The hedgehog signaling pathway plays an important role in vertebrate embryonic development, tissue homeostasis, and tumorigenesis. Constitutive activation of Hh signaling in various human tumors leads to GLI-mediated transcription and tumor progression. Based on the preliminary screening of a large library of known triterpenes that exhibited interesting Hh inhibitory activity, we designed and synthesized a new series of triterpenoid analogues containing aromatic heterocyclic substituents at position C-2 to enhance their interference with Hh signaling. In this study, we evaluated the effect of 15 synthesized triterpenoids on cell proliferation and Hh pathway activity in relevant cancer cell lines. Among these compounds, two derivatives, 11a and 11b, both featuring a furan ring at position C-2, demonstrated potent inhibitory effects on proliferation and induced cell death in nonsmall cell lung cancer (NSCLC) and prostate cancer cell lines exhibiting hyper-activated Hh signaling. Moreover, these compounds significantly reduced GLI-mediated transcription in cell-based reporter assays. Detailed immunoblot analyses revealed that compounds 11a and 11b decreased the expression of endogenous GLI1 protein and its target genes associated with tumor progression and proliferation, such as Cyclin D1, N-Myc, and Bcl-2, in A549 and DU-145 cancer cells. These findings suggest that the antiproliferative effects of 11a and 11b are mediated through inhibition of the Hh signaling pathway and are promising candidates for the development of new anticancer therapies targeting Hh-dependent tumors.

• Publikační typ
• časopisecké články MeSH

Stereoselective synthesis of spirocyclic compounds containing heterocyclic motifs represents a formidable challenge in enantioselective synthesis. Here, we present a cascade reaction between α,β-unsaturated aldehydes and isoxazolones under synergistic catalysis of a chiral secondary amine and a palladium(0) catalyst. This strategy allows access to chiral spiroisoxazolone derivatives with a large substrate scope tolerance and high levels of diastereoselectivity (dr up to 20:1) and enantioselectivity (up to 99% ee). Furthermore, the utility of this methodology is showcased by the transformation of chiral spiroisoxazolones into structurally attractive and enantiomerically enriched cyclopentene carboxylic acids with two stereogenic centers.

• Publikační typ
• časopisecké články MeSH

Background: Lung cancer is the leading cause of cancer-related deaths globally, with epidermal growth factor receptor (EGFR) mutations present in approximately 17-39% of non-small cell lung cancer (NSCLC) cases. Osimertinib, a third-generation oral EGFR tyrosine kinase inhibitor (EGFR-TKI), has become a cornerstone in the treatment of EGFR-mutated NSCLC. However, the full scope of its potentially life-threatening adverse effects, particularly cardiomyopathy, remains underexplored. Methods: This retrospective study was conducted using data from a multi-center registry of NSCLC patients with EGFR mutations treated with first-line osimertinib therapy between December 2018 and April 2024. Osimertinib-related cardiotoxicity was defined as a composite of reduced ejection fraction (EF) and cardiac death. Results: The study cohort consisted of 17 patients, and most of the patients had a history of smoking. Cardiac toxicity onset varied from 1 to 28 months following osimertinib initiation, with 70.59% of the patients experiencing symptoms within the first 6 months of treatment. Fourteen patients showed some degree of symptom improvement and EF recovery, although most did not return to baseline EF levels. Comorbidities, including heart failure, hypertension, and dyslipidemia, were prevalent across the cohort. Conclusions: While osimertinib remains an effective treatment for EGFR-mutated NSCLC, its associated cardiac toxicity, particularly in patients with pre-existing conditions, presents a significant challenge. Close monitoring, early intervention, and individualized management strategies are critical in mitigating these risks. Patients with mild cardiac toxicity may be suitable for rechallenge, while those with more severe or persistent toxicity should generally be excluded from further osimertinib treatment.

• Publikační typ
• časopisecké články MeSH

Many small molecules require derivatization to increase their volatility and to be amenable to gas chromatographic (GC) separation. Derivatization is usually time-consuming, and typical batch-wise procedures increase sample variability. Sequential automation of derivatization via robotic liquid handling enables the overlapping of sample preparation and analysis, maximizing time efficiency and minimizing variability. Herein, a protocol for the fully automated, two-stage derivatization of human blood-based samples in line with GC-[Orbitrap] mass spectrometry (MS)-based metabolomics is described. The protocol delivers a sample-to-sample runtime of 31 min, being suitable for better throughput routine metabolomic analysis. Key features • Direct and rapid methoximation on vial followed by silylation of metabolites in various blood matrices. • Measure ~40 samples per 24 h, identifying > 70 metabolites. • Quantitative reproducibility of routinely measured metabolites with coefficients of variation (CVs) < 30%. • Requires a Thermo ScientificTM TriPlusTM RSH (or comparable) autosampler equipped with incubator/agitator, cooled drawer, and automatic tool change (ATC) station equipped with liquid handling tools. Graphical overview Workflow for profiling metabolites in human blood using automated derivatization.

