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Homoharringtonine (HHT), a plant alkaloid from Cephalotaxus harringtonia, exhibits a unique anticancer mechanism and has been widely used in China to treat patients with acute myeloid leukemia (AML) since the 1970s. Trial SCMC-AML-2009 presented herein was a randomized clinical study designed based on our previous findings that pediatric AML patients younger than two years old may benefit from HHT-containing chemotherapy regimens. Patients randomized to arm A were treated with a standard chemotherapy regimen comprising mainly of anthracyclines and cytarabine (Ara-C), whereas patients in arm B were treated with HHT-containing regimens in which anthracyclines in all but the initial induction therapy were replaced by HHT. From February 2009 to November 2015, 59 patients less than 2 years old with de novo AML (other than acute promyelocytic leukemia) were recruited. A total of 42 patients achieved a morphologic complete remission (CR) after the first course, with similar rates in both arms (70.6% vs.72.0%). At the end of the follow-up period, 40 patients remained in CR and 5 patients underwent hematopoietic stem cell transplantation in CR, which could not be considered as events but censors. The 5-year event-free survival (EFS) was 60.2%±9.6% for arm A and 88.0%±6.5% for arm B (P= 0.024). Patients in arm B experienced shorter durations of leukopenia, neutropenia, and thrombocytopenia and had a lower risk of infection during consolidation chemotherapy with high-dosage Ara-C. Consequently, the homoharringtonine-based regimen achieved excellent EFS and alleviated hematologic toxicity for children aged younger than 2 years with de novo AML compared with the anthracycline-based regimen.
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Objective@#To evaluate the long-term efficacy and prognostic factors of childhood acute lymphoblastic leukemia (ALL) enrolled in Shanghai Children's Medical Center-Acute Lymphoblastic Leukemia-2005(SCMC-ALL-2005) multicenter study.@*Methods@#Between May 2005 and December 2014, 1 497 newly diagnosed ALL patients were enrolled and treated in 5 hospitals of SCMC-ALL-2005 study group, using risk-stratified SCMC-ALL-2005 protocol. Risk group classification and treatment intensity were based on clinical features, genetic abnormalities, early response to treatment and levels of minimal residual disease (MRD). Kaplan-Meier method was used to generate overall survival (OS) and event-free survival(EFS) curves. Cox proportional hazards models were used for multivariate analyses.@*Results@#The patients were followed up to December 31, 2016, the median follow-up time was 69 months (24-141 months). The 5-year and 10-year OS rates were (80.0±1.0)% and (76.0±2.0)%. The 5-year and 10-year EFS rates were (69.0±1.0)% and (66.0±2.0)%. The 5-year and 10-year relapse rates were (23.0±1.0)% and (25.0±2.0)%. The 5-year OS and EFS for low risk (LR), intermediate risk (IR) and high risk (HR) were (91.1±1.4)% and (83.3±1.8)%, (79.2±1.5)% and (68.9±1.7)%, (52.9±4.4)% and (30.0±3.8)%, respectively. MRD negative status (<0.01%) on day 55 was seen in 792 patients (82.8%) and positive MRD on day 55 was associated with poor prognosis (OR=1.9, 95%CI: 1.3-2.7, P=0.001). Twenty-four HR patients received allogeneic hematopoietic stem cell transplantation and 17(70.8%) of them were alive and in remission. A total of 164 severe adverse events occurred, 46 of them died, treatment-related mortality was 3.1%.@*Conclusions@#In this large sample research, the overall outcome for multi-center SCMC-ALL-2005 study was favorable. This helps to promote the standardized treatment of childhood ALL to the whole country. MRD results on day 55 of induction therapy have important prognostic and therapeutic implications.
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Objective To evaluate the outcomes of mature B-cell acute lymphoblastic leukemia(mature B-ALL) and to assess the safety and efficacy of the treatment protocol.Methods From February of 2003 to December of 2012,15 children were diagnosed as mature B-cell acute lymphoblastic leukemia/lymphoma possible (mature B-ALL/NHLp) in Shanghai Children's Medical Center(SCMC) were enrolled,and they were treated with SCMC-mature B-ALL/NHLp-2003 protocol.All of the clinical characteristics,therapeutic effects and long-term outcomes were analyzed.The statistical data were processed by SPSS 21.0.Results The median age on diagnosis was 8.7 years (1 year and 5 months to 14 years and 4 months).Among them,4 cases presented with local mass including maxillofacial tumors,neck and abdominal mass.The others had systemic manifestations such as fever and pale face.These neoplastic cells retained the expressions of surface membrane immunoglobulin M,terminal deoxynucleotidyl transferase,Cμ,CD10,CD19,cCD79 a differently.Follow-up was updated to November 30,2013.The median follow-up period was 80 months (39-128 months).Theestimated 5-year event free survival rate was (80.0 ± 10.3) ％.According to univariate analysis,increased lactate dehydrogenase level (＞ 4-times the normal value),increased serum ferritin level (＞ 2-times the normal value),no small residual disease markers were indepen-dent poor prognostic factors(x2 =5.49,4.89,5.49,all P ＜ 0.05).Conclusions SCMC-mature B-NHL/ALLp-2003 protocol is feasible and safe for children with mature B-ALL/NHLp,but more sample cases need to be investigated.
