A dual specificity kinase, DYRK1A, as a potential therapeutic target for head and neck squamous cell carcinoma

Despite advances in clinical management, 5-year survival rate in patients with late-stage head and neck squamous cell carcinoma (HNSCC) has not improved significantly over the past decade. Targeted therapies have emerged as one of the most promising approaches to treat several malignancies. Though tyrosine phosphorylation accounts for a minority of total phosphorylation, it is critical for activation of signaling pathways and plays a significant role in driving cancers. To identify activated tyrosine kinase signaling pathways in HNSCC, we compared the phosphotyrosine profiles of a panel of HNSCC cell lines to a normal oral keratinocyte cell line. Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) was one of the kinases hyperphosphorylated at Tyr-321 in all HNSCC cell lines. Inhibition of DYRK1A resulted in an increased apoptosis and decrease in invasion and colony formation ability of HNSCC cell lines. Further, administration of the small molecular inhibitor against DYRK1A in mice bearing HNSCC xenograft tumors induced regression of tumor growth. Immunohistochemical labeling of DYRK1A in primary tumor tissues using tissue microarrays revealed strong to moderate staining of DYRK1A in 97.5% (39/40) of HNSCC tissues analyzed. Taken together our results suggest that DYRK1A could be a novel therapeutic target in HNSCC

Strong inheritance of texture between perovskite and post-perovskite in the D′′ layer

The main mineral in the lower mantle, magnesium-silicate perovskite, transforms into a high-pressure, post-perovskite, phase at pressures and temperatures corresponding to the D'' seismic discontinuity approximately 200 km above the core-mantle boundary. The strong elastic anisotropy of post-perovskite has been invoked to explain the observed seismic anisotropy and to infer flow in the D'' region, based on models of textured post-perovskite. Such inferences rely on a knowledge of the mechanisms by which the post-perovskite can obtain texture. It is generally thought that seismic anisotropy in D'' is produced from lattice-preferred orientation generated during plastic deformation; however, it is difficult to explain all of the observed seismic anisotropy in D'' using a single deformation mechanism in post-perovskite. Here we show that strong texture inheritance is possible during transformation from perovskite to post-perovskite using a recently developed fluoride analogue system. If a similar transformation mechanism operates in the Earth, post-perovskite will inherit textures from deformed perovskite and vice versa as lower-mantle material passes into and out of regions of post-perovskite stability. This texture inheritance during the transition from post-perovskite to perovskite, combined with a single slip system in post-perovskite, can explain the seismic anisotropy of the lowermost mantle