Aberrant methylation in promoter-associated CpG islands has been recognized as a major mechanism for tumor suppressor gene silencing in several malignancies. We determined the methylation status of nine tumor suppressor genes in 68 newly diagnosed MM patients by methylation-specific PCR. The frequency of promoter hypermethylation for individual genes was: CDH1, 50%; p16 INK4a , 42.8%; p15 INK4b , 16.2%; SHP1, 14.7%; ER and BNIP3, 13.2%; RARb, 11.8%; DAPK 5.9%; and MGMT 0%. Overall, 79% of patients presented at least one hypermethylated gene. By univariate analysis, hypermethylation of DAPK (P \ 0.001) and RARb (P = 0.01) genes were identified as adverse prognostic features. Median OS of patients with hypermethylation in DAPK (4 months) and RARb (34 months) was significantly lower than in patients without hypermethylation (median survival not reached), with values of P \ 0.001 and P = 0.01, respectively. Our data suggest that DAPK and RARb hypermethylation are adverse prognostic factors in MM. The relevance of these findings as poor prognosis indicators requires confirmation in a larger sample with longer follow-ups.
-We evaluated the frequency, demographic, clinical, disability evolution and genetic association of HLA DRB1*1501, DRB1*1503, DQA1*0102, DQB1*0602 and DPA1*0301 alleles in patients diagnosed as acute disseminated encephalomyelitis (ADEM) among a population of CNS demyelinating diseases. Fifteen patients (8.4%) of our series were diagnosed as ADEM. The mean age onset was 35.23 years (range 12 to 77), 53.3% were male and follow-up range was 8.5 to 16 years. Two cases (13.3%) had a preceding infection before neurological symptoms, one presented a parainfectious demyelinating, and one case had been submitted to hepatitis B vaccination four weeks before the clinical onset. The EDSS range was 3.0 to 9.5. Eight patients (53.3%) presented MRI with multiple large lesions. CSF was normal in 73.3%. The severe disability observed at EDSS onset improved in 86.66% patients. The genetic susceptibility for ADEM was significantly associated with the HLA DQB1*0602, DRB1*1501 and DRB1*1503 alleles (<0.05) in monophasic ADEM.KEy WoRDS: ADEM, HLA class II, demyelinating disease.Encefalomielite aguda disseminada: características clínicas e estudo de associação com os alelos HLA DRB1*1501, HLA DRB1*1503, HLA DQA1*0102, HLA DQB1*0602 e DPA1*0301Resumo -Avaliamos as frequencia, características demográficas, clínicas e de associação genética dos alelos HLA DRB1*1501, DRB1*1503, DQA1*0102, DQB1*0602 e DPA1*0301 em pacientes com diagnóstico de encefalomielite aguda disseminada (ADEM) em população com doença desmielinizante do SNC. Quinze (8,4%) pacientes de nossa série foram diagnosticados como ADEM. A média de idade foi 35,23 anos (variando entre 12 e 77), 53,3% eram homens e o tempo de acompanhamento variou entre 8,5 e 16 anos. Dois casos (13,3%) apresentaram infecção prévia, um apresentou processo desmielinizante para infeccioso e outro havia se submetido a vacinação para hepatite B quatro semanas antes. o EDSS variou entre 3,0 e 9,5. oito pacientes (53,3%) apresentaram grandes lesões na RM. o LCR foi normal em 73,3%. A incapacidade grave quantificada pelo EDSS foi seguida de melhora importante em 86,6% dos pacientes. A susceptibilidade genética na ADEM foi significativamente associada com os alelos HLA DQB1*0602, DRB1*1501 e DRB1*1503 (p<0,05) nos pacientes com quadro monofásico. PALAVRAS-CHAVE: ADEM, HLA classe II, doenças desmielinizantes.
The genetic events associated with transformation of myeloproliferative neoplasms (MPNs) to secondary acute myeloid leukemia (sAML), particularly in the subgroup of essential thrombocythemia (ET) patients, remain incompletely understood. Deep studies using high-throughput methods might lead to a better understanding of genetic landscape of ET patients who transformed to sAML. We performed array-based comparative genomic hybridization (aCGH) and whole exome sequencing (WES) to analyze paired samples from ET and sAML phases. We investigated five patients with previous history of MPN, which four had initial diagnosis of ET (one case harboring JAK2 p.Val617Phe and the remaining three CALR type II p.Lys385fs*47), and one was diagnosed with MPN/myelodysplastic syndrome with thrombocytosis (SF3B1 p.Lys700Glu). All were homogeneously treated with hydroxyurea, but subsequently transformed to sAML (mean time of 6 years/median of 4 years to transformation). Two of them have chromosomal abnormalities, and both acquire 2p gain and 5q deletion at sAML stage. The molecular mechanisms associated with leukemic progression in MPN patients are not clear. Our WES data showed TP53 alterations recurrently observed as mutations (missense and frameshift) and monoallelic loss. On the other hand, aCGH showed novel chromosome abnormalities (+2p and del5q) potentially associated with disease progression. The results reported here add valuable information to the still fragmented molecular basis of ET to sAML evolution. Further studies are necessary to identify minimal deleted/amplified region and genes relevant to sAML transformation.
