Multikinase inhibitors modulate non-constitutive proteasome expression in colorectal cancer cells

Introduction: Proteasomes are multi-subunit protein complexes responsible for protein degradation in cells. Immunoproteasomes and intermediate proteasomes (together non-constitutive proteasomes) are specific forms of proteasomes frequently associated with immune response, antigen presentation, inflammation and stress. Expression of non-constitutive proteasome subunits has a prognostic value in several types of cancer. Thus, factors that modulate non-constitutive proteasome expression in tumors are of particular interest. Multikinase inhibitors (MKIs) demonstrate promising results in treatment of cancer. At the same time, their immunomodulatory properties and effects on non-constitutive proteasome expression in colorectal cancer cells are poorly investigated.Methods: Proteasome subunit expression in colorectal cancer was evaluated by bioinformatic analysis of available datasets. Two colorectal cancer cell lines, expressing fluorescent non-constitutive proteasomes were treated with multikinase inhibitors: regorafenib and sorafenib. The proteasome subunit expression was assessed by real-time PCR, Western blotting and flow cytometry. The proteasome activity was studied using proteasome activity-based probe and fluorescent substrates. Intracellular proteasome localization was revealed by confocal microscopy. Reactive oxygen species levels following treatment were determined in cells. Combined effect of proteasome inhibition and treatment with MKIs on viability of cells was estimated.Results: Expression of non-constitutive proteasomes is increased in BRAF-mutant colorectal tumors. Regorafenib and sorafenib stimulated the activity and synthesis of non-constitutive proteasomes in examined cell lines. MKIs induced oxidative stress and redistribution of proteasomes within cells. Sorafenib stimulated formation of cytoplasmic aggregates, containing proteolyticaly active non-constitutive proteasomes, while regorafenib had no such effect. MKIs caused no synergistic action when were combined with the proteasome inhibitor.Discussion: Obtained results indicate that MKIs might affect the crosstalk between cancer cells and immune cells via modulation of intracellular proteasome pool. Observed phenomenon should be considered when MKI-based therapy is applied

Emotional experiences and psychological well-being in 51 countries during the COVID-19 pandemic

The COVID-19 pandemic presents challenges to psychological well-being, but how can we predict when people suffer or cope during sustained stress? Here, we test the prediction that specific types of momentary emotional experiences are differently linked to psychological well-being during the pandemic. Study 1 used survey data collected from 24,221 participants in 51 countries during the COVID-19 outbreak. We show that, across countries, wellbeing is linked to individuals’ recent emotional experiences, including calm, hope, anxiety, loneliness, and sadness. Consistent results are found in two age, sex, and ethnicity-representative samples in the United Kingdom (n = 971) and the United States (n = 961) with preregistered analyses (Study 2). A prospective 30-day daily diary study conducted in the United Kingdom (n = 110) confirms the key role of these five emotions and demonstrates that emotional experiences precede changes in well-being (Study 3). Our findings highlight differential relationships between specific types of momentary emotional experiences and well-being and point to the cultivation of calm and hope as candidate routes for well-being interventions during periods of sustained stress

Emotional experiences and psychological well-being in 51 countries during the covid-19 pandemic

The COVID-19 pandemic presents challenges to psychological well-being, but how can we predict when people suffer or cope during sustained stress? Here, we test the prediction that specific types of momentary emotional experiences are differently linked to psychological well-being during the pandemic. Study 1 used survey data collected from 24,221 participants in 51 countries during the COVID-19 outbreak. We show that, across countries, well-being is linked to individuals’ recent emotional experiences, including calm, hope, anxiety, loneliness, and sadness. Consistent results are found in two age, sex, and ethnicity-representative samples in the United Kingdom (n = 971) and the United States (n = 961) with preregistered analyses (Study 2). A prospective 30-day daily diary study conducted in the United Kingdom (n = 110) confirms the key role of these five emotions and demonstrates that emotional experiences precede changes in well-being (Study 3). Our findings highlight differential relationships between specific types of momentary emotional experiences and well-being and point to the cultivation of calm and hope as candidate routes for well-being interventions during periods of sustained stress

Emetine in Combination with Chloroquine Induces Oncolytic Potential of HIV-1-Based Lentiviral Particles

Chloroquine and Emetine are drugs used to treat human parasitic infections. In addition, it has been shown that these drugs have an antiviral effect. Both drugs were also found to cause a suppressive effect on the growth of cancer cells of different origins. Here, using the replication-deficient HIV-1-based lentiviral vector particles, we evaluated the ability of the combination of these drugs to reduce viral transduction efficiency. We showed that these drugs act synergistically to decrease cancer cell growth when added in combination with medium containing lentiviral particles. We found that the combination of these drugs with lentiviral particles decreases the viability of treated cells. Taken together, we state the oncolytic potential of the medium containing HIV-1-based particles provoked by the combination of Chloroquine and Emetine

Emotional experiences and psychological wellbeing in 51 countries during the COVID-19 pandemic

Momentary emotional experiences constitute a key ingredient of psychological wellbeing. Here, we examine the role of emotional experiences for wellbeing during the prolonged stress of the COVID-19 pandemic. Study 1 compared the relative importance of emotional experiences for wellbeing before versus during the pandemic using pre-registered analyses with representative samples. Negative emotional experiences were more detrimental and positive emotional experiences less protective for wellbeing during the pandemic. Study 2 examined the role of specific emotional experiences for wellbeing during the pandemic using survey data from 24,221 participants in 51 countries. Momentary feelings of calm, hope, anxiety, loneliness, and sadness were, across countries, central to wellbeing. These results were replicated in pre-registered studies with representative samples and in a diary study. These findings highlight the particular role of momentary emotional experiences for wellbeing during prolonged stress, and point to specific types of momentary emotional experiences as prime candidates for wellbeing interventions

Emotional experiences and psychological wellbeing in 51 countries during the COVID- 19 pandemic

The COVID-19 pandemic presents challenges to psychological wellbeing, but how can we predict when people suffer or cope during sustained stress? Here, we test the prediction that specific types of momentary emotional experiences are differently linked to psychological wellbeing during the pandemic. Study 1 used survey data collected from 24,221 participants in 51 countries during the COVID-19 outbreak. We show that, across countries, wellbeing is linked to individuals’ recent emotional experiences, including calm, hope, anxiety, loneliness, and sadness. Consistent results are found in two age, sex, and ethnicity-representative samples in the United Kingdom (N = 971) and the United States (N=961) with pre-registered analyses (Study 2). A prospective 30-day daily diary study conducted in the United Kingdom (N = 110) confirms the key role of these five emotions, and demonstrates that emotional experiences precede changes in wellbeing (Study 3). Our findings highlight differential relationships between specific types of momentary emotional experiences and wellbeing, and point to the cultivation of calm and hope as candidate routes for wellbeing interventions during periods of sustained stress

The robustness of mental accounting: a global perspective

This pre-registered work tests the replicability of seven studies covering the most important effects associated with mental accounting across 5,589 participants from 21 countries. Findings support the robustness of the original studies across time and culture, confirming the role of mental accounting as a critical driver of human decision-making