A convenient new and efficient commercial synthetic route for dasatinib (Sprycel®)

A new and efficient synthetic route for dual-Src/Abl kinase inhibitor dasatinib (Sprycel®), an anticancer drug, is described. This commercially viable process yields dasatinib monohydrate free of potential impurities with consistent yield of 68% in route A and 61% in route B with HPLC purity >99.80% over four stages.     

Multidimensional Pattern Recognition and Classification of White Blood Cells Using Support Vector Machines

This study introduces a new algorithm to optimize the pattern recognition of different white blood cell types in flow cytometry. The behavior of parametric data clusters in a multidimensional space is analyzed using the learning system known as Support Vector Machines (SVM). Beckman‐Coulter Corporation supplied flow cytometry data of numerous patients to be used as training and testing sets for the algorithm. Subsequently, the characteristics of the cells provided in these sets were used to train a SVM based classifier. The objective in developing this algorithm was to identify the category of a given blood sample and provide information to medical doctors in the form of diagnostic references for a specific disease state, lymphocytic leukemia. With the application of the hypothesis space, the learning bias and the learning algorithm, the SVM classifier was successfully trained to evaluate misclassification ratios in flow cytometry data in an effort to recognize abnormal blood cell patterns and address the ubiquitous problem of data overlap through the use of the maximal margin classifier.     

儿童急性白血病诊治初探

目的：探讨儿童急性白血病转归与治疗的关系。方法；对接受治疗的患儿进行疗效观察，比较。结果：接受正规化疗者骨髓持续完全缓解率[CCR]高，不正规化疗者出现并发症，预后差。结论：正规长期化疗与长期生存呈正相关关系。     

Cytotoxic and apoptotic activities of novel Pd(II) complexes against human leukemia cell lines in vitro

In the investigation for alternative chemotherapeutic strategies against leukemia, Pd(II) complexes were synthesized and investigated for cytotoxic and apoptotic properties on two human leukemia cell lines (HL-60 and K562). Pd(II) complexes (Pd-5a and Pd-6a) with 5a and 6a as ligands were synthesized and characterized by ¹H-NMR and F-TIR. The cytotoxicity of the compounds was quantified using MTT method. Bax, Bcl-2, and caspase 3 gene expression levels were estimated using RT-qPCR. Here we show that Pd(II) complexes have important cytotoxic activity on human leukemia cell lines. RT-qPCR indicated that Bax and caspase 3 gene expression levels were increased after 24 h treatment with Pd-5a and Pd-6a complexes in both HL-60 and K562 cells at some selected dose. Furthermore, Bcl-2 gene expression level decreased after 24 h treatment with Pd-5a and Pd-6a complexes in K562 cells at all selected dose. In HL-60 cells, only one selected Pd-5a dose (25 µM) decreased the gene expression level of Bcl-2. The results obtained in the present investigation indicate that these two newly synthesized Pd(II) complexes have apoptotic effects at appropriate doses through caspase 3 and Bax genes and might represent a novel potentially active agents for the management of human leukemia cell lines.     

Bipartite network analysis reveals metabolic gene expression profiles that are highly associated with the clinical outcomes of acute myeloid leukemia

Dysregulated and reprogrammed metabolism are one of the most important characteristics of cancer, and exploiting cancer cell metabolism can aid in understanding the diverse clinical outcomes for patients. To investigate the differences in metabolic pathways among patients with acute myeloid leukemia (AML) and differential survival outcomes, we systematically conducted microarray data analysis of the metabolic gene expression profiles from 384 patients available from the Gene Expression Omnibus and Cancer Genome Atlas databases. Pathway enrichment analysis of differentially expressed genes (DEGs) showed that the metabolic differences between low-risk and high-risk patients mainly existed in two pathways: biosynthesis of unsaturated fatty acids and oxidative phosphorylation. Using the gene-pathway bipartite network, 62 metabolic genes were identified from 272 DEGs involved in 88 metabolic pathways. Based on the expression patterns of the 62 genes, patients with shorter overall survival (OS) durations in the training set (hazard ratio (HR) = 1.58, p = 0.038) and in two test sets (HR = 1.69 and 1.56 and p = 0.089 and 0.029, respectively) were well discriminated by hierarchical clustering analysis. Notably, the expression profiles of ALAS2, BCAT1, BLVRB, and HK3 showed distinct differences between the low-risk and high-risk patients. In addition, models for predicting the OS outcome of AML from the 62 gene signatures achieved improved performance compared with previous studies. In conclusion, our findings reveal significant differences in metabolic processes of patients with AML with diverse survival durations and provide valuable information for clinical translation.     

