RESUMO
The spread of epileptic seizure activity to brainstem respiratory and autonomic regions can elicit episodes of obstructive apnea and of central apnea with significant oxygen desaturation and bradycardia. Previously, we argued that central apneic events were not consequences of respiratory or autonomic activity failure, but rather an active brainstem behavior equivalent to the diving response resulting from seizure spread. To test the similarities of spontaneous seizure-associated central apneic episodes to evoked diving responses, we used nasopharyngeal irrigation with either cold water or mist for 10 or 60â¯s to elicit the diving response in urethane-anesthetized animals with or without kainic acid-induced seizure activity. Diving responses included larger cardiovascular changes during mist stimuli than during water stimuli. Apneic responses lasted longer than 10â¯s in response to 10â¯s stimuli or about 40â¯s in response to 60â¯s stimuli, and outlasted bradycardia. Repeated 10â¯s mist applications led to an uncoupling of the apneic episodes (which always occurred) from the bradycardia (which became less pronounced with repetition). These uncoupled events matched the features of observed spontaneous seizure-associated central apneic episodes. The duration of spontaneous central apneic episodes correlated with their frequency, i.e. longer events occurred when there were more events. Based on our ability to replicate the properties of seizure-associated central apneic events with evoked diving responses during seizure activity, we conclude that seizure-associated central apnea and the diving response share a common neural basis and may reflect an attempt by brainstem networks to protect core physiology during seizure activity.
Assuntos
Reflexo de Mergulho/fisiologia , Convulsões/complicações , Apneia do Sono Tipo Central/etiologia , Apneia do Sono Tipo Central/fisiopatologia , Animais , Fenômenos Fisiológicos Cardiovasculares , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Respiratory derangements, including irregular, tachypnic breathing and central or obstructive apnea can be consequences of seizure activity in epilepsy patients and animal models. Periods of seizure-associated central apnea, defined as periods >1s with rapid onset and offset of no airflow during plethysmography, suggest that seizures spread to brainstem respiratory regions to disrupt breathing. We sought to characterize seizure-associated central apneic episodes as an indicator of seizure impact on the respiratory rhythm in rats anesthetized with urethane and given parenteral kainic acid to induce recurring seizures. We measured central apneic period onsets and offsets to determine if onset-offset relations were a consequence of 1) a reset of the respiratory rhythm, 2) a transient pausing of the respiratory rhythm, resuming from the pause point at the end of the apneic period, 3) a transient suppression of respiratory behavior with apnea offset predicted by a continuation of the breathing pattern preceding apnea, or 4) a random re-entry into the respiratory cycle. Animals were monitored with continuous ECG, EEG, and plethysmography. One hundred ninety central apnea episodes (1.04 to 36.18s, mean: 3.2±3.7s) were recorded during seizure activity from 7 rats with multiple apneic episodes. The majority of apneic period onsets occurred during expiration (125/161 apneic episodes, 78%). In either expiration or inspiration, apneic onsets tended to occur late in the cycle, i.e. between the time of the peak and end of expiration (82/125, 66%) or inspiration (34/36, 94%). Apneic period offsets were more uniformly distributed between early and late expiration (27%, 34%) and inspiration (16%, 23%). Differences between the respiratory phase at the onset of apnea and the corresponding offset phase varied widely, even within individual animals. Each central apneic episode was associated with a high frequency event in EEG or ECG records at onset. High frequency events that were not associated with flatline plethysmographs revealed a constant plethysmograph pattern within each animal, suggesting a clear reset of the respiratory rhythm. The respiratory rhythm became highly variable after about 1s, however, accounting for the unpredictability of the offset phase. The dissociation of respiratory rhythm reset from the cessation of airflow also suggested that central apneic periods involved activation of brainstem regions serving the diving reflex to eliminate the expression of respiratory movements. This conclusion was supported by the decreased heart rate as a function of apnea duration. We conclude that seizure-associated central apnea episodes are associated with 1) a reset of the respiratory rhythm, and 2) activation of brainstem regions serving the diving reflex to suppress respiratory behavior. The significance of these conclusions is that these details of seizure impact on brainstem circuitry represent metrics for assessing seizure spread and potentially subclassifying seizure patterns.
