RESUMO
Clinical impact of imatinib was evaluated in 20 patients (median age, 37 years; range, 15-67 years) with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), who were administered with induction chemotherapy of daunorubicin, vincristine, prednisolone, and L-asparaginase, along with imatinib 600 mg/day during remission induction and 400 mg/day during consolidation courses. One patient died on day 14 from septic shock, while the remaining 19 achieved complete remission (CR). In total, 15 patients underwent allogeneic hematopoietic cell transplantation (HCT) during first CR. After median follow-up period of 799 days, six patients experienced recurrence; two with early recurrence within 100 days, one with leptomeningeal recurrence at 11 month, and three with post-HCT recurrence. Eight patients died. Median CR duration (821 days) and median patient survival (894 days) in the study were significantly longer by 2.9- and 2.3-fold, respectively, when compared to those of 18 historical patients treated with same regimen of combination chemotherapy without imatinib. Toxicities of the combined treatment were manageable and included grade 4 myelosuppression (n = 20) and reversible > or = grade 3 hyperbilirubinemia (n = 4). Beneficial clinical effects were observed when imatinib was added to combination chemotherapy in patients with newly diagnosed Ph+ ALL. Further studies with larger number of patients are necessary.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Piperazinas/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Pirimidinas/administração & dosagem , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Estudos Prospectivos , Pirimidinas/efeitos adversos , Indução de Remissão , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sobrevida , Resultado do TratamentoRESUMO
Most colon cancers exhibiting microsatellite instability (MI), a mutator phenotype of mismatch repair failure, are associated with mutations of the transforming growth factor-beta receptor type II genes (TGF-beta RII). Of intestinal- and diffuse-type gastric carcinomas, the former have been thought to arise from intestinal metaplasia in which gastric mucosa resembles intestinal mucosa. To evaluate the preferential histological type of MI-associated mutations in the development of gastric carcinoma, mutations of TGF-beta RII, p53, and p16 were analyzed for the two types of primary gastric carcinomas showing MI. Of 50 primary gastric carcinomas, including 33 intestinal types and 17 diffuse types, 15 cases (30%) demonstrated MI at 1 or more of the 11 microsatellite markers tested. The 15 MI cases were classified into two groups, widespread MI and low-level MI, based on the number of markers exhibiting the instability. Eleven were widespread MIs, and the remaining four cases were low-level MIs. Ten of the 11 (91%) widespread MIs were of the intestinal type, and 1 case (9%) was of the diffuse type. Of the 11 widespread MIs, 10 cases (91%) demonstrated frameshift mutations within the polyadenylate tract of the TGF-beta RII. The frameshift mutation was rarely detected at p53 and p16 (1 of 11, 9%). In contrast, the four low-level MI cases had no frameshift mutations within the repeat sequences of TGF-beta RII, p53, and p16, but two of the four cases demonstrated base substitution mutations within p53. Our results suggest that mismatch repair failure can mutate the TGF-beta RII and may provide one of the pathways for the development of the intestinal-type gastric carcinoma in high-risk populations.
Assuntos
Adenocarcinoma/genética , Genes Supressores de Tumor/genética , Repetições de Microssatélites/genética , Mutação Puntual/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Neoplasias Gástricas/genética , Mutação da Fase de Leitura/genética , Genes p53/genética , Humanos , Proteínas Serina-Treonina Quinases , Receptor do Fator de Crescimento Transformador beta Tipo IIRESUMO
INTRODUCTION: This study investigates the benefits of using multiplex reverse transcriptase-PCR (RT-PCR) in addition to standard karyotyping during the initial evaluation of acute leukemia. METHODS: A total of 1114 consecutive specimens from patients with acute leukemia were tested using a commercial multiplex RT-PCR kit (HemaVision, DNA Diagnostic). NPM1 and CEBPA mutations were selectively tested in acute myeloid leukemia (AML) patients with multiplex RT-PCR negativity. RESULTS: In specimens with optimal cytogenetics, the frequency of recurrent translocations was 31.3%, and cryptic translocations were detected in 2.1% of samples. The concordance rate between karyotyping and multiplex RT-PCR was 97.5%. In addition to the established functions, we demonstrated the additional benefits of multiplex RT-PCR, including successful molecular characterization, even in cytogenetically suboptimal specimens (5.7%); detection of submicroscopic aberrations (1.0%); detection of rare but potentially significant translocations or variants (2.5%); selection of AML candidates for mutation analysis (68.3%); and finally exclusion of recurrent translocations in patients with acute lymphoblastic leukemia or mixed phenotype acute leukemia (22.5%). CONCLUSION: We reconfirmed the accuracy and reliability of multiplex RT-PCR for diagnosing acute leukemia and demonstrated additional advantages of this system for the initial evaluation of acute leukemia. Thus, multiplex RT-PCR is worth considering in diagnostic testing of acute leukemias.
