Einfluss von Thiophanat-Methyl und Methyl-Benzimidazol-2yl-Carbamat auf mykotoxinbildende Fusarium spp.

ZusammenfassungBei der Untersuchung des Einflusses von Thiophanat-Methyl und Methyl-Benzimidazol-2yl-Carbamat auf mykotoxinbildende Arten von Fusarium spp. konnte beobachtet werden, dass Thiophanat-Methyl einen deutlich stärkeren Einfluss auf die Biosynthese der Mykotoxine als auf das Wachstum der Pilze aufwies und die Respiration von Fusarium spp. im Flüssigmedium unabhängig vom Myzelwachstum gehemmt wurde. Die Ergebnisse weisen somit auf einen zusätzlichen Wirkungsmechanismus von Thiophanat-Methyl in Fusarium spp. hin. AbstractInvestigations into the effect of thiophanat-methyl and methyl-benzimidazole-2yl-carbamat on mycotoxinproducing species of Fusarium spp. showed that the influence on the biosynthesis of mycotoxins was more distinct than on the growth of the fungi. Moreover Fusarium spp. showed a reduced respiration at certain levels of TM that was not associated with an inhibited growth. The data indicate that there may be a mechanism of thiophanat-methyl by which the mycotoxinformation of Fusarium spp. could be inhibited independant from the growth of the mycelium.Keywords: Fusarium spp., thiophanat-methyl, carbendazim, mycotoxinproductio

A novel anti-B7-H3 chimeric antigen receptor from a single-chain antibody library for immunotherapy of solid cancers

B7-H3 (CD276) has emerged as a target for cancer immunotherapy by virtue of consistent expression in many malignancies, relative absence from healthy tissues, and an emerging role as a driver of tumor immune inhibition. Recent studies have reported B7-H3 to be a suitable target for chimeric antigen receptor-modified T cell (CAR-T) therapy using CARs constructed from established anti-B7-H3 antibodies converted into single-chain Fv format (scFv). We constructed and screened binders in an scFv library to generate a new anti-B7-H3 CAR-T with favorable properties. This allowed access to numerous specificities ready formatted for CAR evaluation. Selected anti-human B7-H3 scFvs were readily cloned into CAR-T and evaluated for anti-tumor reactivity in cytotoxicity, cytokine, and proliferation assays. Two binders with divergent complementarity determining regions were found to show optimal antigen-specific cytotoxicity and cytokine secretion. One binder in second-generation CD28-CD3ζ CAR format induced sustained in vitro proliferation on repeat antigen challenge. The lead candidate CAR-T also demonstrated in vivo activity in a resistant neuroblastoma model. An empirical approach to B7-H3 CAR-T discovery through screening of novel scFv sequences in CAR-T format has led to the identification of a new construct with sustained proliferative capacity warranting further evaluation

Molecular reorientation in pyrene hexafluoroarsenate salts

The quasi-one dimensional pyrene (PY) organic conductor (PY)7(PY)4(AsF6)4 ${\cdot}$4CH2Cl2  shows parallel as well as 60$^{\circ}$ rotated PY radical cations in its stacks, but crystallizes in two different modifications I and II. One of the seven intra-stack pyrene molecules is susceptible to a reorientation by 60$^{\circ}$, that is stable already at room temperature for modification II, but occurs at a hysteretic first order transition between 170 K and 240 K for modification I. Crystal structure, microwave conductivity and static magnetic susceptibility are typical for a quasi-one dimensional organic conductor with Peierls transition at TP = 73 K (mod. I) or TP = 105 K (mod. II). The pyrene radical packing is analysed by continuous wave and pulsed electron spin resonance measurements, using 9.45 GHz as well as 425 MHz as measuring frequency. Anisotropy of the conduction electron diffusion constant exceeds 1000 in the metallic phase

Effects of iron modulation on mesenchymal stem cell-induced drug resistance in estrogen receptor-positive breast cancer

Patients with estrogen receptor-positive (ER+) breast cancer, the most common subtype, remain at risk for lethal metastatic disease years after diagnosis. Recurrence arises partly because tumor cells in bone marrow become resistant to estrogen-targeted therapy. Here, we utilized a co-culture model of bone marrow mesenchymal stem cells (MSCs) and ER+ breast cancer cells to recapitulate interactions of cancer cells in bone marrow niches. ER+ breast cancer cells in direct contact with MSCs acquire cancer stem-like (CSC) phenotypes with increased resistance to standard antiestrogenic drugs. We confirmed that co-culture with MSCs increased labile iron in breast cancer cells, a phenotype associated with CSCs and disease progression. Clinically approved iron chelators and in-house lysosomal iron-targeting compounds restored sensitivity to antiestrogenic therapy. These findings establish iron modulation as a mechanism to reverse MSC-induced drug resistance and suggest iron modulation in combination with estrogen-targeted therapy as a promising, translatable strategy to treat ER+ breast cancer

Enhanced mitochondrial fission inhibits triple-negative breast cancer cell migration through an ROS-dependent mechanism

Summary: Mitochondria produce reactive oxygen species (ROS), which function in signal transduction. Mitochondrial dynamics, encompassing morphological shifts between fission and fusion, can directly impact ROS levels in cancer cells. In this study, we identified an ROS-dependent mechanism for how enhanced mitochondrial fission inhibits triple negative breast cancer (TNBC) cell migration. We found that enforcing mitochondrial fission in TNBC resulted in an increase in intracellular ROS levels and reduced cell migration and the formation of actin-rich migratory structures. Consistent with mitochondrial fission, increasing ROS levels in cells inhibited cell migration. Conversely, reducing ROS levels with either a global or mitochondrially targeted scavenger overcame the inhibitory effects of mitochondrial fission. Mechanistically, we found that the ROS sensitive SHP-1/2 phosphatases partially regulate inhibitory effects of mitochondrial fission on TNBC migration. Overall, our work reveals the inhibitory effects of ROS in TNBC and supports mitochondrial dynamics as a potential therapeutic target for cancer

Perylene hexafluoroantimonate: Suppression of the Peierls transition by anion-chain disorder

Crystal growth and X-ray structural analysis are reported for the new quasi-one-dimensional organic conductor perylene hexafluoroantimonate. Due to deviation from exact 4:3 stoichiometry and anion-chain disorder the three-dimensional Peierls transition is suppressed to temperatures below 30 K in spite of a molecular field transition temperature of 330 K. Anisotropy of the microwave conductivity exceeds 3000:1 at room temperature. Curie paramagnetic defects with comparatively small electron spin resonance line width predominate at low temperature. Thermally activated paramagnetic defects, giving rise to pronounced Overhauser shift, are separated in the 30-100 K range. They are explained by neutral Perylene intra-stack defects, whose concentration can be reduced by both aging and annealing. The angular and temperature dependence of the conduction electron spin resonance line is analysed in detail, exhibiting the influence of intra-stack dipole interaction growing with temperature. Restricted diffusion of the conduction electron spins with diffusion coefficient of about 6 cm2/s parallel to the stacking direction is detected by fixed gradient pulsed electron spin resonance at room temperature