Aberrant methylation in promoter-associated CpG islands has been recognized as a major mechanism for silencing tumor suppressor genes in many malignant diseases. In multiple myeloma (MM), a limited number of studies of gene methylation have been reported, with conflicting results. We determined the methylation status of 9 suppressor tumor genes in 68 newly diagnosed MM patients by methylation specific PCR (MSP). Ten DNA of normal healthy donors were used as controls. The target genes chosen are involved in many cellular pathways as DNA repair (MGMT), cell cycle regulation (p15INK4b and p16INK4a), cell-cell adherence (E-cadherin), apoptosis (DAP-k and BNIP3), hormonal response (RARb and ER) and Jak/STAT3 signaling pathway (SHP1). An association between hypermethylation and loss of expression of these genes has been demonstrated. The correlation between methylation status and risk factors was assessed by Fisher exact test or Chi-square test (categorical variables) or Student’s t-test (continuous variables). Overall survival (OS) was estimated using the Kaplan-Meier method. Differences between survival curves were estimated by the log-rank test. Multivariate analysis of factors associated with OS was performed by Cox regression. With a median follow-up of 15.5 months, 16 patients died (23%). Healthy donor samples were negative for methylation in all 9 genes tested. Hypermethylation was detected in 50% of patients for E-cadherin, 43% for p16, 16% for p15, 15% for SHP1, 13% for ER and BNIP3, 12% for RARb, 6% for DAP-k, and 0% for MGMT. Overall, 54 patients (79%) presented at least one hypermethylated gene (1 in 19 patients, 2 in 17 patients, 3 in 12 patients, 4 in 5 patients, and 5 in 1 patient). By univariate analysis, hypermethylation of DAP-k (p<0.001) and RARb (p=0.01) genes, platelet counts <100,000/mm3 (p<0.001) and serum calcium >9.5 mg/dL (p=0.03) were identified as adverse prognostic features. The median OS of patients with hypermethylation in DAP-k (4 months) and RARb (34 months) were considerably lower compared to patients without aberrant methylation (median survival not reached, p<0.001 and p=0.01, respectively). Patients with hypermethylation of DAP-k were more likely to have a serum creatinine >2.0 mg/dL (p=0.006), serum calcium >9.5 mg/dL (p=0.05), and Durie-Salmon stage III (p=0.04). No correlation was observed between methylation status of any gene and the presence of chromosome 13 abnormalities, t(4;14)(p16;q32), or t(11;14)(q23;q32). By multivariate analysis, hypermethylation of DAP-k (odds ratio [OR] 5.56, 95% confidence interval [95% CI] 1.4 – 22, p=0.01) and platelet counts <100,000/mm3 (OR 4.13, 95% CI 1.32 – 12.8, p=0.01) were associated with poor prognosis. Our data suggest that hypermethylation of DAP-k is an independent prognostic factor in MM. The impact of these features in identifying a group of poor prognosis beyond the classical prognostic factors warrants a higher sample size and longer follow-up.
Este estudo procura traçar um panorama sobre o tema câncer na mídia brasileira on-line e impressa. Foram analisadas 195 reportagens de 54 diferentes jornais das regiões Norte, Nordeste, Sudeste, Centro-Oeste e Sul, entre os anos 2003 e 2005. Vários aspectos foram observados durante a análise, dentre os quais foram verificados: se as produções das reportagens foram realizadas por jornalistas brasileiros ou se eram originárias de agências de notícias internacionais; quais os tumores malignos foram mais noticiados; qual o enfoque principal das matérias: prevenção, diagnóstico, tratamento, epidemiologia e/ou cura; o uso de fenômenos de linguagem como as analogias para explicar determinados processos; a seriedade no tratamento dos temas versus os erros mais freqüentes cometidos por jornalistas; e a referência a periódicos internacionais e nacionais nos estudos divulgados.
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