Assuntos
Testes Genéticos/métodos , Leucemia/diagnóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Doença Aguda , Proteínas Estimuladoras de Ligação a CCAAT/genética , Humanos , Leucemia/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Mutação , Proteínas Nucleares/genética , Nucleofosmina , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Reprodutibilidade dos Testes , Translocação GenéticaRESUMO
Mutator phenotype tumors provide unique opportunities to unravel malignant progression because of various gene alterations acquired during clonal tumor evolution. Gastric carcinomas, which have been known to show frequent genetic instability, would be composed of initial gene alterations shared by most tumor areas and subsequent alterations restricted to particular tumor sites. To analyse the timing of genetic events, we examined separate sites of tumor tissue obtained from a given gastric carcinoma patient with microsatellite instability (MSI). Our study included 95 normal/tumor area pairs from 25 patients. Six of the 25 patients (24%) demonstrated various levels of MSI ranging from 7% (two of 30) to 97% (28 of 29) of markers tested in multiple tumor sites. Of the six patients, five manifested frameshift mutations in a tract of ten deoxyadenosines within transforming growth factor beta receptor type II and four demonstrated frameshift mutations in a tract of eight deoxyguanosines within BAX. These mutations were common to all tumor sites regardless of the various level of MSI phenotype, indicating initial events. Two of the six patients exhibited frameshift mutations in mononucleotide repeats of mismatch repair genes, hMSH3 and hMSH6, and the insulin-like growth factor II receptor in restricted tumor areas, indicating additional alterations. Insulin-like growth factor II receptor mutations appear to be caused by hMSH3 and hMSH6 mutations because the former mutations were confined to tumor portions with the latter two mismatch repair lesions. These results provide genetic progression evidence for gastric carcinomas of the mutator pathway. In this pathway, mismatch repair insufficiency initially targets mononucleotide tracts of transforming growth factor beta receptor type II and BAX. During tumorigenesis, primary mismatch repair failure may give rise to the secondary mismatch repair lesions, frameshift mutations of hMSH3 and hMSH6, which result in another tumorigenic mutation in the insulin-like growth factor II receptor.
Assuntos
Carcinoma/genética , DNA de Neoplasias/genética , Repetições de Microssatélites , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Proteínas Proto-Oncogênicas c-bcl-2 , Neoplasias Gástricas/genética , Expansão das Repetições de Trinucleotídeos , Adulto , Idoso , Proteínas de Ligação a DNA/genética , Feminino , Mutação da Fase de Leitura , Genes p53 , Marcadores Genéticos , Humanos , Fator de Crescimento Insulin-Like II/genética , Perda de Heterozigosidade , Masculino , Proteína 3 Homóloga a MutS , Proteínas Proto-Oncogênicas/genética , Fatores de Tempo , Fator de Crescimento Transformador beta/genética , Proteína X Associada a bcl-2RESUMO
Serpin (serine protease inhibitor) proteins are involved in diverse physiological processes including inflammation, coagulation, matrix remodeling, and cell differentiation. Deficiency of normal serpin functions leads to various hereditary diseases. Besides their clinical importance, serpin proteins draw much attention due to the large conformational changes that occur upon interaction with proteases. We present here the crystal structure of an uncleaved alpha(1)-antitrypsin determined by the multiple isomorphous replacement method and refined to 2.1 A resolution. The structure, which is the first active serpin structure based on experimental phases, reveals novel conformations in the flexible loops, including the proximal hinge region of the reactive center loop and the surface cavity region in the central beta-sheet, sheet A. The determined loop conformation explains the results of recent mutagenesis studies and provides detailed insights into the protease inhibition mechanism. The high-resolution structure of active alpha(1)-antitrypsin also provides evidence for the existence of localized van-der-Waals strain in the central hydrophobic core.
