PD-L1 is expressed on human platelets and is affected by immune checkpoint therapy

Cancer immunotherapy has been revolutionised by drugs that enhance the ability of the immune system to detect and fight tumors. Immune checkpoint therapies that target the programmed death-1 receptor (PD-1), or its ligand (PD-L1) have shown unprecedented rates of durable clinical responses in patients with various cancer types. However, there is still a large fraction of patients that do not respond to checkpoint inhibitors, and the challenge remains to find cellular and molecular cues that could predict which patients would benefit from these therapies. Using a series of qualitative and quantitative methods we show here that PBMCs and platelets from smokers and patients with head and neck squamous cell carcinoma (HNSCC) or lung cancer express and up-regulate PD-L1 independently of tumor stage. Furthermore, treatment with Atezolizumab, a fully humanised monoclonal antibody against PD-L1, in 4 patients with lung cancer caused a decrease in PD-L1 expression in platelets, which was restored over 20 days. Altogether, our findings reveal the expression of the main therapeutic target in current checkpoint therapies in human platelets and highlight their potential as biomarkers to predict successful therapeutic outcomes

PD-L1 is expressed on human platelets and is affected by immune checkpoint therapy

Cancer immunotherapy has been revolutionised by drugs that enhance the ability of the immune system to detect and fight tumors. Immune checkpoint therapies that target the programmed death-1 receptor (PD-1), or its ligand (PD-L1) have shown unprecedented rates of durable clinical responses in patients with various cancer types. However, there is still a large fraction of patients that do not respond to checkpoint inhibitors, and the challenge remains to find cellular and molecular cues that could predict which patients would benefit from these therapies. Using a series of qualitative and quantitative methods we show here that PBMCs and platelets from smokers and patients with head and neck squamous cell carcinoma (HNSCC) or lung cancer express and up-regulate PD-L1 independently of tumor stage. Furthermore, treatment with Atezolizumab, a fully humanised monoclonal antibody against PD-L1, in 4 patients with lung cancer caused a decrease in PD-L1 expression in platelets, which was restored over 20 days. Altogether, our findings reveal the expression of the main therapeutic target in current checkpoint therapies in human platelets and highlight their potential as biomarkers to predict successful therapeutic outcomes

Nanomechanics and Sodium Permeability of Endothelial Surface Layer Modulated by Hawthorn Extract WS 1442

The endothelial glycocalyx (eGC) plays a pivotal role in the physiology of the vasculature. By binding plasma proteins, the eGC forms the endothelial surface layer (ESL) which acts as an interface between bloodstream and endothelial cell surface. The functions of the eGC include mechanosensing of blood flow induced shear stress and thus flow dependent vasodilation. There are indications that levels of plasma sodium concentrations in the upper range of normal and beyond impair flow dependent regulation of blood pressure and may therefore increase the risk for hypertension. Substances, therefore, that prevent sodium induced endothelial dysfunction may be attractive for the treatment of cardiovascular disease. By means of combined atomic force - epifluorescence microscopy we studied the impact of the hawthorn (Crataegus spp.) extract WS 1442, a herbal therapeutic with unknown mechanism of action, on the mechanics of the ESL of ex vivo murine aortae. Furthermore, we measured the impact of WS 1442 on the sodium permeability of endothelial EA.hy 926 cell monolayer. The data show that (i) the ESL contributes by about 11% to the total endothelial barrier resistance for sodium and (ii) WS 1442 strengthens the ESL resistance for sodium up to about 45%. This mechanism may explain some of the vasoprotective actions of this herbal therapeutic

Zwischen Vermarktlichung und Europäisierung: Die wachsende Bedeutung transnational agierender Vermittlungsagenturen in der häuslichen Pflege in Deutschland

