Reduced intensity of early intensification does not increase the risk of relapse in children with standard risk acute lymphoblastic leukemia - a multi-centric clinical study of GD-2008-ALL protocol.

BACKGROUND: The prognosis of childhood acute lymphoblastic leukemia (ALL) is optimistic with a 5-year event-free survival (EFS) rate of 70-85%. However, the major causes of mortality are chemotherapy toxicity, infection and relapse. The Guangdong (GD)-2008-ALL collaborative protocol was carried out to study the effect of reduced intensity on treatment related mortality (TRM) based on Berlin-Frankfurt-Münster (BFM) 2002 backbone treatment. The study was designed to elucidate whether the reduced intensity is effective and safe for children with ALL. METHODS: The clinical data were obtained from February 28, 2008 to June 30, 2016. A total of 1765 childhood ALL cases from 9 medical centers were collected and data were retrospectively analyzed. Patients were stratified into 3 groups according to bone marrow morphology, prednisone response, age, genotype, and karyotype information: standard risk (SR), intermediate risk (IR) and high risk (HR). For SR group, daunorubicin was decreased in induction IA while duration was reduced in Induction Ib (2 weeks in place of 4 weeks). Doses for CAM were same in all risk groups - SR patients received one CAM, others got two CAMs. RESULTS: The 5-year and 8-year overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) were 83.5±0.9% and 83.1±1.0%, 71.9±1.1% and 70.9±1.2%, and 19.5±1.0% and 20.5±1.1%, respectively. The 2-year treatment-related mortality (TRM) was 5.2±0.5%. The 5-year and 8-year OS were 90.7±1.4% and 89.6±1.6% in the SR group, while the 5-year and 8-year EFS were 81.5±1.8% and 80.0±2.0%. In the SR group, 74 (15.2%) patients measured minimal residual disease (MRD) on Day 15 and Day 33 of induction therapy. Among them, 7 patients (9.46%) were MRD positive (≥ 0.01%) on Day 33. The incidence of relapse in the MRD Day 33 positive group (n=7) was 28.6%, while in the MRD Day 33 negative group (n=67) was 7.5% (p=0.129). CONCLUSIONS: The results of GD-2008-ALL protocol are outstanding for reducing TRM in childhood ALL in China with excellent long term EFS. This protocol provided the evidence for further reducing intensity of induction therapy in the SR group according to the risk stratification. MRD levels on Day 15 and Day 33 are appropriate indexes for stratification.

Determination of salsolinol N-methyltransferase activity in 6-OHDA-lesioned rats / 中国比较医学杂志

Objective The aim of this study was to establish a rat model of Parkinson''s disease ( PD) by using 6-hydroxydopamine (6-OHDA) and detect the salsolinol N-methyltransferase ( SNMT) activity in peripheral lymphocytes of PD rats for the development of a biomarker for early diagnosis of PD. Methods Rat model of PD was established by unilateral double-pointed injection of 6-OHDA into the striatum and was verified by behavior observation. An analytical method was developed based on multiple reaction monitoring with HPLC-ESI-QQQ to determine the SNMT activity in peripheral lymphocytes. Results Seven of 18 rats injected with 6-OHDA showed steadily apomorphine-induced rotation ( >7 r/min) . The success rate was 38. 9%. A sensitive and stable quantitative method with internal standard added was created, based on multiple reaction monitoring mode to analyze SNMT activity. The limit of detection ( LOD) and limit of quantitation ( LQD) of N-methyl-salsolinol, which is the product of Salsolinol catalyzed by SNMT, were 49 pmol/L and 98 pmol/L, respectively. The precisions of intra-day and inter-day assays both were below 6. 0%. SNMT activity of peripheral lymphocytes in the 6-OHDA-lesioned rats was significantly increased [43. 37 ±9. 49 pmol/(h·mg)NMSal] in comparison with that in the normal group [2. 16 ±5. 82 pmol/(h·mg)NMSal] and the sham-operated group [0. 58 ±2. 32 pmol/(h· mg)NMSal](P< 0. 01, n=5). There was no significant difference between the normal group and sham-operated group (P< 0. 05, n =5). Conclusions Our results indicate that SNMT activity may reflect the changes in the course of Parkison''s disease and may become a potential clinical biomarker in diagnosis of this disease.

Novel Algorithm for Identification and Quantification of Proteins Based on Strategy of Isobaric Peptide Termini Labelling / 分析化学

Isobaric peptide termini labeling ( IPTL) is a technology which uses light and heavy isotopes to label C-terminus and N-terminus of peptides. As the masses of labeled peptides are equivalent, the complexity of sample is low when analyzing MS data produced by this technology. Besides, paired b and y ions are helpful while analyzing MS/MS data in this kind of experiments. On the basis of this, a novel scoring algorithm, all ions scoring algorithm (AISA), has been designed for IPTL experiments. The information of quantification and qualification can be acquired at the same time using AISA. On Q-Exactive HeLa 2D RPLC dataset, peptide spectrum matches ( PSMs) , distinct peptides and protein groups identified by AISA are 15%, 26%and 22% higher than Morpheus. On human-HCC-HL dataset, PSMs, distinct peptides and protein groups identified by AISA are 24%, 39% and 27% higher than Morpheus. Quantification ratio on Q-Exactive HeLa and human-HCC-HL datasets are 1. 18 and 0. 90, respectively, which are very close to 1. Besides, quantification ratios between 0. 5 and 2. 0 are 91% and 94%, respectively.