• Publikační typ
• časopisecké články MeSH

The rising burden of fungal infections presents a significant challenge to global healthcare, particularly with increasing antifungal resistance limiting treatment efficacy. Early detection and timely intervention remain critical, yet fungal pathogens employ diverse mechanisms to evade host immunity and develop resistance, undermining existing therapeutic options. Limited antifungal options and rising resistance necessitate novel treatment strategies. This review provides a comprehensive overview of conventional antifungal agents, their mechanisms of action, and emerging resistance pathways. Furthermore, it highlights recently approved and investigational antifungal compounds while evaluating innovative approaches such as nanotechnology, drug repurposing, and immunotherapy. Addressing antifungal resistance requires a multifaceted strategy that integrates novel therapeutics, enhanced diagnostic tools, and future research efforts to develop sustainable and effective treatment solutions.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Circular RNAs (circRNAs) make up approximately 10% of the human transcriptome. CircRNAs belong to the broad group of non-coding RNAs and characteristically are formed by backsplicing into a stable circular loop. Their main role is to regulate transcription through the inhibition of miRNAs' expression, termed miRNA sponging. CircRNAs promote tumorigenesis/lymphomagenesis by competitively binding to miRNAs at miRNA binding sites. In diffuse large B-cell lymphoma (DLBCL), several circRNAs have been identified and their expression is related to both progression and response to therapy. DLBCL is the most prevalent and aggressive subtype of B-cell lymphomas and accounts for about 25% to 30% of all non-Hodgkin lymphomas. DLBCL displays great heterogeneity concerning histopathology, biology, and genetics. Patients who have relapsed or have refractory disease after first-line therapy have a very poor prognosis, demonstrating an important unmet need for new treatment options. As more circRNAs are identified in the future, we will better understand their biological roles and potential use in treating cancer, including DLBCL. For example, circAmotl1 promotes nuclear translocation of MYC and upregulation of translational targets of MYC, thus enhancing lymphomagenesis. Another example is circAPC, which is significantly downregulated in DLBCL and correlates with disease aggressiveness and poor prognosis. CircAPC increases expression of the host gene adenomatous polyposis coli (APC), and in doing so inactivates the canonical Wnt/β-catenin signaling and restrains DLBCL growth. MiRNAs belong to the non-coding regulatory molecules that significantly contribute to lymphomagenesis through their target mRNAs. In DLBCL, among the highly expressed miRNAs, are miR-155-5p and miR-21-5p, which regulate NF-ĸB and PI3K/AKT signaling pathways. The aim of this review is to describe the function and mechanism of regulation of circRNAs on miRNAs' expression in DLBCL. This will help us to better understand the regulatory network of circRNA/miRNA/mRNA, and to propose novel therapeutic targets to treat DLBCL.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Příručka, která se zaměřuje na psychologii a komunikaci mezi rodiči a dětmi a na vztah k a interakce v online prostoru. Určeno široké veřejnosti.

• MeSH
• chování dětí MeSH
• chování mladistvých MeSH
• dětská psychologie MeSH
• internet MeSH
• komunikace MeSH
• kyberšikana MeSH
• netholismus * MeSH
• psychologie adolescentů MeSH
• vztahy mezi rodiči a dětmi MeSH
• Publikační typ
• populární práce MeSH
• příručky MeSH

• Konspekt
• Sociální interakce
• NLK Obory
• psychologie, klinická psychologie
• sociologie

• MeSH
• dějiny 15. století MeSH
• dějiny 16. století MeSH
• dějiny 17. století MeSH
• dějiny 18. století MeSH
• dějiny 19. století MeSH
• dějiny 20. století MeSH
• dějiny středověku MeSH
• rituální chování MeSH
• sociologické faktory MeSH
• významné osobnosti MeSH
• ženská práva dějiny   MeSH
• ženy dějiny   MeSH
• Check Tag
• dějiny 15. století MeSH
• dějiny 16. století MeSH
• dějiny 17. století MeSH
• dějiny 18. století MeSH
• dějiny 19. století MeSH
• dějiny 20. století MeSH
• dějiny středověku MeSH
• Publikační typ
• monografie MeSH
• Geografické názvy
• Česká republika MeSH

• Konspekt
• Globální společnosti. Sociální struktura. Sociální skupiny
• NLK Obory
• sociologie

Encyklopedie a příručka, která se zaměřuje na diabetes mellitus a jeho možné komplikace a na jejich management. Určeno široké veřejnosti.

• MeSH
• diabetes mellitus * MeSH
• komplikace diabetu MeSH
• self-management MeSH
• Publikační typ
• encyklopedie MeSH
• populární práce MeSH
• příručky MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• diabetologie
• zdravotní výchova