34 biópsias cirúrgicas de pulmão de pacientes com FPI, caracterizados, à histopatologia, pelo padrão de PIU. As expressões de telomerase por fibroblastos, de α-AMS por miofibroblastos e tecidual de interleucina-4 (IL-4), de fator de crescimento transformador-β (TGF- β) e de fator de crescimento de fibroblastos básico (bFGF) foram avaliados por imunohistoquímica e quantificadas pela técnica de contagem de pontos nas áreas pulmonares de colapso (COL), de fibrose mural (FM) e de faveolamento (FV). Resultados: A expressão de telomerase foi significativamente maior nas áreas de COL que nas áreas de FM e FV. O mesmo foi observado para a expressão de bFGF. Interleucina-4 e α-AMS tiveram expressão significativamente maior nas áreas de FM. A expressão de TGF-β foi maior nas áreas de COL e FV. Observamos uma associação positiva entre expressão de telomerase e bFGF nas áreas COL, FM e FV. O mesmo ocorreu com a expressão de α-AMS e IL-4. Nas áreas de FM, houve uma correlação negativa entre IL-4 e bFGF, e TGF-β apresentou tendência a associação positiva com α-AMS. Análise multivariada revelou que a expressão de IL-4 e α-AMS nas áreas de FM são indicadores independentes de menor sobrevida em modelo estatístico significante incluindo idade, tabagismoe FVC (capacidade vital forçada). Pacientes com expressão de IL-4 menor que 13,5% nas áreas de FM apresentaram melhor sobrevida. O mesmo foi observado para expressão de α-AMS menor que 8,5%. Conclusão: Fibroblastos, com capacidade multiplicativa caracterizada pela expressão de telomerase e de bFGF tecidual, tendem a predominar no estágio precoce de remodelamento da FPI/PIU; enquanto a diferenciação de miofibroblastos, caracterizada pela expressão de α-AMS e IL-4, parece ser responsável pelo estágio tardio da resposta fibrótica. A sobrevida dos pacientes parece ser influenciada por tais processos
DIABETE COMO MODELO DE NEUROPATIA AUTONÔMICA
Authors: Sato Karina L. , Migliaccio Vanessa , Carmo Jussara M. , Oliveti Maria Carolina DBB , Ferreira Renata S. , Fazan Valéria PS 
Published: June 2014

Modelo do Estudo: O presente estudo é uma revisão de literatura sobre a neuropatia diabética, especialmente a neuropatia autonômica diabética, enfatizando as recentes descobertas sobre o assunto, com modelos experimentais da doença. Importância do problema: Comprometimento do sistema nervoso autônomo ocorre em uma variedade de doenças sistêmicas, das quais o diabetes mellitus é a mais comum. Alterações no sistema nervoso periférico em animais geneticamente diabéticos ou com diabete induzida experimentalmente têm sido amplamente investigadas, na esperança de que as alterações encontradas em modelos animais possam reproduzir algumas das alterações da neuropatia diabética humana precoce, levando ao melhor entendimento sobre o mecanismo da doença. Vários agentes químicos são citotóxicos para as células beta do pâncreas porém, apenas o aloxane e a estreptozotocina (STZ) tem sido sistematicamente investigados e são amplamente empregados para induzir diabete nos animais. Em geral, STZ é mais eficaz e mais específica para as células beta do pâncreas que o aloxane. Embora estudos morfológicos tenham sido realizados em vários nervos periféricos de ratos diabéticos induzidos com STZ, tais como sural, fibular e tibial, informações sobre alterações patológicas em nervos autonômicos são limitadas. Comentários: Recentemente, estudamos as alterações do nervo depressor aórtico (NDA) em ratos diabéticos agudos (15 dias após injeção de STZ). Nossos resultados mostraram características de atrofia axonal em 5 dos 10 nervos estudados. Um estudo de microscopia de luz, conduzido em nosso laboratório, o nervo vago cervical de ratos diabéticos crônicos (12 semanas após injeção de STZ), mostrou resultados discretos, a favor da perda de fibras mielínicas finas. Outro estudo recente do nosso laboratório mostrou uma redução do número de fibras mielínicas pequenas dos nervos renais, nos ratos diabéticos crônicos, resultado mais evidente que o observado no nervo vago. Por outro lado, as alterações do NDA (atrofia axonal) se assemelham mais aos resultados obtidos com outros nervos somáticos, confirmando o caráter altamente variável do diabete, no acometimento dos nervos periféricos.
OS NÚCLEOS VASOMOTORES DO BULBO E A REGULAÇÃO CARDIOVASCULAR: NOVAS EVIDÊNCIAS E NOVAS QUESTÕES
Authors: Cravo Sergio L. , Rosa Daniel A. , Kalassa Fernanda , Korim Willian S. , Hinrichs Julia M. , Ferreira-Neto Marcos L. , Di Mônaco Luciana R. , Pedrino Gustavo R. 
Published: June 2014