Assuntos
Reflexo de Mergulho/fisiologia , Respiração , Convulsões/fisiopatologia , Animais , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Eletrocardiografia , Eletroencefalografia , Frequência Cardíaca/fisiologia , Ácido Caínico , Masculino , Pletismografia , Ratos Sprague-Dawley , Apneia do Sono Tipo CentralRESUMO
Seizure spread into the autonomic nervous system can result in life-threatening cardiovascular and respiratory dysfunction. Here we report on a less-studied consequence of such autonomic derangements-the possibility of laryngospasm and upper-airway occlusion. We used parenteral kainic acid to induce recurring seizures in urethane-anesthetized Sprague Dawley rats. EEG recordings and combinations of cardiopulmonary monitoring, including video laryngoscopy, were performed during multi-unit recordings of recurrent laryngeal nerve (RLN) activity or head-out plethysmography with or without endotracheal intubation. Controlled occlusions of a tracheal tube were used to study the kinetics of cardiac and respiratory changes after sudden obstruction. Seizure activity caused significant firing increases in the RLN that were associated with abnormal, high-frequency movements of the vocal folds. Partial airway obstruction from laryngospasm was evident in plethysmograms and was prevented by intubation. Complete glottic closure (confirmed by laryngoscopy) occurred in a subset of non-intubated animals in association with the largest increases in RLN activity, and cessation of airflow was followed in all obstructed animals within tens of seconds by ST-segment elevation, bradycardia, and death. Periods of central apnea occurred in both intubated and non-intubated rats during seizures for periods up to 33s and were associated with modestly increased RLN activity, minimal cardiac derangements, and an open airway on laryngoscopy. In controlled complete airway occlusions, respiratory effort to inspire progressively increased, then ceased, usually in less than 1min. Respiratory arrest was associated with left ventricular dilatation and eventual asystole, an elevation of systemic blood pressure, and complete glottic closure. Severe laryngospasm contributed to the seizure- and hypoxemia-induced conditions that resulted in sudden death in our rat model, and we suggest that this mechanism could contribute to sudden death in epilepsy.
Assuntos
Morte Súbita , Laringismo/fisiopatologia , Convulsões/fisiopatologia , Apneia do Sono Tipo Central/fisiopatologia , Apneia Obstrutiva do Sono/fisiopatologia , Animais , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Parada Cardíaca/etiologia , Parada Cardíaca/fisiopatologia , Hipóxia/etiologia , Hipóxia/fisiopatologia , Isquemia/etiologia , Isquemia/fisiopatologia , Ácido Caínico , Nervos Laríngeos/fisiopatologia , Laringismo/complicações , Masculino , Movimento/fisiologia , Ratos Sprague-Dawley , Convulsões/complicações , Apneia do Sono Tipo Central/complicações , Apneia Obstrutiva do Sono/complicações , Prega Vocal/fisiopatologiaAssuntos
Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Melfalan/administração & dosagem , Condicionamento Pré-Transplante , Vidarabina/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Aloenxertos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Vidarabina/administração & dosagemRESUMO
We quantitatively assessed the expression of cytokine receptors (interleukin-2 receptor (IL-2R), IL-3R, IL-4R, IL-5R, IL-6R, IL-7R, granulocyte-macrophage colony-stimulating factor R (GM-CSFR), G-CSFR, c-fms, c-mpl, c-kit and FLT3) in cells from 211 adults with acute lymphoblastic leukemia (ALL) by flow cytometry and determined their prevalence and clinical significance. Although all cytokine receptors were expressed to various degrees, the levels of IL-3R alpha-chain (IL-3Ralpha), IL-2Ralpha, IL-2Rbeta, IL-7Ralpha, common-Rgamma(gammac), c-mpl, c-kit and FLT3 exhibited a wide spectrum > or =2000 sites/cell. Among them, IL-3Ralpha, IL-2Ralpha and FLT3 were highly expressed in B-lineage ALL, whereas IL-7Ralpha, gammac and c-kit predominated in T-lineage ALL. Higher levels of IL-3Ralpha, IL-2Ralpha, c-kit and FLT3 correlated with the expression of CD13/33. Increased IL-2Ralpha levels related to the presence of Philadelphia chromosome (Ph), leukocytosis and shorter event-free survival (EFS). C-kit preferred in male. Elevated FLT3 levels correlated with age > or =60 years. Multivariate analysis in B-lineage ALL revealed only IL-2Ralpha (P=0.028) and Ph (P=0.020) as independent factors for EFS. These findings suggest that several cytokine receptors associated with certain cellular and clinical features, but IL-2Ralpha solely had a prognostic value and should be considered as a major prognostic factor for adult ALL that is comparable with Ph.