Assuntos
alfa 1-Antitripsina/química , alfa 1-Antitripsina/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Cristalografia por Raios X , Modelos Moleculares , Dados de Sequência Molecular , Maleabilidade , Estrutura Secundária de Proteína , Alinhamento de Sequência , TermodinâmicaRESUMO
We retrospectively studied 227 patients with MDS (1) to identify the prognostic factors of survival and acute leukemia evolution in Korean patients with MDS, (2) to apply different prognostic scoring systems to the same group of patients, and (3) to compare the FAB with the WHO classification. Six scoring systems were applied to the patients, and the FAB and WHO classifications were compared. The patients' median age was 57 years. The median survival time was 21 months, and age, dysgranulopoiesis and the IPSS cytogenetic groups were independent prognostic factors for survival. Acute leukemia occurred in 34 patients, and the cumulative incidence was 27.1% at 3 years. Marrow blast percentage was the only independent prognostic factor for acute leukemia evolution. Most scoring systems successfully discriminated risk groups for survival and acute leukemia evolution, but patient distribution into risk groups varied according to the scoring systems. Refractory cytopenia with multilineage dysplasia and RAEB II seemed to have different prognoses from RA or RARS and RAEB I, respectively. In summary, our MDS patients had different disease natures from those of Western countries regarding clinical features, prognostic factors and cytogenetic profiles. Although the WHO classification seems to improve the FAB classification, further studies are warranted to validate the utility of the WHO classification before it is accepted for routine clinical use. Our study has the limitations of retrospective analysis, and our results should be verified in future prospective studies.
Assuntos
Leucemia/classificação , Síndromes Mielodisplásicas/classificação , Análise Atuarial , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Células da Medula Óssea/patologia , Deleção Cromossômica , Cromossomos Humanos Y , Feminino , Seguimentos , Humanos , Cariotipagem , Coreia (Geográfico) , Leucemia/epidemiologia , Leucemia/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/mortalidade , Contagem de Plaquetas , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Fatores de Tempo , Trissomia , Organização Mundial da SaúdeRESUMO
Chronic nephropathy involving glomerular sclerosis markedly progresses in severity with age in male Fischer 344 rats fed ad libitum. Restricting food intake by 40% almost totally prevents progression of these lesions. Restricting food intake by 40% without restricting protein intake is also highly effective although somewhat less so than food restriction that includes protein restriction. These findings indicate that reducing the intake of protein is not the major reason for the retardation by food restriction of the age-associated progression of nephropathy in rats.
Assuntos
Envelhecimento , Proteínas Alimentares/administração & dosagem , Privação de Alimentos , Nefropatias/prevenção & controle , Animais , Peso Corporal , Ingestão de Alimentos , Gastroenteropatias/prevenção & controle , Cardiopatias/prevenção & controle , Hepatopatias/prevenção & controle , Longevidade , Masculino , Neoplasias Experimentais/prevenção & controle , Tamanho do Órgão , Ratos , Ratos Endogâmicos F344 , ReproduçãoRESUMO
We analyzed the p53 protein expression and gene mutations to evaluate the role of ultraviolet radiation or other carcinogens, and possible racial differences in 17 samples from 12 Korean patients with Bowen's disease. A simple microdissection technique was used to collect the tumor cells selectively. p53 protein expression was found in eight of 17 (47%) samples. Abnormalities in polymerase chain reaction (PCR)-single-strand conformation polymorphism (SSCP) analysis were observed in 16 (94%) samples. A total of 14 missense mutations were detected in eight (47%) samples; 11 were clustered in exon 5 and the remaining three were located in exon 8. UV-like mutations were seen in five of 14 (36%) mutations, but no CC to TT transitions, UV-fingerprint mutations were observed. Multiple mutations were present in two cases and double mutation in a single case. Each lesion in multiple Bowen's disease showed different mutations and was suggested to be of different clonal origins. TP53-loss of heterozygosity (LOH) was detected in four out of 15 (27%) informative samples. Clustering of mutations in exon 5 suggests the role of another carcinogen in Koreans or Asians other than the UVR. Microdissection would increase the detection rate of the p53 gene mutations and LOH not only in skin cancer but also in precancerous lesions.
