HSP90β Impedes STUB1‐Induced Ubiquitination of YTHDF2 to Drive Sorafenib Resistance in Hepatocellular Carcinoma

Abstract YTH domain family 2 (YTHDF2) is the first identified N6‐methyladenosine (m6A) reader that regulates the status of mRNA. It has been reported that overexpressed YTHDF2 promotes carcinogenesis; yet, its role in hepatocellular carcinoma (HCC) is elusive. Herein, it is demonstrated that YTHDF2 is upregulated and can predict poor outcomes in HCC. Decreased ubiquitination levels of YTHDF2 contribute to the upregulation of YTHDF2. Furthermore, heat shock protein 90 beta (HSP90β) and STIP1 homology and U‐box‐containing protein 1 (STUB1) physically interact with YTHDF2 in the cytoplasm. Mechanically, the large and small middle domain of HSP90β is required for its interaction with STUB1 and YTHDF2. HSP90β inhibits the STUB1‐induced degradation of YTHDF2 to elevate the expression of YTHDF2 and to further boost the proliferation and sorafenib resistance of HCC. Moreover, HSP90β and YTHDF2 are upregulated, while STUB1 is downregulated in HCC tissues. The expression of HSP90β is positively correlated with the YTHDF2 protein level, whereas the expression of STUB1 is negatively correlated with the protein levels of YTHDF2 and HSP90β. These findings deepen the understanding of how YTHDF2 is regulated to drive HCC progression and provide potential targets for treating HCC

Transmission of ST45 and ST2407 extended-spectrum β-lactamase-producing Klebsiella pneumoniae in neonatal intensive care units, associated with contaminated environments

ABSTRACT: Objectives: Given the increasing frequency of infections due to extended-spectrum β-lactamase (EBSL)-producing Klebsiella pneumoniae in humans over recent decades, infection control against this pathogen is of high importance. Methods: In this study, the transmission mode of ESBL-producing K. pneumoniae in neonatal intensive care units (NICU) was investigated. We collected K. pneumoniae isolates from patients admitted to the NICU and performed environmental screening of the NICU and nearby obstetrics department. All isolates were analysed using antimicrobial susceptibility testing, whole-genome sequencing, molecular typing, and antimicrobial and virulence determinant screening. The phylogenetic relationships of all the isolates were analysed using core-genome multi-locus sequence type and single-nucleotide polymorphism-based analysis, and their plasmids harbouring antimicrobial resistance genes in ST2407 were compared. Results: Eighteen K. pneumoniae isolates were collected, of which 10 isolates from patients belonged to ST45 and ST2407, and eight isolates from the environment belonged to various other clones. Although 80% and 100% of isolates from patients were ESBL-positive (blaCTX-M-14 and blaCTX-M-55) and possessed siderophores, respectively; fewer environmental isolates harboured antimicrobial resistance and virulence genes. For both ST45 and ST2407 isolates, the phylogenetic assessment revealed a close relationship between clinical and environmental isolates, indicating that bloodstream infections were associated with the contaminated environments. Conclusions: Based on these results, the environmental prevalence of K. pneumoniae should be considered given its pathogenicity in humans. Early and active infection control measures could decrease the spread of multidrug-resistant K. pneumoniae