Assuntos
Subunidade alfa de Receptor de Interleucina-2/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Adulto , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Receptores de Interleucina/genéticaRESUMO
Adult T-cell leukaemia/lymphoma (ATLL) is a highly aggressive haematological malignancy. More than 40 cases of ATLL treated by allogeneic bone marrow transplantation (BMT) from sibling donors have been reported, while there have been only a few cases of unrelated BMT for treatment of this disease. We began performing allogeneic BMT from unrelated donors in 1999 to improve the outcome of ATLL patients with no suitable sibling donors. Eight ATLL patients underwent unrelated BMT; five received the conventional conditioning regimen consisting of cyclophosphamide and total body irradiation, while three received a reduced-intensity preparative regimen. Two patients died due to encephalopathy of unknown aetiology on days 10 and 35, and one patient died due to progression of ATLL 25 months after BMT. Five patients are currently alive and disease-free at a median of 20 months after BMT. Proviral human T-lymphotropic virus type-I (HTLV-I) DNA load in peripheral blood mononuclear cells (PBMCs) was assessed in four cases before and after BMT. HTLV-I proviral DNA load was reduced significantly after transplantation. Unrelated BMT is feasible for treatment of ATLL. Further studies in a larger number of cases are required to determine the optimal conditioning regimen and stem cell source.
Assuntos
Transplante de Medula Óssea , Leucemia-Linfoma de Células T do Adulto/terapia , Doadores Vivos , Condicionamento Pré-Transplante , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Feminino , Teste de Histocompatibilidade , Humanos , Leucemia-Linfoma de Células T do Adulto/sangue , Leucemia-Linfoma de Células T do Adulto/mortalidade , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/administração & dosagem , Estudos Retrospectivos , Transplante Homólogo , Irradiação Corporal Total/métodosRESUMO
Fourteen adult patients with haematological malignancies (eight non-Hodgkin's lymphoma, one multiple myeloma, one chronic lymphocytic leukaemia, two acute lymphoblastic leukaemia and two acute myeloid leukaemia) developed acute interstitial pneumonitis (IP) during the course of chemotherapy. All patients manifested high fever over 38 degrees C, bilateral diffuse pulmonary interstitial infiltrates in the chest radiograph and severe hypoxia without hypercapnia in the arterial blood gas analysis. Pathogenic microorganisms were not detected in repeated examinations in any patient. Chemotherapy given included various anti-neoplastic drugs. Five patients had received granulocyte colony-stimulating factor (G-CSF) for chemotherapy-induced leucopenia. The onset was associated with an increase of leucocytes in 10 patients. All patients were treated with high dose steroid hormone and broad spectrum antibiotics with or without anti-fungal agents, and three required mechanical ventilation. Eleven patients quickly recovered from these situations, whereas three died. Autopsies were done in two patients and disclosed pneumocystis carinii (PC) pneumonitis in one and non-specific pulmonary congestive oedema and fibrosis in the other. In conclusion, IP of unknown cause could develop in patients with various haematological malignancies especially at the recovery phase of chemotherapy-induced leucopenia irrespective of the previous G-CSF administration. High dose steroid hormone should be used as therapy for such patients as soon as possible after exclusion of an infective aetiology.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Doenças Pulmonares Intersticiais/etiologia , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Infecciosos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Feminino , Humanos , Hospedeiro Imunocomprometido , Contagem de Leucócitos , Pulmão/diagnóstico por imagem , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/tratamento farmacológico , Masculino , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Radiografia , Resultado do TratamentoRESUMO
