Indole derivative interacts with estrogen receptor beta and inhibits human ovarian cancer cell growth

Ovarian cancer remains the leading cause of mortality among gynecological tumors. Estrogen receptor beta (ERβ) expression has been suggested to act as a tumor suppressor in epithelial ovarian cancer by reducing both tumor growth and metastasis. ERβ expression abnormalities represent a critical step in the development and progression of ovarian cancer: for these reasons, its re‐expression by genetic engineering, as well as the use of targeted ERβ therapies, still constitute an important therapeutic approach. 3‐{[2‐chloro‐1‐(4‐chlorobenzyl)‐5‐methoxy‐6-methyl‐1H‐indol‐3‐yl]methylene}‐5‐hydroxy‐6‐methyl‐1,3‐dihydro‐2H‐indol‐2‐one, referred to here as compound 3, has been shown to have cytostatic as well cytotoxic effects on various hormone-dependent cancer cell lines. However, the mechanism of its anti‐carcinogenic activity is not well understood. Here, we offer a possible explanation of such an effect in the human ovarian cancer cell line IGROV1. Chromatin binding protein assay and liquid chromatography mass spectrometry were exploited to localize and quantify compound 3 in cells. Molecular docking was used to prove compound 3 binding to ERβ. Mass spectrometry‐based approaches were used to analyze histone post‐translational modifications. Finally, gene expression analyses revealed a set of genes regulated by the ERβ/3 complex, namely CCND1, MYC, CDKN2A, and ESR2, providing possible molecular mechanisms that underline the observed antiproliferative effects

Exploring the Needs and Expectations of Expectant and New Parents for an mHealth Application to Support the First 1000 Days of Life: Steps toward a Co-Design Approach

To improve maternal and child health, it is essential to adhere to health-promoting and preventive measures. However, reliable information as well as effective tools are not easy to identify in this field. Our cross-sectional study investigated the needs and expectations of expectant and new mothers and fathers as potential primary users of a hypothetical application supporting the first 1000 days of life. Between May and August 2022, we recruited expectant and new parents by administering an 83-item 5-point Likert scale questionnaire related to the content, functionalities, and technical features of the hypothetical app. We stratified responses using sociodemographic characteristics and then performed ward hierarchical clustering. The 94 women and 69 men involved in our study generally agreed with the proposed content, but expressed low interest in certain app functionalities or features, including those related to the interaction mechanism and interactivity. Women were generally more demanding than men. Our findings, resulting from the engagement of end-users, may be useful for designers and technology providers to implement mHealth solutions that, in addition to conveying reliable information, are tailored to the needs and preferences of end-users in the first 1000 days of life

Human iPSC-Derived 3D Hepatic Organoids in a Miniaturized Dynamic Culture System

The process of identifying and approving a new drug is a time-consuming and expensive procedure. One of the biggest issues to overcome is the risk of hepatotoxicity, which is one of the main reasons for drug withdrawal from the market. While animal models are the gold standard in preclinical drug testing, the translation of results into therapeutic intervention is often ambiguous due to interspecies differences in hepatic metabolism. The discovery of human induced pluripotent stem cells (hiPSCs) and their derivatives has opened new possibilities for drug testing. We used mesenchymal stem cells and hepatocytes both derived from hiPSCs, together with endothelial cells, to miniaturize the process of generating hepatic organoids. These organoids were then cultivated in vitro using both static and dynamic cultures. Additionally, we tested spheroids solely composed by induced hepatocytes. By miniaturizing the system, we demonstrated the possibility of maintaining the organoids, but not the spheroids, in culture for up to 1 week. This timeframe may be sufficient to carry out a hypothetical pharmacological test or screening. In conclusion, we propose that the hiPSCderived liver organoid model could complement or, in the near future, replace the pharmacological and toxicological tests conducted on animals

Multivariate analysis as a tool for selecting the vine pruning pretreatment towards the highest enzymatic hydrolysis yield

