Experimental African trypanosome infection suppresses the development of multiple myeloma in mice by inducing intrinsic apoptosis of malignant plasma cells

Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells in the bone marrow (BM). Recently, several studies have highlighted the role of pathogens in either promoting or dampening malignancies of unrelated origin. Trypanosoma brucei is an extracellular protozoan parasite which causes sleeping sickness. Our group has previously demonstrated that trypanosome infection affects effector plasma B cells. Therefore, we hypothesized that T. brucei infection could have an impact on MM development. Using the immunocompetent 5T33MM model, we demonstrated a significant reduction in BM-plasmacytosis and M-protein levels in mice infected with T. brucei, resulting in an increased survival of these mice. Blocking IFN. could only partially abrogate these effects, suggesting that other mechanisms are involved in the destruction of malignant plasma cells. We found that T. brucei induces intrinsic apoptosis of 5T33MM cells in vivo, and that this was associated with reduced endogenous unfolded protein response (UPR) activation. Interestingly, pharmacological inhibition of IRE1 alpha and PERK was sufficient to induce apoptosis in these cells. Together, these results demonstrate that trypanosome infections can interfere with MM development by suppressing endogenous UPR activation and promoting intrinsic apoptosis

Maternal embryonic leucine zipper kinase is a novel target for diffuse large B cell lymphoma and mantle cell lymphoma

Diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) are among the most aggressive B cell non-Hodgkin lymphomas. Maternal embryonic leucine zipper kinase (MELK) plays a role in cancer cell cycle progression and is associated with poor prognosis in several cancer cell types. In this study, the role of MELK in DLBCL and MCL and the therapeutic potential of MELK targeting is evaluated. MELK is highly expressed in DLBCL and MCL patient samples, correlating with a worse clinical outcome in DLBCL. Targeting MELK, using the small molecule OTSSP167, impaired cell growth and survival and induced caspase-mediated apoptosis in the lymphoma cells. Western blot analysis revealed that MELK targeting decreased the phosphorylation of FOXM1 and the protein levels of EZH2 and several mitotic regulators, such as Cdc25B, cyclin B1, Plk-1, and Aurora kinases. In addition, OTSSP167 also sensitized the lymphoma cells to the clinically relevant Bcl-2 inhibitor venetoclax by strongly reducing Mcl1 levels. Finally, OTSSP167 treatment of A20-inoculated mice resulted in a significant prolonged survival. In conclusion, targeting MELK with OTSSP167 induced strong anti-lymphoma activity both in vitro and in vivo. These findings suggest that MELK could be a potential new target in these aggressive B cell malignancies

The Epigenome in Multiple Myeloma: Impact on Tumor Cell Plasticity and Drug Response

Multiple myeloma (MM) is a clonal plasma cell malignancy that develops primarily in the bone marrow (BM), where reciprocal interactions with the BM niche foster MM cell survival, growth, and drug resistance. MM cells furthermore reshape the BM to their own needs by affecting the different BM stromal cell types resulting in angiogenesis, bone destruction, and immune suppression. Despite recent advances in treatment modalities, MM remains most often incurable due to the development of drug resistance to all standard of care agents. This underscores the unmet need for these heavily treated relapsed/refractory patients. Disruptions in epigenetic regulation are a well-known hallmark of cancer cells, contributing to both cancer onset and progression. In MM, sequencing and gene expression profiling studies have also identified numerous epigenetic defects, including locus-specific DNA hypermethylation of cancer-related and B cell specific genes, genome-wide DNA hypomethylation and genetic defects, copy number variations and/or abnormal expression patterns of various chromatin modifying enzymes. Importantly, these so-called epimutations contribute to genomic instability, disease progression, and a worse outcome. Moreover, the frequency of mutations observed in genes encoding for histone methyltransferases and DNA methylation modifiers increases following treatment, indicating a role in the emergence of drug resistance. In support of this, accumulating evidence also suggest a role for the epigenetic machinery in MM cell plasticity, driving the differentiation of the malignant cells to a less mature and drug resistant state. This review discusses the current state of knowledge on the role of epigenetics in MM, with a focus on deregulated histone methylation modifiers and the impact on MM cell plasticity and drug resistance. We also provide insight into the potential of epigenetic modulating agents to enhance clinical drug responses and avoid disease relapse

The anaphase-promoting complex/cyclosome : a new promising target in diffuse large B-cell lymphoma and mantle cell lymphoma

BACKGROUND: The aggressive B-cell non-Hodgkin lymphomas diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) are characterised by a high proliferation rate. The anaphase-promoting complex/cyclosome (APC/C) and its co-activators Cdc20 and Cdh1 represent an important checkpoint in mitosis. Here, the role of the APC/C and its co-activators is examined in DLBCL and MCL. METHODS: The expression and prognostic value of Cdc20 and Cdh1 was investigated using GEP data and immunohistochemistry. Moreover, the therapeutic potential of APC/C targeting was evaluated using the small-molecule inhibitor proTAME and the underlying mechanisms of action were investigated by western blot. RESULTS: We demonstrated that Cdc20 is highly expressed in DLBCL and aggressive MCL, correlating with a poor prognosis in DLBCL. ProTAME induced a prolonged metaphase, resulting in accumulation of the APC/C-Cdc20 substrate cyclin B1, inactivation/degradation of Bcl-2 and Bcl-xL and caspase-dependent apoptosis. In addition, proTAME strongly enhanced the anti-lymphoma effect of the clinically relevant agents doxorubicin and venetoclax. CONCLUSION: We identified for the first time APC/C as a new, promising target in DLBCL and MCL. Moreover, we provide evidence that Cdc20 might be a novel, independent prognostic factor in DLBCL and MCL

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

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

Metabolic Features of Multiple Myeloma

Cancer is known for its cellular changes contributing to tumour growth and cell proliferation. As part of these changes, metabolic rearrangements are identified in several cancers, including multiple myeloma (MM), which is a condition whereby malignant plasma cells accumulate in the bone marrow (BM). These metabolic changes consist of generation, inhibition and accumulation of metabolites and metabolic shifts in MM cells. Changes in the BM micro-environment could be the reason for such adjustments. Enhancement of glycolysis and glutaminolysis is found in MM cells compared to healthy cells. Metabolites and enzymes can be upregulated or downregulated and play a crucial role in drug resistance. Therefore, this review will focus on changes in glucose and glutamine metabolism linked with the emergence of drug resistance. Moreover, metabolites do not only affect other metabolic components to benefit cancer development; they also interfere with transcription factors involved in proliferation and apoptotic regulation