Gesellschaft für Mikroelektronikanwendung Chemnitz (Germany)

Two-dimensional (2D) square, rectangular and hexagonal lattices and 3D parallelepipedic lattices of spin crossover (SCO) compounds which represent typical examples of first order phase transitions compounds are studied in terms of their size, shape and model through an Ising-like Hamiltonian in which the fictitious spin states are coupled via the respective short and long-range interaction parameters J, and G. Furthermore, an environmental L parameter accounting for surface effects is also introduced. The wealth of SCO transition properties between its bi-stable low spin (LS) and high spin (HS) states are simulated using Monte Carlo Entropic Sampling (MCES) method which favors the scanning of macro states of weak probability occurrences. For given J and G, the focus is on surface effects through parameter L. It is shown that the combined first-order phase transition effects of the parameters of the Hamiltonian can be highlighted through two typical temperatures, TO.D., the critical order-disorder temperature and Teq the equilibrium temperature that is fixed at zero effective ligand field. The relative positions of TO.D. and Teq control the nature of the transition and mediate the width and position of the thermal hysteresis curves with size and shape. When surface effects are negligible (L = 0), the equilibrium transition temperature, Teq. becomes constant, while the thermal hysteresis’ width increases with size. When surface effects are considered, L ≠ 0, Teq. increases with size and the first order transition vanishes in favor of a gradual transition until reaching a threshold size, below which a reentrance phenomenon occurs and the thermal hysteresis reappears again, as shown for hexagonal configuration.

ABSTRACTChimeric antigen receptor (CAR) T cells have shown impressive therapeutic potential. Due to the lack of direct control mechanisms, therapy-related adverse reactions including cytokine release- and tumor lysis syndrome can even become life-threatening. In case of target antigen expression on non-malignant cells, CAR T cells can also attack healthy tissues. To overcome such side effects, we have established a modular CAR platform termed UniCAR: UniCAR T cells per se are inert as they recognize a peptide epitope (UniCAR epitope) that is not accessible on the surface of living cells. Bifunctional adapter molecules termed target modules (TM) can cross-link UniCAR T cells with target cells. In the absence of TMs, UniCAR T cells automatically turn off. Until now, all UniCAR TMs were constructed by fusion of the UniCAR epitope to an antibody domain. To open up the wide field of low-molecular-weight compounds for retargeting of UniCAR T cells to tumor cells, and to follow in parallel the progress of UniCAR T cell therapy by PET imaging we challenged the idea to convert a PET tracer into a UniCAR-TM. For proof of concept, we selected the clinically used PET tracer PSMA-11, which binds to the prostate-specific membrane antigen overexpressed in prostate carcinoma. Here we show that fusion of the UniCAR epitope to PSMA-11 results in a low-molecular-weight theranostic compound that can be used for both retargeting of UniCAR T cells to tumor cells, and for non-invasive PET imaging and thus represents a member of a novel class of theranostics.

Known as a prominent recombination path at high excitation densities, exciton-exciton annihilation (EEA) is evidenced in bulk hexagonal boron nitride (hBN) by cathodoluminescence at low temperature. Thanks to a careful tune of the the exciton density by varying either the current or the focus of the incident electron beam, we could estimate an EEA rate of 2$\times$10$^{-6}$ cm$^{3}$.s$^{-1}$ at $T=10$ K, the highest reported so far for a bulk semiconductor. Expected to be even stronger in nanotubes or atomic layers, EEA probablly contributes to the luminescence quenching observed in low-dimensionality BN materials.

ABSTRACTThe universal modular chimeric antigen receptor (UniCAR) platform redirects CAR-T cells using a separated, soluble targeting module with a short half-life. This segregation allows precise controllability and flexibility. Herein we show that the UniCAR platform can be used to efficiently target solid cancers in vitro and in vivo using a pre-clinical prostate cancer model which overexpresses prostate stem cell antigen (PSCA). Short-term administration of the targeting module to tumor bearing immunocompromised mice engrafted with human UniCAR-T cells significantly delayed tumor growth and prolonged survival of recipient mice both in a low and high tumor burden model. In addition, we analyzed phenotypic and functional changes of cancer cells and UniCAR-T cells in association with the administration of the targeting module to reveal potential immunoevasive mechanisms. Most notably, UniCAR-T cell activation induced upregulation of immune-inhibitory molecules such as programmed death ligands. In conclusion, this work illustrates that the UniCAR platform mediates potent anti-tumor activity in a relevant in vitro and in vivo solid tumor model.

Die Bedeutung des Nachweises von Candida albians auf Schleimhauten des Respirations- oder Intesinaltraktes ist bei Patienten auf Intensivstationen noch immer nicht endgultig geklart. Viele Patienten sind besiedelt, invasive Infektionen treten jedoch trotz eines erhohten Risikos insgesamt selten auf. Aus diesem Grund wird eine Gabe von Antimykotika als ungerechtfertigt angesehen, dennoch erfolgt bei nicht wenigen Patienten als ultima ratio eine antimykotische Therapie. Allerdings werfen neue Erkenntnisse aus der Grundlagenforschung uber die Pathomechanismen von C.albicans ein neues Licht auf die Bedeutung dieser empirischen Therapie. Offensichtlich ist C.albicans auch ohne invasiv zu werden, in der Lage uber wenigstens zwei voneinander unabhangige Mechanismen das Immunsystem im Sinne einer anti-inflammatorischen Immunantwort (Th2) negativ zu beeinflussen. C.albicans wachst in Biofilmen, wie sie sich auf Schleimhauten bilden, in Hyphenform, diese wiederum interagiert mit „toll-like“ Rezeptoren (TLR2) antigenprasentierender Zellen, was zu einem Anstieg der IL-10 Produktion als Ausdruck einer anti-inflammatorischen Immunantwort fuhrt. Gleichzeitig bildet C.albicans Farnesol, eine Substanz, welches als „quorum sensing molecule“ die Kommunikation unter Hefezellen beeinflusst und die Transition von der Blastokonidie zur Hyphe steuert. Im Tierexperiment kann gezeigt werden, dass Farnesol ebenfalls das Immunsystem im Sinne einer anti-inflammatorischen Antwort beeinflusst, beispielsweise steigen bei LPS-Gabe zusammen mit Farnesol die IL-12 Spiegel nicht adaquat an. Befinden sich Patienten im Krankheitsverlauf in der Phase des „Compensatory Anti-inflammatory Response Syndrome“ (CARS) bzw. des „Mixed Antagonising Response Syndrome“ (MARS), so kann nach heutiger Datenlage davon ausgegangen werden, dass eine gleichzeitig bestehende C.albicans-Besiedlung die Immunantwort bei besiedelten Patienten zusatzlich negativ, d.h. „anti-inflammatorisch“ verandern kann. Werden in dieser Krankheitsphase allerdings Azolpraparate wie beispielsweise Fluconazol appliziert, so ist eine zusatzliche negative Auswirkung auf den Patienten moglich, da durch die Storung der Ergosterolsynthese in einer negativen Ruckkopplung vermehrt Farnesol gebildet wird. Aus den Ergebnissen der Grundlagenforschung ergibt sich daher die Notwendigkeit, die im Tierexperiment gewonnenen Erkenntnisse uber die Beeinflussung des Immunsystems und die daraus folgenden therapeutischen Konsequenzen in klinischen Studien zu verifizieren.