The E3 ligase HUWE1 inhibition as a therapeutic strategy to target MYC in multiple myeloma

Proteasome inhibitors have provided a significant advance in the treatment of multiple myeloma (MM). Consequently, there is increasing interest in developing strategies to target E3 ligases, de-ubiquitinases, and/or ubiquitin receptors within the ubiquitin proteasome pathway, with an aim to achieve more specificity and reduced side-effects. Previous studies have shown a role for the E3 ligase HUWE1 in modulating c-MYC, an oncogene frequently dysregulated in MM. Here we investigated HUWE1 in MM. We identified elevated expression of HUWE1 in MM compared with normal cells. Small molecule-mediated inhibition of HUWE1 resulted in growth arrest of MM cell lines without significantly effecting the growth of normal bone marrow cells, suggesting a favorable therapeutic index. Studies using a HUWE1 knockdown model showed similar growth inhibition. HUWE1 expression positively correlated with MYC expression in MM bone marrow cells and correspondingly, genetic knockdown and biochemical inhibition of HUWE1 reduced MYC expression in MM cell lines. Proteomic identification of HUWE1 substrates revealed a strong association of HUWE1 with metabolic processes in MM cells. Intracellular glutamine levels are decreased in the absence of HUWE1 and may contribute to MYC degradation. Finally, HUWE1 depletion in combination with lenalidomide resulted in synergistic anti-MM activity in both in vitro and in vivo models. Taken together, our data demonstrate an important role of HUWE1 in MM cell growth and provides preclinical rationale for therapeutic strategies targeting HUWE1 in MM

Hardness, Decay and Water Resistance of Polypropylene/Montmorillonite/Almond Shell Flour Composites

The effect of montmorillonite (MMT) loading (0, 2.5, and 5 wt%) and almond shell flour (ASF) content (30, 35, and 40 wt%) on the decay resistance, hardness, water resistance of injection molded polypropylene (PP) composites was investigated. The amount of maleic anhydride grafted polypropylene was kept constant at 2% for all formulations. White-rot (Trametes versicolor) fungal treatment was applied to the produced composites for 14 weeks according to BS 838:1961 with the Petri dishes method. The weight loss of the composites decreased with increasing MMT content. The highest hardness (66 Shore D) was noted in the undecayed control composites (40ASF60PP0MMT) while the lowest hardness (61.3 Shore D) was recorded in the decayed control composites (30ASF70PP0MMT). The water absorption of the undecayed and decayed composites decreased with increasing amount montmorillonite at 30-40 wt% content of the ASF loading level. The water absorption of the decayed composites was higher than that of the undecayed composites but their thickness swelling was lower. Based on the findings obtained from the present study, a 35/5/65/2 formulation of the ASF/MMT/PP/MAPP can be used in outdoor applications requiring a high dimensional stability

Influence of coupling agent in compatibility of post-consumer HDPE in thermoplastic composites reinforced with eucalyptus fiber

This study investigates the feasibility of using recycled high density polyethylene (HDPE) and wood fiber from species Eucalyptus grandis (EU) to manufacture experimental composite panels. The use of maleated polyethylene as coupling agent (CA) improved the compatibility between the fiber and plastic matrix. The mechanical properties of the resultant composites were compared with polymer with and without compatibilizer. The influence of the coupling agent (CA) in the polymer matrices and composites were evaluated at different concentrations, checking the physical, mechanical and thermal properties of wood plastic composites (WPC). Results of mechanical, physical and thermal properties showed that concentration of 3% w/w CA in the polymer matrices was that which showed the best results, but in the composites properties were very similar in all formulations. Based on the findings in this work, it appears that recycled materials can be used to manufacture value-added panels without having any significant adverse influence on material properties