Há mais de 30 anos foi proposto um modelo para explicar como o sistema nervoso central promove a regulação do sistema cardiovascular, onde os núcleos vasomotores do bulbo seriam as principais estruturas envolvidas no controle do reflexo cardiovascular. Segundo este modelo, o núcleo do trato solitário (NTS) é o primeiro núcleo a integrar as informações cardiovasculares vindas dos baroceptores e também parece integrar vias descendentes provenientes de núcleos superiores como o hipotálamo, importantes para as reações de alerta e defesa. Do NTS saem projeções excitatórias para a região caudoventrolateral (CVL) do bulbo, a qual inibe a região rostroventrolateral (RVL). Esta última região constitui a principal fonte de eferências excitatórias para os neurônios simpáticos pré-ganglionares (SPN), sendo responsável pelo tonus simpático para o coração e vasos. Projeções importantes do CVL para estruturas diencefálicas (núcleo preóptico mediano, núcleo paraventricular do hipotálamo e núcleo supraóptico) também estão envolvidas no controle da composição e/ou volume do compartimento extracelular. A área depressora gigantocelular (GiDA) constitui outro possível centro vasomotor envolvido nos ajustes de fluxo sangüíneo por meio de projeções diretas para o SPN. No entanto, o meio pelo qual a GiDA exerce seu efeito vasodepressor ainda é desconhecido. Nos últimos 10 anos, nosso laboratório tem se dedicado a deslindar as vias e mecanismos neurais associados à regulação do fluxo sangüíneo visceral e muscular. Resultados obtidos ao longo destes estudos resultaram em evidências que são incompatíveis com o modelo proposto.
AVALIAÇÃO DA PRESCRIÇÃO DIETÉTICA DE CRIANÇAS HOSPITALIZADAS
Authors: Almada Maria Olímpia R V , Vilela Lidiane B F , Resende Cristina M M , Monteiro Jacqueline P. 
Published: June 2014

Modelo do estudo: Estudo de prevalência. Objetivo: A subnutrição é freqüentemente observada em crianças hospitalizadas e está associada a um pior prognóstico. A correta abordagem nutricional, incluindo a prescrição dietética, melhora a evolução clínica. O objetivo desse estudo foi avaliar a adequação da prescrição dietética em crianças hospitalizadas. Métodos : Vinte e uma crianças foram acompanhadas de Julho a Setembro de 2004. Foi realizado a avaliação das prescrições dietéticas de crianças recebendo nutrição enteral durante três períodos da internação. Houve inadequação do peso durante a hospitalização (dia 1 =76.4 ± 18.2%; dia 2 = 76.1 ± 18.6%; dia 3 = 76.7 ± 19.6%), sem alteração durante o período do estudo. A prescrição energética foi inadequada, porém as de proteínas e micronutrientes apresentaram-se dentro da recomendação. Conclusão: A condição clínica pode afetar de maneira negativa a prescrição nutricional. A equipe multidisciplinar deve se empenhar ao máximo para atingir as necessidades energéticas das crianças hospitalizadas.
DADOS MÉDICO-LEGAIS SOBRE AFOGAMENTOS NA REGIÃO DE RIBEIRÃO PRETO (SP, BRASIL): UM PASSO PARA A PREVENÇÃO
Authors: Araújo Rodrigo T. , Martin Carmen C. S. , Martinis Bruno S. , Evison Martin P. , Guimarães Marco Aurelio 
Published: June 2014

