Dimeric peroxiredoxins are druggable targets in human Burkitt lymphoma

Burkitt lymphoma is a fast-growing tumor derived from germinal center B cells. It is mainly treated with aggressive chemotherapy, therefore novel therapeutic approaches are needed due to treatment toxicity and developing resistance. Disturbance of red-ox homeostasis has recently emerged as an efficient antitumor strategy. Peroxiredoxins (PRDXs) are thioredoxin-family antioxidant enzymes that scavenge cellular peroxides and contribute to red-ox homeostasis. PRDXs are robustly expressed in various malignancies and critically involved in cell proliferation, differentiation and apoptosis. To elucidate potential role of PRDXs in lymphoma, we studied their expression level in B cell-derived primary lymphoma cells as well as in cell lines. We found that PRDX1 and PRDX2 are upregulated in tumor B cells as compared with normal counterparts. Concomitant knockdown of PRDX1 and PRDX2 significantly attenuated the growth rate of lymphoma cells. Furthermore, in human Burkitt lymphoma cell lines, we isolated dimeric 2-cysteine peroxiredoxins as targets for SK053, a novel thiol-specific small-molecule peptidomimetic with antitumor activity. We observed that treatment of lymphoma cells with SK053 triggers formation of covalent PRDX dimers, accumulation of intracellular reactive oxygen species, phosphorylation of ERK1/2 and AKT and leads to cell cycle arrest and apoptosis. Based on site-directed mutagenesis and modeling studies, we propose a mechanism of SK053-mediated PRDX crosslinking, involving double thioalkylation of active site cysteine residues. Altogether, our results suggest that peroxiredoxins are novel therapeutic targets in Burkitt lymphoma and provide the basis for new approaches to the treatment of this disease

Inhibition of protein disulfide isomerase induces differentiation of acute myeloid leukemia cells

Acute myeloid leukemia is a malignant disease of immature myeloid cells. Despite significant therapeutic effects of differentiation-inducing agents in some acute myeloid leukemia subtypes, the disease remains incurable in a large fraction of patients. Here we show that SK053, a thioredoxin inhibitor, induces differentiation and cell death of acute myeloid leukemia cells. Considering that thioredoxin knock-down with short hairpin RNA failed to exert antiproliferative effects in one of the acute myeloid leukemia cell lines, we used a biotin affinity probe-labeling approach to identify potential molecular targets for the effects of SK053. Mass spectrometry of proteins precipitated from acute myeloid leukemia cells incubated with biotinylated SK053 used as a bait revealed protein disulfide isomerase as a potential binding partner for the compound. Biochemical, enzymatic and functional assays using fluorescence lifetime imaging confirmed that SK053 binds to and inhibits the activity of protein disulfide isomerase. Protein disulfide isomerase knockdown with short hairpin RNA was associated with inhibition of cell growth, increased CCAAT enhancer-binding protein α levels, and induction of differentiation of HL-60 cells. Molecular dynamics simulation followed by the covalent docking indicated that SK053 binds to the fourth thioredoxin-like domain of protein disulfide isomerase. Differentiation of myeloid precursor cells requires the activity of CCAAT enhancer-binding protein α, the function of which is impaired in acute myeloid leukemia cells through various mechanisms, including translational block by protein disulfide isomerase. SK053 increased the levels of CCAAT enhancer-binding protein α and upregulated mRNA levels for differentiation-associated genes. Finally, SK053 decreased the survival of blasts and increased the percentage of cells expressing the maturation-associated CD11b marker in primary cells isolated from bone marrow or peripheral blood of patients with acute myeloid leukemia. Collectively, these results provide a proof-of-concept that protein disulfide isomerase inhibition has potential as a therapeutic strategy for the treatment of acute myeloid leukemia and for the development of small-molecule inhibitors of protein disulfide isomerase

International Academic Conference Central and Eastern Europe in the International Politics of the Twentieth and Twenty-First Centuries 7–8 November 2022, Kraków

