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1.
Autops. Case Rep ; 10(2): e2020154, Apr.-June 2020. tab, graf
Artículo en Inglés | LILACS | ID: biblio-1131819

RESUMEN

Langerhans cell histiocytosis (LCH), a disorder of antigen-presenting cells, is the commonest disorder of the mononuclear phagocytic system. Diagnosis is always challenging due to heterogeneous clinical presentation. However, with the evolution and better understanding of its biology, many of these children are being diagnosed early and offered appropriate therapy. Despite these advances, in developing countries, an early diagnosis is still challenging due to resource constraints for specialized tests. As a result, many patients succumb to their disease. Autopsy data on LCH is notably lacking in the literature. We sought to analyze the clinical (including mutational) and morphologic features at autopsy in six proven cases of LCH. This study includes a detailed clinico-pathological and mutational analysis of 6 proven cases of LCH. Presence of BRAF V600E mutation was assessed by both Real Time PCR and Sanger sequencing. A varied spectrum of organ involvement was noted with some rare and novel morphological findings, like nodular bronchiolocentric infiltration of LCH cells, lymphovascular emboli of LCH cells, and paucity of eosinophils within the infiltrate; these features have not been described earlier. Surprisingly, all cases were negative for BRAF V600E mutation on both RQ-PCR and Sanger sequencing. The present study is perhaps the first autopsy series on LCH. This extensive autopsy analysis represents a correlation of pathological features with clinical symptoms which provides clues for a timely diagnosis and appropriate therapeutic intervention. Also, our findings hint at the low frequency of BRAF V600E mutation in our LCH patients.


Asunto(s)
Humanos , Masculino , Lactante , Preescolar , Histiocitosis de Células de Langerhans/patología , Autopsia , Proteínas Proto-Oncogénicas c-abl , Quinasas de Proteína Quinasa Activadas por Mitógenos , Diagnóstico Precoz
2.
Artículo en Inglés | WPRIM | ID: wpr-1010442

RESUMEN

Interferon-γ (IFN-γ) has been used to control cancers in clinical treatment. However, an increasing number of reports have suggested that in some cases effectiveness declines after a long treatment period, the reason being unclear. We have reported previously that long-term IFN-γ treatment induces malignant transformation of healthy lactating bovine mammary epithelial cells (BMECs) in vitro. In this study, we investigated the mechanisms underlying the malignant proliferation of BMECs under IFN-γ treatment. The primary BMECs used in this study were stimulated by IFN-γ (10 ng/mL) for a long term to promote malignancy. We observed that IFN-γ could promote malignant cell proliferation, increase the expression of cyclin D1/cyclin-dependent kinase 4 (CDK4), decrease the expression of p21, and upregulate the expression of cellular-abelsongene (c-Abl) and histone deacetylase 2 (HDAC2). The HDAC2 inhibitor, valproate (VPA) and the c-Abl inhibitor, imatinib, lowered the expression level of cyclin D1/CDK4, and increased the expression level of p21, leading to an inhibitory effect on IFN-γ-induced malignant cell growth. When c-Abl was downregulated, the HDAC2 level was also decreased by promoted proteasome degradation. These data suggest that IFN-γ promotes the growth of malignant BMECs through the c-Abl/HDAC2 signaling pathway. Our findings suggest that long-term application of IFN-γ may be closely associated with the promotion of cell growth and even the carcinogenesis of breast cancer.


Asunto(s)
Animales , Bovinos , Femenino , Carcinogénesis/patología , Proteínas de Ciclo Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Transformación Celular Neoplásica/patología , Células Cultivadas , Células Epiteliales/patología , Histona Desacetilasa 2/metabolismo , Mesilato de Imatinib/farmacología , Interferón gamma/farmacología , Glándulas Mamarias Animales/patología , Neoplasias Mamarias Experimentales/patología , Proteínas Proto-Oncogénicas c-abl/metabolismo , Transducción de Señal , Ácido Valproico/farmacología
3.
Zhongguo dangdai erke zazhi ; Zhongguo dangdai erke zazhi;(12): 1213-1218, 2017.
Artículo en Chino | WPRIM | ID: wpr-300419

RESUMEN

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a subtype of B-lineage ALL (B-ALL) that displays a gene expression profile (GEP) similar to Philadelphia chromosome-positive ALL (PhALL). It has a diverse range of genetic alterations that activate cytokine receptor genes and kinase signaling pathways, frequently accompanied by abnormal transcription factors related to lymphatic development. Children with Ph-like ALL account for 15% of children with high-risk B-ALL. It has adverse clinical features and a poor prognosis. Tyrosine kinase inhibitors combined with chemotherapy can significantly improve the prognosis of children with PhALL, suggesting that targeted therapy based on the molecular cytogenetic abnormalities of Ph-like ALL has good research prospects. This paper expounds the genetic alterations, pathogenesis, clinical features, diagnostic measures, and potential therapeutic approaches of Ph-like childhood ALL based on recent research progress in Ph-like ALL.


