Persister state-directed transitioning and vulnerability in melanoma

©2022. This manuscript version is made available under the CC-BY 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ This document is the Published Manuscript version of a Published Work that appeared in final form in Nature Communications. To access the final edited and published work see https://doi.org/10.1038/s41467-022-30641-9Item en revisión. Pendiente de cumplimentar metadatos.Melanoma is a highly plastic tumor characterized by dynamic interconversion of different cell identities depending on the biological context. Melanoma cells with high expression of the H3K4 demethylase KDM5B (JARID1B) rest in a slow-cycling, yet reversible persister state. Over time, KDM5Bhigh cells can promote rapid tumor repopulation with equilibrated KDM5B expression heterogeneity. The cellular identity of KDM5Bhigh persister cells has not been studied so far, missing an important cell state-directed treatment opportunity in melanoma. Here, we have established a doxycycline-titratable system for genetic induction of permanent intratumor expression of KDM5B and screened for chemical agents that phenocopy this effect. Transcriptional profiling and cell functional assays confirmed that the dihydropyridine 2-phenoxyethyl 4-(2-fluorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxylate (termed Cpd1) supports high KDM5B expression and directs melanoma cells towards differentiation along the melanocytic lineage and to cell cycle-arrest. The high KDM5B state additionally prevents cell proliferation through negative regulation of cytokinetic abscission. Moreover, treatment with Cpd1 promoted the expression of the melanocyte-specific tyrosinase gene specifically sensitizing melanoma cells for the tyrosinase-processed antifolate prodrug 3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin (TMECG). In summary, our study provides proof-of-concept for a dual hit strategy in melanoma, in which persister state-directed transitioning limits tumor plasticity and primes melanoma cells towards lineage-specific eliminatio

The Constrained Maximal Expression Level Owing to Haploidy Shapes Gene Content on the Mammalian X Chromosome.

X chromosomes are unusual in many regards, not least of which is their nonrandom gene content. The causes of this bias are commonly discussed in the context of sexual antagonism and the avoidance of activity in the male germline. Here, we examine the notion that, at least in some taxa, functionally biased gene content may more profoundly be shaped by limits imposed on gene expression owing to haploid expression of the X chromosome. Notably, if the X, as in primates, is transcribed at rates comparable to the ancestral rate (per promoter) prior to the X chromosome formation, then the X is not a tolerable environment for genes with very high maximal net levels of expression, owing to transcriptional traffic jams. We test this hypothesis using The Encyclopedia of DNA Elements (ENCODE) and data from the Functional Annotation of the Mammalian Genome (FANTOM5) project. As predicted, the maximal expression of human X-linked genes is much lower than that of genes on autosomes: on average, maximal expression is three times lower on the X chromosome than on autosomes. Similarly, autosome-to-X retroposition events are associated with lower maximal expression of retrogenes on the X than seen for X-to-autosome retrogenes on autosomes. Also as expected, X-linked genes have a lesser degree of increase in gene expression than autosomal ones (compared to the human/Chimpanzee common ancestor) if highly expressed, but not if lowly expressed. The traffic jam model also explains the known lower breadth of expression for genes on the X (and the Z of birds), as genes with broad expression are, on average, those with high maximal expression. As then further predicted, highly expressed tissue-specific genes are also rare on the X and broadly expressed genes on the X tend to be lowly expressed, both indicating that the trend is shaped by the maximal expression level not the breadth of expression per se. Importantly, a limit to the maximal expression level explains biased tissue of expression profiles of X-linked genes. Tissues whose tissue-specific genes are very highly expressed (e.g., secretory tissues, tissues abundant in structural proteins) are also tissues in which gene expression is relatively rare on the X chromosome. These trends cannot be fully accounted for in terms of alternative models of biased expression. In conclusion, the notion that it is hard for genes on the Therian X to be highly expressed, owing to transcriptional traffic jams, provides a simple yet robustly supported rationale of many peculiar features of X's gene content, gene expression, and evolution

Die Entwicklung des eulitoralen Miesmuschelbestandes (Mytilus edulis) in den deutschen Wattgebieten. (Development of intertidal blue mussel stocks (Mytilus edulis) in the German tidal flats)