Ectopic hormone production is very rare in hematological malignancy. Here, we describe an interesting case of acute lymphoblastic leukemia (ALL) with adrenocorticotropic hormone (ACTH) production. A 47-year-old man was admitted to our hospital with a 7-month history of hyperpigmentation. The plasma level of ACTH was markedly elevated without a circadian rhythm and the level of cortisol was normal. Examination of bone marrow aspiration revealed ALL, and no other disease as a cause of the elevated ACTH was detected. Sephadex G-75 chromatography of plasma ACTH extract revealed the existence of an abnormally large molecular ACTH (probably proopiomelanocortin) in addition to authentic 1-39 ACTH. Ectopic ACTH of low biological activity is considered to be the reason for a discrepancy in the plasma levels of ACTH and cortisol. Shortly after remission induction chemotherapy, blast cells in the peripheral blood disappeared, and the plasma level of ACTH became normal, leading to an improvement of skin pigmentation. These clinical findings and laboratory data suggested that leukemia cells in this case may produce the ACTH.
Assuntos
Hormônio Adrenocorticotrópico/biossíntese , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Hormônio Adrenocorticotrópico/sangue , Ritmo Circadiano , Humanos , Hidrocortisona/sangue , Hiperpigmentação , Masculino , Pessoa de Meia-Idade , Peso Molecular , Indução de RemissãoRESUMO
t(8;21)(q22;q22) is the most frequently observed karyotypic abnormality associated with acute myeloid leukemia (AML), especially in FAB M2. Clinically, this type of AML often shows eosinophilia and has a high complete remission rate with conventional chemotherapy. t(8;21) AML is also frequently associated with additional karyotypic aberrations, such as a loss of the sex chromosome; however, it is unclear whether these aberrations change the biological and clinical characteristics of t(8;21) AML. To investigate this issue, 94 patients with t(8;21) AML were categorized according to their additional karyotypic aberrations, which were detected in more than three cases, and then morphologic features, phenotypes, expression of cytokine receptors, and clinical features were compared to t(8;21) AML without other additional aberrant karyotypes. t(8;21) AML with loss of the sex chromosome and abnormality of chromosome 9 were found in 27 cases (29.3%) and 10 cases (10.6%), respectively; however, no differences were observed from the t(8;21) AML without other additional karyotypes in terms of morphological and phenotypic features. There was also no significant difference in the clinical outcome among these three groups. On the other hand, trisomy 4 was found in three cases (3.2%) and these cells showed low expressions of CD19 (P=0.06) and IL-7 receptor (P=0.05), and high expressions of CD33 (P=0.13), CD18 (P=0.03), and CD56 (P=0.03) when compared to t(8;21) AML without additional karyotypes. Moreover, all three t(8;21) AML cases with trisomy 4 did not show eosinophilia in their bone marrow and died within 2.4 years. These observations suggest that additional karyotypic aberration, t(8;21) with trisomy 4 is rare, but it may constitute a distinctive subtype of t(8;21) AML.
