Delineation and molecular characterization of acute myeloid leukemia patients with coduplication of FLT3 and MLL

Partial tandem (PTD) and internal tandem duplications (ITD) of the MLL or FLT3 genes respectively, have been demonstrated in acute myeloid leukemia (AML). While occurrence of each of these PTD/ITD seem to confer an unfavorable prognosis, the literature contains only sparse information of the occurrence and the prognosis of simultaneous PTD/ITD of these genes. We have therefore attempted to determine the presence and its consequence in AML and with the further aim of characterizing such patients with respect to other genetic aberrations and to prototype variables in this disease. We analyzed blast cells from 250 adult patients treated at the same institution during a 15-year period for FLT3 ITD and MLL PTD and the duplications were found in 24% and 4%, respectively. The four co-duplicated cases (2%) did not differ with respect to sex, age, FAB-type, or immunophenotype, promoter methylation of p15, E-cadherin (CDH1), Estrogen receptor, MDR1, expression of apoptosis-related or multidrug resistance-related genes, though a trend toward decreased gene expression of MDR1 was observed. Two of the patients had a normal karyotypic analysis, while the remaining two showed aberrations in chromosome 11, one with trisomy 11 and the other with a der (11). The extensive molecular characterization of FLT3/MLL coduplicated patients presented here indicates that, even though they do not differ molecularly from the groups of patients with single ITDs, their prognosis and overall survival is universally poor. More patients are needed to determine whether coduplication has independent clinical implications compared to patients with single ITD/PTD.     

Effects of soy-derived isoflavones and a high-fat diet on spontaneous mammary tumor development in Tg.NK (MMTV/c-neu) mice

Phytoestrogens such as isoflavonoids and lignans have been postulated as breast cancer protective constituents in soy and whole-grain cereals. We investigated the ability of isoflavones (IFs) and flaxseed to modulate spontaneous mammary tumor development in female heterozygous Tg.NK (MMTV/c-neu) mice. Two different exposure protocols were applied, either from 4 wk of age onward (postweaning) or during gestation and lactation (perinatal). In the postweaning exposure study, mice were fed IFs or flaxseed in a high-fat diet. In addition, flaxseed in a low-fat diet was tested. Postweaning exposure to IFs and flaxseed tended to accelerate the onset of mammary adenocarcinoma development, although tumor burden at necropsy was not changed significantly. Perinatal IF exposure resulted in enhanced mammary gland differentiation, but palpable mammary tumor onset was not affected. However, tumor burden at necropsy in the perinatal exposure study was significantly increased in the medium- and high-IF dose groups. Comparison of both exposure scenarios revealed a strongly accelerated onset of tumor growth after perinatal high-fat diet exposure compared with the low-fat diet. This study shows that breast cancer-modulating effects of phytoestrogens are dependent both on the background diet and on the timing of exposure in the life cycle.     

Cancer cells as targets for lentivirus-mediated gene transfer and gene therapy

Lentiviruses have been used as gene transfer vectors for almost 10 years and their utility has been demonstrated in a variety of different applications. However, their value in cancer gene therapy has not been studied thoroughly. Here we show that VSV-G pseudotyped HIV-1-based lentiviruses are efficient vectors for human tumor cells in vitro and in vivo. Lentiviral gene transfer efficiency was demonstrated by transducing 42 different cell lines, representing 10 different human tumor types. It was shown that most of the cell lines were good or excellent targets for lentiviral transduction, allowing 50-95% gene transfer efficiency. These results were comparable to those obtained with an E1/E3 deleted, serotype 5 adenovirus vector. Analysis of lentivirus vector structure revealed that virus particles devoid of HIV-1 accessory proteins appeared to be more efficient, but the presence of enhancing elements cPPT and WPRE did not play a major role in transduction efficiency to four different human tumor cell lines. However, their effect on the gene expression level in these cells was apparent. To examine the impact of lentiviral gene expression level on suicide gene therapy approach, human osteosarcoma cells were transduced with lentivirus- or adenovirus vectors carrying the fusion gene HSV-TK-GFP and exposed to ganciclovir. Cell viability analysis after the treatment revealed that both vector types induced similar level of cytotoxicity, suggesting that lentiviral expression of a suicide gene is adequate for tumor cell destruction. Finally, in vivo transduction studies with subcutaneous tumors showed that lentivirus vectors can yield similar gene transfer efficiency than adenovirus vector, despite three orders of magnitude lower titer of the lentiviral preparation. In conclusion, these data show that lentiviruses are efficient gene transfer vehicles for human tumor cells and justify their use in further preclinical cancer gene therapy studies.     

A randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin in the prevention of recurrent miscarriage: evidence for a therapeutic effect in women with secondary recurrent miscarriage

BACKGROUND: Previous trials of intravenous immunoglobulin (IvIg) treatment of women with recurrent miscarriage (RM) have provided diverging results. This may be due to different inclusion criteria and suboptimal treatment protocols in some trials. METHODS: According to a computer-generated list, 58 women with at least four unexplained miscarriages were randomly assigned to receive infusions of high doses of IvIg or placebo starting as soon as the pregnancy test was positive. RESULTS: In the intention-to-treat analysis, a 45% live birth rate was found in both allocation groups. In patients with secondary RM, 50% in the treatment group and 23% in the placebo group had successful pregnancies (P = not significant). When data from the present and a previous placebo-controlled trial of the same treatment were combined, 15/26 (58%) of the patients with secondary RM in the treatment group versus 6/26 (24%) in the placebo group had successful outcomes (P < 0.02). Only 7% of the karyotyped abortuses were abnormal. CONCLUSIONS: IvIg may improve pregnancy outcome in patients with secondary RM. A new placebo-controlled trial focusing on this subgroup should be conducted to confirm the results.     

人工流产术后口服达英-35的临床应用研究

目的采用人工流产术后口服短效避孕药（达英-35）的方法,研究达英-35对人流术后避孕效果及减少人流术后并发症的疗效。方法随机选取行人工流产的早孕（〈10孕周）健康妇女300例,分为观察组和对照组各150例,观察组于人流术后口服达英-35,对照组采用除口服避孕药外的其他避孕方式,观察两组术后出血情况、子宫恢复情况、避孕效果及并发症发生情况。结果观察组患者人流术后阴道出血持续时间少于对照组（P〈0.01）,术后恢复情况优于对照组,且并发症发生率较对照组显著减少（P〈0.01）。结论人流术后口服达英-35避孕效果好,不良反应小,可促进子宫恢复,治疗手段简单、经济,可减少人流术后并发症,具有广阔的临床应用价值,值得进一步研究并推广应用。