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Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. β-Catenin (CTNNB1)-mutated HCC represents 30% of cases of the disease with no precision therapeutics available. Using chemical libraries derived from clinical multi-kinase inhibitor (KI) scaffolds, we screened HCC organoids to identify WNTinib, a KI with exquisite selectivity in CTNNB1-mutated human and murine models, including patient samples. Multiomic and target engagement analyses, combined with rescue experiments and in vitro and in vivo efficacy studies, revealed that WNTinib is superior to clinical KIs and inhibits KIT/mitogen-activated protein kinase (MAPK) signaling at multiple nodes. Moreover, we demonstrate that reduced engagement on BRAF and p38α kinases by WNTinib relative to several multi-KIs is necessary to avoid compensatory feedback signaling-providing a durable and selective transcriptional repression of mutant β-catenin/Wnt targets through nuclear translocation of the EZH2 transcriptional repressor. Our studies uncover a previously unknown mechanism to harness the KIT/MAPK/EZH2 pathway to potently and selectively antagonize CTNNB1-mutant HCC with an unprecedented wide therapeutic index.

Increase of soil fertilization produces an increase of N exported to the hydrosphere. The amount of nitrate that reaches the aquifers is controlled by processes affecting N-species within the soils. The most relevant processes are nitrification, denitrification, assimilation, mineralization, and immobilization. This work studies the fate of N compounds in soil after manure application in a lysimeter study. To this end the isotopic composition of N and O of dissolved nitrate (δ15N-NO3- and δ18O-NO3-) was studied coupled with the evolution of N-compounds retained and leached from the soil. Results showed an increase in the δ15N-NO3- of the leached nitrate towards values similar to the δ15N-NH4+ from the applied manure. The highest δ15N-NO3- values were measured after 100 days of manure application, and thereafter, values decreased progressively towards the initial δ15N-NO3- of the soil before manure application.

Background and Aims: Effective approaches for prevention of hepatocellular carcinoma (HCC) will have a significant impact on HCC-related mortality. There are strong preclinical data and rationale to support targeting epidermal growth factor receptor (EGFR) for HCC chemoprevention. Small molecule inhibitors of EGFR have been Food and Drug Administration–approved for cancer therapy, which provides an opportunity to repurpose one of these drugs for chemoprevention of HCC. Unfortunately, the frequency of side effects associated with administration of these drugs at oncology doses renders them ineffective for chemoprevention. This clinical trial assesses whether lower doses of one of these inhibitors, erlotinib, still engages EGFR in the liver to block signaling (eg, EGFR phosphorylation). The objective of this clinical trial was determination of a safe and minimum effective dose of erlorinib for which ≥ 50% reduction phospho-EGFR immunohistochemical staining in the liver was observed. Methods: Forty six participants were preregistered and 25 participants were registered in this multicenter trial. By dose de-escalation trial design, cohorts of participants received a 7-day course of erlotinib 75 mg/day, 50 mg/day or 25 mg/day with liver tissue acquisition prior to and after erlotinib. Results: A ≥50% reduction phospho-EGFR immunohistochemical staining in the liver was observed in a minimum of 40% of participants (predetermined threshhold) at each of the dose levels. Erlotinib was very well tolerated with few side effects observed, particularly at the dose of 25 mg/day. Favorable modulation of the Prognostic Liver Signature was observed in participants who received erlotinib. Conclusion: These data support the selection of erlotinib doses as low as 25 mg/day of for a longer intervention to assess for evidence of efficacy as an HCC chemoprevention drug (ClinicalTrials.gov NCT02273362).

Abstract Background To assess whether a trifocal intraocular lens (IOL) with neutral spherical aberration (SA) provides better visual and refractive outcomes than a trifocal IOL with negative SA after hyperopic corneal laser ablation. Methods This is a retrospective comparative study. Patients were classified according to the IOL implanted after cataract or clear lens phacoemulsification [group 1, PhysIOL FineVision Pod-F (negative SA); group 2, Rayner RayOne Trifocal (neutral SA)]. We evaluated uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), uncorrected intermediate visual acuity (UIVA), uncorrected near visual acuity (UNVA), predictability, safety, efficacy, and satisfaction. Results 198 eyes of 119 patients met the inclusion criteria. Group 1 comprised 120 eyes and group 2 comprised 78 eyes. At completion, the refractive and predictability results were significantly better in group 1 than in group 2 for manifest refraction spherical equivalent (MRSE) (P 0.05, all items). Conclusion In eyes previously treated with hyperopic corneal ablation, implantation of a trifocal IOL with neutral SA provided better efficacy and safety outcomes but worse predictability outcomes than those obtained with a trifocal model with negative SA.

