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1.
Artigo em Inglês | MEDLINE | ID: mdl-32222985

RESUMO

A disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) was mainly generated and secreted from endothelial cells (ECs). Our previous study showed that tryptophan (Trp) residues at 387 and 390 in ADAMTS13 are required for its secretion and enzymatic activity. However, the effects on its host cell as well as the potential mechanism have not been clear. The aim of the study was to examine the effects of Trp residues 387 and 390 of ADAMTS13 on the biological processes of ECs. Herein, Trp was substituted with alanine in ADAMTS13 to generate ADAMTS13 mutants at 387 (W387A), 390 (W390A), and double mutants at 387 and 390 (2WA), respectively. We found that substitution mutation impaired vascular endothelial growth factor (VEGF) secretion and the downstream JAK1/STAT3 activation, the binding ability to Von Willebrand factor (VWF), cell proliferation, migration, and vascular tube formation. Overall, our study concluded that Trp387 and Trp390 of ADAMTS13 play vital roles in the biological function of ECs.

2.
JAMA Oncol ; 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31944221

RESUMO

Importance: A randomized clinical trial is needed to determine whether the second-generation Abl-tyrosine kinase inhibitor dasatinib is more effective than the first-generation inhibitor imatinib mesylate for childhood Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). Objective: To determine whether dasatinib given at a daily dosage of 80 mg/m2 is more effective than imatinib mesylate at a daily dosage of 300 mg/m2 to improve event-free survival of children with Philadelphia chromosome-positive ALL in the context of intensive chemotherapy without prophylactic cranial irradiation. Design, Setting, and Participants: This open-label, phase 3 randomized clinical trial was conducted at 20 hospitals in China. Enrollment occurred from January 1, 2015, through September 18, 2018, and randomization was stopped on October 4, 2018, when the early stopping criterion of the trial was met. Patients aged 0 to 18 years were recruited. Of the 225 patients with the diagnosis, 35 declined participation and 1 died before treatment, leaving 189 patients available for analysis. Data were analyzed from January 1 through August 4, 2019. Interventions: Patients were randomized to receive daily dasatinib (n = 92) or imatinib (n = 97) continuously for the entire duration of ALL therapy from the time of diagnosis made during remission induction to the end of continuation therapy. Main Outcomes and Measures: The primary outcome was event-free survival, analyzed based on intention to treat. The secondary outcomes were relapse, death due to toxic effects, and overall survival. Results: Among the 189 participants (136 male [72.0%]; median age, 7.8 [interquartile range (IQR), 5.2-11.3] years) and a median follow-up of 26.4 (IQR, 16.3-34.1) months, the 4-year event-free survival and overall survival rates were 71.0% (95% CI, 56.2%-89.6%) and 88.4% (95% CI, 81.3%-96.1%), respectively, in the dasatinib group and 48.9% (95% CI, 32.0%-74.5%; P = .005, log-rank test) and 69.2% (95% CI, 55.6%-86.2%; P = .04, log-rank test), respectively, in the imatinib group. The 4-year cumulative risk of any relapse was 19.8% (95% CI, 4.2%-35.4%) in the dasatinib group and 34.4% (95% CI, 15.6%-53.2%) in the imatinib group (P = .01, Gray test), whereas the 4-year cumulative risk of an isolated central nervous system relapse was 2.7% (95% CI, 0.0%-8.1%) in the dasatinib group and 8.4% (95% CI, 1.2%-15.6%) in the imatinib group (P = .06, Gray test). There were no significant differences in the frequency of severe toxic effects between the 2 treatment groups. Conclusions and Relevance: Intensive chemotherapy including dasatinib at a dosage of 80 mg/m2 per day yielded superior results in the treatment of Philadelphia chromosome-positive ALL compared with imatinib mesylate at a dosage of 300 mg/m2 per day and provided excellent control of central nervous system leukemia without the use of prophylactic cranial irradiation. Trial Registration: Chinese Clinical Trial Registry: ChiCTR-IPR-14005706.

