Targeting angiogenesis in multiple myeloma by the VEGF and HGF blocking DARPin® protein MP0250: a preclinical study

The investigational drug MP0250 is a multi-specific DARPin® molecule that simultaneously binds and neutralizes VEGF and HGF with high specificity and affinity. Here we studied the antiangiogenic effects of the MP0250 in multiple myeloma (MM). In endothelial cells (EC) isolated from bone marrow (BM) of MM patients (MMEC) MP0250 reduces VEGFR2 and cMet phosphorylation and affects their downstream signaling cascades. MP0250 influences the secretory profile of MMEC and inhibits their in vitro angiogenic activities (spontaneous and chemotactic migration, adhesion, spreading and capillarogenesis). Compared to anti-VEGF or anti-HGF neutralizing mAbs, MP0250 strongly reduces capillary network formation and vessel-sprouting in a Matrigel angiogenesis assay. MP0250 potentiates the effect of bortezomib in the same in vitro setting. It significantly reduces the number of newly formed vessels in the choriollantoic membrane assay (CAM) and the Matrigel plug assay. In the syngeneic 5T33MM tumor model, MP0250 decreases the microvessel density (MVD) and the combination MP0250/bortezomib lowers the percentage of idiotype positive cells and the serum levels of M-protein. Overall results define MP0250 as a strong antiangiogenic agent with potential as a novel combination drug for treatment of MM patients

Language of CTO interventions – Focus on hardware

AbstractThe knowledge of variety of chronic total occlusion (CTO) hardware and the ability to use them represents the key to success of any CTO interventions. However, the multiplicity of CTO hardware and their physical character and the terminology used by experts create confusion in the mind of an average interventional cardiologist, particularly a beginner in this field. This knowledge is available but is scattered. We aim to classify and compare the currently used devices based on their properties focusing on how physical character of each device can be utilized in a specific situation, thus clarifying and simplifying the technical discourse

Tasquinimod suppresses tumor cell growth and bone resorption by targeting immunosuppressive myeloid cells and inhibiting c-MYC expression in multiple myeloma

Background: Immunotherapy emerged as a promising treatment option for multiple myeloma (MM) patients. However, therapeutic efficacy can be hampered by the presence of an immunosuppressive bone marrow microenvironment including myeloid cells. S100A9 was previously identified as a key regulator of myeloid cell accumulation and suppressive activity. Tasquinimod, a small molecule inhibitor of S100A9, is currently in a phase Ib/IIa clinical trial in MM patients (NCT04405167). We aimed to gain more insights into its mechanisms of action both on the myeloma cells and the immune microenvironment. Methods: We analyzed the effects of tasquinimod on MM cell viability, cell proliferation and downstream signaling pathways in vitro using RNA sequencing, real-time PCR, western blot analysis and multiparameter flow cytometry. Myeloid cells and T cells were cocultured at different ratios to assess tasquinimod-mediated immunomodulatory effects. The in vivo impact on immune cells (myeloid cell subsets, macrophages, dendritic cells), tumor load, survival and bone disease were elucidated using immunocompetent 5TMM models. Results: Tasquinimod treatment significantly decreased myeloma cell proliferation and colony formation in vitro, associated with an inhibition of c-MYC and increased p27 expression. Tasquinimod-mediated targeting of the myeloid cell population resulted in increased T cell proliferation and functionality in vitro. Notably, short-term tasquinimod therapy of 5TMM mice significantly increased the total CD11b+ cells and shifted this population toward a more immunostimulatory state, which resulted in less myeloid-mediated immunosuppression and increased T cell activation ex vivo. Tasquinimod significantly reduced the tumor load and increased the trabecular bone volume, which resulted in prolonged overall survival of MM-bearing mice in vivo. Conclusion: Our study provides novel insights in the dual therapeutic effects of the immunomodulator tasquinimod and fosters its evaluation in combination therapy trials for MM patients

Thermodynamic theory of epitaxial ferroelectric thin films with dense domain structures

A Landau-Ginsburg-Devonshire-type nonlinear phenomenological theory is presented, which enables the thermodynamic description of dense laminar polydomain states in epitaxial ferroelectric thin films. The theory explicitly takes into account the mechanical substrate effect on the polarizations and lattice strains in dissimilar elastic domains (twins). Numerical calculations are performed for PbTiO3 and BaTiO3 films grown on (001)-oriented cubic substrates. The "misfit strain-temperature" phase diagrams are developed for these films, showing stability ranges of various possible polydomain and single-domain states. Three types of polarization instabilities are revealed for polydomain epitaxial ferroelectric films, which may lead to the formation of new polydomain states forbidden in bulk crystals. The total dielectric and piezoelectric small-signal responses of polydomain films are calculated, resulting from both the volume and domain-wall contributions. For BaTiO3 films, strong dielectric anomalies are predicted at room temperature near special values of the misfit strain.Comment: 19 pages, 8 figure

STEM nanoanalysis of Au/Pt/Ti-Si3N4 interfacial defects and reactions during local stress of SiGe HBTs

A new insight on the behavior of metal contact-insulating interfaces in SiGe heterojunction bipolar transistor is given by high-performance aberration-corrected scanning transmission electron microscopy (STEM) analysis tools equipped with sub-nanometric probe size. It is demonstrated that the presence of initial defects introduced during technological processes play a major role in the acceleration of degradation mechanisms of the structure during stress. A combination of energy-filtered transmission electron microscopy analysis with high angle annular dark field STEM and energy dispersive spectroscopy provides strong evidence that migration of Au-Pt from the metal contacts to Ti/Si3N4 interface is one of the precursors to species interdiffusion and reactions. High current densities and related local heating effects induce the evolution of the pure Ti initial layer into mixture layer composed of Ti, O, and N. Local contamination of Ti layers by fluorine atoms is also pointed out, as well as rupture of TiN thin barrier layer

Co-designing Cards on Social Issues for Creating Educational Games

This paper presents a participatory methodology to design cards on social issues with the purpose to democratise knowledge among co-designers on the learning content of educational games. Situated on the topic of everyday sexism, the methodology has been developed through an iterative process involving two collaborative workshops, two iterations of card design and a feedback survey. Extracting findings from the workshops and the feedback gathered on the co- designed cards, this paper presents insights that could be used to inform similar studies using cards to inspire and foster reflection on social issues