RESUMO
BACKGROUND: The survival rate of children with cancer has increased substantially in recent years. Shared decision making (i.e., the ability of children with cancer to express their will and share it with medical personnel) has become a particularly important issue. The nature and developmental processes of children's decision making in hospital should be understood. There is, however, a lack of research in this area. METHODS: From January 2016 to March 2018, we conducted a longitudinal qualitative observational study, within the context of medical anthropology, in a hospital pediatric ward in Japan. We investigated the nature and development of decision making among seven children aged 5-12 years with hematologic cancers. We recorded their everyday behaviors, interactions, narratives, and events in the ward. The recording was conducted systematically and it was analyzed thematically using both variable-oriented and process-oriented modes to assess causal relationships between phenomena. RESULTS: The thematic analysis identified three thematic scenes in which children developed their will regarding cancer treatment: (1) adjusting to hospital life; (2) forming friendships with other children; and (3) communicating with medical personnel. Sharing information, building trusting relationships, and sharing treatment goals with medical personnel were identified as forms of children's participation in medical decision making. Through cultivated friendships, children's peer groups were sources of resilience and strength in overcoming difficulties in hospital life. CONCLUSIONS: The development of children's decision making in a pediatric oncology ward was based on various rich human relationships. Such relationships should be promoted to improve shared decision making substantially.
Assuntos
Tomada de Decisões , Neoplasias , Criança , Humanos , Neoplasias/terapia , Estudos Longitudinais , Pessoal de Saúde , HospitaisRESUMO
Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disorder accompanied by periodic fever and sterile serositis. We report a 5-year-old boy with FMF, who underwent second unrelated cord blood transplantation (CBT) for recurrent familial hemophagocytic lymphohistiocytosis. Periodic attacks of fever and abdominal pain started 6 months after CBT. He was diagnosed with FMF according to the Tel-Hashomer criteria and treated successfully with colchicine. Genetic testing showed heterozygous p.E148Q mutation in the MEFV gene from both donor and recipient cells. Several CBT-related factors including use of an immunosuppressant can potentially be involved in the pathogenesis of FMF in our patient.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Febre Familiar do Mediterrâneo/patologia , Linfo-Histiocitose Hemofagocítica/terapia , Mutação , Pirina/genética , Pré-Escolar , Febre Familiar do Mediterrâneo/etiologia , Humanos , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/patologia , Masculino , PrognósticoRESUMO
A 13-year-old boy developed tetanus, although he had protective antitoxin antibody raised by three doses of tetanus toxoid vaccine. Four days after injury, he presented with muscle rigidity of his posterior neck, excessive diaphoresis, and risus sardonicus and was subsequently diagnosed with tetanus. Tetanus is rare in developed countries, particularly during childhood, but must be promptly diagnosed based on clinical symptoms.
Assuntos
Imunização Passiva , Toxoide Tetânico/imunologia , Tétano/diagnóstico , Vacinação , Adolescente , Anticorpos Antibacterianos/imunologia , Humanos , Injeções Intramusculares , Unidades de Terapia Intensiva Pediátrica , Masculino , Rigidez Muscular , Penicilina G/uso terapêutico , Sudorese , Tétano/prevenção & controle , Tétano/terapia , TrismoRESUMO
BACKGROUND: Immune thrombocytopenic purpura (ITP) is commonly treated with i.v. immunoglobulin (IVIG). METHODS: We retrospectively evaluated whether pretreatment clinical and laboratory finding could predict the short- and long-term response to IVIG. RESULTS: Short-term response was estimated by platelet count 2 weeks after IVIG, and long-term response was assessed on thrombocytopenia-free survival (TFS). TFS was defined as the probability of survival without treatment failure after initial IVIG, such as relapse, requirement for additional therapeutic interventions, or progressing to chronic ITP. Seventy-six patients with newly diagnosed ITP who were initially treated with IVIG were evaluated. Fifty-three patients (69.7%) were determined as responders at 2 weeks after IVIG. On multivariate analysis, age ≥23 months (P = 0.020) and platelet count <9.0 × 109 /L (P = 0.018) were considered to be unfavorable factors for short-term response. Cumulative proportion of long-term (1 year) good prognosis was estimated at 53.0% (95%CI: 40.8-65.2). On multivariate analysis of unfavorable factors for long-term response, age ≥23 months (P = 0.020) was the only significant factor. CONCLUSIONS: For new-onset ITP in patients aged >2 years, corticosteroid therapy in addition to IVIG may be considered as the initial treatment.