3.
Am J Transl Res ; 11(10): 6522-6533, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31737203

RESUMO

Treatment and prognosis of Fanconi anaemia (FA) and acquired aplastic anaemia (AA) differ. However, delayed and inappropriate treatments are administered in FA due to its similarities to AA in presentation. The objective of the current study was to elucidate differences between the molecular mechanisms underlying FA and AA as well as to identify biomarkers and pathways associated with FA via bioinformatics analyses. Proteomic data were obtained from bone marrow samples of patients with FA and AA. Gene ontology analysis was performed using a Database for Annotation, Visualization and Integrated Discovery. KEGG pathway enrichment analyses were conducted using the ClueGO plug-in in Cytoscape. A DEP-associated protein-protein interaction (PPI) network was constructed using STRING and visualized in Cytoscape. A total of 114 DEPs, including 71 upregulated proteins and 43 downregulated proteins, were present in the FA samples, compared with those in the AA samples. Upregulated proteins were enriched in the nucleosome assembly, canonical glycolysis, glycolytic process, and the glycolysis/gluconeogenesis pathway, whereas downregulated proteins were enriched in relation to immune response, negative regulation of apoptosis, proteolysis and CoA biosynthesis. Eight hub proteins with a high degree of connectivity were obtained as follows: alpha-enolase (ENO1), HSP90AA1, phosphoglycerate kinase 1 (PGK1), HSP90AB1, ACTC1, ACTBL2, EEF1A1 and CFL1. Upregulation of ENO1 and CFL1 in patients with FA was confirmed through a WB experiment, and substantiated by the results of data analyses. Bioinformatics analyses are useful for identification of biomarkers and pathways associated with FA and AA. Some crucial DEPs, such as ENO1, PGK1, ACTC1, ACTBL2, EEF1A1 and CFL1, may play an important role in FA and show potential as serological markers for its early diagnosis.

4.
World J Clin Cases ; 7(21): 3622-3631, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31750346

RESUMO

BACKGROUND: Timely reconstitution of a donor-derived immune system is important for recovery and long-term survival of patients after allogeneic hematopoietic stem cell transplantation (HSCT). We describe a case of Wiskott-Aldrich syndrome (WAS) treated by umbilical cord blood transplantation (UCBT) with atypical immune reconstruction. CASE SUMMARY: A 1-year-old Chinese male infant was diagnosed with WAS. WAS gene sequencing identified the mutation c.777 + 1G>A (IVS8). On August 8, 2017, he was admitted to our hospital for HSCT. We selected an unrelated Human leukocyte antigen 6/10-matched donor for UCBT. After HSCT, the immune reconstitution process was atypical, the lymphocytes reached 0.5 × 109/L on day 23, and the neutrophils reached 0.5 × 109/L on day 34. The patient's recovery throughout the year was good. CONCLUSION: An increase in lymphocytes (especially T cells) earlier than granulocytes may be a marker of a good prognosis in UCBT.

5.
J Med Econ ; 22(8): 742-750, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30939962

RESUMO

Aims: To conduct a lifetime cost-effectiveness analysis (CEA) of rasburicase compared with standard of care (SOC) for tumor lysis syndrome (TLS) in children with hematologic malignancies from the Chinese healthcare system perspective. Materials and methods: The CEA was performed using a decision tree model with a lifetime horizon. The model explores the cost-effectiveness of rasburicase vs SOC for both preventing TLS and treating established TLS among pediatric patients with acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), and non-Hodgkin's lymphoma (NHL). Both the prophylaxis-use model and treatment-use model incorporate long-term health states of the diseases: survival without TLS and death. The efficacy data of rasburicase and SOC were obtained from published literature. Drug costs, healthcare resource utilization (HRU), and adverse event (AE) management costs were obtained via a published study with clinical experts. Costs in US dollar and quality-adjusted life year (QALY) are reported, and incremental cost-effectiveness ratios (ICERs) were also calculated. Uncertainties due to parameter fluctuations in the model were assessed through one-way sensitivity analysis and probabilistic sensitivity analysis (PSA). Results: During TLS prevention, compared with SOC, the ICER of rasburicase treatment in China are $17,580.04/QALY, $5,783.45/QALY, and $5,391.00/QALY for pediatric patients with AML, ALL, and NHL, respectively. For the established TLS treatment, compared with SOC, the ICERs of rasburicase treatment are $2,031.18/QALY, $1,142.93/QALY, and $990.37/QALY for pediatric patients with AML, ALL, and NHL, respectively. Limitations: The clinical data for SOC are based on the published study in China, and the rasburicase prevention or treatment failure rate was either calculated based on the risk ratio or directly from the clinical study among non-Chinese pediatric patients. Another study limitation was the lack of utility data for pediatric patients with TLS and without TLS. Thus, the utility scores of pediatric cancer survivors were used as an alternative. Conclusion: Rasburicase is estimated to be a cost-effective alternative to SOC in the prevention and treatment of TLS among Chinese pediatric patients with AML, ALL, and NHL.


