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Venetoclax and obinutuzumab are becoming frontline therapies for chronic lymphocytic leukemia (CLL) patients. Unfortunately, drug resistance still occurs, and the combination could be immunosuppressive. Lysosomes have previously been identified as a target for obinutuzumab cytotoxicity in CLL cells, but the mechanism remains unclear. In addition, studies have shown that lysosomotropic agents can cause synergistic cell death in vitro when combined with the BTK inhibitor, ibrutinib, in primary CLL cells. This indicates that targeting lysosomes could be a treatment strategy for CLL. In this study, we have shown that obinutuzumab induces lysosome membrane permeabilization (LMP) and cathepsin D release in CLL cells. Inhibition of cathepsins reduced obinutuzumab-induced cell death in CLL cells. We further determined that the lysosomotropic agent siramesine in combination with venetoclax increased cell death in primary CLL cells through an increase in reactive oxygen species (ROS) and cathepsin release. Siramesine treatment also induced synergistic cytotoxicity when combined with venetoclax. Microenvironmental factors IL4 and CD40L or incubation with HS-5 stromal cells failed to significantly protect CLL cells from siramesine- and venetoclax-induced apoptosis. We also found that siramesine treatment inhibited autophagy through reduced autolysosomes. Finally, the autophagy inhibitor chloroquine failed to further increase siramesine-induced cell death. Taken together, lysosome-targeting drugs could be an effective strategy in combination with venetoclax to overcome drug resistance in CLL. [ABSTRACT FROM AUTHOR]

The interaction between fig wasps and their host fig trees (Ficus spp.) is a striking example of an obligate pollination mutualism. Male and female fig wasps are confined within their natal patch instead of panmictic; under this circumstance, mating only occurs between individuals of the same patch. This is known as a local mate competition (LMC). It pays foundresses to invest mainly in daughters and to only produce enough sons to ensure that all female offspring can be fertilized, but in nature, pollinating fig wasps may face many problems with host quality, such as limitation of oviposition sites and the nutrition deficiency of the host fig. The sex ratio of wasps can determine the stability of fig–fig wasp mutualistic system and, thus, the stability of other species associated with it. In this study, we controlled the quality of host figs in three ways. The results showed that the host fig age can influence the sex ratio of pollinator offspring, while the foundress numbers and the presence of pollen have no significant effect on it. A compelling explanation for this result is that the sex-dependent mortality occurs. This is a novel finding of how host quality influences the interaction of fig and fig wasps, which can also help us understand the evolution and stability mechanism of this symbiotic system. [ABSTRACT FROM AUTHOR]