CssRS is a two-component system that plays a pivotal role in mediating the secretion stress response in Bacillus subtilis. This system upregulates the synthesis of membrane-bound HtrA family proteases that cope with misfolded proteins that accumulate within the cell envelope as a result of overexpression or heat shock. Recent studies have shown the induction of CssRS-regulated genes in response to cell envelope stress. We investigated the induction of the CssRS-regulated htrA promoter in the presence of different cell wall- and membrane-active substances and observed induction of the CssRS-controlled genes by glycopeptides (vancomycin and teicoplanin), polymyxins B and E, certain β-lactams, and detergents. Teicoplanin was shown to elicit remarkably stronger induction than vancomycin and polymyxin B. Teicoplanin and polymyxin B induced the spxO gene expression in a CssRS-dependent fashion, resulting in increased activity of Spx, a master regulator of disulfide stress in Bacillus subtilis. The CssRS signaling pathway and Spx activity were demonstrated to be involved in Bacillus subtilis resistance to teicoplanin and polymyxin B.

• MeSH
• antibakteriální látky * farmakologie   MeSH
• Bacillus subtilis * genetika   účinky léků   metabolismus   MeSH
• bakteriální proteiny * genetika   metabolismus   MeSH
• polymyxin B * farmakologie   MeSH
• promotorové oblasti (genetika) MeSH
• regulace genové exprese u bakterií * účinky léků   MeSH
• signální transdukce MeSH
• teikoplanin * farmakologie   MeSH
• Publikační typ
• časopisecké články MeSH

Poznatky, získané hlavne v posledných dvoch desaťročiach, umožnili lepšie porozumieť mechanizmom a dráham, prostredníctvom ktorých nervový systém, a tým aj stres, ovplyvňuje procesy súvisiace so vznikom a progresiou nádorových chorôb. Neurobiologický výskum nádorových chorôb pritom nie len rozšíril poznanie etiopatogenézy nádorového procesu, ale vytvoril podklady aj pre zavedenie nových terapeutických metód v onkológii, založených na modulácii prenosu signálov medzi nervovým systémom a nádorovým tkanivom. Bolo tiež zistené, že monitorovanie aktivity zložiek autonómneho nervového systému je možné využiť nie len na určenie miery stresu u daného pacienta, ale aj na posúdenie prognózy jeho onkologickej choroby. Jednu z efektívnych metód, umožňujúcich sledovanie flexibility a rovnováhy pôsobenia zložiek autonómneho nervového systému a nepriamo aj miery stresu u onkologických pacientov, predstavuje určovanie variability srdcovej frekvencie (HRV). Na opodstatnenosť využitia tejto metódy v onkológii poukazujú aj zistenia, že pacienti s vyššími hodnotami HRV vykazujú dlhšie prežívanie v porovnaní s pacientmi, u ktorých sú hodnoty HRV nižšie. Zámerom tohto textu je priblížiť súčasné poznatky týkajúce sa vplyvu stresu na nádory hlavy a krku a načrtnúť možnosti využitia stanovenia HRV ako prognostického markera u týchto pacientov. Diskutované sú aj možnosti využitia metód, ktoré sú zamerané na zvýšenie HRV a ich prípadné využitie v liečbe pacientov s nádormi hlavy a krku.

Knowledge, mainly gained in the last two decades, has provided a better understanding of the mechanisms and pathways through which the nervous system, and thus stress, influences processes related to cancer initiation and progression. Neurobiological research on cancer has not only increased the knowledge of the aetiopathogenesis of the tumour process, but also has laid the foundation for the introduction of new therapeutic methods in oncology based on the modulation of the transmission of signals between the nervous system andtumour tissue. It also has been found that monitoring the activity of components of the autonomic nervous system can be used not only to determine the degree of stress in a given patient, but also to assess the prognosis of his or her oncological disease. One of the effective methods to monitor the flexibility and balance of the autonomic nervous system components and indirectly the level of stress in cancer patients is the determination of heart rate variability (HRV). The validity of the use of this method in oncology is indicated by the findings that patients with higher HRV values show longer survival compared to patients with lower HRV values. The aim of this text is to review the current knowledge regarding the impact of stress on head and neck cancer and to outline the possibilities of using HRV determination as a prognostic marker in these patients. The potential use of methods aimed at increasing HRV and their potential use in the management of patients with head and neck tumours are also discussed.

