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- ItemDuring early stages of cancer, neutrophils initiate anti-tumor immune responses in tumor-draining lymph nodes(Maryland Heights, MO : Cell Press, 2022) Pylaeva, Ekaterina; Korschunow, Georg; Spyra, Ilona; Bordbari, Sharareh; Siakaeva, Elena; Ozel, Irem; Domnich, Maksim; Squire, Anthony; Hasenberg, Anja; Thangavelu, Kruthika; Hussain, Timon; Goetz, Moritz; Lang, Karl S; Gunzer, Matthias; Hansen, Wiebke; Buer, Jan; Bankfalvi, Agnes; Lang, Stephan; Jablonska, JadwigaTumor-draining lymph nodes (LNs) play a crucial role during cancer spread and in initiation of anti-cancer adaptive immunity. Neutrophils form a substantial population of cells in LNs with poorly understood functions. Here, we demonstrate that, during head and neck cancer (HNC) progression, tumor-associated neutrophils transmigrate to LNs and shape anti-tumor responses in a stage-dependent manner. In metastasis-free stages (N0), neutrophils develop an antigen-presenting phenotype (HLA-DR+CD80+CD86+ICAM1+PD-L1-) and stimulate T cells (CD27+Ki67highPD-1-). LN metastases release GM-CSF and via STAT3 trigger development of PD-L1+ immunosuppressive neutrophils, which repress T cell responses. The accumulation of neutrophils in T cell-rich zones of LNs in N0 constitutes a positive predictor for 5-year survival, while increased numbers of neutrophils in LNs of N1-3 stages predict poor prognosis in HNC. These results suggest a dual role of neutrophils as essential regulators of anti-cancer immunity in LNs and argue for approaches fostering immunostimulatory activity of these cells during cancer therapy.
- ItemAutophagy-related deubiquitinating enzymes involved in health and disease(Basel : MDPI, 2015) El Magraoui, Fouzi; Reidick, Christina; Meyer, Hemut E.; Platta, Harald W.Autophagy is an evolutionarily-conserved process that delivers diverse cytoplasmic components to the lysosomal compartment for either recycling or degradation. This involves the removal of protein aggregates, the turnover of organelles, as well as the elimination of intracellular pathogens. In this situation, when only specific cargoes should be targeted to the lysosome, the potential targets can be selectively marked by the attachment of ubiquitin in order to be recognized by autophagy-receptors. Ubiquitination plays a central role in this process, because it regulates early signaling events during the induction of autophagy and is also used as a degradation-tag on the potential autophagic cargo protein. Here, we review how the ubiquitin-dependent steps of autophagy are balanced or counteracted by deubiquitination events. Moreover, we highlight the functional role of the corresponding deubiquitinating enzymes and discuss how they might be involved in the occurrence of cancer, neurodegenerative diseases or infection with pathogenic bacteria.
- ItemDiscrimination of different cell monolayers before and after exposure to nanosecond pulsed electric fields based on Cole-Cole and multivariate analysis(Bristol : IOP Publ., 2019) Shi, Fukun; Zhuang, Jie; Kolb, Juergen F.Normal and cancer cells, which were grown in monolayers, were investigated and discriminated by electrical bioimpedance spectroscopy (EBIS) before and after exposures to nanosecond pulsed electric fields (nsPEFs). Bioimpedance data were analysed with a Cole-Cole model and the principal component analysis (PCA). Normal and cancer cells could be clearly distinguished from each other either from Cole parameters (R 0, a, t) or from two dominant principal components. The trend of changes for Cole parameters indicated distinctively different post-nsPEF-effects between normal and cancer cells. PCA was also able to distinguish characteristic impedance spectra 30 min after exposures. The first principal component suggested that post-nsPEF-effects for normal cells were revealed especially at lower frequencies. The results indicated further that the extracellular resistance, which is dominated by cell-cell connections, might be an important factor with respect to selective nsPEF-effects on cancer cells that are organized in a monolayer or a tissue, respectively. Accordingly, the results support the application of EBIS as an early, non-invasive, label-free, and time-saving approach for the classification of cells to provide in particular predictive information on the success of cancer treatments with nsPEFs. © 2019 IOP Publishing Ltd.