Este é um estudo de prevalência com a primeira descrição específica de casos de afogamento em uma área não-costeira do Brasil, em Ribeirão Preto, estado de São Paulo, uma região com padrão de vida comparável ao de países desenvolvidos, com o objetivo de estabelecer medidas preventivas para este tipo específico de trauma. Metodologia : Uma análise da documentação médico-legal de 89 casos de afogamento ocorridos entre 2001 e 2004. O padrão de mortes por afogamento foi estudado através de parâmetros como idade, sexo, características sócio-econômicas e avaliação do consumo de álcool. Resultados: um índice de 2,69 casos por 100.000 habitantes foi observado. O perfil predominante entre as vítimas de afogamento foi o do homem caucasiano em idade economicamente produtiva (15-59 anos), afogados acidentalmente em rios e represas na área rural durante o verão e o outono, sendo inviável a avaliação do consumo de álcool. Conclusão e Relevância : a observação do perfil da vítima de afogamento através dos relatórios médico-legais permitiu o desenvolvimento de um projeto piloto de sucesso na prevenção de afogamentos que pode ser expandido para outras áreas não-costeiras do Brasil, visando à redução do número de vítimas através da prevenção. As dificuldades de investigar a influência do consumo de álcool são discutidas.
Association Between Shear Stress and Platelet-Derived Transforming Growth Factor-β1 Release and Activation in Animal Models of Aortic Valve Stenosis
Authors: Wang Wei , Vootukuri Spandana , Meyer Alexander , Ahamed Jasimuddin , Coller Barry S. 
Published: June 2014

Objective—
Aortic valve stenosis (AS) is characterized by fibrosis and calcification of valves leading to aortic valve narrowing, resulting in high wall shear stress across the valves. We previously demonstrated that high shear stress can activate platelet-derived transforming growth factor-β1 (TGF-β1), a cytokine that induces fibrosis and calcification. The aim of this study was to investigate the role of shear-induced platelet release of TGF-β1 and its activation in AS.

Approach and Results—

We studied hypercholesterolemic
Ldlr

−
/−

Apob
100/100
/
Mttp
fl/fl
/
Mx1Cre
+/+
(Reversa) mice that develop AS on Western diet and a surgical ascending aortic constriction mouse model that acutely simulates the hemodynamics of AS to study shear-induced platelet TGF-β1 release and activation. Reversa mice on Western diet for 6 months had thickening of the aortic valves, increased wall shear stress, and increased plasma TGF-β1 levels. There were weak and moderate correlations between wall shear stress and TGF-β1 levels in the progression and reversed Reversa groups and a stronger correlation in the ascending aortic constriction model in wild-type mice but not in mice with a targeted deletion of megakaryocyte and platelet TGF-β1 (
Tgfb1
flox
). Plasma total TGF-β1 levels correlated with collagen deposition in the stenotic valves in Reversa mice. Although active TGF-β1 levels were too low to be measured directly, we found (1) canonical TGF-β1 (phosphorylated small mothers against decapentaplegic 2/3) signaling in the leukocytes and canonical and noncanonical (phosphorylated extracellular signal–regulated kinases 1/2) TGF-β1 signaling in aortic valves of Reversa mice on a Western diet, and (2) TGF-β1 signaling of both pathways in the ascending aortic constriction stenotic area in wild-type but not
Tgfb1
flox
mice.

Conclusions—
Shear-induced, platelet-derived TGF-β1 activation may contribute to AS.
Alternative Splicing of Endothelial Fibronectin Is Induced by Disturbed Hemodynamics and Protects Against Hemorrhage of the Vessel Wall
Authors: Murphy Patrick A. , Hynes Richard O. 
Published: June 2014

Objective—
Abnormally low-flow conditions, sensed by the arterial endothelium, promote aneurysm rupture. Fibronectin (FN) is among the most abundant extracellular matrix proteins and is strongly upregulated in human aneurysms, suggesting a possible role in disease progression. Altered FN splicing can result in the inclusion of EIIIA and EIIIB exons, generally not expressed in adult tissues. We sought to explore the regulation of FN and its splicing and their possible roles in the vascular response to disturbed flow.

Approach and Results—

We induced low and reversing flow in mice by partial carotid ligation and assayed
FN
splicing in an endothelium-enriched intimal preparation. Inclusion of EIIIA and EIIIB was increased as early as 48 hours, with negligible increases in total
FN
expression. To test the function of EIIIA and EIIIB inclusion, we induced disturbed flow in
EIIIAB

−/−

mice unable to include these exons and found that they developed focal lesions with hemorrhage and hypertrophy of the vessel wall. Acute deletion of floxed
FN
caused similar defects in response to disturbed flow, consistent with a requirement for the upregulation of the spliced isoforms, rather than a developmental defect. Recruited macrophages promote
FN
splicing because their depletion by clodronate liposomes blocked the increase in endothelial EIIIA and EIIIB inclusion in the carotid model.