• MeSH
• adrenalin MeSH
• biomedicínský výzkum MeSH
• hydrokortison MeSH
• karcinogeneze MeSH
• lidé MeSH
• nádory hlavy a krku * etiologie   patologie   MeSH
• prognóza MeSH
• psychický stres MeSH
• srdeční frekvence MeSH
• sympatický nervový systém MeSH
• Check Tag
• lidé MeSH

Cíl: Správné indikace podání transfuzních přípravků (TP) jsou klíčem k účelné a bezpečné hemoterapii. Cílem této práce bylo zhodnotit indikační kritéria podávání TP, porovnat změny v indikacích TP mezi dvěma obdobími a získat podklady pro zkvalitnění hemoterapie v Krajské nemocnici Liberec, a.s. (KNL). Materiál a metoda: Sledovaným souborem byly všechny TP (erytrocyty, trombocyty, plazma) aplikované v KNL v období od 1. 10. 2020 do 30. 9. 2021 a od 1. 8. 2022 do 31. 7. 2023. Z databáze laboratorního informačního systému byly k jednot- livým TP přiřazeny laboratorní výsledky příjemců TP: hemoglobin (Hb), počet trombocytů a protrombinový čas – poměr (PT-R). Výsledky byly přiřazeny, pokud byly vyšetřeny před výdejem TP do předchozího kalendářního dne, tj. do 48 hodin před výdejem TP. Výsledky: V období 2020/21 bylo 35 % erytrocytů deleukotizovaných (ED) vydáno pacientům s Hb > 80g/l, v období 2022/23 32 % ED. Porovnáním hodnot průměrného Hb nebyl zjištěn statisticky významný rozdíl mezi obdobími (p = 0,61), přístup k indikacím ED se nezměnil. V období 2020/2021 bylo pacientům s počtem trombocytů > 50 × 109/l vydáno 29 % TP trombocytů, v období 2022/2023 16 % TP trombocytů. TP trombocytů byly v období 2022/23 vydávány pacientům s nižším počtem trombocytů než v období 2020/21 (p < 0,001). Zda se jednalo o racionalizaci indikací nebo bylo odlišné složení pacientů, nelze posoudit. V období 2020/2021 bylo pacientům s hodnotou PT-R ≤ 1,5 vydáno 52 % klinické plazmy (P), v období 2022/2023 47 % P. Při porovnání hodnot průměrného PT-R nebyl nalezen statisticky významný rozdíl mezi hodnocenými obdobími (p = 0,45). Závěr: Přístup k indikacím TP erytrocytů stejně jako u klinické plazmy byl konzistentní. U TP plazmy byl v porovnání s lite - raturou uvážlivější přístup v případě hraničních indikací. U TP trombocytů došlo k racionalizaci indikací nebo bylo odlišné složení pacientů. Obecně TP byly indikovány racionálně. S výsledky studie budeme dále pracovat.