Assuntos
Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Adolescente , Biomarcadores/sangue , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Contagem de Plaquetas , Modelos de Riscos Proporcionais , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/diagnóstico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Patients undergoing hematopoietic stem cell transplantation (HSCT) frequently have HHV-6 reactivation typically during the early phase following HSCT. The long-term clinical complications and prognosis, however, remain unclear. METHODS: Between September 2010 and October 2012, whole blood samples from 105 patients collected weekly from prior to 6 weeks after HSCT underwent multiplex polymerase chain reaction (PCR) to screen for viral DNA, followed by real-time PCR for quantitative estimation. In 48 patients, only HHV-6 was detected in at least one sample. In 30 patients, no viral DNA was detected. Long-term clinical records were reviewed in March 2016. All 48 HHV-6-positive patients, and 24 patients in whom no viral DNA detected, were followed up. RESULTS: Median maximum HHV-6 DNA load in the blood of the HHV-6 reactivation group (n = 48) was 11 800 copies/µg peripheral blood leukocyte DNA (range, 52-310 000 000). Hemophagocytic syndrome (HPS) was diagnosed in two subjects with HHV-6 reactivation. Acute graft-versus-host disease (GVHD) developed more frequently in patients with HHV-6 reactivation than in patients without viral reactivation (P = 0.002), but there was no difference in incidence of chronic GVHD. There was no difference in engraftment of neutrophils and platelets between groups. There was also no difference in overall survival between groups. Onset of HPS, however, was associated with lower overall survival (P = 0.009). CONCLUSIONS: Human herpesvirus 6 reactivation was associated with acute GVHD, but not with chronic GVHD, engraftment or overall survival. Onset of HPS, however, predicts lower overall survival.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Herpesvirus Humano 6 , Infecções por Roseolovirus/etiologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Infecções por Roseolovirus/diagnóstico , Infecções por Roseolovirus/imunologia , Taxa de Sobrevida , Adulto JovemRESUMO
Cutaneous polyarteritis nodosa (CPAN) is characterized by a necrotizing vasculitis of small and medium-sized arteries in the skin, which can be associated with fever, arthralgia, myalgia, and neuropathy, but, unlike polyarteritis nodosa (PAN), there is no visceral involvement. CPAN is rare in childhood. We report two siblings who developed CPAN during childhood. Interestingly, both had Mediterranean fever gene (MEFV) mutation, i.e. heterozygous E148Q. They also shared HLA-A24, -DR15 alleles. Simultaneous occurrence of MEFV mutation and HLA alleles with CPAN has never been reported in Japan. These cases could provide some hereditary clue for the development of CPAN.
