RESUMO
We conducted a retrospective audit of the outcomes of patients 15 years of age and older from the greater Auckland region who had a diagnosis of encephalitis over a five-year period. Patients were identified via a database search of all patients who had a cerebrospinal fluid (CSF) viral polymerase chain reaction (PCR) panel requested between 2005 and 2009. All CSF viral PCR were performed at one laboratory. This test was used as a default marker for patients who may have had encephalitis. There were 37 patients who met our definition of encephalitis during the study. Their ages ranged from 15 to 88 years (median 51 years), and 59% were female. There was an admission rate of 7.4 admissions per year or an annual incidence of approximately 0.5 cases per 100,000. An infective cause was found in 10 patients (27%): varicella zoster in five patients (14%), herpes simplex in four (11%) and enterovirus in one patient (3%). An autoimmune paraneoplastic encephalitis was felt most likely in three patients (8%); a paraneoplastic antibody screen was performed in two of these three but was negative in both. The cause of encephalitis was not identified in the other 24 patients (65%). There were five deaths (in-hospital mortality rate 14%). Encephalitis is an uncommon but important disease, because of the significant mortality. The cause of encephalitis remained undetermined in two-thirds of patients.
Assuntos
Encefalite/epidemiologia , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/epidemiologia , Encefalite/etiologia , Encefalite/mortalidade , Encefalite Viral/epidemiologia , Feminino , Mortalidade Hospitalar , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Síndromes Paraneoplásicas/epidemiologia , Síndromes Paraneoplásicas/etiologia , Síndromes Paraneoplásicas/mortalidade , Reação em Cadeia da Polimerase , Estudos Retrospectivos , Adulto JovemRESUMO
Directed by microarray analyses, we report that autocrine human growth hormone (hGH) increased the mRNA and protein expression of DNA methyltransferase 1 (DNMT1), DNMT3A and DNMT3B in mammary carcinoma cells. Autocrine hGH stimulation of DNMT3A and DNMT3B expression was mediated by JAK2 and Src kinases, and treatment of mammary carcinoma cells with the DNMT inhibitor, 5'-aza-2'-deoxycytidine (AZA), abrogated autocrine hGH-stimulated cellular proliferation, apoptosis and anchorage-independent growth. AZA reversed the epitheliomesenchymal transition of mammary carcinoma cells induced by autocrine hGH, to an epithelioid morphology and abrogated cell migration stimulated by autocrine hGH. Autocrine hGH-stimulated hypermethylation of the first exon of the PLAKOGLOBIN gene and AZA abrogated the ability of autocrine hGH to repress plakoglobin gene transcription. Small interfering RNA (siRNA)-mediated depletion of the individual DNMT molecules did not release autocrine hGH repression of PLAKOGLOBIN promoter activity nor did individual DNMT depletion affect autocrine hGH-stimulated migration. However, concomitant siRNA-mediated depletion of both DNMT3A and DNMT3B abrogated hypermethylation of the PLAKOGLOBIN gene stimulated by autocrine hGH and subsequent repression of plakoglobin gene transcription and increased cell migration. Thus, the autocrine hGH-stimulated increases in DNMT3A and DNMT3B expression mediate repression of plakoglobin gene transcription by direct hypermethylation of its promoter and consequent phenotypic conversion of mammary carcinoma cells. Autocrine hGH, therefore, utilizes DNA methylation as a mechanism to exert its oncogenic effects in mammary carcinoma cells.
Assuntos
Comunicação Autócrina , Neoplasias da Mama/metabolismo , DNA (Citosina-5-)-Metiltransferases/biossíntese , Hormônio do Crescimento/metabolismo , Proteínas de Neoplasias/biossíntese , gama Catenina/biossíntese , Antimetabólitos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Comunicação Autócrina/efeitos dos fármacos , Comunicação Autócrina/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Monofosfato de Citidina/análogos & derivados , Monofosfato de Citidina/farmacologia , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA/efeitos dos fármacos , DNA Metiltransferase 3A , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Hormônio do Crescimento/antagonistas & inibidores , Hormônio do Crescimento/genética , Humanos , Proteínas de Neoplasias/genética , Fenótipo , Regiões Promotoras Genéticas/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , RNA Interferente Pequeno/genética , gama Catenina/genética , DNA Metiltransferase 3BRESUMO
By a combination of cDNA library screening, rapid amplification of cDNA ends analysis, and BAC sequencing, a novel human patched-like gene (PTCH2) has been cloned and sequenced. The genomic organization is similar to PTCH1 with 22 exons and, by radiation hybrid mapping, PTCH2 has been localized to chromosome 1p33-34, a region often lost in a variety of tumors. Several alternatively spliced mRNA forms of PTCH2 were identified, including transcripts lacking segments thought to be involved in sonic hedgehog binding and mRNAs with differentially defined 3' terminal exons. In situ hybridization revealed high expression of PTCH2 transcripts in both familial and sporadic basal cell carcinomas in similarity to what has been observed for PTCH1, suggesting a negative regulation of PTCH2 by PTCH1. This finding tightly links PTCH2 with the sonic hedgehog/PTCH signaling pathway, implying that PTCH2 has related, but yet distinct, functions than PTCH1.