Treatment-Induced Tumor Dormancy through YAP-Mediated Transcriptional Reprogramming of the Apoptotic Pathway

Eradicating tumor dormancy that develops following epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment of EGFR-mutant non-small cell lung cancer, is an attractive therapeutic strategy but the mechanisms governing this process are poorly understood. Blockade of ERK1/2 reactivation following EGFR TKI treatment by combined EGFR/MEK inhibition uncovers cells that survive by entering a senescence-like dormant state characterized by high YAP/TEAD activity. YAP/TEAD engage the epithelial-to-mesenchymal transition transcription factor SLUG to directly repress pro-apoptotic BMF, limiting drug-induced apoptosis. Pharmacological co-inhibition of YAP and TEAD, or genetic deletion of YAP1, all deplete dormant cells by enhancing EGFR/MEK inhibition-induced apoptosis. Enhancing the initial efficacy of targeted therapies could ultimately lead to prolonged treatment responses in cancer patients

Understanding unequal ageing: towards a synthesis of intersectionality and life course analyses

Intersectionality has received an increasing amount of attention in health inequalities research in recent years. It suggests that treating social characteristics separately—mainly age, gender, ethnicity, and socio-economic position—does not match the reality that people simultaneously embody multiple characteristics and are therefore potentially subject to multiple forms of discrimination. Yet the intersectionality literature has paid very little attention to the nature of ageing or the life course, and gerontology has rarely incorporated insights from intersectionality. In this paper, we aim to illustrate how intersectionality might be synthesised with a life course perspective to deliver novel insights into unequal ageing, especially with respect to health. First we provide an overview of how intersectionality can be used in research on inequality, focusing on intersectional subgroups, discrimination, categorisation, and individual heterogeneity. We cover two key approaches—the use of interaction terms in conventional models and multilevel models which are particularly focussed on granular subgroup differences. In advancing a conceptual dialogue with the life course perspective, we discuss the concepts of roles, life stages, transitions, age/cohort, cumulative disadvantage/advantage, and trajectories. We conclude that the synergies between intersectionality and the life course hold exciting opportunities to bring new insights to unequal ageing and its attendant health inequalities

Long-Term temperature acclimation of photosynthesis in steady-state cultures of the polar diatom Fragilariopsis cylindrus

Cultures of the obligate psychrophilic diatom Fragilariopsis cylindrus (Grunow) were grown for 4 months under steady-state conditions at -1°C and +7°C (50 µmol photons m-2 s-1) prior to measurements in order to investigate long-term acclimation of photosynthesis to both temperatures. No differences in maximum intrinsic quantum yield of PS II (F V/F M) and relative electron transport rates could be detected at either temperature after 4 months of acclimation. Measurements of photosynthesis (relative electron transport rates) vs. irradiance (P vs. E curves) revealed similar values for relative light utilization efficiency (a = 0.57 at -1°C, a = 0.60 at +7°C) but higher values for irradiance levels at which photosynthesis saturates (E K) at -1°C and, therefore, higher maximum photosynthesis (P MAX = 54 (relative units) at -1°C, P MAX = 49 at +7°C). Nonphotochemical quenching (NPQ) measurements at 385 µmol photons m-2 s -1 indicated higher (37%) NPQ for diatoms grown at -1°C compared to +7°C, which was possibly related to a 2-fold increase in the concentration of the pigment diatoxanthin and a 9-fold up-regulation of a gene encoding a fucoxanthin chlorophyll a,c-binding protein. Expression of the D1 protein encoding gene psbA was ca. 1.5-fold up-regulated at -1°C, whereas expression levels of other genes from Photosystem II (psbC, psbU, psbO), as well as rbcL, the gene encoding the Rubisco large subunit were similar at both temperatures. However, a 2-fold up-regulation of a plastid glyceraldehyde-P dehydrogenase at -1°C indicated enhanced Calvin cycle activity. This study revealed for the first time that a polar diatom could efficiently acclimate photosynthesis over a wide range of polar temperatures given enough time. Acclimation of photosynthesis at -1°C was probably regulated similarly to high light acclimation