Assuntos
Antígeno HLA-A24/genética , Poliarterite Nodosa , Pirina/genética , Dermatopatias Vasculares , Tela Subcutânea , Alelos , Criança , Feminino , Heterozigoto , Humanos , Japão , Mutação , Poliarterite Nodosa/diagnóstico , Poliarterite Nodosa/genética , Poliarterite Nodosa/fisiopatologia , Irmãos , Pele/patologia , Dermatopatias Vasculares/diagnóstico , Dermatopatias Vasculares/genética , Dermatopatias Vasculares/fisiopatologia , Tela Subcutânea/irrigação sanguínea , Tela Subcutânea/diagnóstico por imagem , Tela Subcutânea/patologiaRESUMO
Several studies have indicated that viral reactivations following allogeneic hematopoietic stem cell transplantation (allo-HSCT) are frequent, but viral reactivations after autologous HSCT (auto-HSCT) have not been investigated in detail. We performed multiplex polymerase chain reaction (PCR) assay to examine multiple viral reactivations simultaneously in 24 patients undergoing auto-HSCT between September 2010 and December 2012. Weekly whole blood samples were collected from pre- to 42 days post-HSCT, and tested for the following 13 viruses; herpes simplex virus 1 (HSV-1), HSV-2, varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus 6 (HHV-6), HHV-7, HHV-8, adeno virus (ADV), BK virus (BKV), JC virus (JCV), parvovirus B19 (B19V), and hepatitis B virus (HBV). Fifteen (63%) patients had at least one type of viral reactivation. HHV6 (n = 10; 41.7%) was most frequently detected followed by EBV (n = 7; 29.2%). HHV-6 peaked on day 21 after HSCT and promptly declined. In addition, HBV, CMV, HHV7, and B19V were each detected in one patient. HHV6 reactivation was detected in almost half the auto-HSCT patients, which was similar to the incidence in allo-HSCT patients. The incidence of EBV was unexpectedly high. Viral infections in patients undergoing auto-HSCT were higher than previously reported in other studies. Although there were no particular complications of viral infection, we should pay attention to possible viral reactivations in auto-HSCT patients. J. Med. Virol. 89:358-362, 2017. © 2016 Wiley Periodicals, Inc.
Assuntos
Vírus de DNA/isolamento & purificação , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Reação em Cadeia da Polimerase Multiplex , Transplante Autólogo/efeitos adversos , Ativação Viral , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Vírus de DNA/classificação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Adulto JovemRESUMO
BACKGROUND: The seven-valent pneumococcal conjugate vaccine (PCV7) was introduced to Japan in 2009, after which there was a rapid decline in invasive pneumococcal disease. There are few data, however, on the effectiveness of PCV7 against community-acquired pneumonia (CAP). We conducted an ambispective cohort study among children aged 0-6 years old who attended day-care centers. METHODS: A total of 624 children at 10 day-care centers in Sapporo, Japan participated in the study. The parents reported whether their child had received PCV7 one or more times, as well as the exact dates of vaccination from records in maternal and child health handbooks marked by pediatricians. Each CAP event was reported by parents according to doctor diagnosis. A Cox proportional hazards regression model was used to calculate the hazard ratio (HR) and 95%CI of CAP incidence reduced by PCV7 inoculation. RESULTS: During the observational period, 94 subjects contracted CAP. After adjusting for potentially confounding variables, inoculation with PCV7 was significantly associated with a reduced risk of CAP (HR, 0.22; 95%CI: 0.13-0.34). On stratified analysis by age, PCV7 was significantly associated with a reduced risk of CAP in both children aged <3 years (HR, 0.31; 95%CI: 0.14-0.71), and those ≥3 years (HR, 0.20; 95%CI: 0.09-0.43). CONCLUSION: PCV7 is highly effective in reducing the risk of CAP in children attending day-care centers.