Assuntos
Doença de Bowen/genética , Éxons/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Bowen/etnologia , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Coreia (Geográfico) , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Mutação , Pigmentação da Pele/genética , Raios UltravioletaRESUMO
Polyurethanes (PU) were synthesized from 4,4'-diphenylmethane diisocyanate and polytetramethylene glycol, and subsequently with ethylene diamine as a chain extender. The PU film was exposed to oxygen plasma glow discharge to produce peroxides on the surfaces. These peroxides were then used as catalysts for the copolymerization of acrylic acid (AA) and methyl acrylate (MA) in order to prepare carboxyl group-introduced PU (PU-C). Heparin-immobilized PU was prepared using the coupling reaction of PU-C with polyethylene oxide (PEO) followed by the reaction of grafted PEO with heparin. The surface-modified PUs were then characterized by attenuated total reflection Fourier transform infrared spectroscopy, electron spectroscopy for chemical analysis (ESCA), and a contact angle goniometer. The concentration of carboxylic acid groups on the PU surfaces could be controlled within the range of 0.47-1.68 micromol cm(-2) by the copolymerization of AA and MA. The amounts of heparin coupled to terminus amino groups on PU-6 and PU-33 were 1.30 and 1.16 microg cm(-2), respectively. The water contact angle of the PU was decreased by AA grafting, and further decreased by PEO grafting and heparin immobilization, showing an increased hydrophilicity of the modified PUs. A 3% loss from the originally bound heparin appeared within several hours and thereafter almost no heparin was released when heparin-immobilized PUs were immersed in a physiological solution for 100 h, indicating the covalent immobilization of heparin on the surfaces.
Assuntos
Materiais Biocompatíveis/síntese química , Heparina , Poliuretanos/síntese química , Materiais Biocompatíveis/química , Ácidos Carboxílicos/análise , Catálise , Química Orgânica/métodos , Indicadores e Reagentes , Peróxidos , Poliuretanos/química , Propriedades de SuperfícieRESUMO
A total of 118 consecutive adult patients with acute leukemia (78 AML, 36 ALL, and four acute mixed lineage leukemia) underwent allogeneic hematopoietic cell transplantation (HCT) after conditioning with BuCy (n=113) or a nonmyeloablative regimen of busulfan-fludarabine (n=5). After a median follow-up of 35.8 months (range, 6.4-91.0), 34 patients experienced at least one episode of leukemia relapse. Of 34 initial episodes, 14 (41%) occurred in extramedullary sites, with (n=8) or without (n=6) concomitant bone marrow involvement. The median time to relapse in the extramedullary sites was longer than that of relapse in bone marrow only (13.5 vs 6.1 months, P=0.046). Acute leukemia subtype and disease status at HCT showed an independent predictive value for overall relapse, as well as for extramedullary relapse with or without bone marrow involvement (Philadelphia chromosome positive acute leukemia vs low-risk AML, relative risk 22.68 (95% CI, 2.18-235.64); other than first CR vs first CR, relative risk 5.61 (95% CI, 1.80-17.51)), but not for bone marrow relapse. Our study suggests that there may be different pathogenetic mechanisms for bone marrow vs extramedullary relapse of acute leukemia after allogeneic HCT. The mode of relapse needs to be investigated in future reports of acute leukemia treated with allogeneic HCT.
