Class A G protein-coupled receptors (GPCRs) continue to garner interest for their essential roles in cell signalling and their importance as drug targets. Although numerous drugs in the clinic target these receptors, over 60% GPCRs remain unexploited. Moreover, the adverse effects triggered by the available unbiased GPCR modulators, limit their use and therapeutic value. In this context, the elucidation of biased signalling has opened up new pharmacological avenues holding promise for safer therapeutics. Functionally selective ligands favour receptor conformations facilitating the recruitment of specific effectors and the modulation of the associated pathways. This review surveys the current drug discovery landscape of GPCR-biased modulators with a focus on recent advances. Understanding the biological effects of this preferential coupling is at different stages depending on the Class A GPCR family. Therefore, with a focus on individual GPCR families, we present a compilation of the functionally selective modulators reported over the past few years. In doing so, we dissect their therapeutic relevance, molecular determinants and potential clinical applications. LINKED ARTICLES: This article is part of a themed issue Complexity of GPCR Modulation and Signaling (ERNST). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.14/issuetoc.

• MeSH
• lidé MeSH
• ligandy MeSH
• objevování léků * MeSH
• receptory spřažené s G-proteiny * metabolismus   agonisté   MeSH
• signální transdukce účinky léků   MeSH
• vyvíjení léků MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

INTRODUCTION: The main goal of placenta accreta spectrum (PAS) screening is to enable delivery in an expert center in the presence of an experienced team at an appropriate time. Our study aimed to identify independent risk factors for emergency deliveries within the IS-PAS 2.0 database cohort and establish a multivariate predictive model. MATERIAL AND METHODS: A retrospective analysis of prospectively collected PAS cases from the IS-PAS database between January 2020 and June 2022 by 23 international expert centers was performed. All PAS cases (singleton and multiple pregnancies) managed according to local protocols were included. Individuals with emergent delivery were identified and compared to those with scheduled delivery. A multivariate analysis was conducted to identify the possible risk factors for emergency delivery and was used to establish a predictive model. Maternal outcomes were compared. RESULTS: Overall, 315 women were included in the study. Of these, 182 participants (89 with emergent and 93 with scheduled delivery) were included in the final analysis after exclusion of those with unsuspected PAS antenatally or who lacked information about the urgency of delivery. Gestational age at delivery was higher in the scheduled group (34.7 vs. 32.9, p < 0.001). Antenatal bleeding (OR 2.9, p = 0.02) and a placenta located over a uterine scar (OR 0.38, p = 0.001) were the independent predictive factors for emergent delivery (AUC 0.68). Ultrasound (US) markers: loss of clear zone (p = 0.001), placental lacunae (p = 0.01), placental bulge (p = 0.02), and presence of bridging vessels (p = 0.02) were more frequently documented in the scheduled group. None of these markers improved the predictive values of the model. Higher PAS grades were identified in the scheduled group (p = 0.01). There were no significant differences in maternal outcomes. CONCLUSIONS: Antenatal bleeding and the placental location away from the uterine scar remained the most significant predictors for emergent delivery among patients with PAS, even when combining more predictive risk factors, including US markers. Based on these results, patients who bleed antenatally may benefit from transfer to an expert center, as we found no differences in maternal outcomes between groups delivered in expert centers. Earlier-scheduled delivery is not supported due to the low predictive value of our model.

• MeSH
• císařský řez * statistika a číselné údaje   MeSH
• dospělí MeSH
• lidé MeSH
• náhlé příhody MeSH
• placenta accreta * diagnóza   MeSH
• retrospektivní studie MeSH
• rizikové faktory MeSH
• těhotenství MeSH
• vedení porodu * statistika a číselné údaje   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

PURPOSE OF REVIEW: This review explores the design and endpoints of perioperative platforms in clinical trials for muscle-invasive bladder cancer (MIBC). RECENT FINDINGS: The choice of clinical trial design in perioperative platforms for MIBC must align with specific research objectives to ensure robust and meaningful outcomes. Novel designs in perioperative platforms for MIBC integrate bladder-sparing approaches. Primary endpoints such as pathological complete response and disease-free survival are highlighted for their role in expediting trial results in perioperative setting. Incorporating patient-reported outcomes is important to inform healthcare decision makers about the outcomes most meaningful to patients. Given the growing body of evidence, potential biomarkers, predictive and prognostic tools should be considered and implemented when designing trials in perioperative platforms for MIBC. SUMMARY: Effective perioperative platforms for MIBC trials are critical in enhancing patient outcomes. The careful selection and standardization of study designs and endpoints in the perioperative platform are essential for the successful implementation of new therapies and the advancement of personalized treatment approaches in MIBC.