Słowo wstępne: "Oddajemy w Państwa ręce księgę abstraktów międzynarodowej konferencji naukowej „Europa Środkowo-Wschodnia w polityce międzynarodowej XX i XXI wieku”, która w dniach 7–8 listopada 2022 r. gromadzi w murach Krakowskiej Akademii im. Andrzeja Frycza Modrzewskiego doświadczonych badawczy, doktorantów i studentów z Polski i zagranicy. Konferencja została zorganizowana przez Katedrę Stosunków Międzynarodowych Krakowskiej Akademii im. Andrzeja Frycza Modrzewskiego we współpracy z Instytutem Historii i Archiwistyki Uniwersytetu Pedagogicznego im. KEN w Krakowie (współorganizator). Partnerami naukowymi są Instytut Historyczny Uniwersytetu Szczecińskiego (organizator pierwszej części konferencji, przeprowadzonej w dniu 26 maja 2022 r.), Katedra Badań nad Obszarem Eurazjatyckim Uniwersytetu Jagiellońskiego w Krakowie oraz Instytut Zachodni im. Zygmunta Wojciechowskiego. Celem konferencji jest wniesienie wkładu w dyskusję naukową o historycznych doświadczeniach państw Europy Środkowo-Wschodniej oraz współczesnych wyzwaniach i zagrożeniach, z którymi są konfrontowane rządy i społeczeństwa państw tego regionu."(...)Patronat honorowy Prof. KAAFM dr Klemens Budzowski – Rektor Krakowskiej Akademii im. Andrzeja Frycza Modrzewskiego Oddział Krakowski Polskiego Towarzystwa Studiów Europejskic

Choosing the method for determining the communal waste management fee

The Act on Maintaining Cleanliness and Order in Communes provides the basis for choosing the method of determining the fee based on several criteria. It also states that a communal council may apply various criteria differentiating the rates of payment. According to the current case law of the Supreme Administrative Court, the communal council has no right to introduce an additional criterion – within the chosen method of determining the fee – i.e. a division of households into categories depending on the number of tenants. Though, it cannot be excluded that there is a possibility to differentiate the fee calculated as a product of the number of tenants in the given real estate and the sum of the fee when applying the number of tenants as a criterion of differentiation. It has to be stressed that the stance of acceptance of such differentiation may be questioned by supervisory authorities

Equality between women and men in selected areas and in provisions aimed to counteract gender discrimination in Poland

The author presents constitutional and statutory provisions guaranteeing gender equality and the prohibition of gender discrimination. Promotion, dissemination and propagation of equal treat‑ ment issues, also in the field of gender equality, are the tasks of the Government’s Plenipotentiary for Equal Treatment. Attention was paid to compliance with gender equality principles in, inter alia, education, labour law, public life, health care and business. The implementation of EU legislation in this area was analysed

The bill on transferring to Hungary the codex Epistola de laudibus augustae bibliothecae atque libri quatuor versibus scripti eodem argumento ad serenissimum Mathiam Corvinum Panoniae regem (Sejm Paper No. 2008) – constitutional aspect

The proposed regulation, which provides for ex lege deduction of ownership of a movable property belonging to a local government entity, requires consideration in terms of constitutional protection of communal property and the principle of self-government autonomy of local government units. The Act on the Protection and Care of Monuments allows a permanent removal of a monument on the basis of an appropriate permit, provided that the object has no particular value for cultural heritage, which is the case here. The bill thus sets a precedent by allowing the export of a relic of the past and its transfer to another country

Legal opinion on the effects of the Constitutional Tribunal’s judgement of 5th February 2015 (reference number K 60/13) in relation to the so-called pending members of housing cooperatives

