RESUMO
INTRODUCTION: Among ethnic groups, Asian-American women have the highest incidence of cervical cancer, low cervical cancer screening rates, and are more likely to state they have "never thought about" and/or "do not need" Pap testing. Through a Patient Advocacy grant awarded by the American Society of Cytopathology Foundation, we developed a culturally sensitive educational outreach program to encourage Pap screening among Asian-Americans in our community. MATERIALS AND METHODS: Educational materials, translated into three languages, were shared at nine community events by undergraduate and medical student volunteers. Pre- and post-education surveys on awareness, knowledge, and attitudes towards screening were administered. Results were tallied and reported as raw percentages. RESULTS: A total of 328 surveys were completed; 80% were Asian respondents. Twenty percent of respondents were not up to date (NUTD) with Pap screening. Knowledge of Pap tests reported as "excellent"/"good" rose from 46% before to 85% after education. Those reporting "very likely"/"likely" to schedule a Pap test increased from 72% to 92% in the NUTD group and from 84% to 97% in the 21-29 age group. Those reporting "very likely"/"likely" to recommend a Pap test to others increased from 68% to 98% in the NUTD group and 77% to 97% in those aged 21-29. CONCLUSIONS: A student-led community-based culturally sensitive outreach approach improved Pap test knowledge and awareness among Asian-Americans. The largest increase in likelihood to obtain a Pap test and recommend the test to others was the NUTD and 21-29 age groups, suggesting influence on those in need of screening.
RESUMO
Idiopathic pulmonary arterial hypertension (PAH [IPAH]) is an insidious and potentially fatal disease linked to a mutation or reduced expression of bone morphogenetic protein receptor 2 (BMPR2). Because intravascular inflammatory cells are recruited in IPAH pathogenesis, we hypothesized that reduced BMPR2 enhances production of the potent chemokine granulocyte macrophage colony-stimulating factor (GM-CSF) in response to an inflammatory perturbation. When human pulmonary artery (PA) endothelial cells deficient in BMPR2 were stimulated with tumor necrosis factor (TNF), a twofold increase in GM-CSF was observed and related to enhanced messenger RNA (mRNA) translation. The mechanism was associated with disruption of stress granule formation. Specifically, loss of BMPR2 induced prolonged phospho-p38 mitogen-activated protein kinase (MAPK) in response to TNF, and this increased GADD34-PP1 phosphatase activity, dephosphorylating eukaryotic translation initiation factor (eIF2α), and derepressing GM-CSF mRNA translation. Lungs from IPAH patients versus unused donor controls revealed heightened PA expression of GM-CSF co-distributing with increased TNF and expanded populations of hematopoietic and endothelial GM-CSF receptor α (GM-CSFRα)-positive cells. Moreover, a 3-wk infusion of GM-CSF in mice increased hypoxia-induced PAH, in association with increased perivascular macrophages and muscularized distal arteries, whereas blockade of GM-CSF repressed these features. Thus, reduced BMPR2 can subvert a stress granule response, heighten GM-CSF mRNA translation, increase inflammatory cell recruitment, and exacerbate PAH.
Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo II/deficiência , Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Hipertensão Pulmonar/etiologia , Adolescente , Adulto , Animais , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/antagonistas & inibidores , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Estudos de Casos e Controles , Criança , Células Endoteliais/metabolismo , Fator de Iniciação 2 em Eucariotos/metabolismo , Hipertensão Pulmonar Primária Familiar , Feminino , Humanos , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/metabolismo , Sistema de Sinalização das MAP Quinases , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Miócitos de Músculo Liso/metabolismo , Biossíntese de Proteínas , Proteína Fosfatase 1/metabolismo , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , Ratos , Ratos Sprague-Dawley , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Adulto JovemRESUMO
Dysfunctional bone morphogenetic protein receptor-2 (BMPR2) signaling is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We used a transcriptional high-throughput luciferase reporter assay to screen 3,756 FDA-approved drugs and bioactive compounds for induction of BMPR2 signaling. The best response was achieved with FK506 (tacrolimus), via a dual mechanism of action as a calcineurin inhibitor that also binds FK-binding protein-12 (FKBP12), a repressor of BMP signaling. FK506 released FKBP12 from type I receptors activin receptor-like kinase 1 (ALK1), ALK2, and ALK3 and activated downstream SMAD1/5 and MAPK signaling and ID1 gene regulation in a manner superior to the calcineurin inhibitor cyclosporine and the FKBP12 ligand rapamycin. In pulmonary artery endothelial cells (ECs) from patients with idiopathic PAH, low-dose FK506 reversed dysfunctional BMPR2 signaling. In mice with conditional Bmpr2 deletion in ECs, low-dose FK506 prevented exaggerated chronic hypoxic PAH associated with induction of EC targets of BMP signaling, such as apelin. Low-dose FK506 also reversed severe PAH in rats with medial hypertrophy following monocrotaline and in rats with neointima formation following VEGF receptor blockade and chronic hypoxia. Our studies indicate that low-dose FK506 could be useful in the treatment of PAH.