Assuntos
Cromossomos Humanos Par 21/ultraestrutura , Cromossomos Humanos Par 4 , Cromossomos Humanos Par 8/ultraestrutura , Leucemia Mieloide/genética , Translocação Genética , Trissomia , Adolescente , Idoso , Antígenos CD19/análise , Antígenos de Neoplasias/análise , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aberrações Cromossômicas , Subunidade alfa 2 de Fator de Ligação ao Core , Citometria de Fluxo , Humanos , Hibridização in Situ Fluorescente , Japão , Cariotipagem , Leucemia Mieloide/classificação , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/mortalidade , Tábuas de Vida , Pessoa de Meia-Idade , Proteínas de Neoplasias/análise , Proteínas de Fusão Oncogênica/análise , Estudos Prospectivos , Proteína 1 Parceira de Translocação de RUNX1 , Receptores de Interleucina-7/análise , Análise de Sobrevida , Fatores de Transcrição/análiseRESUMO
We examined the expression of hybrid phenotype in 236 adults with acute lymphoblastic leukemia (ALL; 188 B-lineage ALL and 48 T-lineage ALL). In B-lineage ALL, myeloid antigen (mAg) CD15 was concentrated in CD10-CD20- cases (49%); CD13 (42%); and CD33 (43%) in CD10+CD20- cases. This trend had no correlation with the presence of Ph1 or t(4;11) chromosomal abnormality. T-cell antigen CD2, CD4, and CD7 was seen in four, four, and two cases, respectively, and CD4+ and CD7+ cases commonly expressed CD13 and/or CD33 (CD13/CD33). In T-lineage ALL, expression of mAg, CD11b (47%), CD13 (38%), CD15 (28%), and CD33 (51%) was restricted to CD3- cases. B-cell antigen CD19 was found in two cases with CD7 solely as T-cell antigen, and these cases possessed CD13/CD33. CD21 was detected in three cases with CD3. In whole ALL, CD13/CD33 was associated closely with the presence of stem-cell antigen CD34, and in T-lineage ALL, CD13/CD33 had a significant correlation with additional stem-cell features, such as HLA-DR, multidrug resistance 1 (MDR1) and c-kit gene expression. Our results suggest that immature ALL cells frequently express B+M+, T+M+, and occasionally B+T+M+ phenotype; that B+T+M- phenotype is extremely rare; and that mAg expression in B-lineage ALL is complicated as compared to T-lineage ALL.
Assuntos
Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Antígenos de Neoplasias/análise , Linfoma de Burkitt/imunologia , Leucemia-Linfoma de Células T do Adulto/imunologia , Adolescente , Adulto , Anticorpos Monoclonais , Linfoma de Burkitt/genética , Linfoma de Burkitt/patologia , Antígenos CD13/análise , Resistência a Múltiplos Medicamentos , Humanos , Leucemia-Linfoma de Células T do Adulto/genética , Leucemia-Linfoma de Células T do Adulto/patologia , Antígeno de Macrófago 1/análise , Fenótipo , Proteínas Proto-Oncogênicas c-kit/análise , Proteínas Proto-Oncogênicas c-kit/genética , Lectina 3 Semelhante a Ig de Ligação ao Ácido SiálicoRESUMO
Combined deficiency of factor V and factor VIII is a distinct clinical entity and is an autosomal recessive disorder. Recently identification of the gene, the endoplasmic reticulum-Golgi intermediate compartment (ERGIC-53), responsible for combined factor V-factor VIII deficiency and mutations of the ERGIC-53 gene in affected patients have been reported. In this report we analyzed two Japanese patients with combined factor V-factor VIII deficiency by genomic polymerase chain reaction and sequencing analysis. In one patient we found a point mutation of C to T at nucleotide 604 in exon 5, resulting in a transition of arginine to stop codon, which was reported in previous reports. The DdeI digestion study demonstrated that this patient is homozygous for this nonsense mutation. In the other patient we found no mutation in the ERGIC-53 gene in analysis of the entire coding region and the intron/exon junctions, which is also consistent with the previous reports, suggesting the possibility of defects at other genetic loci.
