N-methylmorpholine incorporation into the structure of biphenyl leads to the bioactive inhibitor of PD-1/PD-L1 interaction.

We present new small-molecular probes targeting the human PD-L1 protein. The molecules were designed by incorporating a newly discovered N-methylmorpholine substituent into a known biphenyl-based structure. Four prototype derivatives of 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile (STD4), comprising a morpholine substituent fused with a biphenyl core at different orientations were first verified for their potential binding to PD-L1 using the molecular docking method.

Structural and biological characterization of pAC65, a macrocyclic peptide that blocks PD-L1 with equivalent potency to the FDA-approved antibodies.

Recent advances in immuno-oncology have opened up new and impressive treatment options for cancer. Notwithstanding, overcoming the limitations of the current FDA-approved therapies with monoclonal antibodies (mAbs) that block the PD-1/PD-L1 pathway continues to lead to the testing of multiple approaches and optimizations. Recently, a series of macrocyclic peptides have been developed that exhibit binding strengths to PD-L1 ranging from sub-micromolar to micromolar.

Monocyte subpopulations display disease-specific miRNA signatures depending on the subform of Spondyloarthropathy.

Spondyloarthropathies (SpA) are a family of rheumatic disorders that could be divided into axial (axSpA) and peripheral (perSpA) sub-forms depending on the disease clinical presentation. The chronic inflammation is believed to be driven by innate immune cells such as monocytes, rather than self-reactive cells of adaptive immune system. The aim of the study was to investigate the micro-RNA (miRNA) profiles in monocyte subpopulations (classical, intermediate and non-classical subpopulations) acquired from SpA patients or healthy individuals in search for prospective disease specific and/or disease subtype differentiating miRNA markers.

Improving the Effect of Cancer Cells Irradiation with X-rays and High-Energy Protons Using Bimetallic Palladium-Platinum Nanoparticles with Various Nanostructures.

Nano-sized radiosensitizers can be used to increase the effectiveness of radiation-based anticancer therapies. In this study, bimetallic, ~30 nm palladium-platinum nanoparticles (PdPt NPs) with different nanostructures (random nano-alloy NPs and ordered core-shell NPs) were prepared. Scanning transmission electron microscopy (STEM), selected area electron diffraction (SAED), energy-dispersive X-ray spectroscopy (EDS), zeta potential measurements, and nanoparticle tracking analysis (NTA) were used to provide the physicochemical characteristics of PdPt NPs.

Supportive, Delegated, and Common Dyadic Coping Mediates the Association between Adult Attachment Representation and Relationship Satisfaction: A Dyadic Approach.

The aim of this study was to examine intrapersonal (actor) and interpersonal (partner) associations between attachment, assessed by the Adult Attachment Interview, and satisfaction with the relationship, as well as to establish the possibility of the mediatory effect of supportive, delegated, and common dyadic coping on the aforementioned associations. A dyadic approach has been introduced, using the actor-partner interdependence mediation model and data from 114 heterosexual couples, aged 26 to 60. It has been shown that one's own secure attachment can be perceived as the predictor of one's own relationship satisfaction in women and men and the predictor of a partner's relationship satisfaction in men.

Gold-Decorated Platinum and Palladium Nanoparticles as Modern Nanocomplexes to Improve the Effectiveness of Simulated Anticancer Proton Therapy.

Noble metal nanoparticles, such as gold (Au NPs), platinum (Pt NPs), or palladium (Pd NPs), due to their highly developed surface, stability, and radiosensitizing properties, can be applied to support proton therapy (PT) of cancer. In this paper, we investigated the potential of bimetallic, c.a.

Terphenyl-Based Small-Molecule Inhibitors of Programmed Cell Death-1/Programmed Death-Ligand 1 Protein-Protein Interaction.

We describe a new class of potent PD-L1/PD-1 inhibitors based on a terphenyl scaffold that is derived from the rigidified biphenyl-inspired structure. Using docking, we designed and then experimentally demonstrated the effectiveness of the terphenyl-based scaffolds in inhibiting PD-1/PD-L1 complex formation using various biophysical and biochemical techniques. We also present a high-resolution structure of the complex of PD-L1 with one of our most potent inhibitors to identify key PD-L1/inhibitor interactions at the molecular level.

Down-Regulation of Dkk-1 in Platelets of Patients With Axial Spondyloarthritis.

