Identification of the transcription factor MAZ as a regulator of erythropoiesis

Erythropoiesis requires a combination of ubiquitous and tissue-specific transcription factors (TFs). Here, through DNA affinity purification followed by mass spectrometry, we have identified the widely expressed protein MAZ (Myc-associated zinc finger) as a TF that binds to the promoter of the erythroid-specific human alpha-globin gene. Genome-wide mapping in primary human erythroid cells revealed that MAZ also occupies active promoters as well as GATA1-bound enhancer elements of key erythroid genes. Consistent with an important role during erythropoiesis, knockdown of MAZ reduces alpha-globin expression in KS62 cells and impairs differentiation in primary human erythroid cells. Genetic variants in the MAZ locus are associated with changes in clinically important human erythroid traits. Taken together, these findings reveal the zinc-finger TF MAZ to be a previously unrecognized regulator of the erythroid differentiation program

Increased lysosomal biomass is responsible for the resistance of triple-negative breast cancers to CDK4/6 inhibition

Breast cancer is the most common type of cancer in women and the second leading cause of cancer death among women. While significant progress has been made in the treatment of hormone receptor (HR) positive, HER2 negative and HER2-amplified breast cancer in the last decades, Triple negative breast cancer (TNBC) is lacking behind. Still today, chemotherapy is the only treatment option, but response rates are low and only a small fraction of patients can successfully be treated. Here we show, that CDK4/6 inhibitors which are FDA-approved for the treatment of HR+/HER2negative breast cancer and significantly improved treatment outcome in this type of breast cancer, also represent a promising therapy option for TNBC in contrast to the current view. We show, that a subset of TNBCs despite being resistant to chemical inhibition of CDK4/6 strictly depend on CDK4/6 kinases for proliferation. We identified lysosomal sequestration of the drug and therefore limited bioavailability at its target site responsible for the discrepancy. We show that increased number of lysosomes correlates with resistance and inhibition of the lysosome renders these cells fully sensitive to CDK4/6 inhibitors. We provide strategies how to overcome resistance by means of FDA-approved lysosomotropic agents that raise lysosomal pH, co-inhibition of CDK2 or the use of structurally altered CDK4/6 inhibitors with decreased basic characteristics. We also provide a biomarker to stratify patients for successful CDK4/6 inhibitor therapy. Moreover, we show that this mechanism of resistance also underlies cases of acquired resistance in HR+/HER2negative breast cancer and importantly we provide evidence that increased lysosomal sequestration operates in patients presenting resistant to treatment with the CDK4/6 inhibitor palbociclib. Our study therefore suggests that CDK4/6 inhibitor therapy could be a treatment option for a subset of TNBCs where new targeted therapeutic intervention is so urgently needed and furthermore, offers strategies how to overcome resistance in HR+/HER2-negative breast cancer where CDK4/6 inhibition is already successfully applied. In summary, our study provides ways on how to improve therapeutic use of this promising new class of anti-cancer agents

Increased lysosomal biomass is responsible for the resistance of triple-negative breast cancers to CDK4/6 inhibition

© 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). Inhibitors of cyclin-dependent kinases CDK4 and CDK6 have been approved for treatment of hormone receptor-positive breast cancers. In contrast, triple-negative breast cancers (TNBCs) are resistant to CDK4/6 inhibition. Here, we demonstrate that a subset of TNBC critically requires CDK4/6 for proliferation, and yet, these TNBC are resistant to CDK4/6 inhibition due to sequestration of CDK4/6 inhibitors into tumor cell lysosomes. This sequestration is caused by enhanced lysosomal biogenesis and increased lysosomal numbers in TNBC cells. We developed new CDK4/6 inhibitor compounds that evade the lysosomal sequestration and are efficacious against resistant TNBC. We also show that coadministration of lysosomotropic or lysosome-destabilizing compounds (an antibiotic azithromycin, an antidepressant siramesine, an antimalaria compound chloroquine) renders resistant tumor cells sensitive to currently used CDK4/6 inhibitors. Lastly, coinhibition of CDK2 arrested proliferation of CDK4/6 inhibitor-resistant cells. These observations may extend the use of CDK4/6 inhibitors to TNBCs that are refractory to current anti-CDK4/6 therapies

Bacterial genotoxins induce T cell senescence

Several types of pathogenic bacteria produce genotoxins that induce DNA damage in host cells. Accumulating evidence suggests that a central function of these genotoxins is to dysregulate the host's immune response, but the underlying mechanisms remain unclear. To address this issue, we investigated the effects of the most widely expressed bacterial genotoxin, the cytolethal distending toxin (CDT), on T cells—the key mediators of adaptive immunity. We show that CDT induces premature senescence in activated CD4 T cells in vitro and provide evidence suggesting that infection with genotoxin-producing bacteria promotes T cell senescence in vivo. Moreover, we demonstrate that genotoxin-induced senescent CD4 T cells assume a senescence-associated secretory phenotype (SASP) which, at least partly, is orchestrated by the ATM-p38 signaling axis. These findings provide insight into the immunomodulatory properties of bacterial genotoxins and uncover a putative link between bacterial infections and T cell senescence

Bacterial genotoxins induce T cell senescence

Several types of pathogenic bacteria produce genotoxins that induce DNA damage in host cells. Accumulating evidence suggests that a central function of these genotoxins is to dysregulate the host's immune response, but the underlying mechanisms remain unclear. To address this issue, we investigated the effects of the most widely expressed bacterial genotoxin, the cytolethal distending toxin (CDT), on T cells-the key mediators of adaptive immunity. We show that CDT induces premature senescence in activated CD4 T cells in vitro and provide evidence suggesting that infection with genotoxin-producing bacteria promotes T cell senescence in vivo. Moreover, we demonstrate that genotoxin-induced senescent CD4 T cells assume a senescence-associated secretory phenotype (SASP) which, at least partly, is orchestrated by the ATMp38 signaling axis. These findings provide insight into the immunomodulatory properties of bacterial genotoxins and uncover a putative link between bacterial infections and T cell senescence

Preschool children's persuasion knowledge: The contribution of theory of mind

Two studies investigate the influence of developmental variables on the emergence of persuasion knowledge in children ages three to five years. Theory of mind (a form of social development) consistently explains a significant amount of variance in children's persuasion knowledge. Theory of mind is a well-researched variable in the developmental psychology literature. This form of social development enables a child to understand the mental states of others and to use that mental state understanding to predict others' future behavior. The results of the current study indicate that before theory-of-mind development, children are unable to recognize persuasion in advertising, most likely because they cannot think about the intentions of the advertiser. The findings are important to the development of child consumer literacy and contribute to the extant literature by demonstrating that developmental factors can explain how persuasion knowledge develops. The authors discuss theoretical, practical, and public policy implications

Public COAPI Toolkit of Open Access Policy Resources

The Coalition of Open Access Policy Institutions (COAPI, https://sparcopen.org/coapi ) is committed to sharing information and resources to assist in the development and implementation of institutional Open Access (OA) policies. The COAPI Toolkit includes a diverse collection of resources that COAPI members have developed in the course of their OA policy initiatives. These resources are openly accessible and published here under Creative Commons Attribution 4.0 licenses, unless otherwise noted on the resources themselves

Analysis of Outcomes in Ischemic vs Nonischemic Cardiomyopathy in Patients With Atrial Fibrillation A Report From the GARFIELD-AF Registry

IMPORTANCE Congestive heart failure (CHF) is commonly associated with nonvalvular atrial fibrillation (AF), and their combination may affect treatment strategies and outcomes