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Objectives To evaluate the clinical features, treatment scheme and long-term outcomes of stage 1、2 childhood neuroblastoma (NB). Methods The retrospective study included 49 newly diagnosed NB stage 1、2 patients from June 1998 to December 2010. Clinical data and long-term outcomes were analyzed. Results Twenty-four patients with stage 1 NB and twenty patients with stage 2 NB were found among all 237 patients with NB enrolled in this study. The median age at diagnosis was 25 months( 2 week to 9 year old),29 males and 20 females. Thirty-one patients (63.6%) without symptoms were discovered with tumor by physical or imaging examination. Thorax and abdomen were the most common sites of primary tumor (21 and 22 cases, accounting for 42.9% and 44.9% of all patients, respectively). Forty (81.6%) NB patients had favorable pathology classification. One patient was of MYCN amplification status. Urine vanilla mandelic acid was normal in 32 (91.4%) patients, and serum lactate dehydrogenase was less than five times of the normal value in all patients. Ten NB patients were treated ac-cording to the low-risk protocol who received surgery alone.Thirty-nine patients were treated according to intermediate-risk protocol who received both surgery and chemotherapy. All the patients achieved very good partial remission (100%).The medi-an follow-up period was 60 months(22 months to148months). Nine patients were lost after a follow up of 3 months in medi-an. The 2-、3-、5-year event free survival and overall survial of all 49 patients was 100%. Conclusions The prognosis for neu-roblastoma of stage 1、2 in this study was with 100%survival, which provides opportunity for further reduction of dosage and/or duration of episodes in chemotherapy.
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Objectives To evaluate the long-term outcomes of childhood low-or intermediate-risk neuroblastoma (NB) and their relevant prognostic factors. Methods A total of 70 new cases of low-or intermediate-risk NB diagnosed and treated by NB-99 protocol between 1999 and 2008 were analyzed retrospectively. Results Of these 70 NB patients, fourteen patients were in low-risk group and 56 were in intermediate-risk group. Sixty-seven patients reached complete remission (CR) or very good partial remission and 3 (5%) achieved partial remission. Ten patients relapsed. One patient occured second malignant neo-plasm. No patients died of chemotherapy-related adverse events or infections. The 5 year overall survival rate was 85.9%, event-free survival rate was 81.0%. Bone marrow infiltration, age at diagnosis, stage, lactate dehydrogenase level had a significant effect on prognosis. Conclusion Develop cytogenetic and molecular biology tests and pretreatment risk stratification are im-portant for further improvement of treatment protocol.
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Objectives To investigate the correlation between single nucleotide polymorphisms (SNP) in interleu-kin-15 (IL-15) and treatment response in childhood acute lymphoblastic leukemia (ALL). Methods Genomic DNA samples extracted from remission bone marrow cells of ALL patients were genotyped by MassArray. Five SNPs (rs10519612, rs10519613, rs17007695, rs17015014 and rs35964658) in IL-15 and their association to minimal residual disease (MRD) status in the end of induction therapy were studied. Results SNP rs17007695 was associated with the early response in children with ALL(P=0.049) and the incidence of positive MRD after induction therapy in CC genotype carriers was 1.8 times more than that in TT genotype carriers. Haplotype analysis of these five SNPs showed that the frequency of haplotype CACGG in MRD positive group was 2.1 times higher than that in MRD negative group (P=0.035). Conclusions IL-15 gene polymorphism was associated with the early treatment response in Han Chinese children with acute lymphoblastic leuke-mia.
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This study investigated the intracellular localization of asparagine synthetase (ASNS) in the relation with chemoresistance in leukemia. pIRES-GFP-ASNS-Flag/Neo expression vector was transiently tansfected into SK-N-MC cells and 297T cells respectively. Immunofluorescence and Western blot analysis were performed for cellular localization of ASNS respectively. U937 cells were treated with L-asparaginase for 48 h and examined for endogenous ASNS expression on plasma membrane by immunofluorescence staining. Immunofluorescence staining showed that the transiently expressed ASNS was partly localized on transfected-SK-N-MC cell surface. Moreover, Western blotting exhibited that ASNS expressed both in cytosol and on plasma membrane of transfected-293T cells. Immunofluorescence staining with anti-ASNS-specific monoclonal antibody revealed that endogenous ASNS was localized on the plasma membrane of U937 cells, except for its distribution in the cytosol. In addition, ASNS exhibited a higher expression on plasma membrane after treatment with L-asparaginase as compared with the untreated cells. It was concluded that the subcellular translocation of ASNS may play an important role in L-asparaginase resistance in leukemia cells.
