The ongoing revolution in the plastic sector is the use of renewable and compostable materials obtained from biomass. However, their mechanical strength and thermal stability are generally not ...sufficient for practical applications. This study investigates the influence of natural additives on the physical-mechanical properties of a new biobased compostable bioplastic, SP-Milk®, produced from milk scraps. To provide this matrix the appropriate mechanical and thermal properties for daily use while leaving its compostability unchanged, the effect of incorporating vegetal fibres and organic particulates into the bulk bioplastic was investigated. Mechanical tests showed that fibres with a length of 2 mm are capable of increasing ductility by up to 97% compared with the original matrix, whereas fibres with a length of 10 mm led to a more effective reinforcement due to the residual resistance effect, increasing the final compressive strain from 20% (original matrix) to 70.9%. The addition of particulate yielded a harder and more resistant material, and the elastic modulus increased by 21%, although with loss of ductility, compared to SP-Milk® alone. The combination of fibres and particles resulted in the preservation of the positive effects of both components, showing a higher elastic modulus (240 ± 20 MPa, compared to 199 ± 12 MPa for the matrix), higher ductility (+50%) and higher strain at failure (+30%), compared with the matrix. Excellent compatibility between the polymeric matrix and both the fibres and the granules was confirmed using scanning electron microscopy. The thermal analysis demonstrated improved thermal stability particularly because of the effect of the combination of granules and fibres. The results validate that natural reinforcement agents are effective and ecologically advantageous.
The ongoing revolution in the plastic sector is the use of renewable and compostable materials obtained from biomass. In this paper the influence of natural reinforcing agents on the properties of a milk-based compostable bioplastic is investigated.
Anti-cancer immune responses may contribute to the control of tumors after conventional chemotherapy, and different observations have indicated that chemotherapeutic agents can induce immune ...responses resulting in cancer cell death and immune-stimulatory side effects. Increasing experimental and clinical evidence highlight the importance of natural killer (NK) cells in immune responses toward multiple myeloma (MM), and combination therapies able to enhance the activity of NK cells against MM are showing promise in treating this hematologic cancer. The epigenetic readers of acetylated histones bromodomain and extra-terminal (BET) proteins are critical regulators of gene expression. In cancer, they can upregulate transcription of key oncogenes such as cMYC, IRF4, and BCL-2. In addition, the activity of these proteins can regulate the expression of osteoclastogenic cytokines during cancer progression. Here, we investigated the effect of BET bromodomain protein inhibition, on the expression of NK cell-activating ligands in MM cells.
Five MM cell lines SKO-007(J3), U266, RPMI-8226, ARP-1, JJN3 and CD138
MM cells isolated from MM patients were used to investigate the activity of BET bromodomain inhibitors (BETi) (JQ1 and I-BET151) and of the selective BRD4-degrader proteolysis targeting chimera (PROTAC) (ARV-825), on the expression and function of several NK cell-activating ligands (NKG2DLs and DNAM-1Ls), using flow cytometry, real-time PCR, transient transfections, and degranulation assays.
Our results indicate that inhibition of BET proteins via small molecule inhibitors or their degradation via a hetero-bifunctional PROTAC probe can enhance the expression of MICA, a ligand of the NKG2D receptor, in human MM cell lines and primary malignant plasma cells, rendering myeloma cells more efficient to activate NK cell degranulation. Noteworthy, similar results were obtained using selective CBP/EP300 bromodomain inhibition. Mechanistically, we found that BETi-mediated inhibition of cMYC correlates with the upregulation of miR-125b-5p and the downregulation of the cMYC/miR-125b-5p target gene IRF4, a transcriptional repressor of MICA.
These findings provide new insights on the immuno-mediated antitumor activities of BETi and further elucidate the molecular mechanisms that regulate NK cell-activating ligand expression in MM.
Immunomodulatory drugs (IMiDs) have potent anti-tumor activities in multiple myeloma (MM) and are able to enhance the cytotoxic function of natural killer (NK) cells, important effectors of the ...immune response against MM. Here, we show that these drugs can enhance the expression of the NKG2D and DNAM-1 activating receptor ligands MICA and PVR/CD155 in human MM cell lines and primary malignant plasma cells. Depletion of cereblon (CRBN) by shRNA interference strongly impaired upregulation of these ligands and, more interestingly, IMiDs/CRBN-mediated downregulation of the transcription factors Ikaros (IKZF1), Aiolos (IKZF3) and IRF4 was critical for these regulatory mechanisms. Indeed, shRNA knockdown of IKZF1 or IKZF3 expression was both necessary and sufficient for the upregulation of MICA and PVR/CD155 expression, suggesting that these transcription factors can repress these genes; accordingly, the direct interaction and the negative role of IKZF1 and IKZF3 proteins on MICA and PVR/CD155 promoters were demonstrated. Finally, MICA expression was enhanced in IRF4-silenced cells, indicating a specific suppressive role of this transcription factor on MICA gene expression in MM cells.Taken together, these findings describe novel molecular pathways involved in the regulation of MICA and PVR/CD155 gene expression and identify the transcription factors IKZF-1/IKZF-3 and IRF4 as repressors of these genes in MM cells.
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