Assuntos
Deficiência do Fator V/genética , Hemofilia A/genética , Lectinas de Ligação a Manose , Proteínas de Membrana/genética , Humanos , Japão , Mutação , Reação em Cadeia da Polimerase , Análise de SequênciaAssuntos
Antibacterianos/farmacologia , Claritromicina/farmacologia , Mucosa Respiratória/metabolismo , Escarro/metabolismo , Animais , Antibacterianos/farmacocinética , Claritromicina/farmacocinética , Depressão Química , Modelos Animais de Doenças , Pneumopatias Obstrutivas/fisiopatologia , Masculino , Ratos , Ratos Endogâmicos F344RESUMO
The therapeutic approach to hairy-cell leukemia (HCL) is in some instances still debated. Although management with alpha-interferon and purine analogues is well established, there is an alternative role for therapeutic splenectomy in patients with massive splenomegaly who have failed to respond to systemic therapy. Most patients with HCL will not be suitable for treatment with splenectomy as their ages at diagnosis are high. Here, we report an elderly Japanese HCL patient whose refractory massive splenomegaly responded well to low-dose splenic irradiation.
Assuntos
Leucemia de Células Pilosas/complicações , Esplenomegalia/radioterapia , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Feminino , Humanos , Leucemia de Células Pilosas/sangue , Pentostatina/uso terapêutico , Esplenomegalia/etiologiaRESUMO
The Ikaros gene has been implicated in lymphoid development and proliferation from the results of gene targeting studies in mice. Recently we reported that the Ikaros gene may be involved in the disease progression of chronic myelogenous leukemia (CML). In this report, we investigated Ikaros isoforms in human non-lymphoid leukemia cell lines and normal granulocyte/macrophage (CFU-GM) and erythroid (BFU-E)-derived colonies. We evaluated Ikaros gene expression by RT-PCR, Southern blotting, sequencing analysis, Northern blotting, and immunoblotting.Ikaros isoforms Ik-1 and Ik-2, 3 were predominantly expressed in human non-lymphoid leukemia cell lines. Ik-4 and Ik-8 were also detectable as a minor population. In contrast to the previous report in mice, multiple Ikaros isoforms were expressed in human CFU-GM and BFU-E-derived colonies, and the dominant-negative isoform Ik-6 was not detectable. We also showed that human Ikaros isoforms contained an additional coding sequence in the N-terminal region, which was highly homologous to the sequence reported in mice. These observations suggest that the Ikaros gene may play some role in the development of human non-lymphoid lineage hematopoiesis. Moreover, the finding that the dominant-negative isoform Ik-6, which was overexpressed in patients with blast crisis of CML, was rarely detectable in non-lymphoid lineages supports its pathogenetic role in human hematologic malignancies.
Assuntos
Proteínas de Ligação a DNA , Regulação da Expressão Gênica no Desenvolvimento , Hematopoese/genética , Isoformas de Proteínas/genética , Fatores de Transcrição/genética , Animais , Linhagem da Célula/genética , Humanos , Fator de Transcrição Ikaros , Camundongos , Isoformas de Proteínas/biossíntese , Fatores de Transcrição/biossíntese , Dedos de ZincoRESUMO
Gene targeting studies in mice have shown that the transcription factor Ikaros plays an essential role in lymphoid development and as a tumor suppressor in T cells, whereas the related gene Aiolos functions as a tumor suppressor in B cells. We analyzed the expression levels of the Ikaros gene family, Ikaros and Aiolos, in human bone marrow samples from patients with adult acute lymphoblastic leukemia [ALL (n = 46; B-cell ALL = 41; T-cell ALL = 5)]. Overexpression of the dominant negative isoform of Ikaros gene Ik-6 was observed in 14 of 41 B-cell ALL patients by reverse transcription-PCR, and the results were confirmed by sequencing analysis and immunoblotting. None of the other dominant negative isoforms of the Ikaros gene were detected by reverse transcription-PCR analysis. Southern blotting analysis with PstI digestion revealed that those patients with the dominant negative isoform Ik-6 might have small mutations in the Ikaros locus. We did not detect any overexpression of dominant negative isoforms of Aiolos in adult ALL patients. These results suggest that Ikaros plays a key role in human B-cell malignancies through the dominant negative isoform Ik-6.