Many institutions, social and political groups are warning of the risks associated with the early sexualization of childhood. These agents appeal to the responsibility of the media to avoid creating content that may lead to childhood sexualization and that is easily accessible to all audiences. Responding to this demand and through a cross-cultural Spain-China approach, this work focuses on the analysis of the perception of girls' sexualization in the fashion stylings disseminated by the media. A survey of 750 Communication and Advertising university students in Spain (N=449) and in China (N=301) was carried out. Five latent sexualization factors identified confirm that perceived sexualization in girls' fashion styling is a multi-dimensional phenomenon that occurs from the combined use of multiple sexualizing attributes. The country of origin (Spain or China) has been associated with the perception of sexualization and the identified latent sexualizing factors. Finally, an explanatory and highly effective predictive model has been obtained for this type of childhood sexualization in terms of the factors and country of origin. Conclusions suggest that it is necessary to reinforce the training of communication professionals and minors to avoid creating images of sexualized girls through certain styling codes.

Background: Inflammatory bowel disease (IBD) has a major economic impact on healthcare costs. Objectives: The aim of this study was to evaluate the current healthcare expenditure associated with IBD in a population-wide study in Catalonia. Design: Retrospective observational study. Methods: All patients with IBD included in the Catalan Health Surveillance System (CHSS) were considered eligible. The CHSS compiles data on more than 7 million individuals in 2020 (34,823 with IBD). Data on the use of healthcare resources and its economic impact were extracted applying the International Classification of Diseases, 10th revision, Clinical Modification codes (ICD-10-CM codes). Health expenditure, comorbidities, and hospitalization were calculated according to the standard costs of each service provided by the Department of Health of the Catalan government. The data on the IBD population were compared with non-IBD population adjusted for age, sex, and income level. IBD costs were recorded separately for Crohn’s disease (CD) and ulcerative colitis (UC). Results: Prevalence of comorbidities was higher in patients with IBD than in those without. The risk of hospitalization was twice as high in the IBD population. The overall healthcare expenditure on IBD patients amounted to 164M€. The pharmacy cost represents the 60%. The average annual per capita expenditure on IBD patients was more than 3.4-fold higher (IBD 4200€, non-IBD 1200€). Average costs of UC were 3400€ and 5700€ for CD. Conclusion: The risk of comorbidities was twice as high in patients with IBD and their use of healthcare resources was also higher than that of their non-IBD counterparts. Per capita healthcare expenditure was approximately 3.4 times higher in the population with IBD. Trial registration: The study was not previously registered.

Hepatocellular carcinoma (HCC) remains one of the most prevalent and deadliest cancers. The poor outcome associated with HCC is dramatically changing due to the advent of effective systemic therapies. Here we discuss the molecular pathogenesis of HCC, molecular classes and determinants of heterogeneity. In addition, effective single-agent and combination systemic therapies involving immunotherapies as standard of care are analyzed. Finally, we propose a flowchart of sequential therapies, explore mechanisms of resistance and address the need for predictive biomarkers.

Abstract Recent studies have reported the significant role of Au-bearing nanoparticles in the formation of hydrothermal gold deposits. Despite the ever-increasing understanding of the genesis and stability of Au-bearing nanoparticles, it is still unknown how they behave when exposed to hydrothermal fluids. Here, we study the nanostructural evolution of Au–Ag nanoparticles hosted within Co-rich diarsenides and sulfarsenides of a natural hydrothermal deposit. We use high-resolution transmission electron microscopy to provide a singular glimpse of the complete melting sequence of Au–Ag nanoparticles exposed to the hydrothermal fluid during coupled dissolution–precipitation reactions of their host minerals. The interaction of Au–Ag nanoparticles with hydrothermal fluids at temperatures (400–500 ºC) common to most hydrothermal gold deposits may promote melting and generation of Au–Ag nanomelts. This process has important implications in noble metal remobilization and accumulation during the formation of these deposits.

