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    • br Results We evaluated MM

    2019-05-23


    Results We evaluated 148 MM patients, 87 women and 61 men, age range 29–69 years, 58 of whom developed bacteremia during the early post-transplant period (Table 1). The genotypes were in Hardy–Weinberg equilibrium. We did not observe any statistically significant association between the genotypes of TNF-α and IL-6 polymorphisms and bacteremia (Table 2). However, analyzing the association between bacteremia and the interaction of polymorphisms, we found a significant interaction between TNF-α −308G>A and IL-6 −174G>C polymorphisms, with a CVC of 10/10 and balanced accuracy of 0.6021 (p=0.04). Using this method, we could identify two risk groups: the high risk group comprised patients with wild genotype of TNF-α −308G>A and mutated genotype of IL-6 −174G>C, wild genotype of TNF-α −308G>A and heterozygous genotype of IL-6 −174G>C, and heterozygous for both genes (dark gray buy BLU 9931 in Fig. 1). The low-risk group comprised all other combinations (light gray cells in Fig. 1). As shown in Table 3, the frequency of bacteremia overall (50.7% vs. 29.6%, p=0.009) and of Gram-positive bacteremia (34.3% vs. 12.5%, p=0.002) was significantly higher in the high risk group compared with the low risk group. We analyzed the impact of quinolone use on the frequency of bacteremia. The frequency of bacteremia was significantly lower in patients receiving quinolone prophylaxis (16.7% vs. 43.5% in patients not receiving quinolones, p=0.01). We then run a bivariate analysis to evaluate the influence of quinolone use and the interaction of polymorphisms on the occurrence of bacteremia. Receipt of quinolones decreased the risk of bacteremia (odds ratio [OR] 0.25, 95% confidence interval [95% CI] 0.08–0.81, p=0.02) while the high risk group (as defined by the analysis of interaction of polymorphisms) was associated with an increased risk of bacteremia (OR 2.47, 95% CI 1.24–4.94, p=0.01). Therefore, the high risk group was associated with an increased risk of bacteremia independent of quinolone use.
    Discussion The patterns of high risk and low risk cells shown in Fig. 1 differ across each of the different multilocus dimensions, which may be interpreted as evidence of epistasis, or gene–gene interaction [8]. TNF-stimulates the secretion of IL-6 in bone marrow stromal cells [9], which are associated with a worst prognosis in MM patients [1]. The analysis of gene interaction efficiently discriminated two risk groups, with very different incidences of bacteremia. Furthermore, the association of the interaction of polymorphisms and bacteremia was still present after controlling for the use of quinolones.
    Introduction Acute myeloid leukemia (AML) is a biologically heterogeneous group of related diseases in urgent need of better therapeutic options. Despite sensitivity to initial treatment, 70–90% of elderly patients relapse within 5 years. There is accumulating evidence that a small population of primitive cells, called putative leukemic stem cells (pLSCs), resistant to treatment in bone marrow niche sites is responsible for disease relapse [1,2]. Anti-apoptotic Bcl-2 proteins have long been known to play a major role in the long-term survival of hematopoietic stem and progenitor cells [3]. Pluripotent hematopoietic stem cells identified as CD34+/lin−/CD38− abundantly express Bcl-XL, while progenitor cells (CD34+) produce high amounts of Bcl-2 [3]. Additionally, treatment with chemotherapeutics have been shown to induce anti-apoptotic Bcl-2 protein expression and minimal residual disease cells also express high levels of Bcl-2/Bcl-XL[4]. Despite this long-known feature of primitive hematopoietic cells and pLSCs, the potential of the recently developed Bcl-2/Bcl-XL/Bcl-W inhibitor, ABT-737 in eradicating AML putative leukemic stem cells has not been thoroughly examined. In this study, we show that ABT-737 is potent and equally effective in killing both AML blasts and CD34+/CD38− progenitors. The effect did not depend on the source of the AML cells (bone marrow or peripheral blood), or the resistance of the pLSCs to the mainstream chemotherapeutic drug combination of cytarabine (AraC) and daunorubicin (DnR).