👤 Daniela Melnik

Hypercytokinemia, found in SARS-CoV-2 infection, contributes to multiple organ dysfunctions with acute respiratory distress syndrome, shock etc. The aim of this study was to describe cytokine storm signatures in patients with acute COVID-19 and to investigate their influence on severity of the infection. Plasma levels of 47 cytokines were investigated in 73 patients with moderate and severe COVID-19 (41 and 32, respectively) and 11 healthy donors (HD). The most elevated levels comparing patients and the HD were observed for seven pro-inflammatory cytokines (IL-6, IL-8, IL-15, IL-18, IL-27, IFNγ, TNFα), three chemokines (GROα, IP-10, MIG), two anti-inflammatory cytokines (IL-1RA, IL-10), and two growth factors (G-CSF, M-CSF). The patients with severe disease had significantly higher levels of FGF-2/FGF-basic, IL-1β, and IL-7 compared to the HD. The two groups of patients differed from each other only based on the levels of EGF, eotaxin, and IL-12 p40. Pneumonia lung injury, characterized by computer tomography, positively correlated with levels of EGF, IP-10, MCP-3 levels and negatively with IL-12 p40. Pro-inflammatory factors including IL-6, TNFα, and IP-10 negatively correlated with the frequency of the circulating T-helper17-like cells (Th17-like) and follicular Th cells that are crucial to develop SARS-CoV-2-specific plasma cells and memory B cells. Obtained data on the cytokine levels illustrate their influence on progression and severity of COVID-19. Show less

Detachment and the formation of spheroids under microgravity conditions can be observed with various types of intrinsically adherent human cells. In particular, for cancer cells this process mimics metastasis and may provide insights into cancer biology and progression that can be used to identify new drug/target combinations for future therapies. By using the synthetic glucocorticoid dexamethasone (DEX), we were able to suppress spheroid formation in a culture of follicular thyroid cancer (FTC)-133 cells that were exposed to altered gravity conditions on a random positioning machine. DEX inhibited the growth of three-dimensional cell aggregates in a dose-dependent manner. In the first approach, we analyzed the expression of several factors that are known to be involved in key processes of cancer progression such as autocrine signaling, proliferation, epithelial-mesenchymal transition, and anoikis. Wnt/β-catenin signaling and expression patterns of important genes in cancer cell growth and survival, which were further suggested to play a role in three-dimensional aggregation, such as Show less

Components of the mitogen-activated protein kinase (MAPK) cascade have been implicated in apoptotic regulation. This study used gene expression profiling analysis to identify and implicate mitogen-activated protein kinase kinase (MEK5)-BMK1 (big mitogen-activated kinase-1)/extracellular signal related protein kinase (ERK5) pathway as a novel target involved in chemoresistance. Differential gene expression between apoptotically sensitive (APO+) and apoptotically resistant (APO-) MCF-7 cell variants was determined by using microarray and confirmed by reverse transcriptase- polymerase chain reaction (RT-PCR). An apoptotic/viability reporter gene assay was used to deter-mine the effects of the transfection of a dominant-negative mutant of BMK1 (BMK1/DN) in conjunction with apoptotic-inducing agents (etoposide, tumor necrosis factor-alpha [TNF], or TNF-related apoptosis-inducing ligand [TRAIL]), with or without phorbol ester (PMA). Of the 1186 genes detected through microarray analysis, MEK5 was increased 22-fold in APO- cells. Overexpression of MEK5 was confirmed by using RT-PCR analysis. Expression of BMK1/DN alone resulted in a dose-dependent increase in cell death versus control (P <.05). In addition, BMK1/DN enhanced the sensitivity of MCF-7 cells to treatment-induced cell death (P <.05). The ability of PMA to partially suppress TRAIL- and TNF-induced cell death was inhibited by BMK1/DN. However, only TRAIL-induced activity suppression reached statistical significance (P <.05). The overexpression of MEK5 in APO- MCF-7 breast carcinoma cells shows that this MAPK signaling protein represents a potent survival molecule. Molecular inhibition of MEK5 signaling may represent a mechanism for sensitizing cancer cells to chemotherapeutic regimens. Show less