36 research outputs found
OneâPot Covalent Functionalization of 2D Black Phosphorus by Anionic Ring Opening Polymerization
In this work, a oneâpot approach for the covalent functionalization of fewâlayer black phosphorus (BP) by anionic ring opening polymerization of glycidol to obtain multifunctional BPâpolyglycerol (BPâPG) with high amphiphilicity for nearâinfraredâresponsive drug delivery and biocompatibility is reported. Straightforward synthesis in combination with exceptional biological and physicochemical properties designates functionalized BPâPG as a promising candidate for a broad range of biomedical applications
Wrinkle in the plan: miR-34a-5p impacts chemokine signaling by modulating CXCL10/CXCL11/CXCR3-axis in CD4+, CD8+ T cells, and M1 macrophages
Background In 2016 the first-in-human phase I study of a miRNA-based cancer therapy with a liposomal mimic of microRNA-34a-5p (miR-34a-5p) was closed due to five immune related serious adverse events (SAEs) resulting in four patient deaths. For future applications of miRNA mimics in cancer therapy it is mandatory to unravel the miRNA effects both on the tumor tissue and on immune cells. Here, we set out to analyze the impact of miR-34a-5p over-expression on the CXCL10/CXCL11/CXCR3 axis, which is central for the development of an effective cancer control.
Methods We performed a whole genome expression analysis of miR-34a-5p transfected M1 macrophages followed by an over-representation and a proteinâprotein network analysis. In-silico miRNA target prediction and dual luciferase assays were used for target identification and verification. Target genes involved in chemokine signaling were functionally analyzed in M1 macrophages, CD4+ and CD8+ T cells.
Results A whole genome expression analysis of M1 macrophages with induced miR-34a-5p over-expression revealed an interaction network of downregulated target mRNAs including CXCL10 and CXCL11. In-silico target prediction in combination with dual luciferase assays identified direct binding of miR-34a-5p to the 3âČUTRs of CXCL10 and CXCL11. Decreased CXCL10 and CXCL11 secretion was shown on the endogenous protein level and in the supernatant of miR-34a-5p transfected and activated M1 macrophages. To complete the analysis of the CXCL10/CXCL11/CXCR3 axis, we activated miR-34a-5p transfected CD4+ and CD8+ T cells by PMA/Ionomycin and found reduced levels of endogenous CXCR3 and CXCR3 on the cell surface.
Conclusions MiR-34a-5p mimic administered by intravenous administration will likely not only be up-taken by the tumor cells but also by the immune cells. Our results indicate that miR-34a-5p over-expression leads in M1 macrophages to a reduced secretion of CXCL10 and CXCL11 chemokines and in CD4+ and CD8+ T cells to a reduced expression of CXCR3. As a result, less immune cells will be attracted to the tumor site. Furthermore, high levels of miR-34a-5p in naive CD4+ T cells can in turn hinder Th1 cell polarization through the downregulation of CXCR3 leading to a less pronounced activation of cytotoxic T lymphocytes, natural killer, and natural killer T cells and possibly contributing to lymphocytopenia
Entangling gates on degenerate spin qubits dressed by a global field
Coherently dressed spins have shown promising results as building blocks for
future quantum computers owing to their resilience to environmental noise and
their compatibility with global control fields. This mode of operation allows
for more amenable qubit architecture requirements and simplifies signal routing
on the chip. However, multi-qubit operations, such as qubit addressability and
two-qubit gates, are yet to be demonstrated to establish global control in
combination with dressed qubits as a viable path to universal quantum
computing. Here we demonstrate simultaneous on-resonance driving of degenerate
qubits using a global field while retaining addressability for qubits with
equal Larmor frequencies. Furthermore, we implement SWAP oscillations during
on-resonance driving, constituting the demonstration of driven two-qubit gates.
Significantly, our findings highlight the fragility of entangling gates between
superposition states and how dressing can increase the noise robustness. These
results represent a crucial milestone towards global control operation with
dressed qubits. It also opens a door to interesting spin physics on degenerate
spins
Characterization and optimization of the tumor microenvironment in patient-derived organotypic slices and organoid models of glioblastoma
While glioblastoma (GBM) is still challenging to treat, novel immunotherapeutic approaches have shown promising effects in preclinical settings. However, their clinical breakthrough is hampered by complex interactions of GBM with the tumor microenvironment (TME). Here, we present an analysis of TME composition in a patient-derived organoid model (PDO) as well as in organotypic slice cultures (OSC). To obtain a more realistic model for immunotherapeutic testing, we introduce an enhanced PDO model. We manufactured PDOs and OSCs from fresh tissue of GBM patients and analyzed the TME. Enhanced PDOs (ePDOs) were obtained via co-culture with PBMCs (peripheral blood mononuclear cells) and compared to normal PDOs (nPDOs) and PT (primary tissue). At first, we showed that TME was not sustained in PDOs after a short time of culture. In contrast, TME was largely maintained in OSCs. Unfortunately, OSCs can only be cultured for up to 9 days. Thus, we enhanced the TME in PDOs by co-culturing PDOs and PBMCs from healthy donors. These cellular TME patterns could be preserved until day 21. The ePDO approach could mirror the interaction of GBM, TME and immunotherapeutic agents and may consequently represent a realistic model for individual immunotherapeutic drug testing in the future