A Cell Model Suitable for a High-Throughput Screening of Inhibitors of the Wnt/β-Catenin Pathway

A constitutive activation of the Wnt/β-catenin pathway is an initiating event in colon carcinogenesis. We developed colon cancer cells models that highlight the non-selectivity of previously described inhibitors of the Wnt pathway and we propose our model as a suitable screening system for inhibitors of the pathway

Tunable FDM 3D printing of flexible poly(butylene adipate terephthalate)-based biocomposite filaments

Poly(butylene adipate-co-terephthalate), PBAT, is a synthetic and 100% biodegradable polymer based on fossil resources, with high elongation at break and high flexibility. These properties are comparable to lowdensity polyethylene, making PBAT a very promising biodegradable material that could replace it in some industrial applications. However, its lower mechanical properties have limited its application range. The reinforcement of PBAT with rigid filler, such as zein-TiO2 (ZTC) complex microparticles, has the purpose to expand its application fields, from the food and agricultural packaging to healthcare sector. The 3D printability of bio-based composites was demonstrated by realizing complex structures with a commercial FDM printer

Flexible PBAT-Based Composite Filaments for Tunable FDM 3D Printing

Biobased composites with peculiar properties offer an attractive route for producing environmentally friendly materials. The reinforcement for poly(butylene adipate-co-terephthalate) (PBAT), based on zein-titanium dioxide (TiO2) complex (ZTC) microparticles, is presented and used to produce composite filaments, successfully 3-dimensionally (3D) printed by fused deposition modeling (FDM). The outcome of ZTC addition, ranging from 5 to 40 wt %, on the thermo-mechanical properties of composite materials was analyzed. Results reveal that storage modulus increased with increasing the ZTC content, leading to a slight increase in the glass transition temperature. The creep compliance varies with the ZTC concentration, denoting a better resistance to deformation under constant stress conditions for composites with higher complex content. Scanning electron microscopy was used to assess the quality of interphase adhesion between PBAT and ZTC, showing good dispersion and distribution of complex microparticles in the polymer matrix. Infrared spectroscopy confirmed the formation of a valid interface due to the formation of hydrogen bonds between filler and polymer matrix. Preliminary tests on the biocompatibility of these materials were also performed, showing no cytotoxic effects on cell viability. Finally, the 3D printability of biobased composites was demonstrated by realizing complex structures with a commercial FDM printer

Selectivity of natural, synthetic and environmental estrogens for zebrafish estrogen receptors.

International audience: Zebrafish, Danio rerio, is increasingly used as an animal model to study the effects of pharmaceuticals and environmental estrogens. As most of these estrogens have only been tested on human estrogen receptors (ERs), it is necessary to measure their effects on zebrafish ERs. In humans there are two distinct nuclear ERs (hERα and hERβ), whereas the zebrafish genome encodes three ERs, zfERα and two zfERβs (zfERβ1 and zfERβ2). In this study, we established HeLa-based reporter cell lines stably expressing each of the three zfERs. We first reported that estrogens more efficiently activate the zfERs at 28°C as compared to 37°C, thus reflecting the physiological temperature of zebrafish in wildlife. We then showed significant differences in the ability of agonist and antagonist estrogens to modulate activation of the three zfER isotypes in comparison to hERs. Environmental compounds (bisphenol A, alkylphenols, mycoestrogens) which are hER panagonists and hERβ selective agonists displayed greater potency for zfERα as compared to zfERβs. Among hERα selective synthetic agonists, PPT did not activate zfERα while 16α-LE2 was the most zfERα selective compound. Altogether, these results confirm that all hER ligands control in a similar manner the transcriptional activity of zfERs although significant differences in selectivity were observed among subtypes. The zfER subtype selective ligands that we identified thus represent new valuable tools to dissect the physiological roles of the different zfERs. Finally, our work also points out that care has to be taken in transposing the results obtained using the zebrafish as a model for human physiopathology

Punctual and kinetic MRD analysis from the Fondazione Italiana Linfomi MCL0208 phase III trial in mantle cell lymphoma