Conclusions—
These results uncover a protective mechanism in the inflamed intima that develops under disturbed flow, by showing that splicing of FN mRNA in the endothelium, induced by macrophages, inhibits hemorrhage of the vessel wall.
Oxidized Low-Density Lipoprotein Induces Long-Term Proinflammatory Cytokine Production and Foam Cell Formation via Epigenetic Reprogramming of Monocytes
Authors: Bekkering Siroon , Quintin Jessica , Joosten Leo A.B. , van der Meer Jos W.M. , Netea Mihai G. , Riksen Niels P. 
Published: June 2014

Objective—
Although the role of monocytes in the pathogenesis of atherosclerosis is well established, the persistent vascular inflammation remains largely unexplained. Recently, our group reported that stimulation of monocytes with various microbial products can induce a long-lasting proinflammatory phenotype via epigenetic reprogramming, a process termed trained immunity. We now hypothesize that oxidized low-density lipoprotein (oxLDL) also induces a long-lasting proinflammatory phenotype in monocytes, which accelerates atherosclerosis by proinflammatory cytokine production and foam cell formation.

Approach and Results—

Isolated human monocytes were exposed for 24 hours to medium or oxLDL. After washing and resting for 6 days, the cells were exposed to toll-like receptor 2 and 4 agonists. Pre-exposure to oxLDL increased mRNA expression and protein formation on toll-like receptor 2 and 4 stimulation of several proatherogenic proteins, including interleukin-6, interleukin-18, interleukin-8, tumor necrosis factor-α, monocyte chemoattractant protein 1, and matrix metalloproteinase 2 and 9. In addition, foam cell formation was enhanced after oxLDL exposure, which was associated with an upregulation of scavenger receptors CD36 and scavenger receptor-A and downregulation of ATP-binding cassette transporters, ABCA1 and ABCG1. Chromatin immunoprecipitation performed 6 days after oxLDL stimulation demonstrated increased trimethylation of lysine 4 at histone 3 in promoter regions of
tnfα
,
il-6
,
il-18
,
mcp-1
,
mmp2
,
mmp9
,
cd36
, and
sr-a.
Finally, pretreatment of the monocytes with the histone methyltransferase inhibitor methylthioadenosine completely prevented the oxLDL-induced long-lasting proinflammatory phenotype.

Conclusions—
Brief exposure of monocytes to a low concentration of oxLDL induces a long-lasting proatherogenic macrophage phenotype via epigenetic histone modifications, characterized by increased proinflammatory cytokine production and foam cell formation.
Phosphoinositide 3-Kinases p110α and p110β Have Differential Roles in Insulin-Like Growth Factor-1–Mediated Akt Phosphorylation and Platelet Priming
Authors: Blair Thomas A. , Moore Samantha F. , Williams Christopher M. , Poole Alastair W. , Vanhaesebroeck Bart , Hers Ingeborg 
Published: June 2014

Objective—
Platelet hyperactivity is a contributing factor in the pathogenesis of cardiovascular disease and can be induced by elevated levels of circulating growth factors, such as insulin-like growth factor-1 (IGF-1). IGF-1 is a primer that cannot stimulate platelet activation by itself, but in combination with physiological stimuli can potentiate platelet functional responses via a phosphoinositide 3-kinase–dependent mechanism. In this study, we explored the role of the phosphoinositide 3-kinase p110α isoform in IGF-1–mediated enhancement of platelet function.

Approach and Results—
Using a platelet-specific p110α knockout murine model, we demonstrate that genetic deletion, similar to pharmacological inactivation of p110α, did not affect proteinase-activated receptor 4 signaling to Akt/protein kinase B but significantly reduced IGF-1–mediated Akt phosphorylation. The p110β inhibitor TGX-221 abolished IGF-1–induced Akt phosphorylation in p110α-deficient platelets, demonstrating that both p110α and p110β contribute to IGF-1–mediated Akt phosphorylation. Genetic deletion of p110α had no effect on IGF-1–mediated increases in thrombus formation on collagen and enhancement of proteinase-activated receptor 4–mediated integrin activation and α-granule secretion. In contrast, pharmacological inhibition of p110α blocked IGF-1–mediated potentiation of integrin activation and α-granule secretion. Functional enhancement by IGF-1 in p110α knockout samples was lost after TGX-221 treatment, suggesting that p110β drives priming in the absence of the p110α isoform.

