Comprehensive molecular characterization of the hippo signaling pathway in cancer

Hippo signaling has been recognized as a key tumor suppressor pathway. Here, we perform a comprehensive molecular characterization of 19 Hippo core genes in 9,125 tumor samples across 33 cancer types using multidimensional “omic” data from The Cancer Genome Atlas. We identify somatic drivers among Hippo genes and the related microRNA (miRNA) regulators, and using functional genomic approaches, we experimentally characterize YAP and TAZ mutation effects and miR-590 and miR-200a regulation for TAZ. Hippo pathway activity is best characterized by a YAP/TAZ transcriptional target signature of 22 genes, which shows robust prognostic power across cancer types. Our elastic-net integrated modeling further reveals cancer-type-specific pathway regulators and associated cancer drivers. Our results highlight the importance of Hippo signaling in squamous cell cancers, characterized by frequent amplification of YAP/TAZ, high expression heterogeneity, and significant prognostic patterns. This study represents a systems-biology approach to characterizing key cancer signaling pathways in the post-genomic era

Role of the N-Terminal Seven Residues of Surfactant Protein B (SP-B)

Breathing is enabled by lung surfactant, a mixture of proteins and lipids that forms a surface-active layer and reduces surface tension at the air-water interface in lungs. Surfactant protein B (SP-B) is an essential component of lung surfactant. In this study we probe the mechanism underlying the important functional contributions made by the N-terminal 7 residues of SP-B, a region sometimes called the “insertion sequence”. These studies employed a construct of SP-B, SP-B (1–25,63–78), also called Super Mini-B, which is a 41-residue peptide with internal disulfide bonds comprising the N-terminal 7-residue insertion sequence and the N- and C-terminal helices of SP-B. Circular dichroism, solution NMR, and solid state 2H NMR were used to study the structure of SP-B (1–25,63–78) and its interactions with phospholipid bilayers. Comparison of results for SP-B (8–25,63–78) and SP-B (1–25,63–78) demonstrates that the presence of the 7-residue insertion sequence induces substantial disorder near the centre of the lipid bilayer, but without a major disruption of the overall mechanical orientation of the bilayers. This observation suggests the insertion sequence is unlikely to penetrate deeply into the bilayer. The 7-residue insertion sequence substantially increases the solution NMR linewidths, most likely due to an increase in global dynamics

Low-pressure, water-assisted anatexis of basic dykes in a contact metamorphic aureole, Fuerteventura (Canary Islands): oxygen isotope evidence for a meteoric fluid origin

Migmatites produced by low-pressure anatexis of basic dykes are found in a contact metamorphic aureole around a pyroxenite-gabbro intrusion (PX2), on Fuerteventura. Dykes outside and inside the aureole record interaction with meteoric water, with low or negative delta O-18 whole-rock values (+0.2 to -3.4 parts per thousand), decreasing towards the contact. Recrystallised plagioclase, diopside, biotite and oxides, from within the aureole, show a similar evolution with lowest delta O-18 values (-2.8, -4.2, - 4.4 and -7.6 parts per thousand, respectively) in the migmatite zone, close to the intrusion. Relict clinopyroxene phenocrysts preserved in all dykes, retain typically magmatic delta O-18 values up to the anatectic zone, where the values are lower and more heterogeneous. Low delta O-18 values, decreasing towards the intrusion, can be ascribed to the advection of meteoric water during magma emplacement, with increasing fluid/rock ratios (higher dyke intensities towards the intrusion acting as fluid-pathways) and higher temperatures promoting increasing exchange during recrystallisation