Assuntos
Doenças da Medula Óssea/mortalidade , Transplante de Medula Óssea , Transplante de Células-Tronco Hematopoéticas , Leucemia/mortalidade , Leucemia/terapia , Doença Aguda , Adolescente , Adulto , Doenças da Medula Óssea/patologia , Feminino , Seguimentos , Humanos , Leucemia/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Recidiva , Fatores de Risco , Taxa de Sobrevida , Transplante HomólogoRESUMO
INTRODUCTION: The rearrangement of the mixed-lineage leukemia (MLL) gene occurs through translocations and insertions involving a variety of partner chromosome genes. However, there are few studies on aberrant MLL signal patterns such as concurrent 3' MLL deletion. METHODS: A total of 84 patients with acute leukemia (AL) who had MLL rearrangements detected by florescence in situ hybridization (FISH) were enrolled in the study. The distribution of MLL fusion partner genes was analyzed, and aberrant MLL signals were evaluated. RESULTS: Seventy-seven (91.7%) patients had MLL rearrangements, involving previously described translocation partner genes (TPGs). Among these TPGs, the frequencies of MLLT3, AFF1, MLLT4, and ELL were 29.8%, 17.9%, 15.5%, and 13.1%, respectively. A high frequency of MLLT4 in our study was due to the high proportion of acute myeloid leukemia cases in pediatric and adult patients. Aberrant MLL signals were found in 18 patients: 11 (61.1%) with 3' MLL signal loss and 7 with 3' MLL signal gain. All cases with 3' MLL signal gain were due to an extra derivative partner chromosome. The median overall survival period of patients with 3' MLL gain was shorter than that in patients without aberrant MLL signal patterns. CONCLUSION: Aberrant MLL signals were frequently detected by FISH analysis. The 3' MLL gain was associated with poor prognosis in patients with AL. Therefore, it is important to detect aberrant MLL signal patterns using FISH analysis.
Assuntos
Região 3'-Flanqueadora , Rearranjo Gênico , Leucemia Aguda Bifenotípica/genética , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Histona-Lisina N-Metiltransferase , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Leucemia Aguda Bifenotípica/diagnóstico , Leucemia Aguda Bifenotípica/mortalidade , Leucemia Aguda Bifenotípica/patologia , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Análise de SobrevidaRESUMO
PURPOSE: To review and evaluate the effects of intravitreal bevacizumab injection (IVB) in centralserous chorioretinopathy (CSC) by meta-analysis. PATIENTS AND METHODS: Clinical controlled studies that evaluated the effect of IVB in CSC were identified through systematic searches of Embase, PubMed, and the Cochrane Central Register of Controlled Trials. Data on the best-corrected visual acuity (BCVA) in logMAR and central macular thickness (CMT) in µm at baseline and 6 months after IVB were extracted and compared with those treated by simple observation. RESULTS: Four clinical controlled studies were included in the meta-analysis. The IVB injection group achieved better BCVA at a follow-up of 6 months. However, the analysis showed that there were no significant differences of BCVA at 6 months after injection between IVB group and the observation group (-0.02 logMAR, 95% CI -0.14 to 0.11, P=0.80). The analysis of the reduction in CMT revealed that the difference between groups was not statistically significant (-8.37 µm, 95% CI -97.26 to 80.52, P=0.85). No report assessed severe complications or side effects of IVB in patients with CSC. CONCLUSIONS: Meta-analysis failed to verify the positive effect of IVB in CSC based on the epidemiological literature published to date.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Coriorretinopatia Serosa Central/tratamento farmacológico , Bevacizumab , Coriorretinopatia Serosa Central/fisiopatologia , Humanos , Injeções Intravítreas , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Acuidade Visual/fisiologiaRESUMO
