The small-molecule alkaloid halofuginone (HF) is obtained from febrifugine. Recent studies on HF have aroused widespread attention owing to its universal range of noteworthy biological activities and therapeutic functions, which range from parasite infections and fibrosis to autoimmune diseases. In particular, HF is believed to play an excellent anticancer role by suppressing the proliferation, adhesion, metastasis, and invasion of cancers. This review supports the goal of demonstrating various anticancer effects and molecular mechanisms of HF. In the studies covered in this review, the anticancer molecular mechanisms of HF mainly included transforming growth factor-β (TGF-β)/Smad-3/nuclear factor erythroid 2-related factor 2 (Nrf2), serine/threonine kinase proteins (Akt)/mechanistic target of rapamycin complex 1(mTORC1)/wingless/integrated (Wnt)/β-catenin, the exosomal microRNA-31 (miR-31)/histone deacetylase 2 (HDAC2) signaling pathway, and the interaction of the extracellular matrix (ECM) and immune cells. Notably, HF, as a novel type of adenosine triphosphate (ATP)-dependent inhibitor that is often combined with prolyl transfer RNA synthetase (ProRS) and amino acid starvation therapy (AAS) to suppress the formation of ribosome, further exerts a significant effect on the tumor microenvironment (TME). Additionally, the combination of HF with other drugs or therapies obtained universal attention. Our results showed that HF has significant potential for clinical cancer treatment.
- Publication type
- Journal Article MeSH
- Review MeSH
Vitamin D je skupina steroidních hormonů. Většina v těle vzniká za pomoci UV záření ze slunce, ale je obsažen v různých potravinách, jako jsou oleje z mořských ryb apod. V těle je postupně hydroxylován na účinný metabolit v játrech a ledvinách. V krvi je transportován bílkovinou VDBP (vitamin D binding protein). Váže se v jádře buňky na receptor VDR (vitamin D Rreceptor). Na koncentraci vitaminu D má vliv mnoho faktorů jako zeměpisná poloha, sezóna (délka slunečního svitu), pigmentace kůže i množství tukové a svalové tkáně. Jeho nejznámější funkcí je regulace kalcio-fosfátového metabolizmu, avšak podílí se rovněž na regulaci buněčného cyklu, indukci apoptózy a také hraje roli v regulaci imunitního systému. Obecně lze říci, že jeho působení vede spíše k imunotoleranci. Nedostatek vitaminu D se v populaci projevuje stále častěji, dnes jím trpí až téměř 50 % evropské populace. Deficience se spojuje s vyšší agresivitou nádorů vč. Nehodgkinových lymfomů a je prokázáno, že pacienti s vyššími hladinami vitaminu D vykazují lepší celkové přežití i dobu do progrese. Nabízí se tedy otázka, zda by suplementace vitaminem D mohla příznivě ovlivnit prognózu pacienta s lymfomy. Výsledky publikovaných studií jsou v tomto ohledu dosud rozporuplné. Navzdory ne zcela jednoznačným výsledkům se uvádí, že suplementace by měla být zvážena u pacientů s insuficientními hladinami vitaminu D.
Vitamin D is a group of steroid hormones, produced with the help of UV radiation of the sun in the skin. It is also contained in various foods such as marine fish oils etc. In the body, it is subsequently transformed into its active form in the liver and kidneys. In the blood, it is transported by the VDBP (vitamin D binding protein). In the cell nucleus, it is bound to the VDR receptor (vitamin D receptor). The concentration of vitamin D in plasma is influenced by many factors: geographical latitude, season (length of sunshine), skin pigmentation, amount of fat, and muscle tissue. The best-known function of vitamin D is the regulation of calcium-phosphate metabolism, but it is involved in many processes such as the regulation of the cell cycle and the induction of apoptosis. It plays a role in the regulation of the immune system as well. Its immunomodulatory action is required for adequate anti-infectious and anti-tumoral immune response. It prevents an exaggerated inflammatory reaction and leads to immunotolerance. Deficiency has become more common in our population, affecting up to 50% of Europeans. Deficiency is also associated with a higher aggressiveness of tumours, including non-Hodgkin lymphomas. It has been shown that higher levels of vitamin D are associated with better overall survival and time to progression. The question is, whether vitamin D supplementation could impact and improve prognosis. Despite the ambiguous results of published studies, vitamin D supplementation should be considered in patients with diagnosed deficiency.
