Accurate prediction of HLA class II antigen presentation across all loci using tailored data acquisition and refined machine learning.

Accurate prediction of antigen presentation by human leukocyte antigen (HLA) class II molecules is crucial for rational development of immunotherapies and vaccines targeting CD4 T cell activation. So far, most prediction methods for HLA class II antigen presentation have focused on HLA-DR because of limited availability of immunopeptidomics data for HLA-DQ and HLA-DP while not taking into account alternative peptide binding modes. We present an update to the NetMHCIIpan prediction method, which closes the performance gap between all three HLA class II loci.

Machine learning reveals limited contribution of trans-only encoded variants to the HLA-DQ immunopeptidome.

Human leukocyte antigen (HLA) class II antigen presentation is key for controlling and triggering T cell immune responses. HLA-DQ molecules, which are believed to play a major role in autoimmune diseases, are heterodimers that can be formed as both cis and trans variants depending on whether the α- and β-chains are encoded on the same (cis) or opposite (trans) chromosomes. So far, limited progress has been made for predicting HLA-DQ antigen presentation.

Subcellular location of source proteins improves prediction of neoantigens for immunotherapy.

Antigen presentation via the major histocompatibility complex (MHC) is essential for anti-tumor immunity. However, the rules that determine which tumor-derived peptides will be immunogenic are still incompletely understood. Here, we investigated whether constraints on peptide accessibility to the MHC due to protein subcellular location are associated with peptide immunogenicity potential.

Accurate MHC Motif Deconvolution of Immunopeptidomics Data Reveals a Significant Contribution of DRB3, 4 and 5 to the Total DR Immunopeptidome.

Mass spectrometry (MS) based immunopeptidomics is used in several biomedical applications including neo-epitope discovery in oncology, next-generation vaccine development and protein-drug immunogenicity assessment. Immunopeptidome data are highly complex given the expression of multiple HLA alleles on the cell membrane and presence of co-immunoprecipitated contaminants. The absence of tools that deal with these challenges effectively and guide the analysis and interpretation of this complex type of data is currently a major bottleneck for the large-scale application of this technique.

Nanoparticles for Targeting of Prostate Cancer.

Prostate cancer (PCa) is the leading cause of death by cancer in men. Because of the drastic decline in the survival rate of PCa patients with advanced/metastatic disease, early diagnosis of disease and therapy without toxic side effects is crucial. Chemotherapy is widely used to control the progression of PCa at the later stages; however, it is associated with off-target toxicities and severe adverse effects due to the lack of specificity.

Surface Modification of Liposomes by a Lipopolymer Targeting Prostate Specific Membrane Antigen for Theranostic Delivery in Prostate Cancer.

Prostate specific membrane antigen (PSMA) is a marker for diagnosis and targeted delivery of therapeutics to advanced/metastasized prostate cancer. We report a liposome-based system for theranostic delivery to PSMA-expressing (PSMA⁺) LNCaP cells. A lipopolymer (P³) comprising of PSMA ligand (PSMAL), polyethylene glycol (PEG), and palmitate was synthesized and post-inserted into the surface of preformed liposomes.

Ubiquitin Receptor RPN13 Mediates the Inhibitory Interaction of Diphenyldihaloketones CLEFMA and EF24 With the 26S Proteasome.

The proteasome is a validated target in drug discovery for diseases associated with unusual proteasomal activity. Here we report that two diphenyldihaloketones, CLEFMA and EF24, inhibit the peptidase activity of the 26S proteasome. The objective of this study was to investigate interaction of these compounds with the proteasome and identify a putative target within the protein components of the 26S proteasome.

Induction of gut proteasome activity in hemorrhagic shock and its recovery by treatment with diphenyldihaloketones CLEFMA and EF24.

Multiorgan failure in hemorrhagic shock is triggered by gut barrier dysfunction and consequent systemic infiltration of proinflammatory factors. Our previous study has shown that diphenyldihaloketone drugs 4-[3,5-bis[(2-chlorophenyl)methylene]-4-oxo-1-piperidinyl]-4-oxo-2-butenoic acid (CLEFMA) and 3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone (EF24) restore gut barrier dysfunction and reduce systemic inflammatory response in hemorrhagic shock. We investigated the effect of hemorrhagic shock on proteasome activity of intestinal epithelium and how CLEFMA and EF24 treatments modulate proteasome function in hemorrhagic shock.

Stability study on an anti-cancer drug 4-(3,5-bis(2-chlorobenzylidene)-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid (CLEFMA) using a stability-indicating HPLC method.

CLEFMA, 4-(3,5-bis(2-chlorobenzylidene)-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid, is a new chemical entity with anti-cancer and anti-inflammatory activities. Here, we report its stability in solution against stress conditions of exposure to acid/base, light, oxidant, high temperature, and plasma. The identity of the degradation products was ascertained by mass and proton nuclear magnetic resonance spectroscopy.