Assuntos
Linfoma de Burkitt/genética , Proteínas de Ligação a DNA , Genes Dominantes/genética , Fatores de Transcrição/genética , Dedos de Zinco/genética , Adolescente , Adulto , Processamento Alternativo , Células da Medula Óssea/metabolismo , Linfoma de Burkitt/metabolismo , Feminino , Expressão Gênica , Humanos , Fator de Transcrição Ikaros , Masculino , Pessoa de Meia-Idade , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/biossínteseRESUMO
We describe a unique case of adult T-cell leukemia/lymphoma (ATL). The patient had typical clinicohematological features as ATL, but showed a lack of antibody to human T-cell leukemia virus type-1 (HTLV-1) and was negative for HTLV-1 proviral DNA in the peripheral mononuclear cells by means of polymerase chain reaction. The phenotype of tumor cells revealed CD7+, CD5+, CD2+, CD3+, WT31-, TcR delta 1-, CD4-, CD8-, CD25-, and the karyotype showed a 5q-, t(12;18). HTLV-1 unrelated ATL is very rare, and the karyotype as in our case has not been reported previously.
Assuntos
Vírus Linfotrópico T Tipo 1 Humano/isolamento & purificação , Leucemia de Células T/virologia , Idoso , Humanos , Cariotipagem , Leucemia de Células T/genética , Leucemia de Células T/patologia , Leucemia de Células T/fisiopatologia , MasculinoRESUMO
We assessed a large number of adults (368 from Australia and 494 from Japan) with de novo acute myeloid leukemia (AML) to define the biological differences between the two populations. In this study, AML was classified using the French-American-British (FAB) criteria into seven groups (M1-M7). M2 was more common in Japan than in Australia, whereas M4 occurred more frequently in Australia than in Japan. Other FAB subtypes were evenly distributed. Cytogenetically, Japanese M2 displayed a higher frequency of t(8;21) than Australian (33.1% vs 15.3%, P < 0.05). The t(15;17), inv/del(16), 11q23 aberrations and 5/7/8 abnormalities were seen at similar frequencies. Immunophenotypically, Japanese M4/M5 more frequently displayed CD13 and CD14 than Australian, whereas the stem cell markers, CD34 and HLA-DR were observed at a relatively higher rate in Australian M3 than in Japanese M3. The B cell antigen, CD19 was more frequently seen in Japanese M2 than in Australian M2, but found more often in Australian M5 than in Japanese M5. In both populations, a close relationship was observed between the expression of CD19 and t(8;21). These findings suggest different biological characteristics of AML between the two populations, the main differences being generated by a higher frequency of t(8;21) chromosomal abnormality in Japanese AML. Leukemia(2000) 14, 163-168.
