PURPOSE. The virus-like drug conjugate belzupacap sarotalocan (AU-011), currently under clinical investigation for first-line treatment of primary uveal melanoma (UM), shows enhanced tumor... Show morePURPOSE. The virus-like drug conjugate belzupacap sarotalocan (AU-011), currently under clinical investigation for first-line treatment of primary uveal melanoma (UM), shows enhanced tumor specificity by targeting heparan sulfate proteoglycans (HSPG). Such a treatment may potentially lead to systemic immune responses. We studied the potential of AU-011 treatment to induce immunogenic cell death as the first step to induce systemic immunity. METHODS. We determined binding and uptake of AU-011 in ten primary and metastatic UM cell lines. The subcellular location of AU-011 was assessed by fluorescence microscopy. Following light activation (wavelength 690 nm) of AU-011, the half-maximal effective concentration (EC50) of AU-011 treatment and exposure of damage-associated molecu-lar patterns (DAMPs) were assessed using flow cytometry. DAMPs were measured by RNAseq. RESULTS. Fluorescence microscopy revealed most of the AU-011 was present in the cyto-plasm. AU-011 binding and uptake by UM cells increased over time, with a lower uptake in BAP1-negative than in BAP1-positive cell lines. AU-011 activation induced cell death across all UM cell lines with EC50 values at picomolar concentrations. The AU-011 concen-tration and total light dose (J/cm2) were the most important parameters for the observed cytotoxicity. Finally, light-activated AU-011 induced exposure of DAMPs calreticulin (CRT) and HSP90. CRT exposure by light-activated AU-011 as well as CRT RNA exposure were lower in BAP1-negative compared to BAP1-positive UM cell lines. CONCLUSIONS. AU-011 treatment at low picomolar range induces immunogenic cell death in all 10 UM cell lines. The in vitro cytotoxicity was accompanied by exposure of DAMPs (HSP90 and CRT), suggesting AU-011 may contribute to the development of systemic immunity and be a suitable candidate for combination with immunotherapy in vivo. AU -011 treatment was more effective against BAP1-positive cell lines, with a lower EC50 and CRT Show less
Metastases remain the leading cause of cancer-related death worldwide. Therefore, improving the treatment efficacy against such tumors is essential to enhance patient survival. AU-011 (belzupacap... Show moreMetastases remain the leading cause of cancer-related death worldwide. Therefore, improving the treatment efficacy against such tumors is essential to enhance patient survival. AU-011 (belzupacap sarotalocan) is a new virus-like drug conjugate which is currently in clinical development for the treatment of small choroidal melanoma and high-risk indeterminate lesions in the eye. Upon light activation, AU-011 induces rapid necrotic cell death which is pro-inflammatory and pro-immunogenic, resulting in an anti-tumor immune response. As AU-011 is known to induce systemic anti-tumor immune responses, we investigated whether this combination therapy would also be effective against distant, untreated tumors, as a model for treating local and distant tumors by abscopal immune effects. We compared the efficacy of combining AU-011 with several different checkpoint blockade antibodies to identify optimal treatment regimens in an in vivo tumor model. We show that AU-011 induces immunogenic cell death through the release and exposure of damage-associated molecular patterns (DAMPs), resulting in the maturation of dendritic cells in vitro. Furthermore, we show that AU-011 accumulates in MC38 tumors over time and that ICI enhances the efficacy of AU-011 against established tumors in mice, resulting in complete responses for specific combinations in all treated animals bearing a single MC38 tumor. Finally, we show that AU-011 and anti-PD-L1/anti-LAG-3 antibody treatment was an optimal combination in an abscopal model, inducing complete responses in approximately 75% of animals. Our data show the feasibility of combining AU-011 with PD-L1 and LAG-3 antibodies for the treatment of primary and distant tumors. Show less
Hao, Y.; Ma, S.; Gu, Z.L.; Haghparast, A.; Schomann, T.; Yu, Z.F.; ... ; Dijke, P. ten 2023
The aquatic system is a major sink for engineered nanomaterials released into the environment. Here, we assessed the toxicity of graphene oxide (GO) using the freshwater planarian Dugesia japonica,... Show moreThe aquatic system is a major sink for engineered nanomaterials released into the environment. Here, we assessed the toxicity of graphene oxide (GO) using the freshwater planarian Dugesia japonica, an invertebrate model that has been widely used for studying the effects of toxins on tissue regeneration and neuronal development. GO not only impaired the growth of normal (homeostatic) worms, but also inhibited the regeneration processes of regenerating (amputated) worms, with LC10 values of 9.86 mg/L and 9.32 mg/L for the 48-h acute toxicity test, respectively. High concentration (200 mg/L) of GO killed all the worms after 3 (regenerating) or 4 (homeostasis) days of exposure. Whole-mount in situ hybridization (WISH) and immunofluorescence analyses suggest GO impaired stem cell proliferation and differentiation, and subsequently caused cell apoptosis and oxidative DNA damage during planarian regeneration. Mechanistic analysis suggests that GO disturbed the antioxidative system (enzymatic and non-enzymatic) and energy metabolism in the planarian at both molecular and genetic levels, thus causing reactive oxygen species (ROS) over accumulation and oxidative damage, including oxidative DNA damage, loss of mitochondrial membrane integrity, lack of energy supply for cell differentiation and proliferation leading to retardance of neuron regeneration. The intrinsic oxidative potential of GO contributes to the GO-induced toxicity in planarians. These data suggest that GO in aquatic systems can cause oxidative stress and neurotoxicity in planarians. Overall, regenerated tissues are more sensitive to GO toxicity than homeostatic ones, suggesting that careful handling and appropriate decisions are needed in the application of GO to achieve healing and tissue regeneration. Show less