Assuntos
Supressores da Gota/economia , Supressores da Gota/uso terapêutico , Síndrome de Lise Tumoral/tratamento farmacológico , Síndrome de Lise Tumoral/prevenção & controle , Urato Oxidase/economia , Urato Oxidase/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , China , Análise Custo-Benefício , Recursos em Saúde/economia , Recursos em Saúde/estatística & dados numéricos , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Anos de Vida Ajustados por Qualidade de Vida , Padrão de Cuidado , Síndrome de Lise Tumoral/etiologia
6.
Cancer Med ; 8(5): 2553-2560, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30848099

RESUMO

BACKGROUND: In the past decade, miR-100, miR-146a, and miR-210 were reported to be dysregulated in childhood acute lymphoblastic leukemia (ALL). However, effects of genetic variants in these three microRNAs have not been investigated in Chinese population. METHODS: In this study, we conducted a case-control study to evaluate the relationship between genetic variants in miR-100, miR-146a, and miR-210 and the risk of childhood ALL in Chinese population. Subsequently, plasma expression level of miR-100 was also detected. RESULT: We found that subjects carrying mutant homozygous TT genotype of miR-100 rs543412 had a statistically significantly decreased risk of childhood ALL (adjusted odds ratio [OR] = 0.73, 95% confidence interval [CI] = 0.55-0.97, P = 0.029). This protective effect was also observed among subjects whose parents were ever drinkers (adjusted OR = 0.53, 95% CI = 0.29-0.94), or whose living house were ever painted (adjusted OR = 0.57, 95% CI = 0.34-0.94). Besides, rs543412 variant homozygous TT had a significantly protective role in patients with childhood B-ALL. Finally, we found that expression level of miR-100 in plasma of childhood ALL cases was significantly higher than that of noncancer controls. CONCLUSION: Our study suggested that there was significant association between the polymorphisms in miR-100 (rs543412) and decreased susceptibility to childhood ALL.

7.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(1): 7-13, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-30738440

RESUMO

OBJECTIVE: To investigate the mechanism of Paris forrestii (Takht.) H. Li (PCT3)-suppressing the proliferation of HL-60, K562, KG-1 and HT-93 cells. METHODS: cute myeloid leukemia cell lines such as HL-60, K562, KG-1 and HT-93 were treated with Paris forrestii (Takht.) H. Li (PCT3) for 24, 48, and 72 h, and MTT assay was employed to determine the cells proliferation. Meanwhile, the apoptosis of K562, HL-60, KG-1 and HT-93 cells were detected by flow cytometry after PCT3 (Control, 4 µg/ml, 8 µg/ml) treated for 24 h and the Western blot was performed to detect the expression of PARP,Caspase-3, MCL-1, BAX, BCL-2, P53, and P27. GAPDH was used as an internal loading control. RESULTS: MTT assay showed that Paris forrestii (Takht.) H. Li (PCT3) significantly inhibited the proliferation of HL-60, K562, KG-1 and HT-93 cells in concentration and time-dependent manners. Compared with the control group, the leukemia cell viabilities were significantly suppressed (r =0.9436; r =0.8623; r =0.9922; r =0.8918). Paris forrestii (Takht.) H. Li (PCT3) induced apoptosis of leukemia cells in a concentration dependent manner, compared with the control group (P<0.05 or P<0.01). Western blot revealed that PARP, a major enzyme in DNA damage repair, and Caspase-3 another one of the major executive apoptotic enzymes were cleaved in cell lines examined, and this cleavage was concentration dependent. Anti-apoptotic proteins such as MCL-1 and BCL-2 were down regulated by Paris forrestii (Takht.) H. Li (PCT3), and Pro-apoptotic protein BAX was upregulated. And the protein of tumor suppressor gene P53 and its downstream signaling protein P27 increased. CONCLUSION: Paris forrestii (Takht.) H. Li (PCT3) can inhibit the proliferation of leukemia cells by activating endogenous apoptosis pathway, and provide a potential new drug selection for clinical treatment of AML leukemia.


