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

Lower Limb Unilateral and Bilateral Strength Asymmetry in High-Level Male Senior and Professional Football Players.

This study sought to assess the relationship between different jumping asymmetries and associated performance variables in high-level male senior and professional football players. Nineteen football players with at least 12 years of training experience (23.2 ± 3.1 years of age; 75.2 ± 4.8 kg of body mass and 181 ± 0.06 cm of height) participated in this study performing countermovement jump (CMJ), squat jump (SJ), single-leg CMJ and drop jump (DJ), associated performance variable eccentric utilization ratio (EUR), stretch-shortening cycle (SSC), bilateral deficit (BLD), and limb symmetry index (LSI) were determined. High correlations were observed between different methodologies of jump tests and associated performance indicators (SSC, BLD, EUR), except LSI. Moreover, CMJ and SJ results were different (p 100%), the results highlight the need for individual evaluation since eight players scored negatively. An in-depth and accurate analysis of performance in preseason screening jump tests should be considered, aiming to detect injury risk, specifically evaluating different jumping test methodologies, and determining jumping associated performance variables for each test, namely EUR, SSC, BLD, and LSI. Specific muscle-strengthening exercises could be implemented based on this study results and outcomes, aiming to reduce injury risks and lower extremity asymmetries and to enhance individual football performance in high-level male senior and professional football players. Sports institutions should pay special attention regarding potential health problems in athletes exposed to daily high training loads.post-print642 K

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

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

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

Circulating endothelial cell count: a reliable marker of endothelial damage in patients undergoing hematopoietic stem cell transplantation

The physio-pathologic interrelationships between endothelium and GvHD have been better elucidated and have led to definition of the entity 'endothelial GvHD' as an essential early phase prior to the clinical presentation of acute GvHD. Using the CellSearch system, we analyzed circulating endothelial cells (CEC) in 90 allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients at the following time-points: T1 (pre-conditioning), T2 (pre-transplant), T3 (engraftment), T4 (onset of GvHD) and T5 (1 week after steroid treatment). Although CEC changes in allo-HSCT represent a dynamic phenomenon influenced by many variables (that is, conditioning, immunosuppressive treatments, engraftment syndrome and infections), we showed that CEC peaks were constantly seen at onset of acute GvHD and invariably returned to pre-transplant values after treatment response. Since we showed that CEC changes during allo-HSCT has rapid kinetics that may be easily missed if blood samples are drawn at pre-fixed time-points, we rather suggest an 'on demand' evaluation of CEC counts right at onset of GvHD clinical symptoms to possibly help differentiate GvHD from other non-endothelial complications. We confirm that CEC changes are a suitable biomarker to monitor endothelial damage in patients undergoing allo-transplantation and hold the potential to become a useful tool to support GvHD diagnosis (ClinicalTrials.gov NCT02064972).Bone Marrow Transplantation advance online publication, 11 September 2017; doi:10.1038/bmt.2017.194

Disulfide stabilization of human norovirus GI.1 virus-like particles focuses immune response toward blockade epitopes

Human noroviruses are non-enveloped, single-strand RNA viruses that cause pandemic outbreaks of acute gastroenteritis. A bivalent vaccine containing GI.1 and GII.4 virus-like particles (VLPs) has been shown to be safe and highly immunogenic, but its efficacy and durability have been limited. Here, we show that norovirus GI.1 VLPs are unstable and contain a substantial fraction of dissociated VLP components. Broadly reactive, non-neutralizing antibodies isolated from vaccinated donors bound to the dissociated components, but not to the intact VLPs. Engineering of interprotomer disulfide bonds within the shell domain prevented disassembly of the VLPs, while preserving antibody accessibility to blockade epitopes. Without adjuvant, mice immunized with stabilized GI.1 VLPs developed faster blockade antibody titers compared to immunization with wild-type GI.1 VLPs. In addition, immunization with stabilized particles focused immune responses toward surface-exposed epitopes and away from occluded epitopes. Overall, disulfide-stabilized norovirus GI.1 VLPs elicited improved responses over the non-disulfide-stabilized version, suggesting their promise as candidate vaccines

The TLQP-21 Peptide Activates the G-Protein-Coupled Receptor C3aR1 via a Folding-upon-Binding Mechanism

TLQP-21, a VGF-encoded peptide is emerging as a novel target for obesity-associated disorders. TLQP-21 is found in the sympathetic nerve terminals in the adipose tissue and targets the G-protein-coupled-receptor (GPCR) Complement-3a-Receptor1 (C3aR1). So far, the mechanisms of TLQP-21-induced receptor activation remained unexplored. Here, we report that TLQP-21 is intrinsically disordered and undergoes a disorder-to-order transition, adopting an α-helical conformation, upon targeting cells expressing the C3aR1. We determined that the hot spots for TLQP-21 are located at the C-terminus, with mutations in the last four amino acids progressively reducing the bioactivity and, a single site mutation (R21A) or C-terminal amidation abolishing its function completely. Interestingly, the human TLQP-21 sequence carrying a S20A substitution activates the human C3aR1 receptor with lower potency compared to the rodent sequence. These studies reveal the mechanism of action of TLQP-21 and provide molecular templates for designing agonists and antagonists to modulate C3aR1 functions

The small angle tile calorimeter in the DELPHI experiment

The {\bf S}mall angle {\bf TI}le {\bf C}alorimeter ({\bf STIC}) provides calorimetric coverage in the very forward region of the DELPHI experiment at the CERN LEP collider. The structure of the calorimeters, built with a so-called ``shashlik'' technique, gives a perfectly hermetic calorimeter and still allows for the insertion of tracking detectors within the sampling structure to measure the direction of the showering particle. A charged-particle veto system, composed of two scintillator layers, makes it possible to trigger on single photon events and provides e-$\gamma$ separat ion. Results are presented from the extensive studies of these detectors in the CERN testbeams prior to installation and of the detector performance at LEP