Objective: Axial spondyloarthritis (SpA) is a chronic autoinflammatory disease with new bone formation, which is controlled by Wnt/β-catenin signaling. Dkk-1 is an inhibitor of the Wnt pathway, and in humans, platelets represent a major source of Dkk-1. This study was undertaken to investigate whether levels of Dkk-1 in serum and platelet expression of DKK1 messenger RNA (mRNA) and Dkk-1 protein are affected in patients with axial SpA compared to healthy controls.

Fancy-Shaped Gold-Platinum Nanocauliflowers for Improved Proton Irradiation Effect on Colon Cancer Cells.

Enhancing the effectiveness of colorectal cancer treatment is highly desirable. Radiation-based anticancer therapy-such as proton therapy (PT)-can be used to shrink tumors before subsequent surgical intervention; therefore, improving the effectiveness of this treatment is crucial. The addition of noble metal nanoparticles (NPs), acting as radiosensitizers, increases the PT therapeutic effect.

Di-bromo-Based Small-Molecule Inhibitors of the PD-1/PD-L1 Immune Checkpoint.

Immune checkpoint blockade is one of the most promising strategies of cancer immunotherapy. However, unlike classical targeted therapies, it is currently solely based on expensive monoclonal antibodies, which often inflict immune-related adverse events. Herein, we propose a novel small-molecule inhibitor targeted at the most clinically relevant immune checkpoint, PD-1/PD-L1.

FeO@SiO@Au nanoparticles for MRI-guided chemo/NIR photothermal therapy of cancer cells.

Novel functionalized (biofunctionalization followed by cisplatin immobilization) FeO@SiO@Au nanoparticles (NPs) were designed. The encapsulation of FeO cores inside continuous SiO shells preserves their initial structure and strong magnetic properties, while the shell surface can be decorated by small Au NPs, and then cisplatin (cPt) can be successfully immobilized on their surface. The fabricated NPs exhibit very strong contrasting properties for magnetic resonance imaging (MRI).

Similarities in the General Chemical Composition of Colon Cancer Cells and Their Microvesicles Investigated by Spectroscopic Methods-Potential Clinical Relevance.

Colon cancer constitutes 33% of all cancer cases in humans and the majority of patients with metastatic colon cancer still have poor prognosis. An important role in cancer development is the communication between cancer and normal cells. This may occur, among others, through extracellular vesicles (including microvesicles) (MVs), which are being released by both types of cells.

Transition Metal Containing Particulate Matter Promotes Th1 and Th17 Inflammatory Response by Monocyte Activation in Organic and Inorganic Compounds Dependent Manner.

In recent years, a significant increase in the frequency of disorders caused by air pollutants has been observed. Here we asked whether transition metal-containing particulate matter (TMCPM), a component of air pollution, has an effect on the activity of human CD4+ T cell subsets (Th1, Th2, Th17, and Treg). Peripheral blood mononuclear cells (PBMC) from healthy donors were cultured with or without NIST (SRM 1648a-standard urban particulate matter purchased from the National Institute for Standards and Technology) and LAP (SRM 1648a particulate matter treated within 120 min with cold oxygen plasma) preparations of TMCPM, differing in organic compounds content.

Autologous tumor‑derived microvesicles influence gene expression profiles and enhance protumorigenic chemotactic potential, signal transduction and cellular respiration in gastric cancer cells.

Tumor‑derived microvesicles (TMVs) interact with a variety of different cell types within the immune system, including lymphocytes, monocytes, dendritic cells and tumor cells that they have originated from. In the present study, the effects of autologous‑TMVs (auto‑TMVs) on gene expression, chemotaxis, intercellular signaling and cellular metabolism were examined in cells of the gastric cancer (GC) cell line 1415 (GC1415). The effects of auto‑TMVs on mRNA gene expression in GC1415 cells were assessed using pathway‑focused PCR arrays.

Control of Arms of Au Stars Size and its Dependent Cytotoxicity and Photosensitizer Effects in Photothermal Anticancer Therapy.

Gold nanostars (AuS NPs) are a very attractive nanomaterial, which is characterized by high effective transduction of the electromagnetic radiation into heat energy. Therefore, AuS NPs can be used as photosensitizers in photothermal therapy (PTT). However, understanding the photothermal conversion efficiency in nanostars is very important to select the most appropriate shape and size of AuS NPs.