Assuntos
Vacina Pneumocócica Conjugada Heptavalente , Pneumonia Pneumocócica/prevenção & controle , Criança , Creches , Pré-Escolar , Infecções Comunitárias Adquiridas/epidemiologia , Infecções Comunitárias Adquiridas/prevenção & controle , Feminino , Inquéritos Epidemiológicos , Humanos , Incidência , Lactente , Recém-Nascido , Japão/epidemiologia , Masculino , Pneumonia Pneumocócica/epidemiologia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Estudos RetrospectivosRESUMO
Viral reactivation following hematopoietic stem cell transplantation (HSCT) can cause various complications especially viral encephalitis. In this prospective study, we investigated the correlation of post-HSCT viral reactivation in blood with CNS dysfunction. We employed a multiplex PCR that detects 13 kinds of viruses as a first-line screening test and real-time PCR for subsequent quantitative evaluation. Five hundred ninety-one whole blood samples were collected from 105 patients from before until 42 days after HSCT. Seven patients developed CNS dysfunction such as altered consciousness. In six of the seven, the multiplex PCR test detected HHV-6 DNA in at least one sample. In contrast, DNA from other viruses, such as CMV, EBV, HHV-7, adenovirus, and HBV was never detected in any of the seven patients throughout the study period. Quantitative measurement of whole blood HHV-6 DNA levels demonstrated four of the six HHV-6 DNA loads were elevated at successive time points during the CNS dysfunction. In addition, the virus DNA peaks were temporally associated with the development of CNS dysfunction. CSF was tested in two of the four patients and high HHV-6 DNA levels comparable to those in whole blood were confirmed in both. These four patients were, thus, suspected to have developed HHV-6 encephalitis, a rate of 3.8% in the study population. Our results suggest that early diagnosis of probable HHV-6 encephalitis can be improved by confirming high HHV-6 DNA load in blood.
Assuntos
DNA Viral/isolamento & purificação , Encefalite Viral/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Herpesvirus Humano 6/isolamento & purificação , Reação em Cadeia da Polimerase Multiplex , Reação em Cadeia da Polimerase em Tempo Real , Infecções por Roseolovirus/epidemiologia , Transplante Homólogo/efeitos adversos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , DNA Viral/genética , Feminino , Herpesvirus Humano 6/genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Carga Viral , Ativação Viral , Adulto JovemRESUMO
Viral reactivations following hematopoietic stem cell transplantation are thought to result from the breakdown of both cell-mediated and humoral immunity. As a result, many viruses could be reactivated individually or simultaneously. Using a multiplex polymerase chain reaction (PCR), we prospectively examined many kinds of viral DNAs at a time in 105 patients who underwent allogeneic hematopoietic stem cell transplantation. In total, 591 whole blood samples were collected weekly from pre- to 42 days post-transplantation and the following 13 viruses were tested; herpes simplex virus 1 (HSV-1), HSV-2, varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpes virus 6 (HHV-6), HHV-7, HHV-8, adenovirus, BK virus (BKV), JC virus (JCV), parvovirus B19, and hepatitis B virus (HBV). Several viral DNAs were detected in 12 patients before hematopoietic stem cell transplantation. The detection rate gradually increased after transplantation and peaked at 21 days. The most frequently detected virus was HHV-6 (n = 63; 60.0%), followed by EBV (n = 11; 10.5%), CMV (n = 11; 10.5%), and HHV-7 (n = 9; 8.6%). Adenovirus and HBV were each detected in one patient (1.0%). Detection of HHV-6 DNA was significantly more common among patients undergoing cord blood transplantation or with steroid treatment. EBV DNA tended to be more common in patients treated with anti-thymocyte globulin. Multiplex PCR was useful for detecting many viral reactivations after hematopoietic stem cell transplantation, simultaneously. Cord blood transplantation, steroid treatment, or anti-thymocyte globulin use was confirmed to be risk factors after transplantation.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hospedeiro Imunocomprometido , Técnicas de Diagnóstico Molecular/métodos , Reação em Cadeia da Polimerase Multiplex/métodos , Transplante Homólogo/efeitos adversos , Ativação Viral , Viroses/diagnóstico , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
Malignant transformation by oncogenes requires additional genetic/epigenetic changes to overcome enhanced susceptibility to apoptosis. In the present study, we report that Bif-1 (Sh3glb1), a gene encoding a membrane curvaturedriving endophilin protein, is a haploinsufficient tumor suppressor that plays a key role in the prevention of chromosomal instability and suppresses the acquisition of apoptosis resistance during Myc-driven lymphomagenesis. Although a large portion of Bif-1deficient mice harboring an Eµ-Myc transgene displayed embryonic lethality, allelic loss of Bif-1 dramatically accelerated the onset of Myc-induced lymphoma. At the premalignant stage, hemizygous deletion of Bif-1 resulted in an increase in mitochondrial mass, accumulation of DNA damage, and up-regulation of the antiapoptotic protein Mcl-1. Consistently, allelic loss of Bif-1 suppressed the activation of caspase-3 in Myc-induced lymphoma cells. Moreover, we found that Bif-1 is indispensable for the autophagy-dependent clearance of damaged mitochondria (mitophagy), because loss of Bif-1 resulted in the accumulation of endoplasmic reticulumassociated immature autophagosomes and suppressed the maturation of autophagosomes. The results of the present study indicate that Bif-1 haploinsufficiency attenuates mitophagy and results in the promotion of chromosomal instability, which enables tumor cells to efficiently bypass the oncogenic/metabolic pressures for apoptosis. .