Asunto(s)
Humanos , Janus Quinasa 2 , Genética , Factor de Transcripción PAX5 , Genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Diagnóstico , Quimioterapia , Genética , Proteínas Proto-Oncogénicas c-abl , Genética
4.
Chinese Journal of Hematology ; (12): 105-109, 2016.
Artículo en Chino | WPRIM | ID: wpr-234022

RESUMEN

<p><b>OBJECTIVE</b>To clarify the clinical, cytogenetical and molecular characteristics and prognosis of Ph(+) ALL patients with ABL kinase domain mutations (ABL-KDMs), and to evaluate the therapeutic value of allogeneic hematopoietic stem cell transplantation (allo-HSCT) combined with tyrosine kinase inhibitor (TKI) in these patients.</p><p><b>METHODS</b>Retrospective analysis of clinical features, molecular genetic characteristics, mutation distribution and prognosis of newly diagnosed Ph(+) ALL patients with ABL-KDMs from February 2010 to August 2014 were performed, and the efficacy of treatment regimen of allo-HSCT combined with different TKIs was compared.</p><p><b>RESULTS</b>Of 88 Ph(+) ALL patients during maintenance treatment stage for ABL-KDMs monitoring, mutation was detected in 42 patients with median time of 8 months from diagnosis to mutation occurrence. The median age of mutation group was 40-year-old, older than that of non-mutation group (32.5-year-old) (P=0.023). The incidence of complex chromosome abnormality of mutation group was higher than that of non-mutation group (P=0.043), with alternations in chromosome 7, 5 and +Ph more frequently observed. There were 21 types of mutation at 18 locations detected, with T315I mutation ranking the top followed by E255K/V, Y253H/F and E459K. Mutation group featured no significant difference in complete remission (CR) rate in contrast to nonmutation group, but was remarkably lower in major molecular remission (MMR) rate than non-mutation group. The 2 year and 5 year overall survival rate of mutation group was 45.4% and 35.0% respectively, much shorter than that of non-mutation group (67.8% and 63.3%), (P=0.047). The median survival of patients with T315I and E255K/V was 19 and 10 months, significantly shorter than that of patients with other mutations. Among the 42 patients with mutations, 14 underwent allo-HSCT, and the median survival was 29 months, longer than that of patients received chemotherapy alone (17 months) (P=0.024). Fourteen allo-HSCT patients were given nilotinib or dasatinib at the time of mutation occurrence, and there was no significant difference in the overall survival in contrast to patients who continue to take imatinib.</p><p><b>CONCLUSIONS</b>ABL kinase domain mutations are closely related to the older age and high genomic instability in the newly diagnosed Ph(+) ALL patients. Mutation types showed diversity and complexity, which remarkably affected patients' prognosis and survival. T315I and E255K mutations account for more than half of all cases, characterized by a less favorable prognosis. Currently, allo-HSCT is the only method that has the potential of elongating life expectancy, but the utility of second-generation TKI during relapse does not necessarily have an edge on survival over imatinib.</p>


Asunto(s)
Humanos , Aberraciones Cromosómicas , Dasatinib , Usos Terapéuticos , Trasplante de Células Madre Hematopoyéticas , Mesilato de Imatinib , Usos Terapéuticos , Mutación , Leucemia-Linfoma Linfoblástico de Células Precursoras , Quimioterapia , Genética , Pronóstico , Inhibidores de Proteínas Quinasas , Usos Terapéuticos , Proteínas Proto-Oncogénicas c-abl , Genética , Pirimidinas , Usos Terapéuticos , Inducción de Remisión , Estudios Retrospectivos , Tasa de Supervivencia
5.
Chinese Journal of Hematology ; (12): 703-707, 2014.
Artículo en Chino | WPRIM | ID: wpr-242081