CA-170 - A Potent Small-Molecule PD-L1 Inhibitor or Not?

is currently the only small-molecule modulator in clinical trials targeting PD-L1 and VISTA proteins - important negative checkpoint regulators of immune activation. The reported therapeutic results to some extent mimic those of FDA-approved monoclonal antibodies overcoming the limitations of the high production costs and adverse effects of the latter. However, no conclusive biophysical evidence proving the binding to hPD-L1 has ever been presented.

Sera of patients with axial spondyloarthritis (axSpA) enhance osteoclastogenic potential of monocytes isolated from healthy individuals.

Background: Axial spondyloarthritis (axSpA) is characterized by significant bone loss caused by dysregulation of physiological bone turnover, possibly resulting from intensified differentiation of osteoclasts. The aim of this study was to reevaluate the levels of osteoclastogenesis-mediating factors: soluble RANKL, M-CSF, OPG and other cytokines in sera of untreated, with sDMARDs and/or bDMARDs, axSpA patients and to test whether these sera influence differentiation of healthy monocytes towards osteoclast lineage.

Methods: Bone remodeling molecules (RANKL, M-CSF, OPG, IL-6, OSM, IL-17A, TGFβ, and TNFα) were evaluated in 27 patients with axSpA and 23 age and sex-matched controls.

Secretion of tumoricidal human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by recombinant Lactococcus lactis: optimization of in vitro synthesis conditions.

Background: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively eliminates tumor cells. However, the short biological half-life of this molecule limits its potential use in the clinic. Our aim was to construct a recombinant strain of nonpathogenic Lactococcus lactis bacteria as a vector for effective and prolonged human TRAIL production.

Characterization of human gastric adenocarcinoma cell lines established from peritoneal ascites.

The three cell lines, designated as gastric cancer (GC)1401, GC1415 and GC1436 were derived from peritoneal effusions from patients with gastric adenocarcinoma. Cell lines were established in tissue culture and in immunodeficient, non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. All cell lines were cultured in Dulbecco's modified Eagle's medium supplemented with 5% fetal bovine serum.

The implementation of the Strategy Europe 2020 objectives in European Union countries: the concept analysis and statistical evaluation.

The European Union (EU), striving to create economic dominance on the global market, has prepared a comprehensive development programme, which initially was the Lisbon Strategy and then the Strategy Europe 2020. The attainment of the strategic goals included in the prospective development programmes shall transform the EU into the most competitive economy in the world based on knowledge. This paper presents a statistical evaluation of progress being made by EU member states in meeting Europe 2020.

Inflammasome function in monocyte subsets and a risk of late-onset sepsis in preterm very low birth weight neonates.

Background: Immature immune systems predispose very low birth weight (VLBW) neonates to systemic infections in early life. Defective inflammasome function may increase a neonate's susceptibility to late-onset sepsis (LOS).

Methods: Blood samples were taken on the 5 day of life (DOL) for all VLBW neonates (non-LOS and before-LOS groups; N.

The absolute number of circulating nonclassical (CD14+CD16++) monocytes negatively correlates with DAS28 and swollen joint count in patients with peripheral spondyloarthritis.

INTRODUCTION    A different clinical course and pattern of skeletal involvement in peripheral and axial spondyloarthritis (SpA) suggests a distinct pathophysiology of these 2 phenotypic manifestations of SpA. Monocytes, as part of the innate immune system, seem to play an important role in the pathogenesis of SpA, but the exact inflammatory pathways remain to be elucidated. Regulatory T lymphocytes (Treg) and Th17 lymphocytes are also known to influence proinflammatory and anti‑inflammatory reactions.

Analysis of PD-1 expression in the monocyte subsets from non-septic and septic preterm neonates.

Programmed death-1 (PD-1) receptor system represents a part of recently reported immunoregulatory pathway. PD-1 is an immune checkpoint molecule, which plays an important role in downregulating the immune system proinflammatory activity. Until recently, PD-1 expression was not established on immune cells of the preterm infants.

Analysis of selected aspects of inflammasome function in the monocytes from neonates born extremely and very prematurely.

Background: Inflammasomes regulate activation of caspase-1, which cleaves and activates interleukin (IL)-1β and IL-18, the cytokines that trigger pro-inflammatory and antimicrobial responses. There is very little known about inflammasome function in the subsets of monocytes (MO) isolated from preterm neonates born extremely and very prematurely.

Methods: A group of 76 very low birth weight patients without early-onset sepsis was divided into extremely preterm (<28 gestational week) or very preterm (28-32 gestational week) neonates.