Aim: Correct indications of blood components (BC) are the key to effective and safe haemotherapy. The aim of this study was to evaluate the indication criteria of BC, to compare the changes in BC indications between two periods and to improve the quality of haemotherapy at the Regional Hospital Liberec, as (KNL). Materials and methods: The study population consisted of all BCs (erythrocytes, platelets, plasma) administered in the KNL in the period from 1 October 2020 to 30 September 2021 and from 1 August 2022 to 31 July 2023. From the database of the laboratory information system, the laboratory results of BC recipients were matched to each BC: haemoglobin (Hb), platelet count, and prothrombin time - ratio (PT-R). These results were matched if they were tested before the administration of the BC within the previous calendar day, i.e., within 48 hours before the issue of the BC. Results: In 2020/21, 35% of red blood cells, leucocyte-depleted in additive solution (ED) were administered to patients with Hb > 80 g/l, and in 2022/23, 32% of ED. Comparison of mean Hb values revealed no statistically significant difference between the periods (p = 0.61), and the approach to ED indications did not change. In 2020/2021, 29% of platelet BCs were administered to patients with platelet counts > 50 × 109/l, and in 2022/2023, 16% of platelet BCs. Platelet BCs were issued to patients with lower platelet counts in 2022/23 than in 2020/21 (p < 0.001). Whether this was a rationalization of indications or a different patient make-up, cannot be assessed. In 2020/2021, 52% of plasma, fresh frozen (P) was administered to patients with a PT-R ≤ 1.5, and in 2022/2023, 47% of P. When comparing mean PT-R values, there was no statistically significant difference between the evaluated periods (p = 0.45). Conclusion: The approach to erythrocyte and plasma BC indications was consistent. A more considered approach was taken for plasma BCs for borderline indications, when compared with the literature. For platelet BCs, indications were rationalized or patient make-up was different. In general, BCs were rationally indicated. We will continue to work with the results of the study.

• MeSH
• krevní plazma MeSH
• krevní transfuze metody   MeSH
• lidé MeSH
• převod jednotlivých krevních složek * metody   MeSH
• transfuze erytrocytů metody   MeSH
• transfuze trombocytů metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• klinická studie MeSH

BACKGROUND: The advancement of nanotechnology underscores the imperative need for establishing in silico predictive models to assess safety, particularly in the context of chronic respiratory afflictions such as lung fibrosis, a pathogenic transformation that is irreversible. While the compilation of predictive descriptors is pivotal for in silico model development, key features specifically tailored for predicting lung fibrosis remain elusive. This study aimed to uncover the essential predictive descriptors governing nanoparticle-induced pulmonary fibrosis. METHODS: We conducted a comprehensive analysis of the trajectory of metal oxide nanoparticles (MeONPs) within pulmonary systems. Two biological media (simulated lung fluid and phagolysosomal simulated fluid) and two cell lines (macrophages and epithelial cells) were meticulously chosen to scrutinize MeONP behaviors. Their interactions with MeONPs, also referred to as nano-bio interactions, can lead to alterations in the properties of the MeONPs as well as specific cellular responses. Physicochemical properties of MeONPs were assessed in biological media. The impact of MeONPs on cell membranes, lysosomes, mitochondria, and cytoplasmic components was evaluated using fluorescent probes, colorimetric enzyme substrates, and ELISA. The fibrogenic potential of MeONPs in mouse lungs was assessed by examining collagen deposition and growth factor release. Random forest classification was employed for analyzing in chemico, in vitro and in vivo data to identify predictive descriptors. RESULTS: The nano-bio interactions induced diverse changes in the 4 characteristics of MeONPs and had variable effects on the 14 cellular functions, which were quantitatively evaluated in chemico and in vitro. Among these 18 quantitative features, seven features were found to play key roles in predicting the pro-fibrogenic potential of MeONPs. Notably, IL-1β was identified as the most important feature, contributing 27.8% to the model's prediction. Mitochondrial activity (specifically NADH levels) in macrophages followed closely with a contribution of 17.6%. The remaining five key features include TGF-β1 release and NADH levels in epithelial cells, dissolution in lysosomal simulated fluids, zeta potential, and the hydrodynamic size of MeONPs. CONCLUSIONS: The pro-fibrogenic potential of MeONPs can be predicted by combination of key features at nano-bio interfaces, simulating their behavior and interactions within the lung environment. Among the 18 quantitative features, a combination of seven in chemico and in vitro descriptors could be leveraged to predict lung fibrosis in animals. Our findings offer crucial insights for developing in silico predictive models for nano-induced pulmonary fibrosis.

