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Chromosomal translocations can lead to the formation of chimeric genes encoding fusion proteins such as PML/RARalpha, PLZF/RARalpha, and AML-1/ETO, which are able to induce and maintain acute myeloid leukemia (AML). One key mechanism in leukemogenesis is increased self renewal of leukemic stem cells via aberrant activation of the Wnt signaling pathway. Either X-RAR, PML/RARalpha and PLZF/RARalpha or AML-1/ETO activate Wnt signaling by upregulating gamma-catenin and beta-catenin. In a prospective study, a lower risk of leukemia was observed with aspirin use, which is consistent with numerous studies reporting an inverse association of aspirin with other cancers. Furthermore, a reduction in leukemia risk was associated with use of non-steroidal anti-inflammatory drug (NSAID), where the effects on AML risk was FAB subtype-specific. To better investigate whether NSAID treatment is effective, we used Sulindac Sulfide in X-RARalpha-positive progenitor cell models. Sulindac Sulfide (SSi) is a derivative of Sulindac, a NSAID known to inactivate Wnt signaling. We found that SSi downregulated both beta-catenin and gamma-catenin in X-RARalpha-expressing cells and reversed the leukemic phenotype by reducing stem cell capacity and increasing differentiation potential in X-RARalpha-positive HSCs. The data presented herein show that SSi inhibits the leukemic cell growth as well as hematopoietic progenitors cells (HPCs) expressing PML/RARalpha, and it indicates that Sulindac is a valid molecular therapeutic approach that should be further validated using in vivo leukemia models and in clinical settings.
We study the effect of the chiral symmetry restoration (CSR) on heavy-ion collisions observables in the energy range sNN=3–20GeV within the Parton-Hadron-String Dynamics (PHSD) transport approach. The PHSD includes the deconfinement phase transition as well as essential aspects of CSR in the dense and hot hadronic medium, which are incorporated in the Schwinger mechanism for particle production. Our systematic studies show that chiral symmetry restoration plays a crucial role in the description of heavy-ion collisions at sNN=3–20GeV, realizing an increase of the hadronic particle production in the strangeness sector with respect to the non-strange one. Our results provide a microscopic explanation for the horn structure in the excitation function of the K+/π+ ratio: the CSR in the hadronic phase produces the steep increase of this particle ratio up to sNN≈7GeV, while the drop at higher energies is associated to the appearance of a deconfined partonic medium. Furthermore, the appearance/disappearance of the horn structure is investigated as a function of the system size. We additionally present an analysis of strangeness production in the (T,μB)-plane (as extracted from the PHSD for central Au+Au collisions) and discuss the perspectives to identify a possible critical point in the phase diagram.
The effect of the chiral symmetry restoration (CSR) on observables from heavy-ion collisions is studied in the energy range =3–20 GeV within the Parton-Hadron-String Dynamics (PHSD) transport approach. The PHSD includes the deconfinement phase transition as well as essential aspects of CSR in the dense and hot hadronic medium, which are incorporated in the Schwinger mechanism for the hadronic particle production. We adopt different parametrizations of the nuclear equation of state from the non-linear σ - ω model, which enter in the computation of the quark scalar density for the CSR mechanism, in order to estimate the uncertainty in our calculations. For the pion-nucleon ∑-term we adopt ∑π ≈ 45 MeV which corresponds to a ’world average’. Our systematic studies show that chiral symmetry restoration plays a crucial role in the description of heavy-ion collisions at =3–20 GeV, realizing an increase of the hadronic particle production in the strangeness sector with respect to the non-strange one. We identify particle abundances and rapidity spectra to be suitable probes in order to extract information about CSR, while transverse mass spectra are less sensitive ones. Our results provide a microscopic explanation for the "horn" structure in the excitation function of the K+/π+ ratio: the CSR in the hadronic phase produces the steep increase of this particle ratio up to ≈ 7 GeV, while the drop at higher energies is associated to the appearance of a deconfined partonic medium.