The forskolin-induced swelling assay (FIS) in patient-derived intestinal organoids (PDIOs), used to determine in vitro responsiveness to elexacaftor/tezacaftor/ivacaftor (ETI), showed variability in swelling among PDIOs obtained from people with CF (pwCF) carrying the same F508del/F508del CFTR genotype. We aimed to characterise the effect of ETI on the transcriptional activity of PDIOs-derived cells to understand the intracellular processes triggered by ETI and the differences in treatment response. Six high- and six low-responding PDIOs to ETI, derived from F508del/F508del pwCF, were incubated with or without ETI for 2 to 6 h. Gene expression was assessed using 3'-mRNA sequencing and modelled using negative binomial models. Incubation with ETI resulted in a significant upregulation of several biological processes: mostly related to chemokines and signalling, chemotaxis, and tissue development processes. No changes were observed in abundance of the CFTR transcripts or in CFTR-related gene sets and pathways. The genes and pathways associated with ETI did not overlap with those whose expression changed with time only. PDIOs with a high FIS response did not significantly differ in any interpretable gene from the FIS-low organoids. The changes in the PDIOs gene expression upon the exposure to ETI cannot explain differences in the magnitude of PDIOs FIS-measured response to ETI. In conclusion, on incubation with ETI, genes of the CFTR-related pathways do not change their transcriptional activity; instead, overexpression was observed in genes of inflammatory-like cytokine response and receptor activation pathways.
- MeSH
- Chloride Channel Agonists therapeutic use pharmacology MeSH
- Aminophenols * therapeutic use pharmacology MeSH
- Benzodioxoles * therapeutic use pharmacology MeSH
- Quinolones * pharmacology therapeutic use MeSH
- Cystic Fibrosis * genetics drug therapy MeSH
- Drug Combinations MeSH
- Indoles * pharmacology MeSH
- Humans MeSH
- Organoids * metabolism MeSH
- Cystic Fibrosis Transmembrane Conductance Regulator genetics MeSH
- Pyrazoles * pharmacology MeSH
- Pyridines pharmacology MeSH
- Pyrrolidines pharmacology MeSH
- Pyrroles pharmacology MeSH
- Gene Expression Profiling methods MeSH
- Intestines drug effects MeSH
- Transcriptome MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article 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' Untranslated Regions genetics MeSH
- Alternative Splicing genetics drug effects MeSH
- Receptors, Androgen * metabolism genetics MeSH
- Polymorphism, Single Nucleotide genetics MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Prostatic Neoplasms * genetics metabolism pathology drug therapy MeSH
- Protein Isoforms genetics metabolism MeSH
- Protein Serine-Threonine Kinases genetics metabolism antagonists & inhibitors MeSH
- Gene Expression Regulation, Neoplastic * drug effects MeSH
- Serine-Arginine Splicing Factors * metabolism genetics MeSH
- RNA Splicing genetics MeSH
- Protein-Tyrosine Kinases * genetics metabolism MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article 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-Lymphocytes * immunology MeSH
- Pheochromocytoma * immunology therapy MeSH
- Immunotherapy * methods MeSH
- Disease Models, Animal MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Adrenal Gland Neoplasms * immunology therapy MeSH
- Tumor Necrosis Factor-alpha MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- Research Support, N.I.H., Intramural 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
- Cystectomy methods adverse effects MeSH
- Neoplasm Invasiveness * MeSH
- Clinical Trials as Topic MeSH
- Humans MeSH
- Urinary Bladder Neoplasms * surgery pathology therapy mortality MeSH
- Perioperative Care methods standards MeSH
- Endpoint Determination MeSH
- Treatment Outcome MeSH
- Research Design MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
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
- Adjuvants, Immunologic therapeutic use MeSH
- Administration, Intravesical MeSH
- BCG Vaccine * therapeutic use MeSH
- Neoplasm Invasiveness MeSH
- Middle Aged MeSH
- Humans MeSH
- Non-Muscle Invasive Bladder Neoplasms MeSH
- Urinary Bladder Neoplasms * drug therapy pathology mortality MeSH
- Retrospective Studies MeSH
- Aged MeSH
- Hydroxymethylglutaryl-CoA Reductase Inhibitors * therapeutic use MeSH
- Treatment Outcome MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- 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
AIMS: One treatment option for refractory ventricular arrythmias is stellate ganglion block (SGB). We examined differences in SGB success by patient and arrhythmia characteristics and predictors of successful SGB. METHODS AND RESULTS: This was a multicenter analysis of patients treated for refractory ventricular arrythmias in the Czech Republic and the United States. The primary outcome was absence of ventricular arrythmias at 24 h post SGB. SGB effectiveness was examined according to aetiology of cardiomyopathy, arrhythmia type, laterality of SGB, presence of inotropes, and presence of mechanical circulatory support. Binary logistic regression was used to examine variables associated with the primary outcome. In total there were 117 patients with refractory ventricular arrythmias treated with SGB. Overall, the mean age was 63.5 ± 11.0 years, majority of patients were male (94.0%), White (87.2%), and had an implantable cardioverter defibrillator in situ (70.1%). There were no differences in efficacy of SGB based on aetiology of cardiomyopathy (P = 0.623), arrhythmia type (0.852), laterality of block (P = 0.131), and presence of inotropes (P = 0.083). Multivariable analysis demonstrated that increased age was associated with decreased odds of SGB success (odds ratio: 0.96, confidence interval: 0.92-0.99, P = 0.039) whereas increased left ventricular ejection fraction trended towards increased odds of SGB success (odds ratio: 1.05, confidence interval: 0.995-1.11, P = 0.077). CONCLUSIONS: In this multicentre experience, SGB was similarly effective despite the aetiology of cardiomyopathy, type of arrhythmia, laterality, and inotropic or mechanical support. SGB was less effective for the suppression of ventricular arrythmias at 24 h for the elderly.