• MeSH
• cystektomie metody   škodlivé účinky   MeSH
• invazivní růst nádoru * MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• nádory močového měchýře * chirurgie   patologie   terapie   mortalita   MeSH
• perioperační péče metody   normy   MeSH
• stanovení cílového parametru MeSH
• výsledek terapie MeSH
• výzkumný projekt MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

In advanced prostate cancer (PC), in particular after acquisition of resistance to androgen receptor (AR) signaling inhibitors (ARSI), upregulation of AR splice variants compromises endocrine therapy efficiency. Androgen receptor splice variant-7 (ARV7) is clinically the most relevant and has a distinct 3' untranslated region (3'UTR) compared to the AR full-length variant, suggesting a unique post-transcriptional regulation. Here, we set out to evaluate the applicability of the ARV7 3'UTR as a therapy target. A common single nucleotide polymorphism, rs5918762, was found to affect the splicing rate and thus the expression of ARV7 in cellular models and patient specimens. Serine/arginine-rich splicing factor 9 (SRSF9) was found to bind to and increase the inclusion of the cryptic exon 3 of ARV7 during the splicing process in the alternative C allele of rs5918762. The dual specificity protein kinase CLK2 interferes with the activity of SRSF9 by regulating its expression. Inhibition of the Cdc2-like kinase (CLK) family by the small molecules cirtuvivint or lorecivivint results in the decreased expression of ARV7. Both inhibitors show potent anti-proliferative effects in enzalutamide-treated or -naive PC models. Thus, targeting aberrant alternative splicing at the 3'UTR of ARV7 by disturbing the CLK2/SRSF9 axis might be a valuable therapeutic approach in late stage, ARSI-resistant PC.

• MeSH
• 3' nepřekládaná oblast genetika   MeSH
• alternativní sestřih genetika   účinky léků   MeSH
• androgenní receptory * metabolismus   genetika   MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory prostaty * genetika   metabolismus   patologie   farmakoterapie   MeSH
• protein - isoformy genetika   metabolismus   MeSH
• protein-serin-threoninkinasy genetika   metabolismus   antagonisté a inhibitory   MeSH
• regulace genové exprese u nádorů * účinky léků   MeSH
• serin-arginin sestřihové faktory * metabolismus   genetika   MeSH
• sestřih RNA genetika   MeSH
• tyrosinkinasy * genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Immunotherapy represents a revolutionary advancement in cancer treatment, which has traditionally focused on T cells; however, the role of B cells in cancer immunotherapy has gained interest because of their role in antigen presentation, antibody production, and cytokine release. In this study, we examined the role of B cells in previously developed intratumoral MBTA therapy (mannan-BAM, TLR ligands, and anti-CD40 antibody) in murine models of MTT pheochromocytoma. The results indicated that B cells significantly enhance the success of MBTA therapy, with wild-type mice exhibiting a lower tumor incidence and smaller tumors compared with B cell-deficient mice. Increased IL-6 and TNF-alpha levels indicated severe inflammation and a potential cytokine storm in B cell-deficient mice. Neutralization of TNF-alpha ameliorated these complications but resulted in increased tumor recurrence. The results highlight the important role of B cells in enhancing the immune response and maintaining immune homeostasis during MBTA therapy. Our findings offer new insights into improving therapeutic outcomes.

• MeSH
• B-lymfocyty * imunologie   MeSH
• feochromocytom * imunologie   terapie   MeSH
• imunoterapie * metody   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádory nadledvin * imunologie   terapie   MeSH
• TNF-alfa MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Intramural MeSH

Příručka, která se zaměřuje na pohybovou aktivitu u onkologických pacientů. Slouží také jako deník. Určeno široké veřejnosti, pacientům.

