Transferrin-conjugated polymeric nanomedicine to enhance the anticancer efficacy of edelfosine in acute myeloid leukemia

In this study, transferrin (Tf)-conjugated polyethylene glycol (PEG)-poly-l-lysine (PLL)-poly(lactic-co-glycolic acid) (PLGA) (PEG-PLL-PLGA)-based micellar formulations were successfully prepared for the delivery of edelfosine (EDS) in leukemia treatment. The micelles were nanosized and presented spherical shaped particles. Our in vitro data suggest that the nanoformulations maintain the biological activity of drugs for longer periods and lead to a continuous release of active drug. The enhanced cellular uptake of EDS-TM resulted in significantly higher cytotoxic effect in K562 leukemia cells. Cell cycle analysis further demonstrated the significantly higher G2/M phase arrest of cancer cells. Immunoblot analysis clearly revealed the potential of EDS-TM in inducing apoptosis of cancer cells which could improve the anticancer efficacy in leukemia. Importantly, EDS-M and EDS-TM significantly prolonged the circulation profile of EDS throughout until 24 h, indicating the potential of targeted nanoparticulate delivery system. The prolonged blood circulation potential of micellar formulations might improve the therapeutic potential of drug by increasing its bioavailability in the serum. It would be worthwhile evaluating the effects of the EDS-loaded micelles on cancer cells in vivo for clinical application.     

INTENSIVE CHEMOTHERAPEUTIC REGIMENS AGAINST ACUTE LEUKEMIA TRANSIENTLY SUPPRESS ASTHMA SYMPTOMS BUT DO NOT LEAD TO LONG-TERM RELIEF

In some very rare cases children suffer from a combination of asthma and a malignant disease. This study investigated whether intensive chemotherapy might have a positive effect on asthma in these special cases and whether asthma generally relapses after completion of chemotherapy. The authors monitored clinical outcome and lung function of 43 children with acute lymphoblastic leukemia and non-Hodgkin lymphoma who received chemotherapy at the University Children's Hospital of Greifswald between 1993 and 1998. Cytostatic chemotherapy was administered according to the German treatment protocols. Two of the 43 patients had asthma before leukemia was diagnosed. During the course of chemotherapy, asthma symptoms diminished promptly after beginning of chemotherapy but asthma was rediagnosed after completion of chemotherapy in both cases. The third patient developed asthmatic symptoms shortly after completion of chemotherapy for the first time. It can be stated that chemotherapy does not essentially cure asthma. Therefore, it seems mandatory to perform follow-up lung testings after chemotherapy, especially in patients with asthma.     

雷帕霉素对去甲氧柔红霉素诱导急性髓系白血病THP-1细胞凋亡的影响

目的:探讨雷帕霉素（Rapa）对去甲氧柔红霉素（IDA）诱导急性髓系白血病THP-1细胞凋亡的影响及其分子机制。方法:分别用10、20、40、80 nmol/L Rapa处理THP-1细胞1 h，另设未经Rapa处理的细胞。采用蛋白质印迹法检测THP-1细胞自噬标志物LC3蛋白的转换情况（LC3Ⅱ/LC3Ⅰ），采用流式细胞术检测细胞凋亡，确定Rapa处理浓度。用不同浓度IDA作用THP-1细胞24 h，采用CCK-8法检测IDA对THP-1细胞的增殖抑制率，计算半数抑制浓度（ IC50）。以低于 IC50的IDA作用Rapa处理或未处理的THP-1细胞24 h，CCK-8法检测细胞增殖抑制率，流式细胞术检测细胞凋亡情况，实时荧光定量聚合酶链反应检测自噬相关基因Beclin-1、LC3和p62的表达变化，蛋白质印迹法检测自噬标志物LC3蛋白的转换情况。 结果:20 nmol/L Rapa处理的THP-1细胞LC3Ⅱ/LC3Ⅰ高于未处理的细胞（ P=0.002 4）；80 nmol/L Rapa处理的细胞凋亡率高于未处理的细胞（ P=0.007 3）。根据蛋白质印迹法和流式细胞术检测结果，选取20 nmol/L Rapa作为预处理浓度。IDA对THP-1细胞作用24 h的 IC50为59.874 nmol/L。50 nmol/L IDA作用24 h后，Rapa预处理的THP-1细胞增殖抑制率[（69.67±5.03）%比（41.67±3.51）%]和细胞凋亡率[（74.35±4.83）%比（41.25±5.24）%]均高于未预处理的细胞（均 P<0.05）；Rapa预处理的THP-1细胞Beclin-1、LC3 mRNA表达水平及LC3Ⅱ/LC3Ⅰ均高于未预处理的细胞，p62 mRNA表达水平低于未预处理的细胞（均 P<0.05）。 结论:Rapa能增强较低剂量IDA诱导的THP-1细胞凋亡，此效应可能是通过其引起THP-1细胞过度自噬实现的。     