Minimal residual disease (MRD) analysis is a known predictive tool in mantle cell lymphoma (MCL). We describe MRD results from the Fondazione Italiana Linfomi phase III MCL0208 prospective clinical trial assessing lenalidomide maintenance vs observation after autologous transplantation (ASCT), in the first prospective comprehensive analysis of different techniques, molecular markers, and tissues (peripheral blood, PB, and bone marrow, BM), taken at well-defined timepoints. Among the 300 patients enrolled, a molecular marker was identified in 250 (83%), allowing us to analyze 234 patients and 4351 analytical findings from 10 timepoints. ASCT induced high rates of molecular remission (91% in PB and 83% in BM, by quantitative real-time PCR [RQ-PCR]). Nevertheless, the number of patients with persistent clinical and molecular remission decreased over time in both arms (up to 30% after 36 months). MRD predicted early progression and long-term outcome, particularly from 6 months after ASCT (6-month TTP HR 3.83, p<0.001). In single-timepoint analysis, BM outperformed PB, and RQ-PCR was more reliable, while nested PCR appeared applicable to a larger number of patients (234 vs 176). To improve MRD performance we developed a time-varying kinetic model, based on regularly updated MRD results and the Mantle Cell Lymphoma International Prognostic Index, showing an area under the ROC curve (AUROC) of up to 0.87 using BM. Most notably, PB reached an AUROC of up to 0.81: with kinetic analysis it was comparable to BM in performance. MRD is a powerful predictor over the entire natural history of MCL and suitable for models with continuous adaptation of patient risk. Study can be found in EudraCT N. 2009-012807-25 https://eudract.ema.europa.eu/

PPARα and PPARγ activation is associated with pleural mesothelioma invasion but therapeutic inhibition is ineffective

Mesothelioma is a cancer that typically originates in the pleura of the lungs. It rapidly invades the surrounding tissues, causing pain and shortness of breath. We compared cell lines injected either subcutaneously or intrapleurally and found that only the latter resulted in invasive and rapid growth. Pleural tumors displayed a transcriptional signature consistent with increased activity of nuclear receptors PPARα and PPARγ and with an increased abundance of endogenous PPAR-activating ligands. We found that chemical probe GW6471 is a potent, dual PPARα/γ antagonist with anti-invasive and anti-proliferative activity in vitro. However, administration of GW6471 at doses that provided sustained plasma exposure levels sufficient for inhibition of PPARα/γ transcriptional activity did not result in significant anti-mesothelioma activity in mice. Lastly, we demonstrate that the in vitro anti-tumor effect of GW6471 is off-target. We conclude that dual PPARα/γ antagonism alone is not a viable treatment modality for mesothelioma

The Impact of the COVID-19 Pandemic on Women's Perinatal Mental Health: Preliminary Data on the Risk of Perinatal Depression/Anxiety from a National Survey in Italy

Increasing evidence suggests that during the COVID-19 pandemic, anxiety and depression during the perinatal period increased. The aim of the study is to estimate the prevalence of risk for both maternal depression and anxiety among women attending 18 healthcare centres in Italy during the SARS-COV-2 pandemic and to investigate the psychosocial risks and protective factors associated. It was divided into a retrospective phase (2019, 2020, and the first nine months of 2021) and a prospective phase (which began in November 2021 and it is still ongoing), which screened 12,479 and 2349 women, respectively, for a total of 14,828 women in the perinatal period. To evaluate the risk of anxiety and depression, the General Anxiety Disorder-7 (GAD-7), the Edinburgh Postnatal Depression Scale (EPDS), and an ad hoc form were used to collect sociodemographic variables. In the prospective study, the average age of the women is 31 (range 18-52) years. Results showed that the percentage of women who had EPDS score ≥9 increased from 11.6% in 2019 to 25.5% in the period ranging from November 2021 to April 2022. In logistic regression models, the variables associated with the risk of depression at a level ≤0.01 include having economic problems (OR 2.16) and not being able to rely on support from relatives or friends (OR 2.36). Having the professional status of the housewife is a lower risk (OR 0.52). Those associated with the risk of anxiety include being Italian (OR 2.97), having an education below secondary school level (OR 0.47), having some or many economic problems (OR 2.87), being unable to rely on support from relatives or friends (OR 2.48), and not having attended an antenatal course (OR 1.41). The data from this survey could be useful to determine the impact of the SARS-COV-2 pandemic on women and to establish a screening program with common and uniformly applied criteria which are consistent with national and international women's mental health programs