Treatment with b-AP15 to Inhibit UCHL5 and USP14 Deubiquitinating Activity and Enhance p27 and Cyclin E1 for Tumors with p53 Deficiency.

Background: TP53 protein is lost or mutated in about half of all types of human cancers and small molecules to regulate mutant p53 repair, or interrupt ubiquitination degradation of p53 induced by E3-ubiquitin ligase Mdm2 have a potential application in clinical application. Methods: To inhibit the deubiquitinase activity of 19S proteasome and restore the p53 protein level, in this study, we utilized p53 knockout mice to test the anti-cancer effect of a specific USP14 and UCH37 inhibitor b-AP15. Results: Our results show that UCHL5, USP14 and COPS5 are upregulated in p53-related tumors, and higher expression of these genes results in a shorter overall survival in patients with p53 deficiency. Treatment with b-AP15, a UCHL5 and USP14 deubiquitinating activity inhibitor in 19S regulatory subunit, induces tumor regression and prolong the survival period of tumor-loaded mice through down-regulation of COPS5 and its downstream AP-1 and E2F1, and up-regulation of the cell cycle-related proteins p27 and Cyclin E1. Conclusions: Thus, our results suggested that inhibition of UCHL5 and USP14 deubiquitinating activity in 19S proteasome may contribute an extensive approach to preventing tumor progress due to p53 deficiency.

Patterns and Trends of the Mortality From Bone Cancer in Pudong, Shanghai: A Population-Based Study.

Introduction: The burden of cancer-related mortality of common malignancies has been reported worldwide. However, whether bone cancer (BC), as a highly aggressive and heterogeneous group of rare cancers, followed a similar or distinct epidemiological pattern during such process remains largely unknown. We aimed to analyze the mortality and the temporal trends of BC in relation to gender, age, and premature death in Shanghai, China. Methods: We conducted a population-based analysis of the mortality data of BC in Shanghai Pudong New Area (PNA) from 2005 to 2020. The epidemiological characteristics and long-term trends in crude mortality rates (CMRs), age-standardized mortality rates worldwide (ASMRWs), and rate of years of life lost (YLL) was analyzed using the Joinpoint regression program. The demographic and non-demographic factors affecting the mortality rate were evaluated by the decomposition method. Results: There are 519 BC-specific deaths accounting for 0.15% of all 336,823 deaths and 0.49% of cancer-specific death in PNA. The CMR and ASMRW of BC were 1.15/105 person-year and 0.61/105 person-year, respectively. The YLL due to premature death from BC was 6,539.39 years, with the age group of 60-69 years having the highest YLL of 1,440.79 years. The long-term trend of CMR, ASMRW, and YLL rate significantly decreased by -5.14%, -7.64%, and -7.27%, respectively, per year (all p < 0.05) in the past 16 years. However, the proportion of BC-specific death within the total cancer-specific death dropped to a plateau without further improvement since 2016, and a remarkable gender and age disparity was noticed in the observed reduction in mortality. Specifically, the elderly benefited less but accounted for a larger percentage of BC population in the last decades. Although the overall mortality of BC decreased, there was still a significant upward trend toward an increased mortality rate caused by the aging of the BC patients. Conclusion: Our study provides novel insights on the epidemiological characteristics and longitudinal dynamics of BC in a fast urbanization and transitioning city. As a rare disease affecting all ages, the burden of BC among the elderly emerged to form an understudied and unmet medical need in an aging society.

[Study on the pH-sensitive secondary structure of gamma-PGA embedded with magnetite nanoparticles].

The conformational transition of poly gamma-glutamic acid (gamma-PGA) embedded with magnetite nanoparticles under various pH conditions was investigated by Fourier transform infrared spectroscopy (FTIR). The secondary structure content was determined through the analysis of amide I bands of Fourier deconvolution spectra, secondary derivative spectra and the Gaussian curve fitting of the original infrared spectra. The results showed that the conformation of the gamma-PGA was affected by solution pH. The total contents of beta-sheet and beta-turn were higher than 65%, while alpha-helix and random coil were low. The content of beta-turn increased with increasing pH, while the beta-sheet decreased. Additionally, the zeta potential results showed that the pH-sensitive secondary structure of gamma-PGA had influence on the stability of suspension of magnetic gamma-PGA nanospheres. The minimum value of zeta potential (-35. 4 mV) was obtained at pH 10.2.