Cancer immunotherapy is increasingly used in clinical practice, but its success rate is reduced by tumor escape from the immune system. This may be due to the genetic instability of tumor cells, which allows them to adapt to the immune response and leads to intratumoral immune heterogeneity. The study investigated spatial immune heterogeneity in the tumor microenvironment and its possible drivers in a mouse model of tumors induced by human papillomaviruses (HPV) following immunotherapy. Gene expression was determined by RNA sequencing and mutations by whole exome sequencing. A comparison of different tumor areas revealed heterogeneity in immune cell infiltration, gene expression, and mutation composition. While the mean numbers of mutations with every impact on gene expression or protein function were comparable in treated and control tumors, mutations with high or moderate impact were increased after immunotherapy. The genes mutated in treated tumors were significantly enriched in genes associated with ECM metabolism, degradation, and interactions, HPV infection and carcinogenesis, and immune processes such as antigen processing and presentation, Toll-like receptor signaling, and cytokine production. Gene expression analysis of DNA damage and repair factors revealed that immunotherapy upregulated Apobec1 and Apobec3 genes and downregulated genes related to homologous recombination and translesion synthesis. In conclusion, this study describes the intratumoral immune heterogeneity, that could lead to tumor immune escape, and suggests the potential mechanisms involved.

• MeSH
• Immunotherapy * methods   MeSH
• Papillomavirus Infections immunology   virology   MeSH
• Humans MeSH
• Disease Models, Animal * MeSH
• Mutation * MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Tumor Microenvironment * immunology   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Exome Sequencing MeSH
• Tumor Escape genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Heavy metals are naturally occurring components of the Earth's crust and persistent environmental pollutants. Human exposure to heavy metals occurs via various pathways, including inhalation of air/dust particles, ingesting contaminated water or soil, or through the food chain. Their bioaccumulation may lead to diverse toxic effects affecting different body tissues and organ systems. The toxicity of heavy metals depends on the properties of the given metal, dose, route, duration of exposure (acute or chronic), and extent of bioaccumulation. The detrimental impacts of heavy metals on human health are largely linked to their capacity to interfere with antioxidant defense mechanisms, primarily through their interaction with intracellular glutathione (GSH) or sulfhydryl groups (R-SH) of antioxidant enzymes such as superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR), and other enzyme systems. Although arsenic (As) is believed to bind directly to critical thiols, alternative hydrogen peroxide production processes have also been postulated. Heavy metals are known to interfere with signaling pathways and affect a variety of cellular processes, including cell growth, proliferation, survival, metabolism, and apoptosis. For example, cadmium can affect the BLC-2 family of proteins involved in mitochondrial death via the overexpression of antiapoptotic Bcl-2 and the suppression of proapoptotic (BAX, BAK) mechanisms, thus increasing the resistance of various cells to undergo malignant transformation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important regulator of antioxidant enzymes, the level of oxidative stress, and cellular resistance to oxidants and has been shown to act as a double-edged sword in response to arsenic-induced oxidative stress. Another mechanism of significant health threats and heavy metal (e.g., Pb) toxicity involves the substitution of essential metals (e.g., calcium (Ca), copper (Cu), and iron (Fe)) with structurally similar heavy metals (e.g., cadmium (Cd) and lead (Pb)) in the metal-binding sites of proteins. Displaced essential redox metals (copper, iron, manganese) from their natural metal-binding sites can catalyze the decomposition of hydrogen peroxide via the Fenton reaction and generate damaging ROS such as hydroxyl radicals, causing damage to lipids, proteins, and DNA. Conversely, some heavy metals, such as cadmium, can suppress the synthesis of nitric oxide radical (NO·), manifested by altered vasorelaxation and, consequently, blood pressure regulation. Pb-induced oxidative stress has been shown to be indirectly responsible for the depletion of nitric oxide due to its interaction with superoxide radical (O2·-), resulting in the formation of a potent biological oxidant, peroxynitrite (ONOO-). This review comprehensively discusses the mechanisms of heavy metal toxicity and their health effects. Aluminum (Al), cadmium (Cd), arsenic (As), mercury (Hg), lead (Pb), and chromium (Cr) and their roles in the development of gastrointestinal, pulmonary, kidney, reproductive, neurodegenerative (Alzheimer's and Parkinson's diseases), cardiovascular, and cancer (e.g. renal, lung, skin, stomach) diseases are discussed. A short account is devoted to the detoxification of heavy metals by chelation via the use of ethylenediaminetetraacetic acid (EDTA), dimercaprol (BAL), 2,3-dimercaptosuccinic acid (DMSA), 2,3-dimercapto-1-propane sulfonic acid (DMPS), and penicillamine chelators.

