Optimization of Potent and Selective Cyclohexyl Acid ERAP1 Inhibitors Using Structure- and Property-Based Drug Design.

Endoplasmic reticulum aminopeptidase 1 (ERAP1) cleaves the -terminal amino acids of peptides, which can then bind onto major histocompatibility class I (MHC-I) molecules for presentation onto the cell surface, driving the activation of adaptive immune responses. In cancer, overtrimming of mature antigenic peptides can reduce cytotoxic T-cell responses, and ERAP1 can generate self-antigenic peptides which contribute to autoimmune cellular responses. Therefore, modulation of ERAP1 activity has potential therapeutic indications for cancer immunotherapy and in autoimmune disease.

Differential diagnosis of adipocytic differentiation in androgen-secreting mature ovarian teratoma with Leydig cell hyperplasia.

Mature cystic teratomas (dermoid cysts) of the ovary are very rarely associated with androgen production. The source of androgens in these cysts may be tumours such as Sertoli-Leydig cell tumour or Leydig cell hyperplasia. In this study, we present a case of virilisation in a postmenopausal female patient, where Leydig cell hyperplasia in a mature cystic teratoma was found to be responsible for the production of testosterone.

Comparison of surgical skill acquisition by UK surgical trainees and Sierra Leonean associate clinicians in a task-sharing programme.

Background: Task-sharing in surgery is well established, with associate clinicians performing successful surgery in many countries. Little is known about the process of surgical skill acquisition by associate clinicians, or whether this differs from that of doctors.

Methods: A blinded experimental study compared surgical skill acquisition by Sierra Leonean associate clinicians enrolled in an essential and emergency surgery training programme with that of a matched group of UK surgical trainees.

Structure-based design of targeted covalent inhibitors.

Covalent inhibition is a rapidly growing discipline within drug discovery. Many historical covalent inhibitors were discovered by serendipity, with such a mechanism of action often regarded as undesirable due to potential toxicity issues. Recent progress has seen a major shift in this outlook, as covalent inhibition shows promise for targets where previous efforts to identify non-covalent small molecule inhibitors have failed.