A new Caenorhabditis elegans model to study copper toxicity in Wilson disease.

Wilson disease (WD) is caused by mutations in the ATP7B gene that encodes a copper (Cu) transporting ATPase whose trafficking from the Golgi to endo-lysosomal compartments drives sequestration of excess Cu and its further excretion from hepatocytes into the bile. Loss of ATP7B function leads to toxic Cu overload in the liver and subsequently in the brain, causing fatal hepatic and neurological abnormalities. The limitations of existing WD therapies call for the development of new therapeutic approaches, which require an amenable animal model system for screening and validation of drugs and molecular targets. To achieve this objective, we generated a mutant Caenorhabditis elegans strain with a substitution of a conserved histidine (H828Q) in the ATP7B ortholog cua-1 corresponding to the most common ATP7B variant (H1069Q) that causes WD. cua-1 mutant animals exhibited very poor resistance to Cu compared to the wild-type strain. This manifested in a strong delay in larval development, a shorter lifespan, impaired motility, oxidative stress pathway activation, and mitochondrial damage. In addition, morphological analysis revealed several neuronal abnormalities in cua-1 mutant animals exposed to Cu. Further investigation suggested that mutant CUA-1 is retained and degraded in the endoplasmic reticulum, similarly to human ATP7B-H1069Q. As a consequence, the mutant protein does not allow animals to counteract Cu toxicity. Notably, pharmacological correctors of ATP7B-H1069Q reduced Cu toxicity in cua-1 mutants indicating that similar pathogenic molecular pathways might be activated by the H/Q substitution and, therefore, targeted for rescue of ATP7B/CUA-1 function. Taken together, our findings suggest that the newly generated cua-1 mutant strain represents an excellent model for Cu toxicity studies in WD.

Nasal and systemic eosinophilia associated with solid intestinal tumors, a case report and review of the literature.

The authors report the study of a clinical case, which presented eosinophilia both in the secretion of the nasal mucosa and in the blood count. After a careful examination of all the pathologies related to hypereosinophilia, through a clinical study, they have documented the presence of an adenocarcinoma located in the ileocecal junction of the colon. From what has been documented it is clear that only a clinical observation of precision, carried out above all through nasal cytology and colonoscopy, is able to diagnose an important pathology, such as oncology. For the literature review we used the Scopus and PubMed search engines to analyze other authors who were interested in the relationship between eosinophilia and colorectal cancer. Much of the studies analyzed reported a close relationship between the presence of tissue eosinophilia and tumor, and the prognosis of colorectal cancer. KEY WORD: Colorectal cancer, Eosinophils, Hypereosinophilia.