• MeSH
• Antioxidants metabolism   MeSH
• Bioaccumulation MeSH
• Environmental Pollutants toxicity   MeSH
• Humans MeSH
• Oxidative Stress * drug effects   MeSH
• Metals, Heavy * toxicity   MeSH
• Environmental Exposure adverse effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

CONTEXT: Adjuvant immune checkpoint inhibitors (ICIs) have recently emerged as guideline-recommended treatments of high-risk muscle-invasive urothelial carcinoma (MIUC). However, there is limited evidence regarding the optimal candidates and the differential efficacy of adjuvant ICI regimens. OBJECTIVE: To synthesize and compare the efficacy and safety of adjuvant ICIs for high-risk MIUC using updated data from phase III randomized controlled trials. EVIDENCE ACQUISITION: In April 2024, three databases were searched for eligible randomized controlled trials that evaluated oncologic outcomes in patients with MIUC treated with adjuvant ICIs. Pairwise meta-analysis (MA) and network meta-analyses were performed to compare the hazard ratios of oncological outcomes, including disease-free survival (DFS), overall survival (OS), and adverse events. Subgroup analyses were conducted on the basis of predefined clinicopathological features. EVIDENCE SYNTHESIS: Three randomized controlled trials that assessed the efficacy of adjuvant nivolumab, pembrolizumab, and atezolizumab were included in the MAs and network meta-analyses groups. Pairwise MAs showed that treatment with adjuvant ICIs significantly improved DFS [hazards ratio: 0.77, 95% confidence interval (CI): 0.66-0.90] as well as OS (hazards ratio: 0.87, 95% CI 0.76-1.00) in patients with MIUC compared with in the placebo/observation group. The DFS benefit was prominent in patients who underwent neoadjuvant chemotherapy (P = 0.041) and in those with bladder cancer (P = 0.013) but did not differ across programmed death-ligand 1 and lymph node status. Adjuvant ICI therapy was associated with increased risk of any (OR: 2.98, 95% CI 2.06-4.33) and severe adverse events (OR: 1.78, 95% CI 1.49-2.13). The treatment rankings revealed that pembrolizumab for DFS (84%) and nivolumab for OS (93%) had the highest likelihood of improving survival. CONCLUSIONS: Our analyses demonstrated the DFS and OS benefits of adjuvant ICIs for high-risk MIUC. Furthermore, patients with bladder cancer who underwent neoadjuvant chemotherapy appeared to be the optimal candidates for adjuvant ICIs regarding prolonged DFS. Adjuvant ICIs are the standard of care for high-risk MIUC, and differential clinical behaviors and efficacy will enrich clinical decision-making.

• MeSH
• Chemotherapy, Adjuvant methods   MeSH
• Immune Checkpoint Inhibitors * therapeutic use   pharmacology   MeSH
• Neoplasm Invasiveness MeSH
• Carcinoma, Transitional Cell drug therapy   pathology   MeSH
• Humans MeSH
• Urinary Bladder Neoplasms drug therapy   pathology   MeSH
• Network Meta-Analysis as Topic MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH
• Systematic Review MeSH

Bacterial resistance has become a global concern for public health agencies. Various resistance mechanisms found in Staphylococcus aureus strains grant this bacterium resistance to a wide range of antibiotics, contributing to the rise in human mortality worldwide. Resistance mediated by efflux pumps is one of the most prevalent mechanisms in multi-resistant bacteria, which has aroused the interest of several researchers in the search for possible efflux pump inhibitors. In view of the aforementioned considerations, it is important that new strategies, such as the synthesis of chalcones, be made available as a viable strategy in antimicrobial therapy. In this study, the synthesized chalcone (2E)-1-(3'-aminophenyl)-3-(4-dimethylaminophenyl)-prop-2-en-1-one was tested for its antibacterial activity, focusing on antibiotic modification and the inhibition of the MepA efflux pump present in S. aureus strain K2068. The broth microdilution method, using microdilution plates, was employed in microbiological tests to determine the minimum inhibitory concentration of the chalcone, antibiotics, and ethidium bromide. The results show that while the chalcone did not exhibit direct antibacterial activity, it synergistically enhanced the effects of ciprofloxacin and ethidium bromide, as evidenced by the reduction in MICs. In addition, computer simulations of molecular docking demonstrate that the tested chalcone acts on the same binding site as the efflux pump inhibitor chlorpromazine, interacting with essentially the same residues. These data suggest that the chalcone may act as a MepA inhibitor.