• MeSH
• buňky A549 MeSH
• kovové nanočástice * toxicita   chemie   MeSH
• lidé MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• plíce účinky léků   patologie   metabolismus   MeSH
• plicní fibróza * chemicky indukované   metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: The Statutory Health Insurance scheme is one of two main schemes of health care system financing in Europe. This scheme mainly relies on wage-based contributions from employers and employees and is thus prone to business cycle fluctuations. This turned out to be a problem especially after the 2008 crisis. We estimate the magnitude of the effect of the business cycle on health insurance funds' revenues in the Czech Republic where the health care system financing is based on the Statutory Health Insurance scheme. The relationship between the business cycle and healthcare system's revenues has not been quantified to this date. METHODS: We use static and lagged regression models to estimate the impact of business cycle on health care system's revenues. The business cycle is proxied by eight different indicators (nominal GDP, unemployment, industrial production, recession index, business cycle index, GDP gap, consumer price index and consumer expenditure). Using quarterly data from 2000-2017, we examine the effect of business cycle on total revenues and its two main components: the employer-employee contributions and state contributions. RESULTS: Health insurance funds' revenues display significant pro-cyclicality, which is mainly driven by employer-employee contributions. Out of all eight business cycle indicators, nominal GDP has the largest effect. In particular, the model estimates that if quarter-over-quarter GDP increases by 1%, then quarter-over-quarter healthcare system's revenues increase by 0.7% and quarter-over-quarter employer-employee contributions increase by 1.1%. The lagged effect of business cycle on healthcare system's revenues is smaller in magnitude. State contributions on behalf of economically inactive people do not display a significant relationship with business cycle in the static nor lagged model. The effect is consistent across different business cycle indicators, although the magnitudes of the effect vary. CONCLUSION: The results show large pro-cyclicality in healthcare system's revenues in Statutory Health Insurance schemes. Counter-cyclical mechanisms are needed to offset this loss of revenues during economic downturns to ensure sufficient resources in healthcare.

• Publikační typ
• časopisecké články MeSH

Two benign adenomatous lesions are commonly recognized within the sinonasal tract, namely respiratory epithelial adenomatoid hamartoma (REAH) and seromucinous hamartoma (SH). We present 10 hitherto unrecognized benign polypoid nasal and sinonasal tumoriform lesions having in average 3.6 cm in largest dimension, which are histogenetically related to SH and REAH. In addition to typical structures of REAH and SH, these lesions contained an additional characteristic and slightly atypical adenomatous component, which we termed atypical sinonasal glands arising in SH (ASGSH). ASGSH often produced deep red colored secretion with peripheral clearing similar to that seen in thyroid follicles. In contrast to SH, ASGSH was endowed by both secretory and myoepithelial layers and had mostly angulated shapes with snout-like protrusions into the lumens. Both layers were formed by an irregular, disorganized, and often incomplete cell lining, which had slightly atypical cytological features without mitoses. In 3 cases, ASGSHs revealed sebaceous differentiation, and in 3 cases the stroma produced a well-differentiated cartilage. Neoplastic nature of ASGSH was supported by finding of various mutations as revealed by next generation sequencing in five cases. In two cases each, we found identical mutations in BRAF gene (Val600Glu), and RET gene (Arg912Trp), respectively and in one case FAT1 gene alteration (Pro1665Leu).

• MeSH
• adenom patologie   genetika   MeSH
• dospělí MeSH
• hamartom * patologie   genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace MeSH
• nádory nosu patologie   genetika   MeSH
• nádory vedlejších dutin nosních patologie   genetika   MeSH
• respirační sliznice patologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The cytokine TNF can trigger highly proinflammatory RIPK1-dependent cell death. Here, we show that the two adapter proteins, TANK and AZI2, suppress TNF-induced cell death by regulating the activation of TBK1 kinase. Mice lacking either TANK or AZI2 do not show an overt phenotype. Conversely, animals deficient in both adapters are born in a sub-Mendelian ratio and suffer from severe multi-organ inflammation, excessive antibody production, male sterility, and early mortality, which can be rescued by TNFR1 deficiency and significantly improved by expressing a kinase-dead form of RIPK1. Mechanistically, TANK and AZI2 both recruit TBK1 to the TNF receptor signaling complex, but with distinct kinetics due to interaction with different complex components. While TANK binds directly to the adapter NEMO, AZI2 is recruited later via deubiquitinase A20. In summary, our data show that TANK and AZI2 cooperatively sustain TBK1 activity during different stages of TNF receptor assembly to protect against autoinflammation.

