Inhibition of 19S proteasome deubiquitinases as a promising strategy in cancer therapy

The ubiquitin proteasome system (UPS) is the main degradation system in the eukaryotic cell and it is involved in the regulation of many crucial cellular pathways; such as signal transduction, proliferation, DNA repair, cell death, and cell cycle regulation. In comparison to cells in healthy tissues, cancer cells proliferate faster and have increased protein synthesis rate; therefore in order to preserve cellular fitness they are more dependent on UPS than normal cells. This therapeutic window has been investigated for more than 30 years and intensive studies led to the discovery of first and second generation 20S proteasome inhibitors that have been successfully applied in the treatment of multiple myeloma and mantle cell lymphoma. However; in spite of initial positive outcomes, patients eventually gain resistance and suffer from the disease relapse. Therefore there is a strong interest in the development of new drugs targeting the UPS through alternative mechanisms. b-AP15/VLX1570 is a novel inhibitor of proteasome, recently discovered in our group, which does not block the activity of 20S catalytic core, but instead it inhibits two 19S deubiquitinating enzymes, USP14 and UCHL5. It is a small molecule with α,β- unsaturated carbonyl units that binds reversibly to cysteine deubiquitinases via Michael reaction. Despite reversible binding of the drug, commitment to death induced by b- AP15/VLX1570 is irreversible, which is due to the rapid uptake of the drug and subsequent retention in the cellular compartment. To some extent cellular response to the treatment with b-AP15/VLX1570 and bortezomib are similar: it results in the accumulation of polyubiquitinated proteins, induction of ER stress and eventually apoptosis and cell death. Treatment with b-AP15/VLX1570 however, induces higher level of proteotoxic stress, higher level of ROS and more rapid and potent apoptotic response. We found that VLX1570, a b- AP15 analogue optimized for clinical administration, has strong anti-cancer activity against multiple myeloma and acute lymphoblastic leukemia. In addition we found that the DUB inhibitor is active on cells resistant to bortezomib. This findings suggest that VLX1570 is a promising candidate drug and is currently investigated in Phase I clinical trials for the treatment of multiple myeloma resistant to conventional proteasome inhibitors. Application of proteasome inhibitors in the treatment of solid tumors remains limited and primary and acquired resistance continues to be a concern during the development of new therapies. Using multicellular spheroids as solid tumor model, we discovered that overexpression of PA28, a stress-induced regulatory particle of proteasome, can moderate the response of cancer cells to proteasome inhibitors. Taken together our data shows that proteasome DUB inhibitors have potential as a treatment option for malignancies and that differences in UPS expression may have relevance for the survival of different tumor types

Conditions Of Polish Industry Innovativeness

One of the measures of Polish economy development, including its innovativeness and competitiveness is the level of gross domestic expenditures on research and development activity, so called GERD in relation to gross domestic product, i.e. GDP. Poland assigns for R&D one tenth of expenditures, which are assigned by countries with the highest index GERD/GDP: USA and Japan. Scientific and research-development units in our country are characterised by a relatively low level of investment expenditures. As a result, small rebuild scientific-research apparatus and high level of its wear occur. The level of expenditures on R&D per capita in Poland and small share of industry in financing research are reasons of still unsatisfactory pace of decreasing the distance between Poland and well - developed countries (including the EU countries). Lack of mechanisms encouraging industry to greater participation in expenditures on R&D destimulates innovativeness and competitiveness of economy. The paper presents indexes characterising the innovative potential of Polish economy against the background of selected countries. It analyses positive aspects and barriers of innovativeness growth. These problems make a subject of many years research and analyses carried out by authors presented among others in works [1], [2].  The paper described some trends and conditions occurring in Polish economy undergoing transformation.  It presents an example of using a method of artificial neural networks in modelling innovativeness in industry on an example of the innovation intensity index.  Research method proposed by authors, carried out with the use of a method of artificial neural networks confirm that positive trends concerning Polish industry innovativeness in the first years of the XXI century are maintained