Assuntos
Leucemia Mieloide/patologia , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD19/imunologia , Austrália , Cromossomos Humanos Par 21 , Cromossomos Humanos Par 8 , Feminino , Humanos , Imunofenotipagem , Japão , Leucemia Mieloide/etnologia , Leucemia Mieloide/genética , Leucemia Mieloide/imunologia , Masculino , Pessoa de Meia-Idade , Translocação GenéticaRESUMO
We report a unique case of de novo acute promyelocytic leukemia (APL) with cryptic 15;17 rearrangements. Cytogenetically, structural rearrangements of the 6p23 region has been reported mainly in secondary leukemia. This patient had a karyotype of 46, XY, del(6)(p23) and no additional chromosomal abnormalities. Molecular analyses revealed the presence of PML-RAR alpha fusion genes. Deletion of the 6p23 region is extremely rare in APL.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 6/genética , Leucemia Promielocítica Aguda/genética , Proteínas de Neoplasias/genética , Proteínas de Fusão Oncogênica/genética , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 15/ultraestrutura , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 17/ultraestrutura , Cromossomos Humanos Par 6/ultraestrutura , Citarabina/administração & dosagem , Humanos , Idarubicina/administração & dosagem , Cariotipagem , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/patologia , Masculino , Indução de Remissão , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tretinoína/administração & dosagemRESUMO
We cloned and sequenced the gene encoding an NADPH-dependent aldehyde reductase (ARII) in Sporobolomyces salmonicolor AKU4429, which reduces ethyl 4-chloro-3-oxobutanoate (4-COBE) to ethyl (S)-4-chloro-3-hydroxybutanoate. The ARII gene is 1,032 bp long, is interrupted by four introns, and encodes a 37,315-Da polypeptide. The deduced amino acid sequence exhibited significant levels of similarity to the amino acid sequences of members of the mammalian 3beta-hydroxysteroid dehydrogenase-plant dihydroflavonol 4-reductase superfamily but not to the amino acid sequences of members of the aldo-keto reductase superfamily or to the amino acid sequence of an aldehyde reductase previously isolated from the same organism (K. Kita, K. Matsuzaki, T. Hashimoto, H. Yanase, N. Kato, M. C.-M. Chung, M. Kataoka, and S. Shimizu, Appl. Environ. Microbiol. 62:2303-2310, 1996). The ARII protein was overproduced in Escherichia coli about 2, 000-fold compared to the production in the original yeast cells. The enzyme expressed in E. coli was purified to homogeneity and had the same catalytic properties as ARII purified from S. salmonicolor. To examine the contribution of the dinucleotide-binding motif G(19)-X-X-G(22)-X-X-A(25), which is located in the N-terminal region, during ARII catalysis, we replaced three amino acid residues in the motif and purified the resulting mutant enzymes. Substrate inhibition of the G(19)-->A and G(22)-->A mutant enzymes by 4-COBE did not occur. The A(25)-->G mutant enzyme could reduce 4-COBE when NADPH was replaced by an equimolar concentration of NADH.
Assuntos
Acetoacetatos/metabolismo , Aldeído Redutase/genética , Aldeído Redutase/metabolismo , Butiratos/metabolismo , Fungos Mitospóricos/enzimologia , Fungos Mitospóricos/genética , Aldeído Redutase/química , Sequência de Aminoácidos , Animais , Clonagem Molecular , Íntrons , Cinética , Mamíferos , Dados de Sequência Molecular , Peso Molecular , Mutagênese Sítio-Dirigida , Filogenia , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Especificidade por SubstratoRESUMO
Gene targeting studies in mice have shown that the lack of Ikaros activity leads to T-cell hyperproliferation and T-cell neoplasia, establishing the Ikaros gene as a tumor suppressor gene in mice. This prompted us to investigate whether mutations in Ikaros play a role in human hematological malignancies. Reverse transcription-PCR was used to determine the relative expression levels of Ikaros isoforms in a panel of human leukemia/lymphoma cell lines and human bone marrow samples from patients with hematological malignancies. Among the cell lines examined, only BV-173, which was derived from a chronic myelogenous leukemia (CML) patient in lymphoid blast crisis, overexpressed the dominant-negative isoform, Ik-6. In 9 of 17 samples of patients in blast crisis of CML, Ikaros activity had been reduced either by drastically reducing mRNA expression (4 of 17) or by overexpressing the dominant-negative isoform Ik-6 (5 of 17). Significantly, expression of Ikaros isoforms seemed normal in chronic phase CML patients and patients with other hematological malignancies. In some cases, overexpression of the dominant-negative Ik-6 protein was confirmed by Western blot analysis, and Southern blot analysis indicated that decreases in Ikaros activity correlated with a mutation in the Ikaros locus. In summary, these findings suggest that a reduction of Ikaros activity may be an important step in the development of blast crisis in CML and provide further evidence that mutations that alter Ikaros expression may contribute to human hematological malignancies.