RESUMEN

<p><b>OBJECTIVE</b>To analyze the association of different types of ABL tyrosine point mutations and imatinib resistance to probe the relation between ABL tyrosine point mutations and the prognosis of patients with chronic myeloid leukemia (CML).</p><p><b>METHODS</b>Nested reverse transcriptasepolym erase chain reaction was performed on samples from 70 patients to amplify the ABL kinase domain. Then, the amplified product was purified and sequenced in both direction. The homologous analysis was performed in combination of clinical data.</p><p><b>RESULTS</b>The ABL domain point mutations were detected in 32 patients (45.7%) including 16 patients in chronic phase (CP), 6 patients in accelerated phase(AP)and 10 patients in blast phase (BP), which were detected as T315I, E255K, C475Y, Y253H, G321W, G250E, F317L, E258K, F359V, E459K and F311I, respectively. Sokal score with intermediate and high risk and Ph+ chromosome with complex karyotype were important risk factors for ABL domain point mutations. The 5-year overall survival (OS) was not significantly different between the patients with or without ABL domain point mutations (78.1% vs 84.2%, P=0.985), while the 5-year cumulative event-free survival (EFS) of two groups were 34.4% and 68.4% (P=0.034), respectively. The rate of complete cytogenetic response was higher in patients treated with allogenic hematopetic stem cell transplantation (allo-HSCT) compared with patients merely treated with second-generation tyrosine kinase inhibitors or chemotherapeutics (P=0.001).</p><p><b>CONCLUSION</b>Patients with ABL domain point mutations had poor efficacy and prognosis compared to those without ABL domain point mutations. Detection of ABL domain point mutations in CML-CP was helpful for the adjustment of therapeutic options and improvement of prognosis. And allo-HSCT was a more effective therapy for patients with advanced phase.</p>


Asunto(s)
Adolescente , Adulto , Anciano , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Benzamidas , Usos Terapéuticos , Resistencia a Antineoplásicos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva , Quimioterapia , Genética , Piperazinas , Usos Terapéuticos , Mutación Puntual , Pronóstico , Proteínas Proto-Oncogénicas c-abl , Genética , Pirimidinas , Usos Terapéuticos
6.
Korean J. Ophthalmol ; Korean J. Ophthalmol;: 343-350, 2014.
Artículo en Inglés | WPRIM | ID: wpr-156974

RESUMEN

PURPOSE: To investigate the relationship between plasma TDRD7 mRNA and lens transparency, and to evaluate plasma TDRD7 mRNA as a potential marker for cataracts and its sub-type by quantitatively analyzing human peripheral blood. METHODS: Plasma RNA was extracted from 40 patients with cataracts, and 30 normal controls of matched age and gender. Blood cholesterol and fasting glucose were measured, and the RNA extracted from the sample was synthesized into cDNA. After polymerase chain reaction, the results were compared after quantifying the TDRD7 mRNA using ABL1 mRNA for normalization. We analyzed the relative gene expression data via the DeltaDeltaCt method. RESULTS: The normalized 2(-DeltaDeltaCt) of plasma TDRD7 mRNA based on ABL1 mRNA was 1.52 ± 0.63 in the case of the control group and 1.05 ± 0.34 in the case of the cataract patients, and the TDRD7 expression level of the cataract patients was lower than that of the control group (p = 0.048). The comparison of the genetic values of different types of cataracts demonstrated that the TDRD7 expression level of the cortical type and mixed type were lower than those of the nuclear type and posterior subcapsular opacity type (p = 0.017). CONCLUSIONS: Human cataracts and the TDRD7 gene loss-of-function mutations are strongly causally related, as the expression level of plasma TDRD7 mRNA in patients with cataracts was statistically significantly lower than in the normal control group.


Asunto(s)
Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Catarata/sangre , Regulación de la Expresión Génica/fisiología , Proteínas Proto-Oncogénicas c-abl/genética , ARN Mensajero/sangre , Reacción en Cadena en Tiempo Real de la Polimerasa , Ribonucleoproteínas/genética
7.
Chinese Journal of Hematology ; (12): 21-25, 2013.
Artículo en Chino | WPRIM | ID: wpr-323457