• MeSH
• Anti-Bacterial Agents * pharmacology   chemistry   chemical synthesis   MeSH
• Bacterial Proteins * metabolism   genetics   chemistry   antagonists & inhibitors   MeSH
• Chalcone * pharmacology   chemistry   MeSH
• Chalcones * pharmacology   chemistry   MeSH
• Humans MeSH
• Membrane Transport Proteins * metabolism   genetics   chemistry   MeSH
• Microbial Sensitivity Tests MeSH
• Multidrug Resistance-Associated Proteins * metabolism   genetics   chemistry   MeSH
• Molecular Docking Simulation MeSH
• Staphylococcus aureus * drug effects   genetics   metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Článek se zabývá definicí a kategorizací digitálních her. Nejprve analyzuje dosavadní dostupné definice a upozorňuje na jejich úskalí v přesnosti a následné použitelnosti pro vymezení pojmu digitální hra. V návaznosti na tuto analýzu si klade za cíl poskytnout přesnější a komplexnější definici digitálních her založenou na kompilaci předešlých teoretických tezí. Dále se článek věnuje problematice kategorizace digitálních her, upozorňuje na nejednoznačnost označování herních žánrů, která může vést k zavádějícím označením a neshodám v herní komunitě i mezi odborníky. Digitální hry často kombinují prvky několika žánrů, což činí jejich tradiční zařazení obtížným. V reakci na tuto situaci přináší článek návrh alternativní kategorizace se zaměřením na primární herní smyčku, díky čemuž reflektuje současné trendy v herním průmyslu a umožňuje flexibilnější rozdělení her podle jejich dominantních mechanismů. Základní kategorizaci pak doplňuje žánrovými kombinacemi, specifickými doplňkovými žánry, otevřeností herního světa, sociálními aspekty, platebními modely a perspektivami pohledu. Článek reaguje na aktuální společenskou a odbornou potřebu zpřehlednění terminologie v oblasti digitálních her, což je nezbytné nejen pro vědecké bádání, ale i pro preventivní intervence a efektivní pedagogickou praxi. Systematické vymezení pojmů a žánrových kategorií přispívá k lepší orientaci odborníků napříč různými oblastmi, umožňuje přesnější diagnostiku fenoménu nadměrného hraní a zvyšuje srozumitelnost komunikace mezi výzkumníky, terapeuty, odborníky v praxi a jejich klienty. Článek tak nabízí důležitý nástroj pro mezioborové porozumění a efektivní aplikaci poznatků v praxi. Závěrem studie zdůrazňuje nutnost průběžné revize definic i způsobů kategorizace digitálních her s ohledem na jejich nepřetržitý vývoj. Digitální hry se neustále proměňují a rozšiřují o nové prvky, a proto je důležité, aby i teoretické rámce reflektovaly tyto změny a umožňovaly přesnější uchopení tohoto dynamického fenoménu.

The article focuses on the definition and categorization of digital games. It first analyzes existing definitions and highlights their shortcomings in terms of accuracy and applicability for defining the concept of a digital game. Following this analysis, the paper aims to provide a more precise and comprehensive definition of digital games, based on a synthesis of previous theoretical approaches. The article further examines the challenges of categorizing digital games, emphasizing the ambiguity in labeling game genres, which can lead to misleading classifications and disagreements within both the gaming community and experts. Digital games frequently combine elements from multiple genres, making their traditional classification difficult. In response to this issue, the article proposes an alternative categorization approach centred on the primary gameplay loop, reflecting current trends in the gaming industry and enabling a more flexible classification of games based on their dominant mechanics. This core categorization is complemented by genre combinations, specific sub-genres, game world openness, social aspects, monetization models, and perspectives of gameplay. The article responds to the current social and professional need to clarify terminology in the field of digital games, which is essential not only for scientific research but also for preventive interventions and effective pedagogical practice. The systematic definition of terms and genre categories contributes to better orientation for experts across different fields, enables more accurate diagnosis of the phenomenon of excessive gaming, and increases the clarity of communication between researchers, therapists, practitioners, and their clients. The article thus offers an important tool for interdisciplinary understanding and the effective application of knowledge in practice. Finally, the article emphasizes the necessity of continuously revising the definitions and classification methods of digital games in light of their ongoing evolution. As digital games constantly change and incorporate new elements, it is crucial that theoretical frameworks adapt to these transformations, ensuring a more accurate understanding of this dynamic phenomenon.

