Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma

Constitutive activation of the chemokine receptor CXCR4 has been associated with tumor progression, invasion, and chemotherapy resistance in different cancer subtypes. Although the CXCR4 pathway has recently been suggested as an adverse prognostic marker in diffuse large B-cell lymphoma, its biological relevance in this disease remains underexplored. In a homogeneous set of 52 biopsies from patients, an antibody-based cytokine array showed that tissue levels of CXCL12 correlated with high microvessel density and bone marrow involvement at diagnosis, supporting a role for the CXCL12-CXCR4 axis in disease progression. We then identified the tetra-amine IQS-01.01RS as a potent inverse agonist of the receptor, preventing CXCL12-mediated chemotaxis and triggering apoptosis in a panel of 18 cell lines and primary cultures, with superior mobilizing properties in vivo than those of the standard agent. IQS-01.01RS activity was associated with downregulation of p-AKT, p-ERK1/2 and destabilization of MYC, allowing a synergistic interaction with the bromodomain and extra-terminal domain inhibitor, CPI203. In a xenotransplant model of diffuse large B-cell lymphoma, the combination of IQS-01.01RS and CPI203 decreased tumor burden through MYC and p-AKT downregulation, and enhanced the induction of apoptosis. Thus, our results point out an emerging role of CXCL12-CXCR4 in the pathogenesis of diffuse large B-cell lymphoma and support the simultaneous targeting of CXCR4 and bromodomain proteins as a promising, rationale-based strategy for the treatment of this disease

Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma

Constitutive activation of the chemokine receptor CXCR4 has been associated with tumor progression, invasion, and chemotherapy resistance in different cancer subtypes. Although the CXCR4 pathway has recently been suggested as an adverse prognostic marker in diffuse large B-cell lymphoma, its biological relevance in this disease remains underexplored. In a homogeneous set of 52 biopsies from patients, an antibody-based cytokine array showed that tissue levels of CXCL12 correlated with high microvessel density and bone marrow involvement at diagnosis, supporting a role for the CXCL12-CXCR4 axis in disease progression. We then identified the tetra-amine IQS-01.01RS as a potent inverse agonist of the receptor, preventing CXCL12-mediated chemotaxis and triggering apoptosis in a panel of 18 cell lines and primary cultures, with superior mobilizing properties in vivo than those of the standard agent. IQS-01.01RS activity was associated with downregulation of p-AKT, p-ERK1/2 and destabilization of MYC, allowing a synergistic interaction with the bromodomain and extra-terminal domain inhibitor, CPI203. In a xenotransplant model of diffuse large B-cell lymphoma, the combination of IQS-01.01RS and CPI203 decreased tumor burden through MYC and p-AKT downregulation, and enhanced the induction of apoptosis. Thus, our results point out an emerging role of CXCL12-CXCR4 in the pathogenesis of diffuse large B-cell lymphoma and support the simultaneous targeting of CXCR4 and bromodomain proteins as a promising, rationale-based strategy for the treatment of this disease

LA-ICP-MS and EDS characterization of electrode/electrolyte interfaces in IT-SOFCs materials

Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS) in combination with SEM is used for the determination of elemental spatial distribution in ceramic multi-layer systems as those found in Intermediate Temperature Solid Oxide Fuel Cells (IT-SOFCs). Because layer sintering occurs at high temperature (usually well over 1000°C), there may be mutual diffusion of ions from one layer to the other, with dramatic consequences on cell performances. In this work, two model materials have been used to test LA-ICP-MS: La0.83Sr0.17Ga0.83Mg0.17O2.83 (LSGM), one of the most promising electrolytes for IT-SOFCs, and La0.8Sr0.2MnO3 (LSM), a highly representative material of perovskites, which are amply used to design electrode materials. A two-layer system screen-printed onto an LSM pellet (LSM-LSGM-LSM pellet) was successively sintered at a typical processing temperature, i.e. 1300 °C, for a short time (1h). Elemental spatial distribution was determined by line profile analyses carried out on fracture surfaces; for comparison SEM-EDS line profiles were tested on the same surface. LA-ICP-MS line profile analysis evidenced that, notwithstanding the relatively low sintering temperature, and short firing time (1 h per sintering), manganese cation diffusion into LSGM is relatively abundant, in agreement with previous literature reports and present EDS results. While line scan EDX analyses are not conclusive as for Ga and Mg diffusion, LA-ICP-MS shows that both ions diffuse across both interfaces, and Ga diffuses even over very long distances into the LSM pellet; on the contrary, only trace amounts of Mg can be found far from the LSGM/LSM interface