- MeSH
- Autonomic Nerve Block * methods MeSH
- Stellate Ganglion * MeSH
- Tachycardia, Ventricular therapy physiopathology etiology MeSH
- Middle Aged MeSH
- Humans MeSH
- Follow-Up Studies MeSH
- Recurrence MeSH
- Retrospective Studies MeSH
- Aged MeSH
- Treatment Outcome MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Geographicals
- Czech Republic MeSH
- United States MeSH
The soil microbiota exhibits an important function in the ecosystem, and its response to climate change is of paramount importance for sustainable agroecosystems. The macronutrients, micronutrients, and additional constituents vital for the growth of plants are cycled biogeochemically under the regulation of the soil microbiome. Identifying and forecasting the effect of climate change on soil microbiomes and ecosystem services is the need of the hour to address one of the biggest global challenges of the present time. The impact of climate change on the structure and function of the soil microbiota is a major concern, explained by one or more sustainability factors around resilience, reluctance, and rework. However, the past research has revealed that microbial interventions have the potential to regenerate soils and improve crop resilience to climate change factors. The methods used therein include using soil microbes' innate capacity for carbon sequestration, rhizomediation, bio-fertilization, enzyme-mediated breakdown, phyto-stimulation, biocontrol of plant pathogens, antibiosis, inducing the antioxidative defense pathways, induced systemic resistance response (ISR), and releasing volatile organic compounds (VOCs) in the host plant. Microbial phytohormones have a major role in altering root shape in response to exposure to drought, salt, severe temperatures, and heavy metal toxicity and also have an impact on the metabolism of endogenous growth regulators in plant tissue. However, shelf life due to the short lifespan and storage time of microbial formulations is still a major challenge, and efforts should be made to evaluate their effectiveness in crop growth based on climate change. This review focuses on the influence of climate change on soil physico-chemical status, climate change adaptation by the soil microbiome, and its future implications.
This randomized trial tested the effect of metformin on glycemic control and cardiac function in patients with heart failure (HF) and type 2 diabetes while evaluating intestinal effects on selected gut microbiome products reflected by trimethylamine-N-oxide (TMAO) and gut-derived incretins. Metformin treatment improved glycemic control and postprandial metabolism and enhanced postprandial glucagon-like peptide 1 (GLP-1) secretion but did not influence cardiac function or the TMAO levels. Metabolic effects of metformin in HF may be mediated by an improvement in intestinal endocrine function and enhanced secretion of the gut-derived incretin GLP-1.
- Publication type
- Journal Article MeSH
INTRODUCTION: Despite national guidelines and use of intrapartum antibiotic prophylaxis (IAP), Streptococcus agalactiae (group B streptococci (GBS)) is still a leading cause of morbidity and mortality in newborns in Europe and the United States. The European DEVANI (Design of a Vaccine Against Neonatal Infections) program assessed the neonatal GBS infection burden in Europe, the clinical characteristics of colonized women and microbiological data of GBS strains in colonized women and their infants with early-onset disease (EOD). METHODS: Overall, 1083 pregnant women with a GBS-positive culture result from eight European countries were included in the study. Clinical obstetrical information was collected by a standardized questionnaire. GBS strains were characterized by serological and molecular methods. RESULTS: Among GBS carriers included in this study after testing positive for GBS by vaginal or recto-vaginal sampling, 13.4% had at least one additional obstetrical risk factor for EOD. The five most common capsular types (i.e., Ia, Ib, II, III and V) comprised ~ 93% of GBS carried. Of the colonized women, 77.8% received any IAP, and in 49.5% the IAP was considered appropriate. In our cohort, nine neonates presented with GBS early-onset disease (EOD) with significant regional heterogeneity. CONCLUSIONS: Screening methods and IAP rates need to be harmonized across Europe in order to reduce the rates of EOD. The epidemiological data from eight different European countries provides important information for the development of a successful GBS vaccine.
- MeSH
- Antibiotic Prophylaxis MeSH
- Adult MeSH
- Pregnancy Complications, Infectious * epidemiology microbiology MeSH
- Humans MeSH
- Young Adult MeSH
- Infant, Newborn MeSH
- Carrier State epidemiology microbiology MeSH
- Streptococcus agalactiae * isolation & purification classification MeSH
- Streptococcal Infections * epidemiology microbiology prevention & control MeSH
- Pregnancy MeSH
- Vagina microbiology MeSH
- Infectious Disease Transmission, Vertical statistics & numerical data prevention & control MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Young Adult MeSH
- Infant, Newborn MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Geographicals
- Europe MeSH