• MeSH
• adaptorové proteiny signální transdukční * metabolismus   genetika   MeSH
• buněčná smrt MeSH
• endopeptidasy MeSH
• intracelulární signální peptidy a proteiny metabolismus   genetika   MeSH
• lidé MeSH
• myši inbrední C57BL MeSH
• myši knockoutované * MeSH
• myši MeSH
• protein-serin-threoninkinasy * metabolismus   genetika   MeSH
• receptory TNF - typ I * metabolismus   genetika   MeSH
• serin-threoninkinasy interagující s receptory * metabolismus   genetika   MeSH
• signální transdukce MeSH
• TNF-alfa * metabolismus   MeSH
• TNFAIP3 metabolismus   genetika   MeSH
• zánět metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

CONTEXT: Despite the lack of level 1 evidence, metastasis-directed therapy (MDT) is used widely in the management of metastatic prostate cancer (mPCa) patients. Data are continuously emerging from well-designed prospective studies. OBJECTIVE: To summarise and report the evidence on oncological and safety outcomes of MDT in the management of mPCa patients. EVIDENCE ACQUISITION: We searched the PubMed, Scopus, and Web of Science databases for prospective studies assessing progression-free survival (PFS), local control (LC), androgen deprivation therapy (ADT)-free survival (ADT-FS), overall survival (OS), and/or adverse events (AEs) in mPCa patients treated with MDT. A meta-analysis was performed for 1- and 2-yr PFS, LC, ADT-FS, OS, and rate of AEs. Meta-regression and sensitivity analysis were performed to account for heterogeneity and identify moderators. EVIDENCE SYNTHESIS: We identified 22 prospective studies (n = 1137), including two randomised controlled trials (n = 116). Two studies were excluded from the meta-analysis (n = 120). The estimated 2-yr PFS was 46% (95% confidence interval [CI]: 36-56%) or 42% (95% CI: 33-52%) after excluding studies using biochemical or ADT-related endpoints. The estimated 2-yr LC, ADT-FS, and OS were 97% (95% CI: 94-98%), 55% (95% CI: 44-65%), and 97% (95% CI: 95-98%), respectively. Rates of treatment-related grade 2 and ≥3 AEs were 2.4% (95% CI: 0.2-7%) and 0.3% (95% CI: 0-1%), respectively. CONCLUSIONS: MDT is a promising treatment strategy associated with favourable PFS, excellent LC, and a low toxicity profile that allows oligorecurrent hormone-sensitive patients to avoid or defer ADT-related toxicity. Integration of MDT with other therapies offers a promising research direction, in particular, in conjunction with systemic treatments and as a component of definitive care for oligometastatic PCa. However, in the absence of randomised trials, using MDT for treatment intensification remains an experimental approach, and the impact on OS is uncertain. PATIENT SUMMARY: Direct treatment of metastases is a promising option for selected prostate cancer patients. It can delay hormone therapy and is being investigated as a way of intensifying treatment at the expense of manageable toxicity.

• MeSH
• antagonisté androgenů škodlivé účinky   MeSH
• doba přežití bez progrese choroby MeSH
• hormony MeSH
• lidé MeSH
• nádory prostaty * farmakoterapie   MeSH
• prospektivní studie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• přehledy MeSH
• systematický přehled MeSH