The decrease of mussel stocks in the tidal flats of Lower Saxony in the 1980s and 1990s and in Schleswig-Holstein since the early 1990s was not reversed by a strong spatfall in spring 1996. The decrease was only interrupted and delayed. Mussel fisheries in Schleswig-Holstein and Lower Saxony have been subject to a fishery programme and management plan since 1997 and 1999 respectively. These measures are accompanied by monitoring of intertidal mussel stocks. Monitoring in Lower Saxony showed that blue mussel areas and biomass reached their all-time minimum level in the spring of 1996. After the inventory in spring, a strong spatfall took place which led to the largest growth of mussel stocks in 1999. Following several years with a negative trend, mussel stocks have levelled off at a low level for 7 years. But for the past 5 years, there has been a positive trend in biomass. Mussel stocks in the Wadden Sea area of Schleswig-Holstein remained at an average level until 2001. Values then fell to one fifth of their former maximum values (recorded at the end of the 1980s) and, with 1/10 in 2010, dropped to their lowest level since the beginning of monitoring. Mussel stocks have not recovered so far. The shrinking of mussel bed area and biomass is superimposed by the spread of the Pacific oyster; there has been no general regeneration of blue mussel stocks. Between 1980 and 2000, a small but persistent mussel stock existed in the rocky northern intertidal of the island of Helgoland, which is part of Schleswig Holstein, but data from this period is incomplete. Since 2005/2006 the number of recorded individuals in the monitoring area decreased to only approx. 3% in summer 2011 compared to maximum values in 2005/2006. As blue mussel stocks in the „Hamburgisches Wattenmeer” national park are not monitored continuously (pers. comm. Peter Körber), only information about mussel stocks in Lower Saxony and Schleswig-Holstein is presented

Average mussel bed densities in the Wadden Sea

<p>This is figure 1 from our open access Ecosystems paper: Large-Scale Spatial Dynamics of Intertidal Mussel (<em>Mytilus edulis</em> L.) Bed Coverage in the German and Dutch Wadden Sea. It describes the 39 tidal basins of the Wadden Sea with average intertidal mussel bed coverage over the years 1999–2010. Intertidal mussel bed coverage is defined as the percentage of tidal flat area that is covered by mussel beds. The intertidal flats in tidal basins 1–3 in Denmark are colored gray because no comparable mussel bed data were available. The geographic extent of the Wadden Sea ranges between 52°57–55°37 North and 4°44–8°12 East.</p> <p> </p

Grandchild care and welfare state arrangements in europe

As a consequence of increased life expectancies and the overall improved health status of elderly people in industrialized countries, grandparents and grandchildren are now sharing a longer period of their lives together, from which they can both actively benefit. In addition, grandparents help their children by looking after their grandchildren and are consequently an important service provider in the domain of childcare, especially for mothers active in the labour market. The analyses, which are based on the Survey of Health, Aging and Retirement in Europe (Austria, Belgium, Denmark, France, Germany, Greece, Italy, the Netherlands, Spain, Sweden and Switzerland), show significant country differences in the occurrence and intensity of grandchild care in Europe: whereas grandparents in southern Europe engage less often but more intensively in childcare, grandchild care is provided more often but much less intensively in northern Europe. Multilevel logistic regression models show that country-specific differences are associated with welfare state arrangements and, specifically, with public investments in childcare infrastructures. Public investments ‘crowd in’ grandparental willingness to engage in childcare but ‘crowd out’ the intensity of this intergenerational time transfer. Family and state thus complement one another, with grandparents taking over sporadic, less time-intensive care while public institutions provide regular, time-consuming childcare services

Brain metastasis cell lines panel: a public resource of organotropic cell lines

Spread of cancer to the brain remains an unmet clinical need in spite of the increasing number of cases among patients with lung, breast cancer, and melanoma most notably. Although research on brain metastasis was considered a minor aspect in the past due to its untreatable nature and invariable lethality, nowadays, limited but encouraging examples have questioned this statement, making it more attractive for basic and clinical researchers. Evidences of its own biological identity (i.e., specific microenvironment) and particular therapeutic requirements (i.e., presence of blood-brain barrier, blood-tumor barrier, molecular differences with the primary tumor) are thought to be critical aspects that must be functionally exploited using preclinical models. We present the coordinated effort of 19 laboratories to compile comprehensive information related to brain metastasis experimental models. Each laboratory has provided details on the cancer cell lines they have generated or characterized as being capable of forming metastatic colonies in the brain, as well as principle methodologies of brain metastasis research. The Brain Metastasis Cell Lines Panel (BrMPanel) represents the first of its class and includes information about the cell line, how tropism to the brain was established, and the behavior of each model in vivo. These and other aspects described are intended to assist investigators in choosing the most suitable cell line for research on brain metastasis. The main goal of this effort is to facilitate research on this unmet clinical need, to improve models through a collaborative environment, and to promote the exchange of information on these valuable resources