Assuntos
Leucemia Mieloide Aguda , Apoptose , Caspase 3 , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Melanthiaceae , Proteínas Proto-Oncogênicas c-bcl-2
8.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(1): 246-252, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-30738478

RESUMO

OBJECTIVE: To investigate the gene mutation of patients with WAS gene defect and its correlation with clinical manifestations. METHODS: Thirty-one patients consulted in Children's Hospital of Soochow University from January 2013 to February 2018 were enrolled in this study. The hot pot mutations of WAS gene in 31 patients were detected and related clinical phenotypes were analyzed retrospectively. RESULTS: All patients were male. The median onset age was 1 month (range, 0-83 months). Nine mutants were reported as novel mutations among 25 mutants detected in 31 patients, including c.1234_1235dupCC, c.1093-1097delG, c.28-30dupC, c.436G>T, c.273 + 10_273 + 11dupCC, c.995_996insG, c.1010T>A, c.332_333delCC and c.683C>T mutations. There were 25 cases of classic WAS which mutations included missense mutation, deletion mutation, insertion mutation, splicing mutation and nonsense mutation, 2 cases of X-linked thrombocytopenia (XLT) were induced by missense mutation, 1 case of intermittent X-linked thrombocytopenia (IXLT) was induced by splicing mutation, 2 cases of X-linked pancytopenia were induced by missense mutation. Intravenous immunoglobulin (IVIG) and glucocorticoid therapy in IXLT patient was effective, and remission could be sustained, platelets could be increased in the short-term in treated XLT patients, but only a small part of classic WAS patients(8.0%) showed transient response to it, the IVIG and glucocorticoid therapy did not improve the status of platelet in XLP patients. Immune laboratory examination showed that CD3+ was decreased in 60.0% patients, CD19+ was decreased in 12.0% patients, and CD56+CD16+ in 4 patients was decreased, accounting for 16.0%. Out of 24 patients, 22 patients were alive after treated with hematopoietic stem cell transplantation (HSCT), 4 patients who were not given HSCT died of brain bleeding and severe infection, 1 patient diagnosed as IXLT got remission and survived. CONCLUSION: WAS gene defect is an important basis for the diagnosis of WAS and related diseases. IVIG plus glucocorticoid therapy is less effective for fewer patients, the HSCT is an effective treatment for WAS.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X , Trombocitopenia , Proteína da Síndrome de Wiskott-Aldrich/genética , Humanos , Masculino , Mutação , Fenótipo , Estudos Retrospectivos
9.
Arch Dis Child ; 104(6): 522-529, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30705079

RESUMO

OBJECTIVES: Before 2003, most children with acute lymphoblastic leukaemia (ALL) abandoned treatment, with only approximately 30% treated in China. With the development of national insurance for underprivileged patients, we assessed the current frequency and causes of treatment abandonment among patients with ALL who were enrolled in the Chinese Children's Cancer Group ALL protocol between 2015 and 2016. METHODS: Demographic, clinical and laboratory data on patients who abandoned treatment, as well as economic and sociocultural data of their families were collected and analysed. General health-related statistics were retrieved from publicly accessible databanks maintained by the Chinese government. RESULTS: At a median follow-up of 119 weeks, 83 (3.1%, 95% CI 2.5% to 3.8%) of the 2641 patients abandoned treatment. Factors independently associated with abandonment included standard/high-risk ALL (OR 2.62, 95% CI 1.43 to 4.77), presence of minimal residual disease at the end of remission induction (OR 3.57, 95% CI 1.90 to 6.74) and low-income economic region (OR 3.7, 95% CI 1.89 to 7.05). According to the family members, economic constraints (50.6%, p=0.0001) were the main reason for treatment abandonment, followed by the belief of incurability, severe side effects and concern over late complications. CONCLUSIONS: The rate of ALL treatment abandonment has been greatly reduced in China. Standard/high-risk ALL, residence in a low-income region and economic difficulties were associated with treatment abandonment. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR-IPR-14005706, pre-results.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Recusa do Paciente ao Tratamento/estatística & dados numéricos , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , China , Feminino , Seguimentos , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Lactente , Recém-Nascido , Masculino , Neoplasia Residual , Pacientes Desistentes do Tratamento/estatística & dados numéricos , Indução de Remissão , Estudos Retrospectivos , Fatores Socioeconômicos
10.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 26(4): 1033-1037, 2018 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-30111403