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Instabilidade Cromossômica/genética , Genes myc/fisiologia , Haploinsuficiência/fisiologia , Linfoma/genética , Mitofagia/genética , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Animais , Apoptose/genética , Apoptose/fisiologia , Transformação Celular Neoplásica/genética , Células Cultivadas , Regulação para Baixo/genética , Feminino , Linfoma/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Regulação para Cima/genéticaRESUMO
RARA rearrangement-negative acute promyelocytic leukemia (APL) is uncommon, and its extramedullary relapse is extremely rare. We report a 5-year-old girl with RARA rearrangement-negative APL, which recurred solely at the external auditory canal and mastoid air cells. She was successfully treated with chemotherapy, local radiotherapy, and unrelated cord blood transplantation. She has maintained complete remission for 24 months after transplantation. The clinical features and our therapeutic strategy in this patient will provide valuable information for extramedullary relapse of RARA rearrangement-negative APL.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Rearranjo Gênico , Leucemia Promielocítica Aguda/terapia , Receptores do Ácido Retinoico/genética , Aloenxertos , Trióxido de Arsênio , Arsenicais/uso terapêutico , Terapia Combinada , Feminino , Humanos , Lactente , Leucemia Promielocítica Aguda/genética , Óxidos/uso terapêutico , Recidiva , Receptor alfa de Ácido RetinoicoRESUMO
In childhood acute myelogenous leukemia, extramedullary tumor is an occasional clinical symptom. However, extramedullary acute megakaryocytic leukemia is extremely rare. Here, we report an extremely rare case of acute megakaryocytic leukemia in a patient who presented with extramedullary tumor of cerebral falx as a first manifestation before the diagnosis of systemic bone marrow leukemia.
Assuntos
Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/patologia , Leucemia Megacarioblástica Aguda/complicações , Leucemia Megacarioblástica Aguda/patologia , Neoplasias Encefálicas/terapia , Feminino , Humanos , Lactente , Leucemia Megacarioblástica Aguda/terapia , PrognósticoAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Diabetes Mellitus Tipo 1/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Corticosteroides/efeitos adversos , Corticosteroides/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Asparaginase/efeitos adversos , Asparaginase/uso terapêutico , Glicemia/análise , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Citarabina/efeitos adversos , Citarabina/uso terapêutico , Dexametasona/efeitos adversos , Dexametasona/uso terapêutico , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Humanos , Hiperglicemia/induzido quimicamente , Hiperglicemia/diagnóstico , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Tioguanina/efeitos adversos , Tioguanina/uso terapêutico , Resultado do Tratamento , Vincristina/efeitos adversos , Vincristina/uso terapêuticoRESUMO
The genetic diversity of the NSP4 gene of rotavirus G1P[8] strains obtained in Sapporo was analyzed, Japan from 1987 to 2000. Sixty-four strains, which were distributed across the whole study period, were included. All G1P[8] NSP4 genes detected in this study belonged to genotype E1, which divided into at least three lineages. The Sapporo rotavirus G1P[8] isolates were found in each lineage. The mean estimated substitution rate was 1.40 × 10(-3) nucleotide substitutions per site per year, which was comparable to that of the G1P[8] VP7 gene. Comparison of the deduced NSP4 amino acid sequences showed genetic diversity at the center of antigenic site II, but not in the enterotoxic domain. This report represents the first investigation of the genetic diversity and evolution of group A rotavirus NSP4 genes in Asia.
