Follow up Study of Coeliac Disease

In 9 out of 10 adults in whom a diagnosis of coeliac disease had been made in childhood, the diagnosis was confirmed by the finding of a flat intestinal mucosa. None showed abnormal physical signs, but three had a haemoglobin concentration below 10 g./100 ml. and all those not receiving folic acid supplements showed low serum folate levels. Five had moderate to severe symptoms at the time of investigation, but none was receiving treatment with a gluten-free diet.Periodic investigation of these patients may be necessary throughout life, and if they are found to have malnutrition they should be treated with a gluten-free diet.     

Neratinib degrades MST4 via autophagy that reduces membrane stiffness and is essential for the inactivation of PI3K,ERK1/2, and YAP/TAZ signaling

The irreversible ERBB1/2/4 inhibitor neratinib causes plasma membrane-associated K-RAS to mislocalize into intracellular vesicles liminal to the plasma membrane; this effect is enhanced by HDAC inhibitors and is now a Phase I trial (NCT03919292). The combination of neratinib and HDAC inhibitors killed pancreatic cancer and lymphoma T cells. Neratinib plus HDAC inhibitor exposure was as efficacious as (paclitaxel+gemcitabine) at killing pancreatic cancer cells. Neratinib reduced the phosphorylation of PAK1, Merlin, LATS1/2, AKT, mTOR, p70 S6K, and ERK1/2 which required expression of Rubicon, Beclin1, and Merlin. Neratinib altered pancreatic tumor cell morphology which was associated with MST4 degradation reduced Ezrin phosphorylation and enhanced phosphorylation of MAP4K4 and LATS1/2. Knockdown of the MAP4K4 activator and sensor of membrane rigidity RAP2A reduced basal LATS1/2 and YAP phosphorylation but did not prevent neratinib from stimulating LATS1/2 or YAP phosphorylation. Beclin1 knockdown prevented MST4 degradation, Ezrin dephosphorylation and neratinib-induced alterations in tumor cell morphology. Our findings demonstrate that neratinib enhances LATS1/2 phosphorylation independently of RAP2A/MAP4K4 and that MST4 degradation and Ezrin dephosphorylation may represent a universal trigger for the biological actions of neratinib.