RESUMO

OBJECTIVE: To evaluate the therapeutic safety and efficacy of VDMP re-induction regimen in Chinese children with relapsed acute lymphoblastic leukemia (ALL). METHODS: Forty-one patients with relapsed ALL were prospectively enrolled in this study. All the patients were distributed in 3 children's hospitals and treated with VDMP regimen as the first re-induction chemotherapy. Therapeutic efficacy and side-effects were analyzed. RESULTS: The ratio of male to female was 27:14. The median age was 7.9 (2.2-15.4) years old. Patients relapsed at very early, early, and late stage were 7 cases, 11 cases, and 23 cases, respectively.The immunophenotype analysis showed that 38 cases were B-ALL, and 3 cases were T-ALL. All patients suffered from grade 4 of neutropenia and forty(97.6%) cases got infection, of them one case died. Thirty-nine(95.1%) cases had nonhematologic adverse event at least one organ involved grade 3 in 38 out of 41 cases, the VDMP therapy was completed, 34(89.5%) cases achieved a complete remission (CR), 1 case achieved partial remission(PR), and 3 cases didn't get remission. Follow-up data of 38 cases with completing VDMP chemotherapy were obtained, only one case was lost. Among 37 cases available for evaluation, 16 cases received allo-hematopoietic stem cell transplantation(allo-HSCT) after chemotherapy, and 13 patients survived, while 21 cases did not receive allo-HSCT(treated with chemotherapy only), and 8 patients survived.The overall survival rate of allo-HSCT group was significantly higher than that of those treated with chemotherapy only(P<0.05). CONCLUSION: VDMP re-induction regimen is effective and well tolerable for pafients in the treated children with relapsed ALL. After remission, allo-HSCT is recommended with the aim of long survival.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica , Criança , Pré-Escolar , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Quimioterapia de Indução , Masculino , Indução de Remissão , Resultado do Tratamento
11.
Front Pharmacol ; 9: 673, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29997504

RESUMO

Saponins are amphipathic glycosides found in traditional Chinese medicines. In the present study, we isolated a panel of saponins from Paris forrestii (Takht.) H. Li, a unique plant found in Tibet and Yunnan provinces, China. By examining their activities in suppressing acute myeloid leukemia (AML) cell proliferation, total saponins from Paris forrestii (TSPf) displayed more potent activity than individual ones. TSPf induced more than 40% AML cell apoptosis and decreased the viability of all leukemia cell lines. TSPf-induced apoptosis was confirmed by both Annexin V staining and caspase-3 activation. In line with these findings, TSPf downregulated pro-survival proteins Mcl-1, Bcl-xL, and Bcl-2 but upregulated the expression of tumor suppressor proteins p53, p27, Bax, and Beclin 1. The AKT/mTOR signaling pathway is frequently overactivated in various AML cells, and TSPf was found to suppress the activation of both AKT and mTOR, but had no effects on their total protein expression. This was further confirmed by the inactivation of 4EBP-1 and p70S6K, two typical downstream signal molecules in the AKT/mTOR pathway. Moreover, TSPf-inactivated AKT/mTOR signaling was found to be associated with downregulated RNF6, a recently identified oncogene in AML. RNF6 activated AKT/mTOR, and consistently, knockdown of RNF6 led to inactivation of the AKT/mTOR pathway. Furthermore, TSPf suppressed the growth of AML xenografts in nude mice models. Oral administration of TSPf almost fully suppressed tumor growth without gross toxicity. Consistent with the findings in cultured cell lines, TSPf also downregulated RNF6 expression along with inactivated AKT/mTOR signaling in tumor tissues. This study thus demonstrated that TSPf displays potent anti-AML activity by suppressing the RNF6/AKT/mTOR pathway. Given its low toxicity, TSPf could be developed for the treatment of AML.

12.
Clin Exp Pharmacol Physiol ; 45(11): 1181-1186, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29920743

RESUMO

Functional deficiency of A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)13 causally assists in the pathology of thrombotic thrombocytopenic purpura (TTP). Previous study showed that the WXXW motif is very important to the enzymatic activity of ADAMTS13. However, the functional role for a single amino acid residue within WXXW motif is still undetermined. Here, Trp390 residue within WXXW motif was substituted with Ala to generate Trp390Ala (W390A) mutant ADAMTS13. We found that W390A mutant ADAMTS13 had impaired binding affinity to its substrate Von Willebrand factor (VWF). Moreover, W390A mutant retarded ADAMTS13 secretion, leading to its deposition in endoplasmic reticulum. Compared with the wild type ADAMTS13, W390A mutant also had a decreased cleavage activity for multimeric VWF under both static and shear stress conditions. These data indicate that Trp390 residue within the WXXW motif is required for ADAMTS13 secretion and enzymatic activity, which provide insight into understanding the pathological basis of TTP and opens new avenues for exploring potential treatment strategies.