OBJECTIVES: This study aims to assess the accuracy of generative pre-trained transformer 4o (GPT-4o) in answering multiple response questions from the European Diploma in Radiology (EDiR) examination, comparing its performance to that of human candidates. MATERIALS AND METHODS: Results from 42 EDiR candidates across Europe were compared to those from 26 fourth-year medical students who answered exclusively using the ChatGPT-4o in a prospective study (October 2024). The challenge consisted of 52 recall or understanding-based EDiR multiple-response questions, all without visual inputs. RESULTS: The GPT-4o achieved a mean score of 82.1 ± 3.0%, significantly outperforming the EDiR candidates with 49.4 ± 10.5% (p < 0.0001). In particular, chatGPT-4o demonstrated higher true positive rates while maintaining lower false positive rates compared to EDiR candidates, with a higher accuracy rate in all radiology subspecialties (p < 0.0001) except informatics (p = 0.20). There was near-perfect agreement between GPT-4 responses (κ = 0.872) and moderate agreement among EDiR participants (κ = 0.334). Exit surveys revealed that all participants used the copy-and-paste feature, and 73% submitted additional questions to clarify responses. CONCLUSIONS: GPT-4o significantly outperformed human candidates in low-order, text-based EDiR multiple-response questions, demonstrating higher accuracy and reliability. These results highlight GPT-4o's potential in answering text-based radiology questions. Further research is necessary to investigate its performance across different question formats and candidate populations to ensure broader applicability and reliability. CRITICAL RELEVANCE STATEMENT: GPT-4o significantly outperforms human candidates in factual radiology text-based questions in the EDiR, excelling especially in identifying correct responses, with a higher accuracy rate compared to radiologists. KEY POINTS: In EDiR text-based questions, ChatGPT-4o scored higher (82%) than EDiR participants (49%). Compared to radiologists, GPT-4o excelled in identifying correct responses. GPT-4o responses demonstrated higher agreement (κ = 0.87) compared to EDiR candidates (κ = 0.33).
- Publication type
- Journal Article 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.
- Publication type
- Journal Article MeSH
The potentials of electrochemical processes in ideal aqueous media are related to the potential of a normal hydrogen electrode (NHE). However, in non-ideal media, the potentials of a metallocene redox couple are used as a reference. Such measurements with free metallocene in solution are complicated by adsorption and mass transport phenomena and solvation effects. Herein, a platinum electrode with an anchored ferrocene moiety (Pt,Fc) was used for cyclic voltammetric measurements of the potential of ferrocene/ferrocenium (Fc/Fc+) redox transformation in not only non-aqueous but, for the first time, aqueous solutions as well. This enabled us to eliminate the aforementioned problems associated with the application of free metallocene molecules in solution and, thus, to relate the midpoint potential (Epm) of the Fc/Fc+ redox couple to a NHE. After elimination of the liquid junction potential in an aqueous 0.1 M KCl solution at 25 °C, the average intraday Epm value obtained with freshly prepared Pt,Fc electrodes was found to be 0.312 ± 0.008 V versus the secondary Ag|AgCl electrode. The Pt,Fc electrode can be applied for the standardization of electrochemical measurements and investigation of solvation phenomena at interfaces in non-ideal media.
- Publication type
- Journal Article MeSH
The brain's complex organization spans from molecular-level processes within neurons to large-scale networks, making it essential to understand this multiscale structure to uncover brain functions and address neurological disorders. Multiscale brain modeling has emerged as a transformative approach, integrating computational models, advanced imaging, and big data to bridge these levels of organization. This review explores the challenges and opportunities in linking microscopic phenomena to macroscopic brain functions, emphasizing the methodologies driving progress in the field. It also highlights the clinical potential of multiscale models, including their role in advancing artificial intelligence (AI) applications and improving healthcare technologies. By examining current research and proposing future directions for interdisciplinary collaboration, this work demonstrates how multiscale brain modeling can revolutionize both scientific understanding and clinical practice.
