RESUMO
Anemia is the predominant clinical manifestation of myelodysplastic syndromes (MDS). Loss or deletion of chromosome 7 is commonly seen in MDS and leads to a poor prognosis. However, the identity of functionally relevant, dysplasia-causing, genes on 7q remains unclear. Dedicator of cytokinesis 4 (DOCK4) is a GTPase exchange factor, and its gene maps to the commonly deleted 7q region. We demonstrate that DOCK4 is underexpressed in MDS bone marrow samples and that the reduced expression is associated with decreased overall survival in patients. We show that depletion of DOCK4 levels leads to erythroid cells with dysplastic morphology both in vivo and in vitro. We established a novel single-cell assay to quantify disrupted F-actin filament network in erythroblasts and demonstrate that reduced expression of DOCK4 leads to disruption of the actin filaments, resulting in erythroid dysplasia that phenocopies the red blood cell (RBC) defects seen in samples from MDS patients. Reexpression of DOCK4 in -7q MDS patient erythroblasts resulted in significant erythropoietic improvements. Mechanisms underlying F-actin disruption revealed that DOCK4 knockdown reduces ras-related C3 botulinum toxin substrate 1 (RAC1) GTPase activation, leading to increased phosphorylation of the actin-stabilizing protein ADDUCIN in MDS samples. These data identify DOCK4 as a putative 7q gene whose reduced expression can lead to erythroid dysplasia.
Assuntos
Eritroblastos/metabolismo , Proteínas Ativadoras de GTPase/biossíntese , Regulação da Expressão Gênica , Síndromes Mielodisplásicas/metabolismo , Actinas/genética , Actinas/metabolismo , Animais , Proteínas de Ligação a Calmodulina/genética , Proteínas de Ligação a Calmodulina/metabolismo , Eritroblastos/patologia , Feminino , Proteínas Ativadoras de GTPase/genética , Humanos , Masculino , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
PURPOSE: Dental professionals are strategically placed to be the leaders in tobacco prevention and cessation as they provide preventive and therapeutic services to a basically healthy population on a regular basis. The objective of this study was to assess the tobacco cessation knowledge, attitudes and behaviours of dental practitioners in Kochi (Cochin), Kerala, India. MATERIALS AND METHODS: A sampling frame of dentists enrolled in the Indian Dental Association (IDA), Kochi (Cochin) branch, practising in Ernakulam city, was obtained from the IDA. The letter describing the rationale for the study contained a 35-item pre-tested questionnaire and was personally delivered along with a stamped envelope. One hundred fourteen dentists returned a usable questionnaire. Data were entered and analysed using SPSS 12. Frequencies were calculated for all variables. RESULTS: Based on the responding dentists' self-reports, 54.6% were not confident in tobacco cessation counselling, 10.6% never asked, 60.9% asked in 50% of their patients about tobacco use and 17.6% of the dentists surveyed were smokers themselves. Participating dentists perceived that they were interested in using tobacco cessation counselling, but were not sure of quitting rates in their patients. The average time spent counselling patients about tobacco cessation was less than 2 minutes. CONCLUSION: The dentists perceived that lack of formal training leads to less motivation about tobacco counselling and hence infrequently incorporated tobacco cessation into their dental practices. The cessation of tobacco habits among dentists is essential.