Conclusions—
Together, these results demonstrate that both p110α and p110β are involved in Akt signaling by IGF-1, but that it is the p110α isoform that is responsible for IGF-1–mediated potentiation of platelet function.
Elevated Pulmonary Artery Systolic Pressure Predicts Heart Failure Admissions in African Americans
Authors: Choudhary Gaurav , Jankowich Matthew , Wu Wen-Chih 
Published: June 2014

Background—
Although elevated pulmonary artery systolic pressure (PASP) is associated with heart failure (HF), whether PASP measurement can help predict future HF admissions is not known, especially in African Americans who are at increased risk for HF. We hypothesized that elevated PASP is associated with increased risk of HF admission and improves HF prediction in African American population.

Methods and Results—

We conducted a longitudinal analysis using the Jackson Heart Study cohort (n=3125; 32.2% men) with baseline echocardiography-derived PASP and follow-up for HF admissions. Hazard ratio for HF admission was estimated using Cox proportional hazard model adjusted for variables in the Atherosclerosis Risk in Community (ARIC) HF prediction model. During a median follow-up of 3.46 years, 3.42% of the cohort was admitted for HF. Subjects with HF had a higher PASP (35.6±11.4 versus 27.6±6.9 mm Hg;
P
<0.001). The hazard of HF admission increased with higher baseline PASP (adjusted hazard ratio per 10 mm Hg increase in PASP: 2.03; 95% confidence interval, 1.67–2.48; adjusted hazard ratio for highest [≥33 mm Hg] versus lowest quartile [<24 mm Hg] of PASP: 2.69; 95% confidence interval, 1.43–5.06) and remained significant irrespective of history of HF or preserved/reduced ejection fraction. Addition of PASP to the ARIC model resulted in a significant improvement in model discrimination (area under the curve=0.82 before versus 0.84 after;
P
=0.03) and improved net reclassification index (11–15%) using PASP as a continuous or dichotomous (cutoff=33 mm Hg) variable.

Conclusions—
Elevated PASP predicts HF admissions in African Americans and may aid in early identification of at-risk subjects for aggressive risk factor modification.
Left Atrial Passive Emptying Function Determined by Cardiac Magnetic Resonance Predicts Atrial Fibrillation Recurrence After Pulmonary Vein Isolation
Authors: Dodson John A. , Neilan Tomas G. , Shah Ravi V. , Farhad Hoshang , Blankstein Ron , Steigner Michael , Michaud Gregory F. , John Roy , Abbasi Siddique A. , Jerosch-Herold Michael , Kwong Raymond Y. 
Published: June 2014

Background—
Although pulmonary vein isolation has become a mainstream therapy for selected patients with atrial fibrillation (AF), late recurrent AF is common and its risk factors remain poorly defined. The purpose of our study was to test the hypothesis that reduced left atrial passive emptying function (LAPEF) as determined by cardiac magnetic resonance has a strong association with late recurrent AF after pulmonary vein isolation.

Methods and Results—

Three hundred forty-six patients with AF referred for cardiac magnetic resonance pulmonary vein mapping before pulmonary vein isolation were included. Maximum LA volumes (VOL
max
) and volumes before atrial contraction (VOL
bac
) were measured; LAPEF was calculated as (VOL
max
−VOL
bac
)/VOL
max
×100. Kaplan–Meier curves were constructed to determine late recurrent AF stratified by LAPEF quintile. Cox proportional hazards regression was used to adjust for known markers of recurrence. During a median follow-up of 27 months, 124 patients (35.8%) experienced late recurrent AF. Patients with recurrence were more likely to have nonparoxysmal AF (75.8% versus 51.4%;
P
<0.01), higher mean VOL
max
(60.2 versus 52.8 mL/m
2
;
P
<0.01), and lower mean LAPEF (19.1% versus 26.0%;
P
<0.01). Patients in the lowest LAPEF quintile were at highest risk of developing recurrent AF (2-year recurrence for lowest versus highest: 60.5% versus 17.3%;
P
<0.01). After adjusting for known predictors of recurrence, patients with low LAPEF remained significantly more likely to recur (hazard ratio for lowest versus highest quintile, 3.92; 95% confidence interval, 2.01–7.65).

Conclusions—
We found a strong association between LAPEF and recurrent AF after pulmonary vein isolation that persisted after multivariable adjustment.