UNLABELLED: Methotrexate is used to manage moderate to severe psoriasis and psoriatic arthritis. Methotrexate acts by inhibiting the enzymes involved in nucleotide synthesis. Methotrexate polyglutamates (MTXPGs) have a higher potency to inhibit Dihydrofolate reductase (DHFR), 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC), and thymidylate synthase (TS), compared to naïve methotrexate. Among all the MTXPGs, methotrexate polyglutamate three (MTXPG-3) is a more potent inhibitor of DHFR, ATIC, and TS enzymes. MTXPG-3 is anticipated to allow therapeutic drug monitoring in immune-mediated inflammatory diseases. We aim to study MTXPG-3 levels as a biomarker for both efficacy and adverse events among psoriatic patients treated with methotrexate monotherapy. We used the LC-MS/MS (Liquid Chromatography Mass Spectrophotometry) system for measuring erythrocyte MTXPG-3. We recruited 106 patients with psoriasis who were treated with methotrexate. Sixty-one of them had psoriatic arthritis (concomitant or in the past). The mean age was 45.08 ± 13.04 years. After twenty-four weeks of methotrexate treatment, 73(69%) were responders, and 33(31%) were non-responders. Thirty-nine (36%) experienced adverse effects, and 67(64%) did not experience any adverse effects. We observed a significant positive correlation between erythrocyte MTXPG-3 and methotrexate dose per week at weeks 12 and 16 but not at week 24. Erythrocyte MTXPG-3 did not correlate with response or adverse effects. It can be used as a marker of compliance. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12291-024-01269-x.

• Publication type
• Journal Article MeSH

OBJECTIVE: This scoping review aims to identify, catalogue, and characterize previously reported tools, techniques, methods, and processes that have been recommended or used by evidence synthesizers to detect fraudulent or erroneous data and mitigate its impact. INTRODUCTION: Decision-making for policy and practice should always be underpinned by the best available evidence-typically peer-reviewed scientific literature. Evidence synthesis literature should be collated and organized using the appropriate evidence synthesis methodology, best exemplified by the role systematic reviews play in evidence-based health care. However, with the rise of "predatory journals," fraudulent or erroneous data may be invading this literature, which may negatively affect evidence syntheses that use this data. This, in turn, may compromise decision-making processes. INCLUSION CRITERIA: This review will include peer-reviewed articles, commentaries, books, and editorials that describe at least 1 tool, technique, method, or process with the explicit purpose of identifying or mitigating the impact of fraudulent or erroneous data for any evidence synthesis, in any topic area. Manuals, handbooks, and guidance from major organizations, universities, and libraries will also be considered. METHODS: This review will be conducted using the JBI methodology for scoping reviews and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). Databases and relevant organizational websites will be searched for eligible studies. Title and abstract, and, subsequently, full-text screening will be conducted in duplicate. Data from identified full texts will be extracted using a pre-determined checklist, while the findings will be summarized descriptively and presented in tables. REVIEW REGISTRATION: Open Science Framework https://osf.io/u8yrn.

• MeSH
• Humans MeSH
• Fraud prevention & control   MeSH
• Systematic Reviews as Topic MeSH
• Scientific Misconduct * MeSH
• Research Design standards   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Cohort studies are a robust analytical observational study design that explore the difference in outcomes between two cohorts, differentiated by their exposure status. Despite being observational in nature, they are often included in systematic reviews of effectiveness, particularly when randomized controlled trials are limited or not feasible. Like all studies included in a systematic review, cohort studies must undergo a critical appraisal process to assess the extent to which a study has considered potential bias in its design, conduct, or analysis. Critical appraisal tools facilitate this evaluation. This paper introduces the revised critical appraisal tool for cohort studies, completed by the JBI Effectiveness Methodology Group, who are currently revising the suite of JBI critical appraisal tools for quantitative study designs. The revised tool responds to updates in methodological guidance from the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Working Group and reporting guidance from PRISMA 2020, providing a robust framework for evaluating risk of bias in a cohort study. Transparent and rigorous assessment using this tool will assist reviewers in understanding the validity and relevance of the results and conclusions drawn from a systematic review that includes cohort studies. This may contribute to better evidence-based decision-making in health care. This paper discusses the key changes made to the tool, outlines justifications for these changes, and provides practical guidance on how this tool should be interpreted and applied by systematic reviewers.

