Identification of a new class of proteasome inhibitors based on a naphthyl-azotricyclic-urea-phenyl scaffold.

Proteasomes play an important role in protein degradation and regulation of many cellular pathways by maintaining protein balance. Inhibitors of proteasomes disrupt this balance affecting proteins that are key in malignancies and as such have found applications in the treatment of multiple myeloma and mantle cell lymphoma. However, resistance mechanisms have been reported for these proteasome inhibitors including mutations at the β5 site which necessitates the constant development of new inhibitors.

Argyrin B, a non-competitive inhibitor of the human immunoproteasome exhibiting preference for β1i.

Inhibitors of the proteasome have found broad therapeutic applications; however, they show severe toxicity due to the abundance of proteasomes in healthy cells. In contrast, inhibitors of the immunoproteasome, which is upregulated during disease states, are less toxic and have increased therapeutic potential including against autoimmune disorders. In this project, we report argyrin B, a natural product cyclic peptide to be a reversible, non-competitive inhibitor of the immunoproteasome.

Why relatives do not donate organs for transplants: 'sacrifice' or 'gift of life'?

Aim: This paper is a report of a study to explore the reasons family members declined organ donation from a deceased relative.

Background: In the United Kingdom family members' consent is usually sought before organ donation from their deceased relative can proceed. Knowledge of the concerns that may influence families' decision-making could be helpful to nurses supporting bereaved family members.

Traumatic perforation of duodenal diverticulum.

A fragile 72-year-old female with previous coronary artery disease sustained blunt abdominal trauma in a motor vehicle crash. A ruptured duodenum was identified by computed tomography scanning. Exploratory laparotomy revealed that the duodenal rupture was caused by perforation of a diverticulum in the second portion of the duodenum.

Incidence of necrotizing pancreatitis and factors related to mortality.

Of 348 cases of acute pancreatitis presenting between 1980 and 1985, extensive retroperitoneal necrosis with bacterial or fungal superinfection developed in only 17 (4.8 percent). However, in 14 of the 17 patients (80 percent), multiple surgical interventions and intensive supportive therapy failed to control the process, and they died from complications.