- Publication type
- Journal Article MeSH
- Review MeSH
Glomerulonephritis (GN) encompasses a diverse group of immune-mediated diseases that damage the glomerular component of the nephron. While kidney biopsy remains the gold standard for diagnosis, it often fails to provide adequate insight into the underlying etiology of GN. Current classification systems have limited our understanding of the disease's pathophysiology and hinder the development of targeted therapies. Immunosuppressive treatments, such as glucocorticoids, calcineurin inhibitors, cyclophosphamide, and rituximab, remain the mainstay of therapy, though many patients fail to achieve remission or experience significant adverse effects. Moreover, the complex and multifactorial nature of GN pathogenesis calls for more refined therapeutic approaches. In recent years, multitarget therapies-combining different immunosuppressive agents targeting distinct immune pathways-have emerged as promising alternatives. Evidence suggests that multitarget therapy may offer superior outcomes compared to standard treatments. Despite early success, further studies are needed to optimize these regimens, reduce toxicity, and extend benefits to a broader range of GN patients. The development of personalized, biomarker-driven treatments, potentially leveraging innovative drug delivery systems and targeted biologics, holds promise for transforming GN care in the future.
- Publication type
- Journal Article MeSH
The behavior of chemical warfare agents (CWAs) on urban materials, such as concrete, significantly impacts forensic and military responses to chemical incidents. This study examined the persistence and degradation mechanisms of sarin (GB), soman (GD), and sulfur mustard (HD) on three types of commonly used concrete with varying water-cement ratios. Over two months, we evaluated the effects of concrete composition, temperature, and fragment size on CWA behavior. Half-lives and activation energies for CWA dissipation were calculated under various conditions. Results showed that concrete properties and external temperature strongly influenced dissipation rates. G-series agents underwent rapid hydrolysis, forming methylphosphonates, while HD degradation involved elimination, nucleophilic substitution, and oxidation, producing several previously unreported byproducts. Smaller concrete fragments increased recovery values and accelerated degradation due to greater surface area exposure, and higher temperatures further enhanced dissipation rates, particularly for volatile agents. Differences in dissipation among concrete types were linked to their physical and chemical properties, notably water-cement ratios. This study highlights the challenges of detecting CWAs due to their rapid penetration and transformation in concrete and provides insights for improving sampling, identification, and decontamination strategies under realistic conditions.
- Publication type
- Journal Article MeSH
BACKGROUND AND PURPOSE: Pediatric radiotherapy patients and their parents are usually aware of their need for radiotherapy early on, but they meet with a radiation oncologist later in their treatment. Consequently, they search for information online, often encountering unreliable sources. Large language models (LLMs) have the potential to serve as an educational pretreatment tool, providing reliable answers to their questions. We aimed to evaluate the responses provided by generative pre-trained transformers (GPT), the most popular subgroup of LLMs, to questions about pediatric radiation oncology. MATERIALS AND METHODS: We collected pretreatment questions regarding radiotherapy from patients and parents. Responses were generated using GPT-3.5, GPT-4, and fine-tuned GPT-3.5, with fine-tuning based on pediatric radiotherapy guides from various institutions. Additionally, a radiation oncologist prepared answers to these questions. Finally, a multi-institutional group of nine pediatric radiotherapy experts conducted a blind review of responses, assessing reliability, concision, and comprehensibility. RESULTS: The radiation oncologist and GPT-4 provided the highest-quality responses, though GPT-4's answers were often excessively verbose. While fine-tuned GPT-3.5 generally outperformed basic GPT-3.5, it often provided overly simplistic answers. Inadequate responses were rare, occurring in 4% of GPT-generated responses across all models, primarily due to GPT-3.5 generating excessively long responses. CONCLUSIONS: LLMs can be valuable tools for educating patients and their families before treatment in pediatric radiation oncology. Among them, only GPT-4 provides information of a quality comparable to that of a radiation oncologist, although it still occasionally generates poor-quality responses. GPT-3.5 models should be used cautiously, as they are more likely to produce inadequate answers to patient questions.
- Publication type
- Journal Article MeSH