Distress and Retaliatory Aggression in Response to Witnessing Intergroup Exclusion are Greater on Higher Levels of Collective Narcissism

The negative consequences of social exclusion have been demonstrated by multiple studies. Less is known about the consequences of witnessing one’s own group being excluded by other groups, although studies suggest exclusion can be experienced vicariously and negatively affects members of the excluded group. Results of the present lab-based experiment (N = 153), indicate, in line with our predictions, that observed intergroup exclusion (manipulated by an adapted intergroup Cyberball paradigm) produced a sense of personal exclusion. It also increased self-reported emotional distress and behavioral aggression Measured in the Taylor Aggression Paradigm), especially among participants high on collective narcissism: a belief that the exaggerated greatness of the in-group is not sufficiently appreciated by others. Contrary to expectations, a short mindfulness intervention (instructing participants to observe thoughts and emotions as transient mental products without engaging with them) delivered while witnessing intergroup exclusion (vs. inclusion) produced changes in heart rate variability reactivity indicative of emotional arousal especially among collective narcissists. We concluded that people high on collective narcissism are vulnerable to vicarious intergroup exclusion, react aggressively to it, and in consequence are potentially at risk of stress-related health and psychosocial problems. Furthermore, a mindfulness intervention, despite being an effective strategy to reduce maladaptive stress in most people, may be counterproductive in addressing high collective narcissists’ responses to threat to the in-group’s image

The impact of pulmonary regurgitation on right ventricular size and function in patients with repaired tetralogy of Fallot and additional haemodynamic abnormalities

Purpose: Right ventricular (RV) outflow tract obstruction (RVOTO) was demonstrated to be protective against RV dilatation in patients with repaired tetralogy of Fallot and chronic pulmonary regurgitation (PR). We hypothesised that the presence of additional haemodynamic abnormalities (more than mild tricuspid regurgitation, residual ventricular septal defect) reduces this protective association. Accordingly, we aimed to assess the impact of PR on RV size and function in this population. Material and methods: Consecutive patients with additional haemodynamic abnormalities after tetralogy of Fallot (TOF) repair, who had undergone cardiovascular magnetic resonance, were included. Results: Out of 90 patients studied, 18 individuals (mean age 32.5 ± 10.7 years, 72.2% males) met the inclusion criteria. There were no differences in RV volumes and ejection fraction between patients with and without RVOTO. Neither PR fraction (PRF) nor PR volume (PRV) correlated with RV end-diastolic volume (r = 0.36; p = 0.15 and r = 0.37; p = 0.14, respectively, for PRF and PRV) or RV end-systolic volume (r = 0.2; p = 0.42 and r = 0.19; p = 0.45, respectively, for PRF and PRV). Similarly, no significant correlations were observed between PRF or PRV and RV ejection fraction (r = –0.04; p = 0.87 and r = –0.03; p = 0.9, respectively). Conclusions: Additional haemodynamic abnormalities are associated with the abolition of the protective effect of RVOTO on RV size. There was no significant relationship between measures of PR and RV volumes in patients after TOF repair with concomitant haemodynamic abnormalities. These abnormalities acted as confounding factors in the assessment of the impact of pulmonary regurgitation on RV size and function

Virological aspects of non-human primates or swine-to human xenotransplantation

There are a number of human diseases, which can lead to organ failure. The consequence is often the need for a transplant. The number of performed operations is very low due to the shortage of organs for transplantation. As a consequence, the number of people waiting for transplant is still growing. The solution to this situation may be xenotransplantation. Xenotransplantation word comes from the Greek xenos meaning stranger, the other. It is defined as any procedure that involves the transplantation, implantation or infusion of tissues or zoonotic organs into a human recipient, but also human body fluids, cells, tissues, organs (or fragments) that have ex vivo contact with zoonotic cells, tissues or organs. One of the obstacles of the xenograft transplantation is the risk of animal pathogens transmission to the humans. Viruses that pose risk in the non-human primates-to-human xenotransplantation includes: the human immunodeficiency virus - HIV and the Marburg virus described in this paper. In addition viruses, which is a problem in pig-to-human xenotransplantation have also been described, including: porcine endogenous retrovirus - PERV, porcine cytomegalovirus - PCMV, porcine lymphotropic herpesvirus - PLHV and hepatitis E virus - E - HEV. This review of literature is the latest knowledge of the microbiological safety of xenotransplantation

