Efficacy of the cdk4/6 dual inhibitor abemaciclib in egfr-mutated nsclc cell lines with different resistance mechanisms to osimertinib

Abemaciclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6 that inhibits the transition from the G1 to the S phase of the cell cycle by blocking downstream CDK4/6-mediated phosphorylation of Rb. The effects of abemaciclib alone or combined with the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib were examined in a panel of PC9 and HCC827 osimertinib-resistant non-small cell lung cancer (NSCLC) cell lines carrying EGFR-dependent or-independent mechanisms of intrinsic or acquired resistance. Differently from sensitive cells, all the resistant cell lines analyzed maintained p-Rb, which may be considered as a biomarker of osimertinib resistance and a potential target for therapeutic intervention. In these models, abemaciclib inhibited cell growth, spheroid formation, colony formation, and induced senes-cence, and its efficacy was not enhanced in the presence of osimertinib. Interestingly, in osimertinib sensitive PC9, PC9T790M, and H1975 cells the combination of abemaciclib with osimertinib significantly inhibited the onset of resistance in long-term experiments. Our findings provide a preclinical support for using abemaciclib to treat resistance in EGFR mutated NSCLC patients progressed to osimertinib either as single treatment or combined with osimertinib, and suggest the combination of osimertinib with abemaciclib as a potential approach to prevent or delay osimertinib resistance in first-line treatment

Monitoring cfDNA in plasma and in other liquid biopsies of advanced EGFR mutated NSCLC patients: A pilot study and a review of the literature

In order to study alternatives at the tissue biopsy to study EGFR status in NSCLC patients, we evaluated three different liquid biopsy platforms (plasma, urine and exhaled breath condensate, EBC). We also reviewed the literature of the cfDNA biological sources other than plasma and compared our results with it about the sensitivity to EGFR mutation determination. Twenty-two EGFR T790M-mutated NSCLC patients in progression to first-line treatment were enrolled and candidate to osimertinib. Plasma, urine and EBC samples were collected at baseline and every two months until progression. Molecular analysis of cfDNA was performed by ddPCR and compared to tissue results. At progression NGS analysis was performed. The EGFR activating mutation detection reached a sensitivity of 58 and 11% and for the T790M mutation of 45 and 10%, in plasma and urine samples, respectively. Any DNA content was recovered from EBC samples. Considering the plasma monitoring study, the worst survival was associated with positive shedding status; both plasma and urine molecular progression anticipated the radiological worsening. Our results confirmed the role of plasma liquid biopsy in testing EGFR mutational status, but unfortunately, did not evidence any improvement from the combination with alternative sources, as urine and EBC

Biobased supramolecular ionic networks with optimized crystallinity and mechanical properties as promising dynamic materials for eutectogels design

Ionic supramolecular networks are attractive materials for technological applications with unique properties such as ionic conductivity, stimuli-responsiveness, recyclability, and self-healing. Herein, new semicrystalline supramolecular ionic networks are designed from fully biobased building blocks such as tartaric acid, phytic acid, sebacic acid, and a fatty dimer diamine (Priamine™ 1071). The combination of tartaric acid with Priamine™ 1071 results in a crystalline and brittle polymer, but its molecular regularity can be controlled by incorporating sebacic acid or phytic acid, affording tough materials with appropriate mechanical properties (elastic moduli ranging 19–42 MPa). Furthermore, the ionic polymers show network-to-liquid phase transitions between 75 and 127 °C, and in the liquid state, they were found to be miscible with a lithium-based deep eutectic solvent, yielding flexible and conductive eutectogels. Altogether, these dynamic networks could open new prospects for developing fully green soft ionic materials from their combination with other innovative and low-cost eutectic mixtures.Open Access funding provided by the University of Basque Country. The financial support received from CONICET and ANPCyT (PICT 2018-01032) (Argentina) is gratefully acknowledged

A modal theorem-preserving translation of a class of three-valued logics of incomplete information