Novel Algorithm for Identification and Quantification of Proteins Based on Strategy of Isobaric Peptide Termini Labelling / 分析化学

Isobaric peptide termini labeling ( IPTL) is a technology which uses light and heavy isotopes to label C-terminus and N-terminus of peptides. As the masses of labeled peptides are equivalent, the complexity of sample is low when analyzing MS data produced by this technology. Besides, paired b and y ions are helpful while analyzing MS/MS data in this kind of experiments. On the basis of this, a novel scoring algorithm, all ions scoring algorithm (AISA), has been designed for IPTL experiments. The information of quantification and qualification can be acquired at the same time using AISA. On Q-Exactive HeLa 2D RPLC dataset, peptide spectrum matches ( PSMs) , distinct peptides and protein groups identified by AISA are 15%, 26%and 22% higher than Morpheus. On human-HCC-HL dataset, PSMs, distinct peptides and protein groups identified by AISA are 24%, 39% and 27% higher than Morpheus. Quantification ratio on Q-Exactive HeLa and human-HCC-HL datasets are 1. 18 and 0. 90, respectively, which are very close to 1. Besides, quantification ratios between 0. 5 and 2. 0 are 91% and 94%, respectively.

[hnRNP K Contributes to Adriamycin Resistance in Acute Myeloid Leukemia through Regulating Autophagy].

OBJECTIVE: To explore the role of heterogeneous nuclear ribonucleoprotein(hnRNP) K regulating autophagy in the drug resistance of acute myeloid leukemia, so as to provide a new molecular marker for treatment of leukemia. METHODS: The relationship between the expression level of hnRNP K and the drug resistance of myeloid leukemia was verified by fluorescence quantitative PCR; the expression of autophagy related protein LC3I/ II was detected by Western blot after the hnRNP K was modulated by RNA interference technology; the sensitivity of leukemia cells to doxorubicin was analyzed before and after the expression of hnRNP K were modulatd. RESULTS: The expression of hnRNP K and LC3I/II significantly increased in bone marrow nonremission patients and in drug resistant cell line, however, the expression of LC3I/ II decreased when the expression of hnRNP K were reduced, while the sensitivity of cells to adriamycin could be recovered. CONCLUSION: hnRNP K may be involved in the formation of adriamycin resistance in acute myeloid leukemia by regulating autophagy.

[Bioinformatic analysis of chronic myeloid leukemia progression and preliminary experimental verification].

This study was aimed to explore the progression mechanism of chronic myeloid leukemia, so as to provide the new molecular markers for evaluation of CML clinical outcome and selection of treatment. The microarray data of genes related with progression from different phase of chronic myeloid leukemia (CML) were collected from public data depository GEO (Gene expression datasets). SAM analysis, fold change filtering, cross comparison were used to analyze the data and identify different genes. Moreover, MeV and pSTIING sofewares were used to analyze the key differential genes and signal pathways. At last, Q-PCR were used to confirm the predicted key gene. The results indicated that after comparison, 9 genes were differentially expressed from AP to BC, and the integrin-mediated cell adhesion , focal adhesion, regulation of actin cytoskeleton were the principal pathways during CML progression. Network construction analysis found that AP-related genes or pathways may be the original signals; and MLLT4, WDR35 and EPHB4 were the key genes for CML progression. EPHB4 was confirmed by Q-PCR in CML BC patients and CP patients. It is concluded that MLLT4, WDR35, EPHB4, integrin-mediated cell adhesion, focal adhesion and regulation of actin cytoskeleton are the principal genes and pathways during CML progression.

Role of procalcitonin in the diagnosis of severe infection in pediatric patients with fever and Neutropenia--a systemic review and meta-analysis.

OBJECTIVE: The aim of this study was to determine the accuracy of the procalcitonin (PCT) test for diagnosis of bacterial sepsis in pediatric cancer patients with febrile neutropenia. METHODS: Three major databases, MEDLINE, EMBASE and the Cochrane Library were searched for studies that evaluated the diagnostic value of PCT alone or compared with other laboratory markers such as C-reactive protein (CRP) to identify bacterial sepsis in children with fever and neutropenia. A bivariate model was used to derive summary sensitivity and specificity of the diagnostic tests. RESULTS: A total of 10 studies looking into PCT tests and 8 studies looking into CRP tests were included in the final analysis. The prevalence of bacterial sepsis was 304 of 1031 (29.5%) in PCT studies and 741 of 1316 (56.3%) in CRP studies. In terms of area under the receiver operating characteristic curve, PCT had comparable discrimination to CRP (area under the curve: 0.75 versus 0.74). PCT was not as sensitive as the CRP test. The pooled sensitivity of PCT was 0.59 (95% confidence interval [CI]: 0.42-0.74) as compared with 0.75 (95% CI: 0.61-0.85) for CRP. PCT was more specific than sensitive whereas CRP was more sensitive than specific in this population. The pooled specificity was 0.76 (95% CI: 0.64-0.85) for PCT and 0.62 (95% CI: 0.49-0.73) for CRP. PCT had greater likelihood ratio positive (2.50; 95% CI: 1.64-3.81), making it the better rule-in test. CONCLUSIONS: Of three markers potentially useful for diagnosing bacterial sepsis in children with fever and neutropenia, PCT had comparable diagnostic accuracy to CRP.