miRNA-130a targets ATG2B and DICER1 to inhibit autophagy and trigger killing of chronic lymphocytic leukemia cells

Toxicity and relapses from the immunochemotherapy used to treat chronic lymphocytic leukemia (CLL) prompt continued interest in gentle but effective targeted treatment options for the mainly elderly population suffering from this disease. Here, we report the definition of critical CLL cell survival pathways that can be targeted by ectopic reexpression of the miRNA genes miR-130a and miR-143 which are widely downregulated in CLL. Notably, miR-130a inhibited autophagy by reducing autophagosome formation, an effect mediated by downregulation of the genes ATG2B and DICER1, the latter of which is a major component of the miRNA silencing machinery. In support of the concept of a fundamental connection between miRNA disregulation and altered autophagic flux in this cancer, we showed that RNA interference-mediated knockdown of DICER1 expression was sufficient to reduce autophagy in primary or established cultures of CLL cells. Together, our findings show that miR-130a modulates cell survival programs by regulating autophagic flux, and they define roles for miR-130a and Dicer1 in a regulatory feedback loop that mediates CLL cell survival.     

The role of matrix metalloproteinases in rheumatoid tendon disease

In rheumatoid arthritis (RA) invasive tenosynovitis is associated with an increase in tendon rupture, although little is known about the mechanisms involved. We obtained specimens of noninvasive encapsulating tenosynovium, invasive tenosynovium, and wrist joint synovium from 28 rheumatoid patients. In vitro production of the matrix metalloproteinase (MMP) enzymes, MMP-8 and -9, and total collagenase activity were measured. Invasive tenosynovium produced highest levels of the collagenase MMP-8 and displayed significantly greater ability to degrade collagen type I than encapsulating tenosynovium. Levels of the gelatinase enzyme MMP-9 were similar in all groups. These results show that invasive tenosynovium is more destructive than encapsulating tenosynovium at a molecular level, providing an explanation for the increased tendon rupture associated with invasive tenosynovitis in RA.     

Base Plate Preheating Effect on Microstructure of 316L Stainless Steel Single Track Deposition by Directed Energy Deposition

The microstructural morphology in additive manufacturing (AM) has a significant influence on the building structure. High-energy concentric heat source scanning leads to rapid heating and cooling during material deposition. This results in a unique microstructure. The size and morphology of the microstructure have a strong directionality, which depends on laser power, scanning rate, melt pool fluid dynamics, and material thermal properties, etc. The grain structure significantly affects its resistance to solidification cracking and mechanical properties. Microstructure control is challenging for AM considering multiple process parameters. A preheating base plate has a significant influence on residual stress, defect-free AM structure, and it also minimizes thermal mismatch during the deposition. In the present work, a simple single track deposition experiment was designed to analyze base plate preheating on microstructure. The microstructural evolution at different preheating temperatures was studied in detail, keeping process parameters constant. The base plate was heated uniformly from an external heating source and set the stable desired temperature on the surface of the base plate before deposition. A single track was deposited on the base plate at room temperature and preheating temperatures of 200 °C, 300 °C, 400 °C, and 500 °C. Subsequently, the resulting microstructural morphologies were analyzed and compared. The microstructure was evaluated using electron backscattered diffraction (EBSD) imaging in the transverse and longitudinal sections. An increase in grain size area fraction was observed as the preheating temperature increased. Base plate preheating did not show influence on grain boundary misorientation. An increase in the deposition depth was noticed for higher base plate preheating temperatures. The results were convincing that grain morphology and columnar grain orientation can be tailored by base plate preheating.