International audienceThere are several three-valued logical systems that form a scattered landscape, even if all reasonable connectives in three-valued logics can be derived from a few of them. Most papers on this subject neglect the issue of the relevance of such logics in relation with the intended meaning of the third truth-value. Here, we focus on the case where the third truth-value means unknown, as suggested by Kleene. Under such an understanding, we show that any truth-qualified formula in a large range of three-valued logics can be translated into KD as a modal formula of depth 1, with modalities in front of literals only, while preserving all tautologies and inference rules of the original three-valued logic. This simple information logic is a two-tiered classical propositional logic with simple semantics in terms of epistemic states understood as subsets of classical interpretations. We study in particular the translations of Kleene, Gödel, ᴌukasiewicz and Nelson logics. We show that Priest’s logic of paradox, closely connected to Kleene’s, can also be translated into our modal setting, simply by exchanging the modalities possible and necessary. Our work enables the precise expressive power of three-valued logics to be laid bare for the purpose of uncertainty management

Detection of EGFR-Activating and T790M Mutations Using Liquid Biopsy in Patients With EGFR-Mutated Non–Small-Cell Lung Cancer Whose Disease Has Progressed During Treatment With First- and Second-Generation Tyrosine Kinase Inhibitors: A Multicenter Real-Life Retrospective Study

Epidermal growth factor receptor T790M detection using liquid biopsy was evaluated in a real-life setting in 120 advanced non–small-cell lung cancer patients whose disease had progressed during first- or second-generation tyrosine kinase inhibitors. The T790M detection rate was 25.8% using liquid biopsy and 49.2% after tissue rebiopsy. Liquid biopsies performed before disease progression according to Response Evaluation Criteria In Solid Tumors were all negative for T790M and T790M positivity was higher in cases of extrathoracic metastatic sites

Dipping-Induced Azimuthal Helix Orientation in Langmuir-Blodgett Monolayers of α-Helical Amphiphilic Diblock Copolypeptides

The azimuthal helix orientation of the rigid-rod amphiphilic diblock copolypeptides (PLGA-b-PMLGSLGs) of poly(α-L-glutamic acid) (PLGA) and poly(γ-methyl-L-glutamate-ran-γ-stearyl-L-glutamate) with 30 mol % of stearyl substituents (PMLGSLG) in Langmuir-Blodgett (LB) monolayers was investigated using polarized transmission Fourier transform infrared spectroscopy. The relative position of dipping with respect to the previous transfer position can be used to manipulate the azimuthal orientation of the helices parallel to or tilted by an angle of 45° with respect to the dipping direction in the transferred films. The study of the azimuthal order for the LB monolayers of PLGA-b-PMLGSLGs of various block lengths revealed that the observed effect arises mainly from the deformation of the PMLGSLG top brush layer, induced by the flow orientation around the transfer region. In those cases where the PMLGSLG block is tilted by a sufficiently large angle with respect to the surface normal, high azimuthal order parameters of 0.5-0.75 were obtained.

Global public perceptions of genomic data sharing: what shapes the willingness to donate DNA and health data?

Analyzing genomic data across populations is central to understanding the role of genetic factors in health and disease. Successful data sharing relies on public support, which requires attention to whether people around the world are willing to donate their data that are then subsequently shared with others for research. However, studies of such public perceptions are geographically limited and do not enable comparison. This paper presents results from a very large public survey on attitudes toward genomic data sharing. Data from 36,268 individuals across 22 countries (gathered in 15 languages) are presented. In general, publics across the world do not appear to be aware of, nor familiar with, the concepts of DNA, genetics, and genomics. Willingness to donate one's DNA and health data for research is relatively low, and trust in the process of data's being shared with multiple users (e.g., doctors, researchers, governments) is also low. Participants were most willing to donate DNA or health information for research when the recipient was specified as a medical doctor and least willing to donate when the recipient was a for-profit researcher. Those who were familiar with genetics and who were trusting of the users asking for data were more likely to be willing to donate. However, less than half of participants trusted more than one potential user of data, although this varied across countries. Genetic information was not uniformly seen as different from other forms of health information, but there was an association between seeing genetic information as special in some way compared to other health data and increased willingness to donate. The global perspective provided by our "Your DNA, Your Say" study is valuable for informing the development of international policy and practice for sharing genomic data. It highlights that the research community not only needs to be worthy of trust by the public, but also urgent steps need to be taken to authentically communicate why genomic research is necessary and how data donation, and subsequent sharing, is integral to this