Der Beitrag befasst sich mit jüngeren Entwicklungen im Bereich der transnationalen Care-Migration und analysiert in diesem Feld das Zusammenwirken von Prozessen der Vermarktlichung und Europäisierung. Aufgrund von Regulierungs- und Kontrolllücken im EU-Mehrebenensystem, so das hier präsentierte Argument, ist ein boomendes Geschäftsfeld für neue Akteure entstanden: Vermittlungs- und Entsendeagenturen für Live-In-Pflegekräfte aus Mittel- und Osteuropa. Der Beitrag geht in einem ersten Schritt der Frage nach, wie diese Regulierungs- und Kontrolldefizite eines europäisierten Pflegemarktes von den Agenturen und ihren politischen Verbänden (aus-)genutzt und gefüllt werden. In einem zweiten Schritt werden die Implikationen von Vermarktlichung und Europäisierung auf der Ebene der Nutzer*innen analysiert. Präsentiert werden Ergebnisse aus einer qualitativen Studie mit Familien Pflegebedürftiger, die Kund*innen der Vermittlungsagenturen sind.   Between Marketization and Europeanization: The Growing Importance of Transnationally Acting Agencies for Domestic Care Work in Germany This article looks at recent developments in the field of transnational care migration, analysing the interacting processes of marketisation and Europeanisation. We argue that as a result of regulation and control gaps within the EU multilevel system, a burgeoning business sector has emerged, facilitating the establishment of new actors: posting and brokering agencies for live-in care workers from Central and Eastern Europe. First, we address the question of how these regulation and control gaps within a Europeanised care market are being (mis)used by agencies and their political associations. Second, we analyse the implications of marketisation and Europeanisation on the level of the users (households). The analysis is based on results from a qualitative study with families employing an agency brokered transnational care worker. JEL-Klassifizierung: I13

Advantages and challenges of phenotypic screens: The identification of two novel antifungal geranylgeranyltransferase I inhibitors

Phenotypic screens are still the most effective starting points for compounds with desirable activities. To identify novel antifungal leads we have conducted a phenotypic screen in the yeast Saccharomyces cerevisiae and identified two different scaffolds with good growth inhibitory characteristics. Lack of broad spectrum antifungal activity against pathogenic fungi raised the question about the modulated target as required for directed chemical compound optimization. Chemogenomic profiling identified effects on geranylgeranyltransferase I (GGTase I), an enzyme that prenylates proteins involved in cell signaling like Cdc42p and Rho1p. Raising resistant mutants against both compounds confirmed the target hypothesis and allowed mapping of the compound binding site to the substrate binding pocket. Differential resistance conferring mutations and substrate competition for only one chemotype demonstrated a diverse binding mode for the two chemotypes. Exchange of the S.cerevisiae GGTase I complex by that of Candida albicans abolished growth inhibitory activity of both compounds thus confirming the identified target as well as the observed narrow antifungal spectrum. Reported lack of essentiality of this prenylation pathway in pathogenic species challenges the therapeutic value of these leads and demonstrates the importance of an integrated target identification platform following a phenotypic screen

Direct Interaction of Chivosazole F with Actin Elicits Cell Responses Similar to Latrunculin A but Distinct from Chondramide

The microbial metabolite Chivosazole F has been described to affect the cytoskeleton and to inhibit actin polymerization <i>in vitro</i>. Applying orthogonal genomic and proteomics approaches, we now show for the first time that Chivosazole F exerts its effect by directly interacting with actin and demonstrate the cellular impact of Chivosazole F in an unbiased, genome-wide context in yeast and in mammalian cells. Furthermore, mutation-based resistance mapping identifies two SNPs located in the putative Chivosazole F binding site of actin. Comparing chemogenomic profiles and responses to the Chivosazole F-resistant SNPs shows a partially conserved mechanism of action for Chivosazole F and Latrunculin A, but clear divergence from Chondramide. In addition, C14orf80 is an evolutionarily highly conserved ORF, lacking any functional annotation. As editing of C14orf80 leads to Chivosazole F hyper-resistance, we propose a function for this gene product in counteracting perturbation of actin filaments

Direct Interaction of Chivosazole F with Actin Elicits Cell Responses Similar to Latrunculin A but Distinct from Chondramide