白血病患者PICC置管后持续渗血的原因分析及护理研究进展

正白血病是一种源于造血干细胞的恶性克隆性疾病,化疗药物治疗是治疗白血病主要手段之一[1]。近年来,经外周置入中心静脉导管(Peripherally inserted central catheter,PICC)因其创伤小、易操作、保留时间长等优点,已经广泛应用于白血病病人[2]。PICC是指从周围静脉导入,并将导管尖端置于上腔静脉的方法[3]。它的使用既符合标准的规定,避免了     

An atypical occurrence of Aspergillosis in leukemic patient: Brief description of a clinical case

Herein we describe a 43 year-old Caucasian female patient with acute myeloid leukemia that developed an unconventional form of invasive Aspergillosis. For therapeutic reasons, a Groshong-type central venous catheter was positioned. Monitoring the patient's clinical conditions, positive values for C-reactive protein and galactomannan were correlated with a probably Aspergillosis. Surprisingly no pulmonary evidences were observed. Due to worsening conditions, she was re-hospitalized and a blood culture was performed, whom positivity resulted as the first clinical evidence of Aspergillus fumigatus. Further evidence about species identification was obtained by sequencing the fungal ITS region. We support the clinical value of blood culture as a decisive factor to improve the diagnosis of catheter-related Aspergillosis.     

Targeting chronic lymphocytic leukemia using CIGB-300, a clinical-stage CK2-specifc cell-permeable peptide inhibitor

Chronic lymphocytic leukemia (CLL) remains an incurable malignancy, urging for the identifcation of new molecular targets for therapeutic intervention. CLL cells rely on overexpression and hyperactivation of the ubiquitous serine/threonine protein kinase CK2 for their viability in vitro. CIGB-300 is a cell-permeable selective CK2 inhibitor peptide undergoing clinical trials for several cancers. Here, we show that CIGB-300 promotes activation of the tumor suppressor PTEN and abrogates PI3K-mediated downstream signaling in CLL cells. In accordance, CIGB-300 decreases the viability and proliferation of CLL cell lines, promotes apoptosis of primary leukemia cells and displays antitumor efcacy in a xenograft mouse model of human CLL. Our studies provide pre-clinical support for the testing and possible inclusion of CK2 inhibitors in the clinical arsenal against CLL.     

Involvement of extrinsic and intrinsic apoptotic pathways together with endoplasmic reticulum stress in cell death induced by naphthylchalcones in a leukemic cell line: Advantages of multi-target action

Chalcones, naturally occurring open-chain flavonoids abundant in plants, have demonstrated anticancer activity in multiple tumor cells. In a previous work, the potential anticancer activity of three naphthylchalcones named R7, R13 and R15 was shown. In this study, the mechanism of actions of these chalcones was originally shown. The chalcones presented concentration and time-dependent cytotoxicity. To determine the type of cell death induced by chalcones, we assessed a series of assays including measurements of the caspase-8, -9 and -12 activities, expression of important apoptosis-related genes and proteins, changes in the cell calcium concentration and cytochrome c release. The activities of caspase-8, -9 and -12 increased after the treatment of L1210 cells with the three compounds. Chalcones R7 and R13 induced an increase of pro-apoptotic proteins Bax, Bid and Bak (only chalcone R13), as well as a decrease in anti-apoptotic Bcl-2 expression. These chalcones also induced an increase in Fas and a decrease in p21 and p53 expression. Chalcone R15 seems to act by a different mechanism to promote cell death, as it did not change the mitochondrion-related proteins, nor did it induce the cytochrome c release. All compounds induced an increase in cell calcium concentration and an increase in CHOP expression, which together with an increase in caspase-12 activity, suggest that chalcones could induce an endoplasmic reticulum (ER) stress. Taken together, these results suggest that chalcones induce apoptosis by different pathways, being an interesting strategy to suggest for cancer therapy.     

Down syndrome,RASopathies, and other rare syndromes

In this article we discuss the occurrence of myeloid neoplasms in patients with a range of syndromes that are due to germline defects of the RAS signaling pathway and in patients with trisomy 21. Both RAS mutations and trisomy 21 are common somatic events contributing to leukemogenis. Thus, the increased leukemia risk observed in children affected by these conditions is biologically highly plausible. Children with myeloid neoplasms in the context of these syndromes require different treatments than children with sporadic myeloid neoplasms and provide an opportunity to study the role of trisomy 21 and RAS signaling during leukemogenesis and development.