RESUMEN

<p><b>OBJECTIVE</b>To identify the distribution and differentiation of ABL kinase domain mutation in the Chinese Han nationality imatinib resistant chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL).</p><p><b>METHODS</b>Bone marrow or peripheral blood samples of 112 imatinib resistant CML patients and 21 Ph(+)ALL patients were obtained from the first affiliated hospital of Soochow university according to local law. Total RNA was extracted from the mononuclear cells using a TRIzol reagent. ABL kinase domain (KD) mutation was detected by direct sequencing.</p><p><b>RESULTS</b>Of the 112 imatinib resistant CML patients, 54.46%(61 cases) had ABL KD mutation. Twenty-three mutants were identified in 20 amino acid sites and 23.21% (26 cases) ABL KD mutations were in P-loop region. ABL KD mutations were also detected in 71.43% (15 cases) imatinib resistant Ph(+)ALL patients, with 10 mutations in 8 amino acid sites. The most frequent mutation was T315I (28.57%), followed by E255K/V (19.05%) and Y253F/H (14.29%). The frequency of T315I was much higher in imatinib resistant Ph(+) ALL than that in imatinib resistant CML (P = 0.001). Ph(+)ALL with additional chromosomal aberrations also had a higher rate of ABL KD mutation than that of CML (P = 0.010). Ph(+)ALL gained ABL KD mutation faster than CML (P < 0.010).</p><p><b>CONCLUSION</b>Chinese imatinib resistant CML and Ph(+)ALL patients had different characteristics in ABL KD mutation. The rate of ABL KD mutation in Ph(+)ALL with additional chromosomal aberrations was much higher than that of CML with additional chromosomal aberrations.</p>


Asunto(s)
Adolescente , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Adulto Joven , Pueblo Asiatico , Genética , Benzamidas , Farmacología , Aberraciones Cromosómicas , Resistencia a Antineoplásicos , Genética , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva , Genética , Mutación , Cromosoma Filadelfia , Piperazinas , Farmacología , Leucemia-Linfoma Linfoblástico de Células Precursoras , Genética , Proteínas Tirosina Quinasas , Genética , Proteínas Proto-Oncogénicas c-abl , Genética , Pirimidinas , Farmacología
8.
Indian J Cancer ; 2009 Oct-Dec; 46(4): 335-336
Artículo en Inglés | IMSEAR | ID: sea-144271

RESUMEN

Imatinib is a clinically well-tolerated small molecule inhibitor that exerts selective, dual inhibition on the transforming growth factor beta and platelet-derived growth factor pathways. The recognition of an inactive conformation of Abl, in which a catalytically important Asp-Phe-Gly motif is flipped by approximately 180 degrees with respect to the active conformation, underlies the specificity of the cancer drug imatinib, which is used to treat chronic myelogenous leukemia. However, conformational analysis shows that the effect of the drug depends on the potential energy, which varies due to the alpha rotatable angles of the Abl tyrosine kinase domain. In this study, the author determines the change of binding energy between the Abl tyrosine kinase domain, due to the variation in rotatable angles, and bond lengthening. According to this study, the ratio between the required binding energy between the wild and mutated types is equal to 1: 1.16.


Asunto(s)
Antineoplásicos/farmacología , Modelos Moleculares , Piperazinas/química , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-abl/química , Pirimidinas/química
9.
Artículo en Chino | WPRIM | ID: wpr-230298

RESUMEN

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder from hematopoietic stem cell disorder characterized by the consecutive expression of bcr-abl gene, and the translation product of which has enhanced tyrosine kinase activity and can activate a series of downstream signal transduction proteins and results in the occurence of CML. Although the application of imatinib (IM) makes nearly all patients with CML in chronic phase achieve a complete hematologic remission, and 90%of those treated in the early chronic phase achieve a complete cytogenetic remission, but the development of resistance to IM in the course of treatment and even in the beginning of the treatment forced people to develop new agents and to combine the new agents with IM in order to achieve better therapeutic result. This article reviews the experimental advances of targeted therapeutics in CML recent years.


Asunto(s)
Humanos , Antineoplásicos , Benzamidas , Sistemas de Liberación de Medicamentos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva , Quimioterapia , Piperazinas , Inhibidores de Proteínas Quinasas , Proteínas Tirosina Quinasas , Proteínas Proto-Oncogénicas c-abl , Genética , Proteínas Proto-Oncogénicas c-bcr , Genética , Pirimidinas
10.
Artículo en Chino | WPRIM | ID: wpr-230315