Assuntos
Variação Genética , Glicoproteínas/genética , Infecções por Rotavirus/epidemiologia , Infecções por Rotavirus/virologia , Rotavirus/classificação , Rotavirus/genética , Toxinas Biológicas/genética , Proteínas não Estruturais Virais/genética , Criança , Pré-Escolar , Análise por Conglomerados , Evolução Molecular , Genótipo , Humanos , Japão/epidemiologia , Rotavirus/isolamento & purificação , Homologia de SequênciaRESUMO
Sequence analysis of the VP7 gene in 23 group A human rotavirus G2P[4] strains obtained during 1991-2011, that is, the pre-vaccine era, in Sapporo, Japan showed considerable genetic diversity, mainly in variable regions. Recent G2P[4] epidemic strains were located in sublineage IVa with a distinctive substitution of D96N. This study provides background data on the genetic variability of G2P[4] rotavirus-VP7 gene prior to the widespread use of rotavirus vaccines in Japan.
Assuntos
Antígenos Virais/genética , Proteínas do Capsídeo/genética , Gastroenterite/virologia , Variação Genética , Infecções por Rotavirus/virologia , Rotavirus/classificação , Rotavirus/genética , Sequência de Aminoácidos , Gastroenterite/epidemiologia , Genótipo , Humanos , Japão/epidemiologia , Estudos Longitudinais , Epidemiologia Molecular , Rotavirus/isolamento & purificação , Infecções por Rotavirus/epidemiologia , Alinhamento de SequênciaRESUMO
Neuroblastoma is a malignant tumor predominantly occurring in children and usually arising from the adrenal gland or sympathetic ganglia. We describe a neuroblastoma in a 1-month-old boy arising from his left orbital cavity. This tumor was refractory to chemotherapy or radiotherapy, requiring enucleation of the left eye for complete removal of the intraorbital tumor. Thereafter, he received high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation, and has been in complete remission for 3 years. Unlike neuroblastomas arising from the adrenal gland or sympathetic ganglia, primary orbital neuroblastoma may be refractory even in early infancy.
Assuntos
Medula Óssea/patologia , Estadiamento de Neoplasias/métodos , Neuroblastoma/diagnóstico , Neoplasias Orbitárias/diagnóstico , Biópsia , Diagnóstico Diferencial , Humanos , Recém-Nascido , Masculino , Tomografia Computadorizada por Raios XRESUMO
Autophagy and apoptosis are two evolutionarily conserved processes that regulate cell fate in response to cytotoxic stress. However, the functional relationship between these two processes remains far from clear. Here, we demonstrate an autophagy-dependent mechanism of caspase-8 activation and initiation of the apoptotic cascade in response to SKI-I, a pan-sphingosine kinase inhibitor, and bortezomib, a proteasome inhibitor. Autophagy is induced concomitantly with caspase-8 activation, which is responsible for initiation of the caspase cascade and the mitochondrial amplification loop that is required for full execution of apoptosis. Inhibition of autophagosome formation by depletion of Atg5 or Atg3 results in a marked suppression of caspase-8 activation and apoptosis. Although caspase-8 self-association depends on p62/SQSTM1, its self-processing requires the autophagosomal membrane. Caspase-8 forms a complex with Atg5 and colocalizes with LC3 and p62. Moreover, FADD, an adaptor protein for caspase-8 activation, associates with Atg5 on Atg16L- and LC3-positive autophagosomal membranes and loss of FADD suppresses cell death. Taken together, these results indicate that the autophagosomal membrane serves as a platform for an intracellular death-inducing signaling complex (iDISC) that recruits self-associated caspase-8 to initiate the caspase-8/-3 cascade.