Deep Sequencing of MYC DNA-Binding Sites in Burkitt Lymphoma

BACKGROUND: MYC is a key transcription factor involved in central cellular processes such as regulation of the cell cycle, histone acetylation and ribosomal biogenesis. It is overexpressed in the majority of human tumors including aggressive B-cell lymphoma. Especially Burkitt lymphoma (BL) is a highlight example for MYC overexpression due to a chromosomal translocation involving the c-MYC gene. However, no genome-wide analysis of MYC-binding sites by chromatin immunoprecipitation (ChIP) followed by next generation sequencing (ChIP-Seq) has been conducted in BL so far. METHODOLOGY/PRINCIPAL FINDINGS: ChIP-Seq was performed on 5 BL cell lines with a MYC-specific antibody giving rise to 7,054 MYC-binding sites after bioinformatics analysis of a total of approx. 19 million sequence reads. In line with previous findings, binding sites accumulate in gene sets known to be involved in the cell cycle, ribosomal biogenesis, histone acetyltransferase and methyltransferase complexes demonstrating a regulatory role of MYC in these processes. Unexpectedly, MYC-binding sites also accumulate in many B-cell relevant genes. To assess the functional consequences of MYC binding, the ChIP-Seq data were supplemented with siRNA- mediated knock-downs of MYC in BL cell lines followed by gene expression profiling. Interestingly, amongst others, genes involved in the B-cell function were up-regulated in response to MYC silencing. CONCLUSION/SIGNIFICANCE: The 7,054 MYC-binding sites identified by our ChIP-Seq approach greatly extend the knowledge regarding MYC binding in BL and shed further light on the enormous complexity of the MYC regulatory network. Especially our observations that (i) many B-cell relevant genes are targeted by MYC and (ii) that MYC down-regulation leads to an up-regulation of B-cell genes highlight an interesting aspect of BL biology

Cuidados nos pacientes com hemofilia e doença de von Willebrand na cirurgia eletiva otorrinolaringológica Otolaryngology surgery: management of elective surgery in patients with haemophilia and von Willebrand disease

FORMA DE ESTUDO Clínico prospectivo. MATERIAL E MÉTODO: Foi realizado um estudo prospectivo de 10 anos de 20 pacientes com hemofilias ou doença de von Willebrand (DvW) com indicação de cirurgia otorrinolaringológica. Os pacientes foram submetidos a um total de 25 cirurgias otorrinolaringológicas eletivas. A idade média foi de 23,75 anos (2 a 62 anos). O grupo de estudo consistiu em 14 hemofílicos, 11 com hemofilia A grave (1 do sexo feminino), uma portadora com 30% de atividade de fator VIII (FVIII), um hemofílico B leve e uma com deficiência grave de fator X; 6 com DvW, 4 tinham o tipo 1 (3 mulheres), um o tipo 2A e um o tipo 3. Treze hemofílicos tinham síndrome de imunodeficiência adquirida. A duração média do procedimento foi de 1 hora e 37 minutos (15 minutos a 12 horas). O defeito da coagulação foi corrigido com desmopressina (DDAVP), com concentrado de FVIII de pureza intermediária 8Y, com criopreciptado ou com complexo protrombínico não ativado (PPSB), de acordo com os níveis plasmáticos do fator e da severidade da cirurgia. O ácido épsilon aminocapróico também foi usado em associação. Em 1 hemofílico A grave houve sangramento pós-operatório que se resolveu com a elevação do nível mínimo de FVIII para 80% e em 1 paciente com DvW do Tipo 3 houve sangramento pós-operatório pela dificuldade de identificação do melhor concentrado a ser reposto. Após o uso do concentrado de pureza intermediária 8Y, houve controle do sangramento. RESULTADO: Todos os outros pacientes apresentaram a hemostasia considerada normal ou excelente. CONCLUSÃO: Concluiu-se que pacientes com hemofilias ou DvW não apresentam um risco cirúrgico aumentado se for realizada uma terapia adequada.<br>STUD DESIGN: Clinical prospective. MATERIAL AND METHOD: A 10-year prospective research was conducted in 20 patients with hemophilia or von Willebrand disease (vWD). They were submitted to a total of 25 elective otolaryngological surgical events. The average age of the patients was 23.75 years (2-62 years). The study group consisted of 14 hemophiliacs, 11 with severe hemophilia A (1 female), 1 female with 30% of VIII factor (VIIIF) level, 1 male with hemophilia B and 1 female with severe factor X deficiency; and 6 with vWD, 4 type 1 (3 females), 1 male type 2 A and 1 male type 3. Acquired immunodeficiency syndrome was present in 13 hemophilic patients. The mean duration of the surgical events was 1 hour and 37 minutes (15 min-12 hours). The coagulation defect was corrected with desmopressin (DDAVP), intermediate purity VIIIF concentrate 8Y, cryoprecipitated or non-activated prothrombinic complex (PPSB), according to factor levels and the severity of the surgery. Epsilon aminocaproic acid was used in association. In 1 severe hemophiliac A patient, excessive bleeding was observed in the second day of the postoperative period which ceased with elevation of the minimal level of VIIIF to 80%. In another patient, with type 3 vWD, severe postoperative bleeding occurred because of difficulty to identify the best reposition blood coagulation factor for him. After the use of intermediate purity VIIIF concentrate 8Y, the bleeding was controlled. RESULTS: The hemostatic effect in the other patients was rated as normal or excellent. CONCLUSION: It was concluded that patients with vWD or hemophilia do not have an increased operative risk if appropriate therapy is given