RESUMEN

The study was purposed to analyze the relationship between the content of T-cell receptor excision DNA circles (TREC) and bcr-abl mRNA levels in CML patients and to evaluate the prognostic significance of recent thymic output function detection in patients with chronic myelogenous leukemia (CML). Quantitative detection of TREC and bcr-abl fusion gene transcripts in peripheral blood from 15 CML patients were preformed by real-time PCR. The change of bcr-abl levels in 6 patients was followed-up for two years. The results showed that there was no significant correlation between TREC and bcr-abl mRNA levels in peripheral blood from CML patients for the first attack. Patients who had higher TREC at diagnosis had a larger reduction of bcr-abl after 2 years of follow-up. While out of 2 patients who underwent haemopoietic stem cell transplantation (HSCT), one patient with higher level of TREC before transplantation was confirmed to express undetectable level of TREC by three consecutive detections after transplantation, other one patient was identified to express low level of bcr-abl. It is concluded that high thymic output function in CML patients can be beneficial for killing the residual CML cells.


Asunto(s)
Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Fusión bcr-abl , Genética , Reordenamiento Génico , Leucemia Mielógena Crónica BCR-ABL Positiva , Alergia e Inmunología , Proteínas Proto-Oncogénicas c-abl , Genética , Proteínas Proto-Oncogénicas c-bcr , Genética , ARN Mensajero , Genética , Receptores de Antígenos de Linfocitos T , Alergia e Inmunología , Linfocitos T , Química , Alergia e Inmunología , Timo , Alergia e Inmunología
11.
Chinese Journal of Biotechnology ; (12): 698-702, 2005.
Artículo en Inglés | WPRIM | ID: wpr-237088

RESUMEN

The c-Abl nonreceptor tyrosine kinase is activated in the cellular responses to genotoxic, oxidative and other forms of stress. Using tagged forms of c-Abl, the present studies demonstrate that c-Abl forms homodimers in cells. The results show that the c-Abl N-terminal regions interact with the corresponding C-terminal regions of both partners in the dimmer. Specifically, the c-Abl SH3 domain binds to a proline-rich motif at amino acids 958-982 in the c-Abl C-terminal region. Deletion of the proline-rich motif disrupts dimmer formation. These findings provide the first evidence that c-Abl forms homodimers and indicate that homodimerization can contribute to the regulation of c-Abl activity.


Asunto(s)
Humanos , Multimerización de Proteína , Proteínas Proto-Oncogénicas c-abl , Genética , Metabolismo , Dominios Homologos src
12.
Zhongguo yi xue ke xue yuan xue bao ; Zhongguo yi xue ke xue yuan xue bao;(6): 11-14, 2002.
Artículo en Chino | WPRIM | ID: wpr-280974

RESUMEN

<p><b>OBJECTIVE</b>To study the effects of anti-ABL tyrosine kinase intrabody on the growth of human chronic myelogenous leukemia (CML) cells in nude mice.</p><p><b>METHODS</b>A recombinant retroviral vector MSCV-ibE-IRES-eGFP was constructed to express intracellular single-chain antibody (intrabody) against ABL tyrosine kinase domain in CML cells. K562 cells were transduced with the retrovirus, eGFP+ cells were then selected by fluorescence-activated cell sorting (FACS). The intrabody mRNA expression was determined by reverse transcription (RT)-polymerase chain reaction (PCR). BCR/ABL and c-ABL protein tyrosine kinase (PTK) activity in the cells was examined. Transduced cells and control group K562 cells were transplanted into nude mice respectively and the tumor sizes were dynamically observed.</p><p><b>RESULTS</b>K562-ibE cell was obtained. Expression of the BCR/ABL and c-ABL protein tyrosine kinase activity of harvested K562-ibE cells were markedly inhibited. At 14, 21 and 28 days after cell injection, the tumor volumes of experimental mice were obviously smaller than that of control mice, about one half of the control groups (P < 0.05).</p><p><b>CONCLUSION</b>The growth of K562-ibE cells was significantly inhibited in vivo. It is possible that inhibition of the BCR/ABL protein tyrosine kinase activity by the intrabody blocked BCR/ABL signal transduction pathway, promoted apoptosis and reduced tumorigenicity of K562 cells in vivo.</p>


Asunto(s)
Animales , Humanos , Ratones , Anticuerpos , Genética , Apoptosis , División Celular , Proteínas de Fusión bcr-abl , Genética , Alergia e Inmunología , Vectores Genéticos , Células K562 , Ratones Desnudos , Trasplante de Neoplasias , Proteínas Tirosina Quinasas , Alergia e Inmunología , Metabolismo , Proteínas Proto-Oncogénicas c-abl , Genética , Alergia e Inmunología , Retroviridae , Genética
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