The subject of the opinion is providing answer to a question whether, in a view of the indicated Constitutional Tribunal’s judgement, a housing cooperative has the right to deprive a pending person – who paid housing contribution in the shape of saved cash from a housing passbook on account of a flat – of membership of the cooperative. It flows from the Constitutional Tribunal’s judgement that only such natural persons who are entitled to cooperative tenant law for the apartment, cooperative ownership law for the apartment, separate ownership or the promise of separate ownership can be members of the housing cooperative. Admission to the housing cooperative of a person, who does not possess one of the rights indicated in the judgement is not admissible

The Myth of the “Dark” Middle Ages in the Contemporary Social Discourse

W refleksji na temat europejskiej tożsamości kulturowej odwołujemy się do trzech jej źródeł: filozofii greckiej, prawa rzymskiego i chrześcijaństwa. Jeśli chodzi o trzecie źródło — chrześcijaństwo, to stanowi ono serce kultury średniowiecznej, która tworzyła Europę opartą na ewangelicznych wartościach, takich jak: prawda, miłość, współczucie, pokora, równość, braterstwo, wolność, godność osoby ludzkiej. Mimo to epoka średniowieczna, jak żadna inna, jest ciągle deprecjonowana i ignorowana. Mit „ciemnego” średniowiecza, wylansowany w odrodzeniu, przekazywany i pogłębiany w kolejnych epokach, utrwalił się i zajął stałe miejsce w potocznej świadomości. Mediewiści stawiają sobie pytanie, dlaczego tak się dzieje. Ciągle słyszymy w powszechnym dyskursie epitet o „ciemnym” średniowieczu. Celem prezentowanych badań było określenie stanu wiedzy na temat kultury średniowiecznej, a także współczesnego postrzegania tejże epoki. Wyniki badań ankietowych, mających na celu zbadanie obecności mitu „ciemnego” średniowiecza w świadomości dzisiejszego społeczeństwa, mogą stanowić przyczynek do dalszych badań nad tym zjawiskiem. Doniosłość tej problematyki leży w tym, że odzwierciedla ona odniesienie współczesnego człowieka do wartości, jakie reprezentuje kultura średniowieczna.In our reflection on Europe’s cultural identity, we will refer to its three sources: Greek philosophy, Roman law, and Christianity. The third source, Christianity, is considered to be the heart of medieval culture, which created Europe based on evangelical values such as truth, love, compassion, humility, equality, fraternity, freedom, and human dignity. Nevertheless, the medieval era is still being depreciated and ignored like no other. The myth of the “dark” Middle Ages, promoted in the Renaissance, passed on and deepened in subsequent eras, became permanent and has a lasting place in the common consciousness. Medievalists ask: “why is this happening?” In popular discourse, we constantly hear the epithet about the “dark” Middle Ages. The presented research aims to determine the state of knowledge about medieval culture as well as contemporary people’s perceptions of that era. The results of surveys aimed at examining the presence of the myth about the “dark” Middle Ages in the awareness of contemporary society may be a contribution to further research on this phenomenon. The importance of this problem lies in the fact that it reflects contemporary man’s relationship to the values represented by medieval culture

Complement components, proteolysis‑related, and cell communication‑related proteins detected in urine proteomics are associated with IgA nephropathy.