Blockage of Wnt/β‐Catenin Signaling by Nanoparticles Reduces Survival and Proliferation of CLL Cells In Vitro—Preliminary Study

The Wnt/β‐catenin signaling pathway is shown to play a significant role in the control of the survival, proliferation, and differentiation of hematopoietic cells. Studies have confirmed that aberrant activation of canonical Wnt signaling occurs in various forms of leukemia, and is crucial for chronic lymphocytic leukemia (CLL) pathogenesis. The aim of the study is to evaluate the influence of maltotriose (M3) modified fourth generation poly(propylene imine) dendrimers (PPI‐G4) on Wnt/β‐catenin pathway gene expression in CLL (MEC‐1) cells and to compare these findings with those obtained with fludarabine (FA). Microarray data analysis reveals seven of 19 Wnt/β‐catenin pathway genes whose expression changes significantly during dendrimer and FA treatment: WNT10A, WNT6 , and CDH1 among others. PPI‐G4‐M3 is already known to influence MEC‐1 cell apoptosis and proliferation. The obtained results suggest that the reduction in cell survival under the influence of glycodendrimers and FA may be due to loss of Wnt signaling.     

Genotyping of two single nucleotide polymorphisms in 5,10-methylenetetrahydrofolate reductase by multiplex polymerase chain reaction and capillary electrophoresis

Two single nucleotide polymorphisms (SNPs) of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, A1298C and C677T, were widely considered to be related with various neoplasia disorders. We established a simple and effective capillary electrophoresis (CE) method for detection of two SNPs in MTHFR gene simultaneously. DNA samples were amplified by multiplex PCR with universal fluorescence-labeled primer and analyzed by single-strand conformation polymorphism (SSCP)-CE method. The CE method was performed using 1.5% hydroxyethyl cellulose in 1× TBE buffer containing 1 M urea. The PCR products after SSCP procedure were electrokinetically injected at −10 kV, 30 s. Separation voltage was −6 kV and the temperature was set at 20 °C. The optimal SSCP-CE method was applied to detect two polymorphisms in MTHFR gene of acute lymphoblastic leukemia (ALL) and attention-deficit/hyperactivity disorder (ADHD) patients. Genotyping results were evaluated in terms of relationships between outcomes for ADHD patients after ALL chemotherapy and ALL disease. The SSCP-CE method and multiplex PCR with universal fluorescence primer were used as the fast technique for screening two SNPs in MTHFR gene, A1298C and C677T. The genotyping data were coincident with DNA sequencing. This SSCP-CE method was found feasible for detecting mutation of MTHFR gene in populations.     

As2O3联合小剂量化疗治疗急性早幼粒细胞白血病的临床研究

探讨治疗急性早幼粒细胞白血病（APL）更有效的方法，以延长患者的生存期，提高生活质量。采用As2O3注射液10mg/d加入10％葡萄注射液250－500mL静脉滴注，连续28d一个疗程；同时用可糖胞苷50－100mg或高三尖杉酯碱1－2mg加入10％葡萄糖注射250mL静脉滴注，7－10d为1疗程，观察其临床症状、血象及骨髓象的变化，并追踪观察其缓解率及生存期。结果表明，采用A2sO3注射液加小剂量化疗的方法治疗APL，有明显的疗效，能够有效控制APL病情，提高完全缓解率，减少白血病的复发率与患者死亡率。