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Schmitz, E.

Publications and source records attributed to Schmitz, E..

2 recordsLinked to original sources

Using aerial thermography to map terrestrial thermal environments in unprecedented detail

O_LIThe accurate quantification of thermal environments is crucial for predicting the impacts of climate change across ecosystems. C_LIO_LITwo major obstacles exist in mapping biologically relevant thermal landscapes: 1) overcoming the mismatch between the spatial resolution at which environmental data are typically collected and the scale at which a particular organism experiences thermal variation, and 2) quantifying thermal landscapes without substantial measurement gaps in time or space. C_LIO_LIWe present a new method that integrates aerial thermography from uncrewed aerial vehicles with field-deployed operative temperature models to generate fine-scale, spatiotemporally complete maps of operative temperature. C_LIO_LITo ensure the accessibility of our method, we developed an R package, throne, which streamlines the necessary corrections to raw drone data and produces operative thermal landscapes for any day or time during which data loggers were deployed. C_LIO_LIOur method allows researchers to generate detailed and biologically relevant thermal landscapes for species of interest which should enhance our understanding of animal thermal ecology and improve our ability to forecast the responses of organisms to environmental change. C_LI

ecology↗

Novel spirocyclic dimer, SpiD3, targets chronic lymphocytic leukemia survival pathways with potent preclinical effects

Chronic lymphocytic leukemia (CLL) cell survival and growth is fueled by the induction of B-cell receptor (BCR) signaling within the tumor microenvironment (TME) driving activation of NF- {kappa}B signaling and the unfolded protein response (UPR). Malignant cells have higher basal levels of UPR posing a unique therapeutic window to combat CLL cell growth using pharmacological agents that induce accumulation of misfolded proteins. Frontline CLL therapeutics that directly target BCR signaling such as Bruton-tyrosine kinase (BTK) inhibitors (e.g., ibrutinib) have enhanced patient survival. However, resistance mechanisms wherein tumor cells bypass BTK inhibition through acquired BTK mutations, and/or activation of alternative survival mechanisms have rendered ibrutinib ineffective, imposing the need for novel therapeutics. We evaluated SpiD3, a novel spirocyclic dimer, in CLL cell lines, patient-derived CLL samples, ibrutinib-resistant CLL cells, and in the E{micro}-TCL1 mouse model. Our integrated multi-omics and functional analyses revealed BCR signaling, NF-{kappa}B signaling, and endoplasmic reticulum stress among the top pathways modulated by SpiD3. This was accompanied by marked upregulation of the UPR and inhibition of global protein synthesis in CLL cell lines and patient-derived CLL cells. In ibrutinib-resistant CLL cells, SpiD3 retained its anti-leukemic effects, mirrored in reduced activation of key proliferative pathways (e.g., PRAS, ERK, MYC). Translationally, we observed reduced tumor burden in SpiD3-treated E{micro}-TCL1 mice. Our findings reveal that SpiD3 exploits critical vulnerabilities in CLL cells including NF-{kappa}B signaling and the UPR, culminating in profound anti-tumor properties independent of TME stimuli. STATEMENT OF SIGNIFICANCESpiD3 demonstrates cytotoxicity in CLL partially through inhibition of NF-{kappa}B signaling independent of tumor-supportive stimuli. By inducing the accumulation of unfolded proteins, SpiD3 activates the UPR and hinders protein synthesis in CLL cells. Overall, SpiD3 exploits critical CLL vulnerabilities (i.e., the NF-{kappa}B pathway and UPR) highlighting its use in drug-resistant CLL. VISUAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=137 HEIGHT=200 SRC="FIGDIR/small/578283v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1dd7a38org.highwire.dtl.DTLVardef@1831c85org.highwire.dtl.DTLVardef@c571f9org.highwire.dtl.DTLVardef@bdce53_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