Abstract Background RNA modifications are important regulators of transcript activity and an increasingly emerging body of data suggests that the epitranscriptome and its associated enzymes are altered in human tumors. Methods Combining data mining and conventional experimental procedures, NSUN7 methylation and expression status was assessed in liver cancer cell lines and primary tumors. Loss-of-function and transfection-mediated recovery experiments coupled with RNA bisulfite sequencing and proteomics determined the activity of NSUN7 in downstream targets and drug sensitivity. Results In this study, the initial screening for genetic and epigenetic defects of 5-methylcytosine RNA methyltransferases in transformed cell lines, identified that the NOL1/NOP2/Sun domain family member 7 (NSUN7) undergoes promoter CpG island hypermethylation-associated with transcriptional silencing in a cancer-specific manner. NSUN7 epigenetic inactivation was common in liver malignant cells and we coupled bisulfite conversion of cellular RNA with next-generation sequencing (bsRNA-seq) to find the RNA targets of this poorly characterized putative RNA methyltransferase. Using knock-out and restoration-of-function models, we observed that the mRNA of the coiled-coil domain containing 9B (CCDC9B) gene required NSUN7-mediated methylation for transcript stability. Most importantly, proteomic analyses determined that CCDC9B loss impaired protein levels of its partner, the MYC-regulator Influenza Virus NS1A Binding Protein (IVNS1ABP), creating sensitivity to bromodomain inhibitors in liver cancer cells exhibiting NSUN7 epigenetic silencing. The DNA methylation-associated loss of NSUN7 was also observed in primary liver tumors where it was associated with poor overall survival. Interestingly, NSUN7 unmethylated status was enriched in the immune active subclass of liver tumors. Conclusion The 5-methylcytosine RNA methyltransferase NSUN7 undergoes epigenetic inactivation in liver cancer that prevents correct mRNA methylation. Furthermore, NSUN7 DNA methylation-associated silencing is associated with clinical outcome and distinct therapeutic vulnerability.

IntroductionEffective fisheries management requires monitoring and quantifying changes in exploited fish communities. Concerns about global fisheries sustainability have led to innovative approaches. Functional diversity, rooted in ecological theory, offers valuable insights into fishery activities and ecosystem processes. A trait-based approach was used to investigate the functional diversity of landed fish species in the Azores archipelago from 1980 to 2021.MethodsLandings data of exploited Actinopterygii and Elasmobranchii were provided by the Azores Fisheries Auction Services (LOTAÇOR/OKEANOS-UAc Fisheries Database). A trait matrix was built, incorporating 12 functional traits assigned to each species, capturing their importance in marine ecological processes. The Quickhull algorithm for convex hull was employed to calculate the volume occupied by the species in the four-dimensional functional space. Functional diversity (FD) was measured using three indices: functional richness (FRic), functional evenness (FEve), and functional divergence (FDiv). Trends in FD indices over the past 42 years were visualized using Generalized Additive Models (GAM) with interaction terms.Results and discussionGAM analysis revealed significant variations in the functional space and FD metrics over time. FRic exhibited peaks in the 1980s and 2010s, declining in the 1990s and from the 2010s onwards, indicating diversification in target species. The recent decrease in FRic can be attributed to the absence of catches of species with unique traits. The distribution of landings and trait combinations showed higher regularity in the functional space during the 1980s and 1990s (high FEve). Actinopterygii species targeted in the 1980s and 1990s had lower trait divergence (low FDiv) compared to those targeted from the 2000s onwards (high FDiv). Variability in FD can be linked to changes in fishing practices, species availability, market demand, environmental factors, and local regulations. This study underscores the importance of considering FD metrics alongside species richness and abundance when assessing the potential effects of fisheries on marine ecosystems and sustainable use of fishery resources.

Background: Treatment with lenvatinib (dosing for patients who weigh ≥60 kg was 12 mg/day; for patients who weigh

Active felsic magmatism has been rarely probed in situ by drilling but one recent exception is quenched rhyolite sampled during the 2009 Iceland Deep Drilling Project (IDDP). We report finding of rare zircons of up to ∼100 µm in size in rhyolite glasses from the IDDP-1 well products and the host 1724 AD Viti granophyres. The applied SHRIMP U-Th dating for both the IDDP and the Viti granophyre zircons gives zero-age (±2 kyr), and therefore suggests that the IDDP-1 zircons have crystallized from an active magma intrusion rather than due to the 20–80 ka post-caldera magmatic episodes recorded by nearby domes and ridges. Ti-in-zircon geothermometer for Viti granophyre reveals zircon crystallization temperatures ∼800°C–900°C, whereas IDDP-1 rhyolite zircon cores show Ti content higher than 100 ppm, corresponding to temperatures up to ∼1,100°C according to the Ti-in-zircon thermometer. According to our thermochemical model at such elevated temperatures as 1,100°C, rhyolitic magma cannot be saturated with zircon and zircon crystallization is not possible. We explain this controversy by either kinetic effects or non-ideal Ti incorporation into growing zircons at low pressures that start to grow from nucleus at temperatures ∼930°C. High temperatures recorded by IDDP-1 zircon together with an occurrence of baddeleyite require that the rhyolite magma formed by partial melting of the host granophyre due to basaltic magma intrusion. Zr concentration profiles in glass around zircons are flat, suggesting residence in rhyolitic melt for >4 years. In our thermochemical modeling, three scenarios are considered. The host felsite rocks are intruded by: 1) a basaltic sill, 2) rhyolite magma 3) rhyolite sill connected to a deeper magmatic system. Based on the solution of the heat conduction equation accounting for the release of latent heat and effective thermal conductivity, these data confirm that the rhyolite magma could be produced by felsic crust melting as a result of injection of a basaltic or rhyolite sill during the Krafla Fires eruption (1975 AD).