• MeSH
• Cohort Studies MeSH
• Humans MeSH
• Research Design * standards   MeSH
• Bias * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

PURPOSE: Docetaxel resistance is a significant obstacle in the treatment of prostate cancer (PCa), resulting in unfavorable patient prognoses. Intratumoral heterogeneity, often associated with epithelial-to-mesenchymal transition (EMT), has previously emerged as a phenomenon that facilitates adaptation to various stimuli, thus promoting cancer cell diversity and eventually resistance to chemotherapy, including docetaxel. Hence, understanding intratumoral heterogeneity is essential for better patient prognosis and the development of personalized treatment strategies. METHODS: To address this, we employed a high-throughput single-cell flow cytometry approach to identify a specific surface fingerprint associated with docetaxel-resistance in PCa cells and complemented it with proteomic analysis of extracellular vesicles. We further validated selected antigens using docetaxel-resistant patient-derived xenografts in vivo and probed primary PCa specimens to interrogate of their surface fingerprint. RESULTS: Our approaches revealed a 6-molecule surface fingerprint linked to docetaxel resistance in primary PCa specimens. We observed consistent overexpression of CD95 (FAS/APO-1), and SSEA-4 surface antigens in both in vitro and in vivo docetaxel-resistant models, which was also observed in a cell subpopulation of primary PCa tumors exhibiting EMT features. Furthermore, CD95, along with the essential enzymes involved in SSEA-4 synthesis, ST3GAL1, and ST3GAL2, displayed a significant increase in patients with PCa undergoing docetaxel-based therapy, correlating with poor survival outcomes. CONCLUSION: In summary, we demonstrate that the identified 6-molecule surface fingerprint associated with docetaxel resistance pre-exists in a subpopulation of primary PCa tumors before docetaxel treatment. Thus, this fingerprint warrants further validation as a promising predictive tool for docetaxel resistance in PCa patients prior to therapy initiation.

• MeSH
• Drug Resistance, Neoplasm * MeSH
• Docetaxel * pharmacology   therapeutic use   MeSH
• Epithelial-Mesenchymal Transition drug effects   MeSH
• Humans MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Prostatic Neoplasms * pathology   drug therapy   metabolism   MeSH
• Antineoplastic Agents pharmacology   therapeutic use   MeSH
• Xenograft Model Antitumor Assays MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

OBJECTIVES: Differentiating true progression or recurrence (TP/TR) from therapy-related changes (TRC) is complex in brain tumours. Amide proton transfer-weighted (APT) imaging is a chemical exchange saturation transfer (CEST) MRI technique that may improve diagnostic accuracy during radiological follow-up. This systematic review and meta-analysis elucidated the level of evidence and details of state-of-the-art imaging for APT-CEST in glioma and brain metastasis surveillance. METHODS: PubMed, EMBASE, Web of Science, and Cochrane Library were systematically searched for original articles about glioma and metastasis patients who received APT-CEST imaging for suspected TP/TR within 2 years after (chemo)radiotherapy completion. Modified Quality Assessment of Diagnostic Accuracy Studies-2 criteria were applied. A meta-analysis was performed to pool results and to compare subgroups. RESULTS: Fifteen studies were included for a narrative synthesis, twelve of which (500 patients) were deemed sufficiently homogeneous for a meta-analysis. Magnetisation transfer ratio asymmetry performed well in gliomas (sensitivity 0.88 [0.82-0.92], specificity 0.84 [0.72-0.91]) but not in metastases (sensitivity 0.64 [0.38-0.84], specificity 0.56 [0.33-0.77]). APT-CEST combined with conventional/advanced MRI rendered 0.92 [0.86-0.96] and 0.88 [0.72-0.95] in gliomas. Tumour type, TR prevalence, sex, and acquisition protocol were sources of significant inter-study heterogeneity in sensitivity (I2 = 62.25%; p < 0.01) and specificity (I2 = 66.31%; p < 0.001). CONCLUSION: A growing body of literature suggests that APT-CEST is a promising technique for improving the discrimination of TP/TR from TRC in gliomas, with limited data on metastases. CLINICAL RELEVANCE STATEMENT: This meta-analysis identified a utility for APT-CEST imaging regarding the non-invasive discrimination of brain tumour progression from therapy-related changes, providing a critical evaluation of sequence parameters and cut-off values, which can be used to improve response assessment and patient outcome. KEY POINTS: Therapy-related changes mimicking progression complicate brain tumour treatment. Amide proton imaging improves the non-invasive discrimination of glioma progression from therapy-related changes. Magnetisation transfer ratio asymmetry measurement seems not to have added value in brain metastases.

• MeSH
• Amides * MeSH
• Diagnosis, Differential MeSH
• Glioma * diagnostic imaging   pathology   MeSH
• Humans MeSH
• Neoplasm Recurrence, Local diagnostic imaging   MeSH
• Magnetic Resonance Imaging * methods   MeSH
• Brain Neoplasms * diagnostic imaging   secondary   MeSH
• Disease Progression * MeSH
• Protons MeSH
• Sensitivity and Specificity MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH
• Systematic Review MeSH