Key Points• ATRA and ATO affect NPM1 protein levels in AML cells and induce cell growth inhibition and apoptosis.• AML cells with mutated NPM1respond to ATRA/ATO, and this might be exploited therapeutically.Nucleophosmin (NPM1) mutations represent an attractive therapeutic target in acute myeloid leukemia (AML) because they are common (∼30% AML), stable, and behave as a founder genetic lesion. Oncoprotein targeting can be a successful strategy to treat AML, as proved in acute promyelocytic leukemia by treatment with all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO), which degrade the promyelocytic leukemia (PML)-retinoic acid receptor fusion protein. Adjunct of ATRA to chemotherapy was reported to be beneficial for NPM1-mutated AML patients. Leukemic cells with NPM1 mutation also showed sensibility to ATO in vitro. Here, we explore the mechanisms underlying these observations and show that ATO/ATRA induce proteasome-dependent degradation of NPM1 leukemic protein and apoptosis in NPM1-mutated AML cell lines and primary patients' cells. We also show that PML intracellular distribution is altered in NPM1-mutated AML cells and reverted by arsenic through oxidative stress induction. Interestingly, similarly to what was described for PML, oxidative stress also mediates ATO-induced degradation of the NPM1 mutant oncoprotein. Strikingly, NPM1 mutant downregulation by ATO/ATRA was shown to potentiate response to the anthracyclin daunorubicin. These findings provide experimental evidence for further exploring ATO/ATRA in preclinical NPM1-mutated AML in vivo models and a rationale for exploiting these compounds in chemotherapeutic regimens in clinics. (Blood. 2015;125(22):3455-3465)
Multiple Myeloma (MM) is a systemic hematologic disease due to uncontrolled proliferation of monoclonal plasma cells (PC) in bone marrow (BM). Emerging in other solid and liquid cancers, the host immune system and the microenvironment have a pivotal role for PC growth, proliferation, survival, migration, and resistance to drugs and are responsible for some clinical manifestations of MM. In MM, microenvironment is represented by the cellular component of a normal bone marrow together with extracellular matrix proteins, adhesion molecules, cytokines, and growth factors produced by both stromal cells and PC themselves. All these components are able to protect PC from cytotoxic effect of chemo- and radiotherapy. This review is focused on the role of immunome to sustain MM progression, the emerging role of myeloid derived suppressor cells, and their potential clinical implications as novel therapeutic target.
Wardowski [Fixed Point Theory Appl., 2012:94] introduced a new concept of contraction and proved a fixed point theorem which generalizes Banach contraction principle. Following this direction of research, we will present some fixed point results for closed multi-valued F-contractions or multi-valued mappings which satisfy an F-contractive condition of Hardy-Rogers-type, in the setting of complete metric spaces or complete ordered metric spaces. An example and two applications, for the solution of certain functional and integral equations, are given to illustrate the usability of the obtained results.
Very recently, Khojasteh, Shukla and Radenović [F. Khojasteh, S. Shukla, S. Radenović, Filomat, 29 (2015),  introduced the notion of Z-contraction, that is, a nonlinear contraction involving a new class of mappings namely simulation functions. This kind of contractions generalizes the Banach contraction and unifies several known types of nonlinear contractions. In this paper, we consider a pair of nonlinear operators satisfying a nonlinear contraction involving a simulation function in a metric space endowed with a partial order. For this pair of operators, we establish coincidence and common fixed point results. As applications, several related results in fixed point theory in a metric space with a partial order are deduced. c 2015 All rights reserved.
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