Activation of Hepatocyte Growth Factor/MET Signaling as a Mechanism of Acquired Resistance to a Novel YAP1/TEAD Small Molecule Inhibitor.

Many tumor types harbor alterations in the Hippo pathway, including mesothelioma, where a high percentage of cases are considered YAP1/TEAD dependent. Identification of autopalmitoylation sites in the hydrophobic palmitate pocket of TEADs, which may be necessary for YAP1 protein interactions, has enabled modern drug discovery platforms to generate compounds that allosterically inhibit YAP1/TEAD complex formation and transcriptional activity. We report the discovery and characterization of a novel YAP1/TEAD inhibitor MRK-A from an aryl ether chemical series demonstrating potent and specific inhibition of YAP1/TEAD activity.

Single-Cell Analysis Identifies NOTCH3-Mediated Interactions between Stromal Cells That Promote Microenvironment Remodeling and Invasion in Lung Adenocarcinoma.

Unlabelled: Cancer immunotherapy has revolutionized the treatment of lung adenocarcinoma (LUAD); however, a significant proportion of patients do not respond. Recent transcriptomic studies to understand determinants of immunotherapy response have pinpointed stromal-mediated resistance mechanisms. To gain a better understanding of stromal biology at the cellular and molecular level in LUAD, we performed single-cell RNA sequencing of 256,379 cells, including 13,857 mesenchymal cells, from 9 treatment-naïve patients.

Targeting Mutant PPM1D Sensitizes Diffuse Intrinsic Pontine Glioma Cells to the PARP Inhibitor Olaparib.

Diffuse intrinsic pontine glioma (DIPG) is an invariably fatal brain tumor occurring predominantly in children. Up to 90% of pediatric DIPGs harbor a somatic heterozygous mutation resulting in the replacement of lysine 27 with methionine (K27M) in genes encoding histone H3.3 (H3F3A, 65%) or H3.

A PRMT5-RNF168-SMURF2 Axis Controls H2AX Proteostasis.

H2AX safeguards genomic stability in a dose-dependent manner; however, mechanisms governing its proteostasis are poorly understood. Here, we identify a PRMT5-RNF168-SMURF2 cascade that regulates H2AX proteostasis. We show that PRMT5 sustains the expression of RNF168, an E3 ubiquitin ligase essential for DNA damage response (DDR).

Effect of moisture on wheat grains lipid patterns and infection with Fusarium graminearum.

Suitable conditions of temperature and humidity are required to maintain wheat grains quality, but during processing and storage, the grains can be exposed to adverse environmental conditions and presence of infectious fungi. Fusarium graminearum, the main causal agent of Fusarium head blight on wheat, affects crop yields and grain quality by alteration of their biochemical components and mycotoxin contamination, which reduces the possibilities of wheat end use and compromises food safety. Lipid degradation by hydrolytic, oxidative and microbial deterioration is the predominant cause of the loss of sensory acceptability, nutritional value and baking quality.