Assuntos
Proteína ADAMTS13/química , Proteína ADAMTS13/metabolismo , Triptofano , Proteína ADAMTS13/genética , Motivos de Aminoácidos , Sequência de Aminoácidos , Humanos , Mutação , Ligação Proteica , Fator de von Willebrand/metabolismo
13.
Acta Haematol ; 139(3): 176-182, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29614500

RESUMO

The 8p11 myeloproliferative syndrome (EMS) is an aggressive neoplasm associated with chromosomal translocations involving the fibroblast growth factor receptor 1 (FGFR1) tyrosine kinase gene on chromosome 8p11-12. A new case of a 9-year-old boy with leukocytosis, eosinophilia, and general lymphadenopathy is reported in this study. Bone marrow examination showed eosinophilic hyperplasia, with blast cells amounting to 6-7%. Karyotyping revealed cytogenetic abnormalities, including t(8;9)(p11.2;q3?3). Fluorescence in situ hybridization for the FGFR1 gene rearrangement yielded positive results. Lymph node biopsy confirmed the diagnosis of precursor T-lymphoblastic lymphoma. The patient responded to chemotherapy, and unmatched related bone marrow transplantation was performed. A successful outcome was obtained with complete cytogenetic remission maintained for 14 months to date. In the future, FGFR1 inhibitors might be specific and effective therapeutic targets for EMS. Similar cases from the literature are reviewed.


Assuntos
Cromossomos Humanos Par 8 , Cromossomos Humanos Par 9 , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocação Genética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Medula Óssea/patologia , Criança , Bandeamento Cromossômico , Suscetibilidade a Doenças , Estudos de Associação Genética , Humanos , Hibridização in Situ Fluorescente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Resultado do Tratamento
14.
Am J Hematol ; 93(7): 913-920, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29675840

RESUMO

Acute lymphoblastic leukemia (ALL) is the most common malignancy among children. The trial Chinese Children Leukemia Group (CCLG)-ALL 2008 was a prospective clinical trial designed to improve treatment outcome of childhood ALL through the first nation-wide collaborative study in China. Totally 2231 patients were recruited from ten tertiary hospitals in eight cities. The patients were stratified according to clinical-biological characteristics and early treatment response. Standard risk (SR) and intermediate risk (IR) groups were treated with a modified BFM based protocol, and there was 25%-50% dose reduction during intensification phases in the SR group. Patients in high risk (HR) group received a more intensive maintenance treatment. Minimal residual disease (MRD) monitoring with treatment adjustment was performed in two hospitals (the MRD group). Complete remission (CR) was achieved in 2100 patients (94.1%). At five years, the estimate for overall survival (OS) and event-free survival (EFS) of the whole group was 85.3% and 79.9%, respectively. The cumulative incidence of relapse (CIR) was 15.3% at five years. The OS, EFS and CIR for the SR group were 91.5%, 87.9%, and 9.7%, respectively. The outcome of the MRD group is better than the non-MRD group (5y-EFS: 82.4% vs 78.3%, P = .038; 5y-CIR: 10.7% vs 18.0%, P < .001). Our results demonstrated that the large-scale multicenter trial for pediatric ALL was feasible in China. Dose reduction in the SR group could achieve high EFS. MRD-based risk stratification might improve the treatment outcome for childhood ALL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Adolescente , Criança , Pré-Escolar , China , Feminino , Humanos , Masculino , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Estudos Prospectivos , Recidiva , Indução de Remissão , Medição de Risco , Análise de Sobrevida , Centros de Atenção Terciária , Resultado do Tratamento
15.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 26(1): 16-20, 2018 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-29397812

RESUMO

OBJECTIVE: To investigate the effects and mechanism of CCL2 on the migration and invasion of human leukemia cell THP-1. METHODS: The CCL2 gene was recombined with the transfer plasmid-PLVX and transfected into THP-1 cells. The CCL2 expression at RNA level was detected by RT-PCR, the CCL2 expression at protein level was determined by Western blot and ELISA, the influence of overexpression of CCL2 recombinant protein and THP-1 cells on the migration and invasion ability of THP-1 cells was analyzed by transwell migration and invasion tests, the PCR-array of migration-related cytokines was used to clarify the patential mechanism. RESULTS: With the Trans-Matrigel assay, the concentration of CCL2 in THP-1 transfected with CCL2 in the upper cells was higher than that in the lower cells, meanwhile, the invasion ability of CCL2-transfected THP-1 cells decreased. Increasing recombinant protein of CCL2 (rpCCL2) in the lower cells promoted migration of THP-1 cells. Migration RT2 profiler PCR array showed that the cells treated with rpCCL2 had higher levels of expression of CCL2, EPX, SPP1, CX3CL1 and CXCL13, as compared with control group. CONCLUSION: CCL2 affects the migration and invasion of THP-1 by autosecreting a series of inflammatory chemokines.


