面向对象建模语言AML的设计与实现

ＡＭＬ语言吸取了Ａｄａ９５ 基本原理和思想，引进它的基本数据类型、语句等设施，对其作更高层次的抽象和扩充．用３ 种有相同名字不同类型的程序包从不同的侧面描述给定模块的模型，提高了系统的完整性和一致性；同时运用二级并发模型和限制设施，详述了系统的并发性和不确定性的描述问题．     

Pharmaceutical Drug Metformin and MCL1 Inhibitor S63845 Exhibit Anticancer Activity in Myeloid Leukemia Cells via Redox Remodeling

Metabolic landscape and sensitivity to apoptosis induction play a crucial role in acute myeloid leukemia (AML) resistance. Therefore, we investigated the effect of metformin, a medication that also acts as an inhibitor of oxidative phosphorylation (OXPHOS), and MCL-1 inhibitor {"type":"entrez-nucleotide","attrs":{"text":"S63845","term_id":"400540","term_text":"S63845"}}S63845 in AML cell lines NB4, KG1 and chemoresistant KG1A cells. The impact of compounds was evaluated using fluorescence-based metabolic flux analysis, assessment of mitochondrial Δψ and cellular ROS, trypan blue exclusion, Annexin V-PI and XTT tests for cell death and cytotoxicity estimations, also RT-qPCR and Western blot for gene and protein expression. Treatment with metformin resulted in significant downregulation of OXPHOS; however, increase in glycolysis was observed in NB4 and KG1A cells. In contrast, treatment with {"type":"entrez-nucleotide","attrs":{"text":"S63845","term_id":"400540","term_text":"S63845"}}S63845 slightly increased the rate of OXPHOS in KG1 and KG1A cells, although it profoundly diminished the rate of glycolysis. Generally, combined treatment had stronger inhibitory effects on cellular metabolism and ATP levels. Furthermore, results revealed that treatment with metformin, {"type":"entrez-nucleotide","attrs":{"text":"S63845","term_id":"400540","term_text":"S63845"}}S63845 and their combinations induced apoptosis in AML cells. In addition, level of apoptotic cell death correlated with cellular ROS induction, as well as with downregulation of tumor suppressor protein MYC. In summary, we show that modulation of redox-stress could have a potential anticancer activity in AML cells.     

Discovery of [1,2,4]triazolo[1,5-a]pyrimidine derivatives as new bromodomain-containing protein 4 (BRD4) inhibitors

Targeting bromodomain-containing protein 4(BRD4) has been proved to be an effective strategy for cancer therapy.To date,numerous BRD4 inhibitors and degraders have been identified,some of which have advanced into clinical trials.In this work,a focused library of new [1,2,4]triazolo [1,5-a]pyrimidine derivatives were discovered to be able to inhibit BRD4.WS-722 inactivated BRD4(BD1/BD2),BRD2(BD1/BD2) and BRD3(BD1/BD2) broadly with the IC₅₀ values less than 5 μmol/L.Besides,WS-722 inhibited growth of THP-1 cells with an IC₅₀ value of 3.86 μmol/L.Like(+)-JQ1,WS-722 inhibited BRD4 in a reversible manner and enhanced protein stability.Docking studies showed that WS-722 occupied the central acetyl-lysine(Kac) binding cavity and formed a hydrogen bond with Asn140.In THP-1 cells,WS-722 showed target engagement to BRD4.Cellular effects of WS-722 on THP-1 cells were also examined,showing that WS-722 could block c-MYC expression,induce G0/G1 phase arrest and p21 up-regulation,and promote differentiation of THP-1 cells.BRD4 inhibition by WS-722 resulted in cell apoptosis and upregulated expression of cleaved caspased-3/7 and PARP in THP-1 cell lines.The [1,2,4]triazolo[1,5-a]pyrimidine is a new template for the development of new BRD4 inhibitors.     