Enrichment of maternal diet with conjugated linoleic acids influences desaturases activity and fatty acids profile in livers and hepatic microsomes of the offspring with 7,12-dimethylbenz[a] antracene- induces mammary tumors

The aim of this study was to assess the influence of diet supplementation of pregnant and breastfeeding female Sprague-Dawley rats with conjugated linoleic acids (CLA) on the Δ6- and Δ5-desaturase activity in hepatic microsomes as well as on fatty acids profile and lipids peroxidation in liver and hepatic microsomes of the progeny with chemically induced mammary tumors. Rats were divided into two groups with different diet supplementation (vegetable oil (which did not contain CLA) or CLA). Their female offspring was divided within these groups into two subgroups: (1) ñ fed the same diet as mothers (K1 ñ oil, O1 ñ CLA), and (2) ñ fed the standard fodder (K2, O2). At 50th day of life, the progeny obtained carcinogenic agent (7,12- dimethylbenz[a]anthracene). Higher supply of CLA in diet of mothers resulted in lower susceptibility to chemically induced mammary tumors in their offspring (p = 0.0322). It also influenced the fatty acids profile in livers and in hepatic microsomes, especially polyunsaturated n3 and n6 fatty acids. CLA inhibited the activity of the desaturases, which confirmed that CLA can reduce the level of arachidonic acid directly, reducing linoleic acid content in membranes, or indirectly, through the regulation of its metabolism. We were unable to confirm or deny the antioxidative properties of CLA. Our results indicate that the higher supply of CLA in mothersí diet during pregnancy and breastfeeding causes their incorporation into tissues of children, changes the efficiency of fatty acids metabolism and exerts health-promoting effect in their adult life reducing the breast cancer risk

App-based mindfulness training supported eudaimonic wellbeing during the COVID19 pandemic

A randomized-controlled-trial study (N = 219) tested two pre-registered hypotheses that mobile-phone app-based mindfulness training improves wellbeing and increases self-transcendent emotions: gratitude, self-compassion, and awe. Latent change score modeling with a robust maximum likelihood estimator was used to test how those changes are associated in the training versus the waiting-list group. The training increased wellbeing and all self-transcendent emotions regardless of interindividual variance in the changes across time. Changes in all self-transcendent emotions were positively associated with changes in wellbeing. The strength of those associations was comparable in the waiting-list group and the training group. More studies are needed to test whether the effects of mindfulness practice on wellbeing are driven by increases in self-transcendent emotions. The study was conducted over 6 weeks during the COVID19 pandemic. The results indicate that the mindfulness training can be an easily accessible effective intervention supporting eudaimonic wellbeing in face of adversity

The shape of the change: Cumulative and incremental changes in daily mood during mobile-app-supported mindfulness training

Understanding of the exact trajectories of mood improvements during mindfulness practice helps to optimize mindfulness-based interventions. The Mindfulness-to-Meaning model expects mood improvements to be linear, incremental, and cumulative. Our findings align with this expectation. We used multilevel growth curve models to analyze daily changes in positive mood reported by 190 Polish participants during 42 days of a mobile-app-supported, mindfulness-based intervention. The daily positive mood increased among 83.68% of participants. Participants who started the training reported worse mood improved more and faster than participants with better mood at the baseline. Dispositional mindfulness and narcissism – individual difference variables associated with high vs. low emotion regulation ability, respectively – were not associated with mood improvement trajectories. A small group of participants (16.32%) showed a steady decline in positive mood during the intervention. The results underscore the importance of a more comprehensive understanding of individual variability in benefiting from mindfulness-based interventions