p53: The Multifaceted Roles of Covalent Modifications in Cancer.

The p53 protein has attracted huge research interest over several decades due to its role as one of the most important tumor suppressors in mammals, which orchestrates a synchronous response from normal cells in the body to various forms of stress. The diverse cellular activities of the p53 protein are regulated mainly via its post-translational modifications (PTMs). PTMs affect p53 on several levels: at the level of the assembly of tetrameric complexes on DNA to transactivate its target genes, at the level of the assembly of tetrameric complexes on DNA to transactivate its target genes; at the level of proteolysis in the absence of stress; and on the contrary, at the level of augmented protein stability in response to stress signals.

PROTAC-attractive site as a new target for suppressing P-glycoprotein activity.

P-glycoprotein (P-gp) plays an important role in the rapid release of various small molecule substances from the cell. In turn, inhibition of this efflux transporter is an attractive strategy for both overcoming chemoresistance and facilitating oral absorption of drugs or CNS drug delivery. In this work, we adopt an approach typical for PROteolysis Targeting Chimera (PROTAC), which is based on the artificial drawing together of the target protein to E3 ubiquitin ligase, to P-gp.

Evaluation of blood MSI burden dynamics to trace immune checkpoint inhibitor therapy efficacy through the course of treatment.

Analysis of serial liquid biopsy (LB) samples has been found to be a promising approach for the monitoring of tumor dynamics in the course of therapy for patients with colorectal cancer (CRC). Currently, somatic mutations are used for tracing the dynamics of the tumor via LB. However, the analysis of the dynamic changes in the molecular signatures such as microsatellite instability (MSI) is not currently used.

Rational Design Problematics of Peptide Nucleic Acids as SARS-CoV-2 Inhibitors.

The use of viral protein inhibitors has shown to be insufficiently effective in the case of highly variable SARS-CoV-2. In this work, we examined the possibility of designing agents that bind to a highly conserved region of coronavirus (+)RNA. We demonstrated that while the design of antisense RNAs is based on the complementary interaction of nitrogenous bases, it is possible to use semirigid docking methods in the case of unnatural peptide nucleic acids.

Failure of immune checkpoint inhibitors for microsatellite instability-positive pancreatic adenocarcinoma with atypical pattern of short tandem repeat mutation.

Microsatellite instability (MSI) is an important biomarker in cancer. While routine methods can detect MSI in certain tumor types, in other tumor types the results may be incorrect due to differences in the MSI loci pattern. Here, we report the case of a patient with pancreatic adenocarcinoma, with confirmed MSI by two independent next-generation sequencing tests, but not by routine methods, who had progression on pembrolizumab.