- ItemGivinostat-Liposomes: Anti-Tumor Effect on 2D and 3D Glioblastoma Models and Pharmacokinetics(Basel : MDPI, 2022) Taiarol, Lorenzo; Bigogno, Chiara; Sesana, Silvia; Kravicz, Marcelo; Viale, Francesca; Pozzi, Eleonora; Monza, Laura; Carozzi, Valentina Alda; Meregalli, Cristina; Valtorta, Silvia; Moresco, Rosa Maria; Koch, Marcus; Barbugian, Federica; Russo, Laura; Dondio, Giulio; Steinkühler, Christian; Re, FrancescaGlioblastoma is the most common and aggressive brain tumor, associated with poor prognosis and survival, representing a challenging medical issue for neurooncologists. Dysregulation of histone-modifying enzymes (HDACs) is commonly identified in many tumors and has been linked to cancer proliferation, changes in metabolism, and drug resistance. These findings led to the development of HDAC inhibitors, which are limited by their narrow therapeutic index. In this work, we provide the proof of concept for a delivery system that can improve the in vivo half-life and increase the brain delivery of Givinostat, a pan-HDAC inhibitor. Here, 150-nm-sized liposomes composed of cholesterol and sphingomyelin with or without surface decoration with mApoE peptide, inhibited human glioblastoma cell growth in 2D and 3D models by inducing a time-and dose-dependent reduction in cell viability, reduction in the receptors involved in cholesterol metabolism (from −25% to −75% of protein levels), and reduction in HDAC activity (−25% within 30 min). In addition, liposome-Givinostat formulations showed a 2.5-fold increase in the drug half-life in the bloodstream and a 6-fold increase in the amount of drug entering the brain in healthy mice, without any signs of overt toxicity. These features make liposomes loaded with Givinostat valuable as potential candidates for glioblastoma therapy.
- ItemFoundations of plasmas for medical applications(Bristol : IOP Publ., 2022) von Woedtke, T.; Laroussi, M.; Gherardi, M.Plasma medicine refers to the application of nonequilibrium plasmas at approximately body temperature, for therapeutic purposes. Nonequilibrium plasmas are weakly ionized gases which contain charged and neutral species and electric fields, and emit radiation, particularly in the visible and ultraviolet range. Medically-relevant cold atmospheric pressure plasma (CAP) sources and devices are usually dielectric barrier discharges and nonequilibrium atmospheric pressure plasma jets. Plasma diagnostic methods and modelling approaches are used to characterize the densities and fluxes of active plasma species and their interaction with surrounding matter. In addition to the direct application of plasma onto living tissue, the treatment of liquids like water or physiological saline by a CAP source is performed in order to study specific biological activities. A basic understanding of the interaction between plasma and liquids and bio-interfaces is essential to follow biological plasma effects. Charged species, metastable species, and other atomic and molecular reactive species first produced in the main plasma ignition are transported to the discharge afterglow to finally be exposed to the biological targets. Contact with these liquid-dominated bio-interfaces generates other secondary reactive oxygen and nitrogen species (ROS, RNS). Both ROS and RNS possess strong oxidative properties and can trigger redox-related signalling pathways in cells and tissue, leading to various impacts of therapeutic relevance. Dependent on the intensity of plasma exposure, redox balance in cells can be influenced in a way that oxidative eustress leads to stimulation of cellular processes or oxidative distress leads to cell death. Currently, clinical CAP application is realized mainly in wound healing. The use of plasma in cancer treatment (i.e. plasma oncology) is a currently emerging field of research. Future perspectives and challenges in plasma medicine are mainly directed towards the control and optimization of CAP devices, to broaden and establish its medical applications, and to open up new plasma-based therapies in medicine.
- ItemEngineering microrobots for targeted cancer therapies from a medical perspective(Berlin : Springer Nature, 2020) Schmidt, Christine K.; Medina-Sánchez, Mariana; Edmondson, Richard J.; Schmidt, Oliver G.Systemic chemotherapy remains the backbone of many cancer treatments. Due to its untargeted nature and the severe side effects it can cause, numerous nanomedicine approaches have been developed to overcome these issues. However, targeted delivery of therapeutics remains challenging. Engineering microrobots is increasingly receiving attention in this regard. Their functionalities, particularly their motility, allow microrobots to penetrate tissues and reach cancers more efficiently. Here, we highlight how different microrobots, ranging from tailor-made motile bacteria and tiny bubble-propelled microengines to hybrid spermbots, can be engineered to integrate sophisticated features optimised for precision-targeting of a wide range of cancers. Towards this, we highlight the importance of integrating clinicians, the public and cancer patients early on in the development of these novel technologies.