The microbial metabolite Chivosazole F has been described to affect the cytoskeleton and to inhibit actin polymerization <i>in vitro</i>. Applying orthogonal genomic and proteomics approaches, we now show for the first time that Chivosazole F exerts its effect by directly interacting with actin and demonstrate the cellular impact of Chivosazole F in an unbiased, genome-wide context in yeast and in mammalian cells. Furthermore, mutation-based resistance mapping identifies two SNPs located in the putative Chivosazole F binding site of actin. Comparing chemogenomic profiles and responses to the Chivosazole F-resistant SNPs shows a partially conserved mechanism of action for Chivosazole F and Latrunculin A, but clear divergence from Chondramide. In addition, C14orf80 is an evolutionarily highly conserved ORF, lacking any functional annotation. As editing of C14orf80 leads to Chivosazole F hyper-resistance, we propose a function for this gene product in counteracting perturbation of actin filaments

Direct Interaction of Chivosazole F with Actin Elicits Cell Responses Similar to Latrunculin A but Distinct from Chondramide

The microbial metabolite Chivosazole F has been described to affect the cytoskeleton and to inhibit actin polymerization <i>in vitro</i>. Applying orthogonal genomic and proteomics approaches, we now show for the first time that Chivosazole F exerts its effect by directly interacting with actin and demonstrate the cellular impact of Chivosazole F in an unbiased, genome-wide context in yeast and in mammalian cells. Furthermore, mutation-based resistance mapping identifies two SNPs located in the putative Chivosazole F binding site of actin. Comparing chemogenomic profiles and responses to the Chivosazole F-resistant SNPs shows a partially conserved mechanism of action for Chivosazole F and Latrunculin A, but clear divergence from Chondramide. In addition, C14orf80 is an evolutionarily highly conserved ORF, lacking any functional annotation. As editing of C14orf80 leads to Chivosazole F hyper-resistance, we propose a function for this gene product in counteracting perturbation of actin filaments

Direct Interaction of Chivosazole F with Actin Elicits Cell Responses Similar to Latrunculin A but Distinct from Chondramide

The microbial metabolite Chivosazole F has been described to affect the cytoskeleton and to inhibit actin polymerization <i>in vitro</i>. Applying orthogonal genomic and proteomics approaches, we now show for the first time that Chivosazole F exerts its effect by directly interacting with actin and demonstrate the cellular impact of Chivosazole F in an unbiased, genome-wide context in yeast and in mammalian cells. Furthermore, mutation-based resistance mapping identifies two SNPs located in the putative Chivosazole F binding site of actin. Comparing chemogenomic profiles and responses to the Chivosazole F-resistant SNPs shows a partially conserved mechanism of action for Chivosazole F and Latrunculin A, but clear divergence from Chondramide. In addition, C14orf80 is an evolutionarily highly conserved ORF, lacking any functional annotation. As editing of C14orf80 leads to Chivosazole F hyper-resistance, we propose a function for this gene product in counteracting perturbation of actin filaments

Two bifunctional inositol pyrophosphate kinases/phosphatases control plant phosphate homeostasis

Many eukaryotic proteins regulating phosphate (Pi) homeostasis contain SPX domains that are receptors for inositol pyrophosphates (PP-InsP), suggesting that PP-InsPs may regulate Pi homeostasis. Here we report that deletion of two diphosphoinositol pentakisphosphate kinases VIH1/2 impairs plant growth and leads to constitutive Pi starvation responses. Deletion of phosphate starvation response transcription factors partially rescues vih1 vih2 mutant phenotypes, placing diphosphoinositol pentakisphosphate kinases in plant Pi signal transduction cascades. VIH1/2 are bifunctional enzymes able to generate and break-down PP-InsPs. Mutations in the kinase active site lead to increased Pi levels and constitutive Pi starvation responses. ATP levels change significantly in different Pi growth conditions. ATP-Mg2+ concentrations shift the relative kinase and phosphatase activities of diphosphoinositol pentakisphosphate kinases in vitro. Pi inhibits the phosphatase activity of the enzyme. Thus, VIH1 and VIH2 relay changes in cellular ATP and Pi concentrations to changes in PP-InsP levels, allowing plants to maintain sufficient Pi levels