• MeSH
• nádory MeSH
• péče o sebe MeSH
• pohybová aktivita * MeSH
• Publikační typ
• deníky MeSH
• populární práce MeSH
• příručky MeSH

• Konspekt
• Sport. Hry. Tělesná cvičení
• NLK Obory
• zdravotní výchova
• onkologie

Publikace se zaměřuje na metody řešení mezilidských konfliktů a facilitace komunikace pomocí mediátora sporu. Určeno odborné veřejnosti.; V publikaci najdete stručné informace z historie mediace ve světě i v České republice z pohledu neziskového sektoru, poznáte rozdíly mezi facilitativní, evaluativní a transformativní mediací a postupně se seznámíte se základními dovednostmi mediátora a celým procesem facilitativní mediace. Při ní jednání vede neutrální třetí strana a zúčastněné strany vzájemně respektují dohodu jako výsledek dojednaného řešení. V knize je uvedena řada příkladů, vodítek a poznatků z praxe. Knihu doporučujeme jako základní manuál pro začínající mediátory i praktikující mediátory. Text je zaměřen na mediaci v civilní oblasti – v komu¬nitní, rodinné a pracovní sféře –, tedy nikoli na mediaci v rámci trestněprávní justice. Kniha, kterou po autorčině smrti aktualizovala její blízká spolupracovnice Elena Mešková, je určena pro všechny, kdo ve svém pracovním životě pomáhají řešit rodinné, pracovní, komunitní a interetnické konflikty.

• Klíčová slova
• facilitace,
• MeSH
• nesouhlas a spor MeSH
• vyjednávání MeSH
• Publikační typ
• monografie MeSH

• Konspekt
• Druhy sociální pomoci a služeb
• NLK Obory
• psychologie, klinická psychologie
• sociologie

• Klíčová slova
• čeština,
• MeSH
• lékařství MeSH
• terminologie jako téma MeSH

• Konspekt
• Učební osnovy. Vyučovací předměty. Učebnice
• Čeština
• NLK Obory
• lingvistika, lékařská terminologie
• NLK Publikační typ
• učebnice vysokých škol

OBJECTIVE: To investigate the influence of statins on the survival outcomes of patients with non-muscle-invasive bladder cancer (NMIBC) treated with adjuvant intravesical bacille Calmette-Guérin (BCG) immunotherapy. PATIENTS AND METHODS: A retrospective cohort of consecutive patients with NMIBC who received intravesical BCG therapy from 2001 to 2020 and statins prescription were identified. Overall survival (OS), cancer-specific survival (CSS), recurrence-free survival (RFS), and progression-free survival (PFS) were analysed between the Statins Group vs No-Statins Group using Kaplan-Meier method and multivariable Cox regression. RESULTS: A total of 2602 patients with NMIBC who received intravesical BCG were identified. The median follow-up was 11.0 years. On Kaplan-Meier analysis, the Statins Group had significant better OS (P < 0.001), CSS (P < 0.001), and PFS (P < 0.001). Subgroup analysis indicated statins treatment started before BCG treatment had better CSS (P = 0.02) and PFS (P < 0.01). Upon multivariable Cox regression analysis, the 'statins before BCG' group was an independent protective factor for OS (hazard ratio [HR] 0.607, 95% confidence interval [CI] 0.514-0.716), and CSS (HR 0.571, 95% CI 0.376-0.868), but not RFS (HR 0.885, 95% CI 0.736-1.065), and PFS (HR 0.689, 95% CI 0.469-1.013). CONCLUSIONS: Statins treatment appears to offer protective effects on OS and CSS for patients with NMIBC receiving adjuvant intravesical BCG.

• MeSH
• adjuvancia imunologická terapeutické užití   MeSH
• aplikace intravezikální MeSH
• BCG vakcína * terapeutické užití   MeSH
• invazivní růst nádoru MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory močového měchýře neinvadující svalovinu MeSH
• nádory močového měchýře * farmakoterapie   patologie   mortalita   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• statiny * terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články 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
• lidé MeSH
• podvod prevence a kontrola   MeSH
• systematický přehled jako téma MeSH
• vědecký podvod * MeSH
• výzkumný projekt normy   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH