The JNK and Hippo pathways control epithelial integrity and prevent tumor initiation by regulating an overlapping transcriptome.

Epithelial organs maintain their integrity and prevent tumor initiation by actively removing defective cells, such as those that have lost apicobasal polarity. Here, we identify how transcription factors of two key signaling pathways-Jun-N-terminal kinase (JNK) and Hippo-regulate epithelial integrity by controlling transcription of an overlapping set of target genes. Targeted DamID experiments reveal that, in proliferating cells of the Drosophila melanogaster eye, the AP-1 transcription factor Jun and the Hippo pathway transcription regulators Yorkie and Scalloped bind to a common suite of target genes that promote organ growth.

Identification of resistance mechanisms to small-molecule inhibition of TEAD-regulated transcription.

The Hippo tumor suppressor pathway controls transcription by regulating nuclear abundance of YAP and TAZ, which activate transcription with the TEAD1-TEAD4 DNA-binding proteins. Recently, several small-molecule inhibitors of YAP and TEADs have been reported, with some entering clinical trials for different cancers with Hippo pathway deregulation, most notably, mesothelioma. Using genome-wide CRISPR/Cas9 screens we reveal that mutations in genes from the Hippo, MAPK, and JAK-STAT signaling pathways all modulate the response of mesothelioma cell lines to TEAD palmitoylation inhibitors.

Predicting ion mobility collision cross sections and assessing prediction variation by combining conventional and data driven modeling.

The use of collision cross section (CCS) values derived from ion mobility studies is proving to be an increasingly important tool in the characterization and identification of molecules detected in complex mixtures. Here, a novel machine learning (ML) based method for predicting CCS integrating both molecular modeling (MM) and ML methodologies has been devised and shown to be able to accurately predict CCS values for singly charged small molecular weight molecules from a broad range of chemical classes. The model performed favorably compared to existing models, improving compound identifications for isobaric analytes in terms of ranking and assigning identification probability values to the annotation.

Clinical Impact of Comprehensive Molecular Profiling in Adolescents and Young Adults with Sarcoma.

Sarcomas are a heterogenous group of tumours that commonly carry poor prognosis with limited therapeutic options. Adolescents and young adults (AYAs) with sarcoma are a unique and understudied patient population that have only achieved modest survival gains compared to other groups. We present our institutional experience of AYAs with sarcoma who underwent comprehensive molecular profiling (CMP) via either large-panel targeted DNA sequencing or whole genome and transcriptome sequencing and evaluated the feasibility and clinical impact of this approach.

Increasing coverage of the urinary polar metabolome using ultra high-performance hydrophobic interaction liquid chromatography combined with linear and cyclic travelling wave ion mobility and mass spectrometry.

The use of HILIC-based separations for the analysis of polar metabolites in metabolic phenotyping studies is well established. Here, we demonstrate the increased coverage of the polar metabolome obtained by travelling wave (TW) ion mobility (IM) instruments combined with HILIC and mass spectrometry (MS) for metabotyping rat and mouse urine samples. Profiling was performed using either a linear TW IM-MS based instrument with a path length of 40 cm or an instrument with a cyclic travelling wave analyser (cIM) with a path length of 95 cm.