A Novel Potentiometric Detection Strategy for the Determination of Amlodipine Besylate Based on Functionalized Particles

A novel potentiometric strategy based on functionalized magnetite nanoparticles and microparticles were compared with the classical potentiometric strategy. This strategy provided nano‐ and microsized particles that were highly dispersed and coated with ionophore and plasticizer to promote an in situ cooperative ion‐pairing interaction between the ionophore and the analyte present in inner solution of sensor membrane, compared to the classical technique. Three amlodipine (AML) sensors were constructed using functionalized nanoparticles in sensor 1; microparticles in sensor 2, as ionophores, and the polymeric membrane ionophoric property in sensor 3.     

A ɑ-KA fluorescent probe for discrimination of blood cancer serum

Probe CH can quickly detect -KA in human serum with micelles of CTAB and could differentiate cancer from normal blood serum.     

Molecular-Targeted Therapy of Pediatric Acute Myeloid Leukemia

Acute myeloid leukemia (AML) accounts for approximately 15–20% of all childhood leukemia cases. The overall survival of children with acute myeloid leukemia does not exceed 82%, and the 5-year event-free survival rates range from 46% to 69%. Such suboptimal outcomes are the result of numerous mutations and epigenetic changes occurring in this disease that adversely affect the susceptibility to treatment and relapse rate. We describe various molecular-targeted therapies that have been developed in recent years to meet these challenges and were or are currently being studied in clinical trials. First introduced in adult AML, novel forms of treatment are slowly beginning to change the therapeutic approach to pediatric AML. Despite promising results of clinical trials investigating new drugs, further clinical studies involving greater numbers of pediatric patients are still needed to improve the outcomes in childhood AML.     

The Identification of APOBEC3G as a Potential Prognostic Biomarker in Acute Myeloid Leukemia and a Possible Drug Target for Crotonoside

The apolipoprotein B mRNA editing enzyme catalytic subunit 3G (APOBEC3G) converts cytosine to uracil in DNA/RNA. Its role in resisting viral invasion has been well documented. However, its expression pattern and potential function in AML remain unclear. In this study, we carried out a bioinformatics analysis and revealed that the expression of APOBEC3G was significantly upregulated in AML, and high expression of APOBEC3G was significantly associated with short overall survival (OS). APOBEC3G expression was especially increased in non-M3AML, and correlated with the unfavorable cytogenetic risks. Additionally, Cox regression analyses indicated APOBEC3G is a hazard factor that cannot be ignored for OS of AML patients. In molecular docking simulations, the natural product crotonoside was found to interact well with APOBEC3G. The expression of APOBEC3G is the highest in KG-1 cells, and the treatment with crotonoside can reduce the expression of APOBEC3G. Crotonoside can inhibit the viability of different AML cells in vitro, arrest KG-1 and MV-4-11 cells in the S phase of the cell cycle and affect the expression of cycle-related proteins, and induce cell apoptosis. Therefore, APOBEC3G could be a potential drug target of crotonoside, and crotonoside can be considered as a lead compound for APOBEC3G inhibition in non-M3 AML.     

Distinction between normal and leukemic bone marrow by water protons nuclear magnetic resonance relaxation times

Pulsed nuclear magnetic resonance studies have been carried out on bone marrow of normal human subjects and patients with leukemia: chronic myeloid leukemia (CML) and acute myeloid leukemia (AML). It was observed that the proton spin-lattice relaxation time (T₁) value was discriminatory in the normal and leukemic cases with a statistical significance of (p < 0.01). Ouabain treatment of cells did not show any perceptible change of T₁ value when compared with the nontreated cells, indicating that the concomitant cation effluxes do not affect spin-lattice relaxation time. The water contents of normal, leukemic, and ouabain treated cells were in the range 60%–80%. Higher Fe levels were encountered in the normal than the leukemic samples, while levels of Zn, Cu, Mn, Co, and Ni were elevated in the leukemic samples compared with the normals. Despite the T₁ differences observed, the multiparameter studies do not uniquely pinpoint factors responsible for the elevation of T₁ in the malignant state.