Assuntos
Quimiocina CCL2/metabolismo , Western Blotting , Movimento Celular , Proliferação de Células , Humanos , Células THP-1 , Transfecção
16.
BMC Cancer ; 18(1): 67, 2018 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-29321004

RESUMO

BACKGROUND: Small GTP binding protein Rac1 is a component of NADPH oxidases and is essential for superoxide-induced cell death. Rac1 is activated by guanine nucleotide exchange factors (GEFs), and this activation can be blocked by regulator of chromosome condensation 2 (RCC2), which binds the switch regions of Rac1 to prevent access from GEFs. METHODS: Three cancer cell lines with up- or down-regulation of RCC2 were used to evaluate cell proliferation, apoptosis, Rac1 signaling and sensitivity to a group of nine chemotherapeutic drugs. RCC2 expression in lung cancer and ovarian cancer were studied using immunochemistry stain of tumor tissue arrays. RESULTS: Forced RCC2 expression in tumor cells blocked spontaneous- or Staurosporine (STS)-induced apoptosis. In contrast, RCC2 knock down in these cells resulted in increased apoptosis to STS treatment. The protective activity of RCC2 on apoptosis was revoked by a constitutively activated Rac1, confirming a role of RCC2 in apoptosis by regulating Rac1. In an immunohistochemistry evaluation of tissue microarray, RCC2 was over-expressed in 88.3% of primary lung cancer and 65.2% of ovarian cancer as compared to non-neoplastic lung and ovarian tissues, respectively. Because chemotherapeutic drugs can kill tumor cells by activating Rac1/JNK pathway, we suspect that tumors with RCC2 overexpression would be more resistant to these drugs. Tumor cells with forced RCC2 expression indeed had significant difference in drug sensitivity compared to parental cells using a panel of common chemotherapeutic drugs. CONCLUSIONS: RCC2 regulates apoptosis by blocking Rac1 signaling. RCC2 expression in tumor can be a useful marker for predicting chemotherapeutic response.


Assuntos
Proteínas Cromossômicas não Histona/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Neoplasias Pulmonares/genética , Neoplasias Ovarianas/genética , Proteínas rac1 de Ligação ao GTP/genética , Apoptose/efeitos dos fármacos , Biomarcadores Farmacológicos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Estaurosporina/farmacologia
17.
Leuk Res ; 65: 20-24, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29253671

RESUMO

Genomic alterations underlying chemotherapy resistance remains poorly characterized in pediatric acute myeloid leukemia (AML). In this study, we used whole exome sequencing to identify gene mutations associated with chemo-resistance in 44 pediatric AML patients. We identified previously unreported mutations involving epigenetic regulators such as KDM5C, SRIT6, CHD4, and PRPF6 in pediatric AML patients. Despite low prevalence in general pediatric AML, mutations involving epigenetic regulators including splicing factors, were collectively enriched as a group in primary chemo-resistance AML patients. In addition, clonal evolution analysis of secondary chemo-resistance AML patients reveals dominant clone at diagnosis could survive several course of intensified chemotherapy. And gain of new mutations in genes such as MVP, TCF3, SS18, and BCL10, may contribute to chemo-resistance at relapse. These results provide novel insights into the genetic basis of treatment failure in pediatric AML.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Resistencia a Medicamentos Antineoplásicos/genética , Epigênese Genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Sequenciamento Completo do Exoma , Criança , China , Humanos , Leucemia Mieloide Aguda/etnologia
18.
Pediatr Transplant ; 22(1)2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29239497

RESUMO

This multicenter retrospective study included 184 children with malignant and non-malignant diseases who underwent UCBT between January 1998 and August 2012. The malignant disease group included 101 children with ALL, AML, CML, JMML, and MDS, and the non-malignant disease group included 83 children with PID, ß-thalassemia, IMD BMF, and HLH. The median duration to neutrophil and platelet engraftment was 16 and 35 days in the malignant disease group vs 15 and 38 days in the non-malignant disease group. The cumulative incidence of grade II-IV aGVHD and cGVHD was 25.6% and 13.5% in the malignant disease group vs 19.7% and 11.1% in the non-malignant disease group, respectively. The median duration and cumulative incidence of neutrophil and platelet engraftment, and the cumulative incidence of grade II-IV aGVHD and cGVHD were similar between the two groups. Of the 184 pediatric patients, 114 patients survived during a median follow-up period of 14 months (range 4-138). The 5-year OS and DFS were not statistically different between the two groups (56.3% and 46.1% in malignant disease group vs 68.5% and 52.8% in non-malignant disease group). The above results indicate that UCB is a viable source for HSCT for children with malignant or non-malignant diseases, especially in urgent cases.