Electrochemical CO2 reduction (CO2R) is an attractive option for storing renewable electricity and for the sustainable production of valuable chemicals and fuels. In this roadmap, we review recent... Show moreElectrochemical CO2 reduction (CO2R) is an attractive option for storing renewable electricity and for the sustainable production of valuable chemicals and fuels. In this roadmap, we review recent progress in fundamental understanding, catalyst development, and in engineering and scale-up. We discuss the outstanding challenges towards commercialization of electrochemical CO2R technology: energy efficiencies, selectivities, low current densities, and stability. We highlight the opportunities in establishing rigorous standards for benchmarking performance, advances in in operando characterization, the discovery of new materials towards high value products, the investigation of phenomena across multiple-length scales and the application of data science towards doing so. We hope that this collective perspective sparks new research activities that ultimately bring us a step closer towards establishing a low- or zero-emission carbon cycle. Show less
Human society operates on large-scale cooperation. However, individual differences in cooperativeness and incentives to free ride on others' cooperation make large-scale cooperation fragile and can... Show moreHuman society operates on large-scale cooperation. However, individual differences in cooperativeness and incentives to free ride on others' cooperation make large-scale cooperation fragile and can lead to reduced social welfare. Thus, how individual cooperation spreads through human social networks remains puzzling from ecological, evolutionary, and societal perspectives. Here, we identify oxytocin and costly punishment as biobehavioral mechanisms that facilitate the propagation of cooperation in social networks. In three laboratory experiments (n = 870 human participants: 373 males, 497 females), individuals were embedded in heterogeneous networks and made repeated decisions with feedback in games of trust (n = 342), ultimatum bargaining (n = 324), and prisoner's dilemma with punishment (n = 204). In each heterogeneous network, individuals at central positions (hub nodes) were given intranasal oxytocin (or placebo). Giving oxytocin (vs matching placebo) to central individuals increased their trust and enforcement of cooperation norms. Oxytocin-enhanced norm enforcement, but not elevated trust, explained the spreading of cooperation throughout the social network. Moreover, grounded in evolutionary game theory, we simulated computer agents that interacted in heterogeneous networks with central nodes varying in terms of cooperation and punishment levels. Simulation results confirmed that central cooperators' willingness to punish noncooperation allowed the permeation of the network and enabled the evolution of network cooperation. These results identify an oxytocin-initiated proximate mechanism explaining how individual cooperation facilitates network-wide cooperation in human society and shed light on the widespread phenomenon of heterogeneous composition and enforcement systems at all levels of life. Show less
Plant traits – the morphological, anatomical, physiological, biochemical and phenological characteristics of plants and their organs – determine how primary producers respond to environmental... Show morePlant traits – the morphological, anatomical, physiological, biochemical and phenological characteristics of plants and their organs – determine how primary producers respond to environmental factors, affect other trophic levels, influence ecosystem processes and services and provide a link from species richness to ecosystem functional diversity. Trait data thus represent the raw material for a wide range of research from evolutionary biology, community and functional ecology to biogeography. Here we present the global database initiative named TRY, which has united a wide range of the plant trait research community worldwide and gained an unprecedented buy-in of trait data: so far 93 trait databases have been contributed. The data repository currently contains almost three million trait entries for 69 000 out of the world’s 300 000 plant species, with a focus on 52 groups of traits characterizing the vegetative and regeneration stages of the plant life cycle, including growth, dispersal, establishment and persistence. A first data analysis shows that most plant traits are approximately log-normally distributed, with widely differing ranges of variation across traits. Most trait variation is between species (interspecific), but significant intraspecific variation is also documented, up to 40% of the overall variation. Plant functional types (PFTs), as commonly used in vegetation models, capture a substantial fraction of the observed variation – but for several traits most variation occurs within PFTs, up to 75% of the overall variation. In the context of vegetation models these traits would better be represented by state variables rather than fixed parameter values. The improved availability of plant trait data in the unified global database is expected to support a paradigm shift from species to trait-based ecology, offer new opportunities for synthetic plant trait research and enable a more realistic and empirically grounded representation of terrestrial vegetation in Earth system models. Show less