INTRODUCTION: The aim of this study was to characterize clinicopathological features of acute panmyelosis with myelofibrosis (APMF), acute megakaryoblastic leukemia with myelofibrosis (AMKL-MF), primary myelofibrosis (PMF) and myelodysplastic syndrome with myelofibrosis (MDS-MF) in order to provide the keys to the differential diagnosis of bone marrow (BM) fibrosis. METHODS: We compared age, gender, splenomegaly, serum lactate dehydrogenase level, blood cell counts, blast counts in peripheral blood (PB) and BM, megakaryocyte counts, BM cellularity, dysplasia, and the karyotypes of patients with APMF (n = 6), AMKL-MF (n = 7), PMF (n = 44), and MDS-MF (n = 44). RESULTS: APMF showed hyperplasia of all three lineages, increase in megakaryocyte count with dysplasia and frequent abnormal karyotypes. AMKL-MF was associated with elevated BM blast counts, decreased BM megakaryocyte count with rare megakaryocytic dysplasia and chromosome 21 abnormality. PMF patients displayed splenomegaly, rare blasts in PB/BM, and JAK2 V617F mutation. MDS-MF patients showed pancytopenia, dysplasia in all three lineages and recurrent chromosomal abnormalities involving chromosome 5,7,12, and 17. CONCLUSIONS: Although differential diagnosis among APMF, AMKL-MF, PMF, and MDS-MF is very challenging due to the overlapping clinical and morphological features, meticulous investigation of the patient with respect to splenomegaly, blood cell count, PB and BM findings, and karyotype will serve as a guide to correct diagnosis.
Assuntos
Leucemia Megacarioblástica Aguda/diagnóstico , Síndromes Mielodisplásicas/diagnóstico , Mielofibrose Primária/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/patologia , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Cariotipagem , Leucemia Megacarioblástica Aguda/sangue , Leucemia Megacarioblástica Aguda/genética , Leucemia Megacarioblástica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Mielofibrose Primária/sangue , Mielofibrose Primária/genética , Mielofibrose Primária/patologia , Adulto JovemRESUMO
INTRODUCTION: ABL1 kinase mutations represent a major mechanism of imatinib resistance in Philadelphia-positive (Ph+) patients. There is a paucity of data on ABL1 kinase mutations in Ph+ patients in Korea. METHODS: We used restriction fragment mass polymorphism (RFMP) analysis to detect ABL1 kinase mutations in blood or bone marrow specimens from 80 Ph+ patients. RESULTS: Fifty-seven patients met the criteria for inadequate molecular response (IMR). ABL1 kinase mutations were found in 2.6% of patients with chronic-phase chronic myelogenous leukemia (CML), 25.0% of accelerated-phase CML, 66.7% of blast-phase CML, and in 58.3% with Ph+ acute lymphoblastic leukemia. Twelve mutations were identified: 7 T315I, 2 E255V, 1 E255K, 1 F359V, and 1 Y253H. The majority of mutation-positive patients showed an unfavorable clinical course and often had an extra Ph or additional chromosomal abnormalities. Mutations were detected in two patients who had very low or absent BCR-ABL1 normalized ratios. CONCLUSION: Mutation analysis should be performed in Ph+ patients exhibiting an IMR to imatinib. RFMP analysis is helpful for revising therapeutic strategies because it can sensitively detect clinically relevant ABL1 kinase mutations with high frequencies.