Assuntos
Doenças da Medula Óssea/terapia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Síndromes de Imunodeficiência/terapia , Leucemia/terapia , Doenças Linfáticas/terapia , Doenças Metabólicas/terapia , Doadores não Relacionados , Adolescente , Doenças da Medula Óssea/mortalidade , Criança , Pré-Escolar , China , Transplante de Células-Tronco de Sangue do Cordão Umbilical/mortalidade , Feminino , Seguimentos , Humanos , Síndromes de Imunodeficiência/mortalidade , Lactente , Recém-Nascido , Leucemia/mortalidade , Doenças Linfáticas/mortalidade , Masculino , Doenças Metabólicas/mortalidade , Estudos Retrospectivos , Resultado do Tratamento
19.
Oncol Rep ; 38(5): 2705-2716, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29048629

RESUMO

Neuroblastoma is the most common extracranial solid childhood tumor. Despite the availability of advanced multimodal therapy, high-risk patients still have low survival rates. p21-activated kinase 4 (PAK4) has been shown to regulate many cellular processes in cancer cells, including migration, polarization and proliferation. However, the role of PAK4 in neuroblastoma remains unclear. In the present study, we demonstrated that PAK4 was overexpressed in neuroblastoma tissues and was correlated with tumor malignance and prognosis. To investigate the function of PAK4 in neuroblastoma, we used a small-molecule inhibitor that targets PAK4, that is, PF-3758309. Our results showed that PF-3758309 significantly induced cell cycle arrest at the G1 phase and apoptosis in neuroblastoma cell lines. Meanwhile, the inhibition of PAK4 by PF-3758309 increased the expression of CDKN1A, BAD and BAK1 and decreased the expression of Bcl-2 and Bax. In addition, we screened the target genes of PAK4 by PCR array and found that 23 genes were upregulated (including TP53I3, TBX3, EEF1A2, CDKN1A, IFNB1 and MAPK8IP2) and 20 genes were downregulated (including TNFSF8, Bcl2-A1, Bcl2L1, SOCS3, BIRC3 and NFKB1) after PAK4 inhibition by PF-3758309. Moreover, PAK4 was found to regulate the cell cycle and apoptosis via the ERK signaling pathway. In conclusion, the present study demonstrated, for the first time, the expression and function of PAK4 in neuroblastomas and the inhibitory effect of PF-3758309, which deserves further investigation as an alternative strategy for neuroblastoma treatment.


Assuntos
Neuroblastoma/genética , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirróis/farmacologia , Quinases Ativadas por p21/genética , Quinases Ativadas por p21/metabolismo , Adulto , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Estadiamento de Neoplasias , Neuroblastoma/tratamento farmacológico , Neuroblastoma/metabolismo , Regulação para Cima/efeitos dos fármacos
20.
EXCLI J ; 16: 197-209, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28507466

RESUMO

Differential expression of microRNAs (miRNAs) has been implicated in leukemogenesis. We investigate the expression pattern of miR-196b. Using quantitative real-time PCR (qRT-PCR), we detected the expression of miR-196b and its correlated genes (SMC1A/MLH1) in initial pediatric AML. A significant association was observed between overexpression of miR-196b and inferior overall survival of pediatric AML (Log Rank P<0.0001). AML M4/5 subtype, high white blood cell (WBC) count at presentation, MLL rearrangement, or FLT3-ITD mutation at diagnosis and non-remission group after the first induction chemotherapy possessed higher miR-196b expression. Furthermore, a positive relationship was found between the expression of miR-196b and SMC1A/MLH1 (Spearman's r=0.37 and 0.44, P=0.001 and <0.0001, respectively). Taken together, these findings suggest that differentially high expression of miR-196b in diagnostic marrow samples of pediatric AML is associated with unfavorable outcome, and miR-196b potentially can be a novel biomarker for the diagnosis, prognosis and treatment in pediatric AML.

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