Sildenafil citrate has low oral bioavailability, systemic adverse effects, and a relatively delayed action. These issues may be addressed through direct transdermal delivery to the penis. This study aims to investigate the microemulsion formulation of the drug for effective transdermal delivery. Sildenafil citrate was formulated as a microemulsion using clove oil, dimethyl sulphoxide, phosphate buffer (pH 7), propylene glycol, Tween®80, and distilled water. Different proportions of these components were used to create six formulations of the microemulsion (F1-F6), which were then characterised by their physical appearance and clarity, pH, viscosity, conductivity, percent transmission, and droplet size. Furthermore, the stability, content analysis, in-vitro drug release, and transdermal permeation of sildenafil citrate from the generated drug-loaded microemulsions were studied. All prepared formulas contained nano-sized oil droplets (less than 20 nm), and the pH values were within the range of skin pH; however, two formulas were not transparent. Additionally, all formulations were thermodynamically stable, passing freeze-thaw, heating-cooling, and centrifugation tests. Next, the formulas demonstrated zero-order release kinetics, indicating that they can provide a sustained release profile for sildenafil citrate. Finally, the microemulsion formulation exhibited a 2.8-fold enhancement in skin permeation compared with that of the sildenafil citrate suspension. The prepared microemulsions demonstrated beneficial physical properties and skin permeation profiles that are promising for the local administration of sildenafil citrate.

• Klíčová slova
• mikroemulze,
• MeSH
• aplikace kožní * MeSH
• emulze MeSH
• hřebíčkový olej MeSH
• krysa rodu rattus MeSH
• lékové formy MeSH
• modely u zvířat MeSH
• permeabilita MeSH
• příprava léků metody   MeSH
• sildenafil citrát * aplikace a dávkování   farmakokinetika   farmakologie   MeSH
• stabilita léku MeSH
• suspenze MeSH
• uvolňování léčiv MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• klinická studie MeSH

BACKGROUND: Changes in both the vascular system and brain tissues can occur after a prior episode of coronavirus disease 2019 (COVID-19), detectable through modifications in diffusion parameters using magnetic resonance imaging (MRI) techniques. These changes in diffusion parameters may be particularly prominent in highly organized structures such as the corpus callosum (CC), including its major components, which have not been adequately studied following COVID-19 infection. Therefore, the study aimed to evaluate microstructural changes in whole-brain (WB) diffusion, with a specific focus on the CC. METHODS: A total of 101 probands (age range from 18 to 69 years) participated in this retrospective study, consisting of 55 volunteers and 46 post-COVID-19 patients experiencing neurological symptoms. The participants were recruited from April 2022 to September 2023 at the Institute for Clinical and Experimental Medicine in Prague, Czech Republic. All participants underwent MRI examinations on a 3T MR scanner with a diffusion protocol, complemented by additional MRI techniques. Two volunteers and five patients were excluded from the study due to motion artefacts, severe hypoperfusion or the presence of lesions. Participants were selected by a neurologist based on clinical examination and a serological test for COVID-19 antibodies. They were then divided into three groups: a control group of healthy volunteers (n=28), an asymptomatic group (n=25) with a history of infection but no symptoms, and a symptomatic group (n=41) with a history of COVID-19 and neurological symptoms. Symptomatic patients did not exhibit neurological symptoms before contracting COVID-19. Diffusion data underwent eddy current and susceptibility distortion corrections, and fiber tracking was performed using default parameters in DSI studio. Subsequently, various diffusion metrics, were computed within the reconstructed tracts of the WB and CC. To assess the impact of COVID-19 and its associated symptoms on diffusion indices within the white matter of the WB and CC regions, while considering age, we employed a statistical analysis using a linear mixed-effects model within the R framework. RESULTS: Statistical analysis revealed a significant difference in mean diffusivity (MD) between the symptomatic and control groups in the forceps minor (P=0.001) and CC body (P=0.003). In addition to changes in diffusion, alterations in brain perfusion were observed in two post-COVID-19 patients who experienced a severe course. Furthermore, hyperintense lesions were identified in subcortical and deep white matter areas in the vast majority of symptomatic patients. CONCLUSIONS: The main finding of our study was that post-COVID-19 patients exhibit increased MD in the forceps minor and body of the CC. This finding suggests a potential association between microstructural brain changes in post-COVID-19 patients and reported neurological symptoms, with significant implications for research and clinical applications.

• Publikační typ
• časopisecké články MeSH