Assuntos
Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Domínios e Motivos de Interação entre Proteínas/genética , Adolescente , Adulto , Idoso , Criança , Aberrações Cromossômicas , Códon , Análise Mutacional de DNA , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Proteínas de Fusão bcr-abl/química , Humanos , Cariótipo , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
Although most patients with peripheral T-cell lymphoma (PTCL) show clonal rearrangement of T-cell receptor genes, few PTCLs show recurrent chromosomal abnormalities. We describe here a rare chromosomal rearrangement, t(14;19)(q11.2;q13.3), in a Lennert's lymphoma, a variant of PTCL, not otherwise specified. Sequential fluorescence in situ hybridization assays showed that the breakpoint in 19q13.3 was located distal to the BCL3 and PVRL2 genes, both of which may be candidate proto-oncogenes. These findings suggest that another gene is involved in the pathogenic characteristics observed in this patient with Lennert's lymphoma.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 19 , Linfoma de Células T Periférico/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Linfoma de Células T Periférico/patologia , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Interphase fluorescence in situ hybridization (FISH) analysis of multiple myeloma (MM) may indiscriminately count signals of nonplasma cells, thus decreasing specificity and sensitivity. We aimed to evaluate the usefulness of an immune-magnetic sorting method for plasma cells in FISH analysis of MM and define optimal sample preparation conditions. METHODS: Plasma cells were purified using EasySep(®) CD138 Positive Selection Cocktail and Magnetic Nanoparticles (Invitrogen). We compared FISH results with and without plasma cell purification for three sample preparation methods: direct harvest, 24-h culture, and 96-h culture with interleukin-4 in five newly diagnosed MM patients. Archived fixed bone marrow cells of 17 MM patients were also studied. RESULTS: The percentage of abnormal cells identified was significantly higher with plasma cell purification than without purification (median, 88.0%; range, 84.0-100.0%vs. 15.0%, 12.5-29.5%, respectively). The three sample preparation methods showed comparable results. Immune-magnetic sorting also significantly increased the percentage of abnormal cells identified in FISH analysis of archived fixed bone marrow cells (P < 0.001). CONCLUSIONS: Immune-magnetic CD138-positive cell sorting significantly increased the percentage of abnormal cells identified in FISH analysis of MM samples for all sample preparation methods. This method could also be applied for retrospective FISH analysis of archived fixed bone marrow cells.
Assuntos
Separação Imunomagnética/métodos , Hibridização in Situ Fluorescente/métodos , Mieloma Múltiplo/metabolismo , Plasmócitos/metabolismo , Sindecana-1/análise , Contagem de Células , Técnicas de Cultura de Células , Células Cultivadas , Citometria de Fluxo , Humanos , Imunofenotipagem , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Reprodutibilidade dos TestesRESUMO
We analyzed the clinical significance of pre-transplant International Prognostic Scoring System (IPSS) score and comorbidity in 68 patients who underwent allogeneic hematopoietic cell transplantation (HCT) for myelodysplastic syndrome (MDS) (n=48) or acute myeloid leukemia evolved from MDS (n=20) between December 1995 and January 2008 in a single institute. During a median follow-up period of 41.0 months (range, 3.2-132.0 months), 27 patients died, and 7 relapsed. The 5-year probabilities of overall survival (OS) and event-free survival (EFS) were 60.0 and 57.4%, respectively, and the 5-year cumulative incidences of non-relapse mortality (CINRM) and relapse were 32.7 and 9.9%, respectively. OS, EFS, and CINRM were significantly different according to pre-transplant IPSS score and presence of pre-transplant comorbidity, which were independent risk factors along with Karnofsky performance score in multivariate analyses. In conclusion, pre-transplant IPSS score and comorbidity may stratify the risk of post transplant outcomes in MDS.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes Mielodisplásicas/terapia , Adulto , Comorbidade , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/epidemiologia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Adulto JovemAssuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Rearranjo Gênico do Linfócito T , Proteínas com Domínio LIM/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas Proto-Oncogênicas/genética , Medula Óssea/metabolismo , Medula Óssea/patologia , Criança , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 13 , Cromossomos Humanos Par 14 , Humanos , Cariótipo , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Proteína 1 de Leucemia Linfocítica Aguda de Células T , Translocação GenéticaRESUMO
The native form of serpins (serine protease inhibitors) is metastable, which is critical to their biological functions. Spontaneous conversion from the native form of serpins into a more stable conformation, called the "latent" form, is restricted. To examine whether the connectivity of strand 1 of beta-sheet C to the hydrophobic core is critical to the serpin's preferential folding to the metastable native conformation, we designed a circularly-permuted mutant of alpha(1)-antitrypsin, the prototype serpin, in which strand 1C is disconnected from the hydrophobic core. Conformation of the circular permutant was similar to that of the latent form, as revealed by equilibrium unfolding, limited proteolysis, and spectroscopic properties. Our results support the notion that rapid folding of the hydrophobic core with concomitant incorporation of strand 1C into beta-sheet C traps the serpin molecule into its native metastable conformation.