Reconstructing the genomes of bilaterian ancestors is central to our understanding of animal evolution, where knowledge from ancient and/or slow-evolving bilaterian lineages is critical. Here we report a high-quality, chromosome-anchored reference genome for the scallop Patinopecten yessoensis, a bivalve mollusc that has a slow-evolving genome with many ancestral features. Chromosome-based macrosynteny analysis reveals a striking correspondence between the 19 scallop chromosomes and the 17 presumed ancestral bilaterian linkage groups at a level of conservation previously unseen, suggesting that the scallop may have a karyotype close to that of the bilaterian ancestor. Scallop Hox gene expression follows a new mode of subcluster temporal co-linearity that is possibly ancestral and may provide great potential in supporting diverse bilaterian body plans. Transcriptome analysis of scallop mantle eyes finds unexpected diversity in phototransduction cascades and a potentially ancient Pax2/5/8-dependent pathway for noncephalic eyes. The outstanding preservation of ancestral karyotype and developmental control makes the scallop genome a valuable resource for understanding early bilaterian evolution and biology.
Enzalutamide, a nonsteroidal second-generation antiandrogen, has been recently approved for the management of castration-resistant prostate cancer (CRPC). Although patients can benefit from enzalutamide at the beginning of this therapy, acquired enzalutamide resistance usually occurs within a short period. This motivated us to investigate the mechanism involved and possible approaches for overcoming enzalutamide resistance in CRPC. In the present study, we found that 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), a crucial enzyme in the mevalonate pathway for sterol biosynthesis, is elevated in enzalutamide-resistant prostate cancer cell lines. HMGCR knockdown could resensitize these cells to the drug, and HMGCR overexpression conferred resistance to it, suggesting that aberrant HMGCR expression is an important enzalutamide-resistance mechanism in prostate cancer cells. Furthermore, enzalutamide-resistant prostate cancer cells were more sensitive to statins, which are HMGCR inhibitors. Of note, a combination of simvastatin and enzalutamide significantly inhibited the growth of enzalutamide-resistant prostate cancer cells and tumors Mechanistically, simvastatin decreased protein levels of the androgen receptor (AR), which was further reduced in combination with enzalutamide. We observed that the decrease in AR may occur through simvastatin-mediated inhibition of the mTOR pathway, whose activation was associated with increased HMGCR and AR expression. These results indicate that simvastatin enhances the efficacy of enzalutamide-based therapy, highlighting the therapeutic potential of statins to overcome enzalutamide resistance in CRPC.
Blockade of programmed death-ligand 1 (PD-L1) by therapeutic antibodies has shown to be a promising strategy in cancer therapy, yet clinical response in many types of cancer, including prostate cancer (PCa), is limited. Tumor cells secrete PD-L1 through exosomes or splice variants, which has been described as a new mechanism for the resistance to PD-L1 blockade therapy in multiple cancers, including PCa. This suggests that cutting off the secretion or expression of PD-L1 might improve the response rate of PD-L1 blockade therapy in PCa treatment. Here we report that p300/CBP inhibition by a small molecule p300/CBP inhibitor dramatically enhanced the efficacy of PD-L1 blockade treatment in a syngeneic model of PCa by blocking both the intrinsic and interferon gamma (IFN-γ)-induced PD-L1 expression. Mechanistically, p300/CBP could be recruited to the promoter of
CD274
(encoding PD-L1) by the transcription factor IRF-1, which induced the acetylation of Histone H3 at
CD274
promoter followed by the transcription of
CD274
. A485, a p300/CBP inhibitor, abrogated this process and cut off the secretion of exosomal PD-L1 by blocking the transcription of
CD274
, which combined with the anti-PD-L1 antibody to reactivate T cells function for tumor attack. This finding reports a new mechanism of how cancer cells regulate PD-L1 expression through epigenetic factors and provides a novel therapeutic approach to enhance the efficacy of immune checkpoint inhibitors treatment.
Recently, the sonocatalytic technology using various semiconductors combined with ultrasonic irradiation has been received much attention to solve the environmental problems. In this paper, nano-sized titanium dioxide (TiO(2)) powder as a sonocatalyst was irradiated by ultrasound and the generation of reactive oxygen species (ROS) during sonocatalytic reaction process has been estimated by the method of Oxidation-Extraction Photometry (OEP). That is, the 1,5-diphenylcarbohydrazide (DPCI) can be oxidized by ROS into diphenylcarbonzone (DPCO), which can be extracted by the mixed solution of benzene and carbon tetrachloride and show the great absorbance at 563 nm wavelength. The synergistic effect of TiO(2) and ultrasonic irradiation was estimated and some influencing factors, such as ultrasonic irradiation time and TiO(2) addition amount on the generation of ROS were reviewed. The results indicate that the quantities of generated ROS increase with the increase of ultrasonic irradiation time and TiO(2) addition amount. Moreover, the relationship between quantities of generated ROS and DPCI concentration was also studied. And then, several quenchers were used to determine the kind of the generated ROS. At last, the researches on the sonocatalytic degradation of organic dyes and the corresponding reaction kinetics have also been performed, which is found to follow the pseudo first-order kinetics approximately. This paper may offer some important subjects for broadening the applications of sonocatalytic technology.
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