Cancer-associated fibroblasts (CAF) are a poorly characterized cell population in the context of liver cancer. Our study investigates CAF functions in intrahepatic cholangiocarcinoma (ICC), a highly desmoplastic liver tumor. Genetic tracing, single-cell RNA sequencing, and ligand-receptor analyses uncovered hepatic stellate cells (HSC) as the main source of CAF and HSC-derived CAF as the dominant population interacting with tumor cells. In mice, CAF promotes ICC progression, as revealed by HSC-selective CAF depletion. In patients, a high panCAF signature is associated with decreased survival and increased recurrence. Single-cell RNA sequencing segregates CAF into inflammatory and growth factor-enriched (iCAF) and myofibroblastic (myCAF) subpopulations, displaying distinct ligand-receptor interactions. myCAF-expressed hyaluronan synthase 2, but not type I collagen, promotes ICC. iCAF-expressed hepatocyte growth factor enhances ICC growth via tumor-expressed MET, thus directly linking CAF to tumor cells. In summary, our data demonstrate promotion of desmoplastic ICC growth by therapeutically targetable CAF subtype-specific mediators, but not by type I collagen.

Background and aims Non-pharmacological interventions to improve patient-reported outcomes of colonoscopy may be effective at mitigating negative experiences and perceptions of the procedure, but research to characterise the extent and features of studies of these interventions is limited.Methods We conducted a scoping review searching multiple databases for peer-reviewed publications of randomised controlled trials conducted in adults investigating a non-pharmacological intervention to improve patient-reported outcomes of colonoscopy. Study characteristics were tabulated and summarised narratively and graphically.Results We screened 5939 citations and 962 full texts, and included 245 publications from 39 countries published between 1992 and 2022. Of these, 80.8% were full publications and 19.2% were abstracts. Of the 41.9% of studies reporting funding sources, 11.4% were unfunded. The most common interventions were carbon dioxide and/or water insufflation methods (33.9%), complementary and alternative medicines (eg, acupuncture) (20.0%), and colonoscope technology (eg, magnetic scope guide) (21.6%). Pain was as an outcome across 82.0% of studies. Studies most often used a patient-reported outcome examining patient experience during the procedure (60.0%), but 42.9% of studies included an outcome without specifying the time that the patient experienced the outcome. Most intraprocedural patient-reported outcomes were measured retrospectively rather than contemporaneously, although studies varied in terms of when outcomes were assessed.Conclusion Research on non-pharmacological interventions to improve patient-reported outcomes of colonoscopy is unevenly distributed across types of intervention and features high variation in study design and reporting, in particular around outcomes. Future research efforts into non-pharmacological interventions to improve patient-reported outcomes of colonoscopy should be directed at underinvestigated interventions and developing consensus-based guidelines for study design, with particular attention to how and when outcomes are experienced and measured.PROSPERO registration number 42020173906.

Trait-based approaches that complement taxonomy-based studies have increased in popularity among the scientific community over the last decades. The collection of biological and ecological characteristics of species (i.e., traits) provides insight into species and ecosystem vulnerability to environmental and anthropogenic changes, as well as ecosystem functioning. Here, we present the FUN Azores trait database, describe our approach, evaluate its scope, compare it to other marine trait databases, and explore the spatial distribution of its traits with “functional maps.” While most of the available trait databases to date contain essential information to understand the functional diversity of a taxonomic or functional group, our ecosystem-based approach provides a comprehensive assessment of diverse fauna (i.e., meio-, macro-, and megafauna) from benthic and pelagic environments in the Azores Marine Park; including ridges, seamounts, hydrothermal vents, and the overlying water column. We used a collaborative approach involving 30 researchers with different expertise to develop the FUN Azores database, which contains compiled data on 14 traits representing morphological, behavioral, and life history characteristics for 1,210 species across 10 phyla. The “functional maps” show a distinct distribution of the two most common size classes, suggesting different communities with different functionalities. The following traits had the best scoring coverage (i.e., >95% of the species scored): maximum body size, body form, skeleton material, feeding structure, motility, environmental position, substratum affinity, distribution, and depth range; while traits related to species behavior (e.g., sociability or aggregation tendencies) and life history (e.g., developmental mechanism) had lower scoring coverage, highlighting the need for further research to fill these knowledge gaps. We found a larger number of species in the benthic compared to the pelagic environment and differing species composition between areas within the Azores Marine Park resulting from varying biodiversity, ecosystem types, sampling effort, and methodologies used. The FUN Azores database will foster and facilitate trait-based approaches in the area, develop a framework for expansion of cross-ecosystem and cross-taxa trait databases elsewhere, and improve our ecological understanding of the Azores Marine Park and its conservation requirements.