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The Escherichia coli (E.coli) strain from intestinal tract of died newborn swine was isolated and cultured.Preliminary identification of the isolated strain was conducted by conventional biochemical tests,and the molecular biology detections of toxicity gene and typing gene were completed by multi-PCR.Stable toxin and heat-labile enterotoxin genes of E.coli were detected from the isolated strain.By amplifying and sequencing bacterial 16s rDNA and fliC gene,the isolated strain was identified as H10 by Blast analysis.The homology of strain H10 was 99% with bacterial 16s rDNA gene and 98% with fliC gene.
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Objective To assess the diagnostic potential of circulating galactomannan (GM),(1,3)-β-D-glucan (BG), and a combination of both biomarkers among high-risk pediatric patients.Methods Circulating GM antigen was detected by ELISA kits (Platelia~(TM) Aspergillus) and BG antigen by a turbidimetric kinetic method (GKT-5M Set Kinetic Fungus Detection Kit).Positive tests were defined by two consecutive values of GM index ≥0.5 or by a single value ≥0.8, and by BG detection ≥ 10 pg/ml.Results A total of 130 patients were enrolled.Two was identified with proven IFI, twenty probable IFI.Sensitivity, specificity were 81.8%, 82.4% for plasma BG detection, respectively; 75.0%, 94.4% for GM detection, respectively; 50.0%, 96.3% for combined GM and BG detection, respectively.Conclusions Both circulating GM and BG detections are available for most of the common pathogens and demonstrated desirable sensitivity and specificity among pediatric high-risk population.Both assays can be used as prospective screening tools.Combination of detections of both biomarkers would improve specificity for IA diagnosis.
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Single-nucleotide polymorphisms of the MyoG gene were tested using PCR-SSCP from 73 Landrace pigs, 68 Large White pigs, 57 Yimeng pigs and 83 Laiwu pigs. The effects of the MyoG gene on the birth weight, the average daily gain, the meat tenderness, and the backfat thickness were also analyzed. On the basis of the DNA sequence (M14331) of the porcine MyoG gene, primers were designed to amplify MyoG gene. One polymorphism was found in the amplified region of intron 1, in which two alleles ( A, and B) and three genotypes (AA, AB, and BB ) were examined. A G→ C transition was detected at 2 943 locus by sequencing the homozygotes. The results show that: ( 1 ) The Large White breed differed significantly ( P ＜0.05) in genotype distribution from the Landrace, the Laiwu and the Yimeng breeds;and the Laiwu breed differed significantly( P ＜ 0.05) in genotype distribution from the Landrace and the Yimeng breeds; whereas no significant differences( P ＞ 0.05) were found in genotype distribution between the Landrace and the Yimeng breeds. (2) On the basis of the fixed effect model, significant differences ( P ＜ 0.05) were found in the birth weight and the tenderness among the different MyoG genotypes, whereas no significant differences ( P ＞ 0.05)existed in the average daily gain and the backfat thickness. (3) Using least square analysis, it was seen that significant differences ( P ＜ 0.05) exist in the meat tenderness between the individuals of the BB genotypes and those of the AA genotypes; and significant differences ( P ＜ 0.05 ) were found in the backfat thickness compared the pigs of the AA genotypes with the pigs of the AB, BB genotypes. These results suggest that the MyoG genotype has significant effects on the meat quality, the growth rate, and the backfat thickness,therefore MyoG gene can be used in marker-assisted selection to improve meat quality and growth rate, and to accelerate the breeding progress.
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Acute myeloid leukemia (AML) is considered to be a malignancy that is intrinsically resistant to methotrexate (MTX). As compared to acute lymphoblastic leukemia (ALL) blasts, AML blasts, except those of acute monocytic leukemia (AML-M(5)), form fewer amounts of long chain polyglutamate of MTX (MTXPG), when incubated with MTX, thus providing an explanation for their lack of responsiveness to MTX. To explore the novel approach of treatment in patients with AML-M(5), the U937 cell line, which has the monocytic characters, was used. Cell growth inhibition was mearsured by XTT assay after 24 and 48 hours in the continuous presence of various concentrations of MTX ranging from 1 nmol/L to 100 micro mol/L. After 24 hours MTX treatment, the IC(50) value for U937 cells was 0.04 micro mol/L. After 48 hours treatment, the IC(50) was 0.037 micro mol/L and IC(90) was 0.39 micro mol/L. To understand the mechanism of MTX cytotoxicity, the process of cell death was analyzed. A variety of assays, including trypan blue exclusion, flow cytometry, light microscopy (Wright's staining) and DNA fragment electrophoresis, were performed. There were no significant apoptotie changes after shorter exposure of MTX (4 and 6 hours). After 8 hours at various concentrations of MTX treatment ranging from 5 nmol/L to 10 micro mol/L, the percentage of the cells in the pre-G(1) (apoptotic) was 3.2% at 0.1 micro mol/L and it reached a peak of 18.2% at 5.0 micro mol/L. The DNA synthesis in S-phase was inhibited from 41.2% (0.01 micro mol/L) to 19.1% (10 micro mol/L). DNA ladder band, a feature of apoptosis, was observed. The arrest of cell growth and apoptotic properties induced by MTX have lead to its evaluation as a potentially therapeutic agent in the treatment of AML-M(5).