INTRODUCTION IgA nephropathy (IgAN) is the most common primary glomerulonephritis. The first symptoms of IgAN are erytrocyturia or hematuria, proteinuria, and decline in renal function, or any combination of the above. One of the promising diagnostic methods is urine proteomics. OBJECTIVES We studied urine proteomics in patients with IgAN and age- and sex‑matched healthy controls. To minimize the risk of protein degradation, we proposed a new protocol for urine collection and preparation. PATIENTS AND METHODS A total of 30 patients with IgAN and 30 controls were enrolled into the study. Thirty urine samples of the IgAN group were divided into 3 disease pooled samples (DPS I, II, and III) and 30 urine samples of the control group were divided into 3 control pooled samples (CPS I, II, and III). We used isoelectric focusing/liquid chromatography–mass spectrometry/mass spectrometry (IEF/LC‑MS/MS) to detect all proteins larger than 10 kDa. RESULTS Using qualitative analysis, we identified 761, 951, and 956 proteins in each of the 3 IEF/LC‑MS/MS experiments. The results were combined, yielding a dataset with 1238 proteins identified by at least 2 peptides. The statistical analysis of the quantitative results revealed 18 proteins that were differently populated in the urine of IgAN patients compared with healthy controls. We found increased urinary concentrations of complement components, coagulation factors, extracellular matrix, intracellular, transmembrane, and other proteins in patients with IgAN. Some of them have never been linked to IgAN before. CONCLUSIONS We demonstrated that urine proteomics is a promising tool for diagnosing and monitoring patients with IgAN

Dentists’ low back pain

Wstęp. Praca lekarza stomatologa często wymaga długotrwałego utrzymywania wymuszonej, nieergonomicznej pozycji ciała podczas pracy. Powoduje to, że przez wiele godzin kręgosłup stale narażony jest na przeciążenia. To z kolei może objawiać się bólami kręgosłupa. Od pewnego czasu stomatolodzy mają dwie możliwości sposobu pracy. Pracują z prawego boku pacjenta, co wymaga pochylenia się w przód i w prawo lub mają możliwość pracy zza głowy pacjenta wykorzystując specjalnie do tego przystosowane krzesło wymuszające prawidłowe ustawienie kręgosłupa. Materiał i metody. Badania, które zostały przeprowadzone, dotyczyły oceny występowania bólów kręgosłupa lędźwiowego u lekarzy stomatologów z podziałem na dwie grupy w zależności od przyjmowanej pozycji podczas pracy. Badaniami objęto 63 lekarzy. W celu oceny wykorzystano kilka prostych testów oraz ankietę utworzoną na potrzebę badania. Wyniki. W grupie lekarzy pracujących z boku pacjenta 18 badanych (54,5%) wskazywało na szósty stopień bólu, 11 badanych (33,3%) na siódmy oraz czworo badanych (12,1%) na piąty stopień bólu w skali VAS. U stomatologów z grupy pracujących w pozycji zza głowy pacjenta, skala bólu nie przekroczyła trzech. Wnioski. Pozycja podczas pracy lekarza stomatologa ma istotny wpływ na powstawanie dolegliwości bólowych kręgosłupa lędźwiowego. Pozycja lekarza pracującego zza głowy pacjenta jest bardziej ergonomiczna niż z boku pacjenta. Lekarze pracujący z boku pacjenta częściej zgłaszają dolegliwości bólowe kręgosłupa lędźwiowego.Introduction. The work of a dental surgeon often entails remaining in a forced and non-ergonomic body posture for a prolonged time. Consequently, the spine is exposed to overstraining for many hours. This in turn may manifest in spine pain disorders. For some time now, dentists can choose between two working methods. They proceed at the patient’s right-hand side, which requires them to lean forward and rightward, or they may work from behind the patient’s head using a specially adjusted chair that enforces a proper position of the lumbar spine. Material and methods. The research was carried out to assess dentists’ lumbar spine pains. The subjects were divided into two groups depending on the posture they adopted while working. The research included 63 dentists. To analyse the results, a few simple tests and a questionnaire were carried out. Results. Among the dentists proceed at the patient’s right- hand side, 18 of them (54,5%) indicated on the sixth level of pain, 11 patients (33,3%) the seventh level of pain and four (12,1%) dentists suffered from pain at fifth level of the pain scale (0-10). In the group of dentists working in the position from behind the patient’s head pain scale did not exceed third level. Conclusion: dentists’ working posture has a significant impact on the formation of the lumbar spine disorders. Position of the dentists working from behind the patient’s head is more ergonomic than position while working on the patient’s one side. Dentists working on patient’s one side more often report the pain in a low back spine section