Lignocellulosic materials require pretreatment to remove lignin enabling the enzyme access to the cellulose. This work used multivariate analysis to investigate the acid and alkali pretreatments of vine pruning followed by enzymatic hydrolysis. The best acid pretreatment conditions were H2SO4 1.5%, 120 °C for 30 min, removing 68.7% of hemicellulose, enabling 95.8% of cellulose recovery. However, this treatment was not enough to allow the enzyme hydrolysis. A second step of treatment with NaOH 3.0% at 120 °C without agitation for 60 min led to a material with 75.0% of cellulose and 25.0% of lignin. However, the lowest glucose yield (80.86% and 32.26 g L?1 of glucose) was obtained after the enzyme hydrolysis of this material. The highest glucose yield (98.72% with 35.06 g L?1) was obtained using a pretreated material containing 68.1% of cellulose and 31.9% of lignin obtained after a milder condition (NaOH 2% at 100 °C), thus showing that not all the lignin need to be removed to obtain a high saccharification yield. A less severe pretreatment with no adverse effect on the glucose yield with the advantage of preserving the non-cellulose biomass fractions was effective for vine prune valorization.This study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UIDB/04469/2020 unit, BioTecNorte operation (NORTE-01-0145-FEDER000004), the projects Multibiorefinery (POCI-01-0145-FEDER-016403), FoSynBio (POCI-01-0145-FEDER-029549) and Lignozymes (POCI-01- 0145-FEDER-029773) funded by the European Regional Development Fund under the scope of Norte 2020. In Brazil, this study was funded in part by the Coordenaçao ~ de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) - Finance Code 001, Conselho Nacional de Desenvolvimento Científico e Tecnologico (CNPq) and Fundaçao Cearense de Apoio ao Desenvolvimento Científico e Tecnologico (FUNCAP). The authors would like to acknowledge the Central Analytical (Physical Department) of Federal University of Ceara for conducting the SEM analysis and the Centro de Tecnologia Canavieira – CTC/Brazil for the support. E. Gudina and L. Rodrigues acknowledge FCT for the Post-doctoral (CEB-BPD/01/2015/07) and sabbatical (SFRH/BSAB/142991/2019) grants, respectively.info:eu-repo/semantics/publishedVersio

From KIDSCREEN-10 to CHU9D: creating a unique mapping algorithm for application in economic evaluation

Background: The KIDSCREEN-10 index and the Child Health Utility 9D (CHU9D) are two recently developed generic instruments for the measurement of health-related quality of life in children and adolescents. Whilst the CHU9D is a preference based instrument developed specifically for application in cost-utility analyses, the KIDSCREEN-10 is not currently suitable for application in this context. This paper provides an algorithm for mapping the KIDSCREEN-10 index onto the CHU9D utility scores. Methods: A sample of 590 Australian adolescents (aged 11–17) completed both the KIDSCREEN-10 and the CHU9D. Several econometric models were estimated, including ordinary least squares estimator, censored least absolute deviations estimator, robust MM-estimator and generalised linear model, using a range of explanatory variables with KIDSCREEN-10 items scores as key predictors. The predictive performance of each model was judged using mean absolute error (MAE) and root mean squared error (RMSE). Results: The MM-estimator with stepwise-selected KIDSCREEN-10 items scores as explanatory variables had the best predictive accuracy using MAE, whilst the equivalent ordinary least squares model had the best predictive accuracy using RMSE. Conclusions: The preferred mapping algorithm (i.e. the MM-estimate with stepwise selected KIDSCREEN-10 item scores as the predictors) can be used to predict CHU9D utility from KIDSCREEN-10 index with a high degree of accuracy. The algorithm may be usefully applied within cost-utility analyses to generate cost per quality adjusted life year estimates where KIDSCREEN-10 data only are available

The highly attenuated oncolytic recombinant vaccinia virus GLV-1h68: comparative genomic features and the contribution of F14.5L inactivation

As a new anticancer treatment option, vaccinia virus (VACV) has shown remarkable antitumor activities (oncolysis) in preclinical studies, but potential infection of other organs remains a safety concern. We present here genome comparisons between the de novo sequence of GLV-1h68, a recombinant VACV, and other VACVs. The identified differences in open reading frames (ORFs) include genes encoding host-range selection, virulence and immune modulation proteins, e.g., ankyrin-like proteins, serine proteinase inhibitor SPI-2/CrmA, tumor necrosis factor (TNF) receptor homolog CrmC, semaphorin-like and interleukin-1 receptor homolog proteins. Phylogenetic analyses indicate that GLV-1h68 is closest to Lister strains but has lost several ORFs present in its parental LIVP strain, including genes encoding CrmE and a viral Golgi anti-apoptotic protein, v-GAAP. The reduced pathogenicity of GLV-1h68 is confirmed in male mice bearing C6 rat glioma and in immunocompetent mice bearing B16-F10 murine melanoma. The contribution of foreign gene expression cassettes in the F14.5L, J2R and A56R loci is analyzed, in particular the contribution of F14.5L inactivation to the reduced virulence is demonstrated by comparing the virulence of GLV-1h68 with its F14.5L-null and revertant viruses. GLV-1h68 is a promising engineered VACV variant for anticancer therapy with tumor-specific replication, reduced pathogenicity and benign tissue tropism