Identification and Structure-Guided Development of Pyrimidinone Based USP7 Inhibitors

Ubiquitin specific protease 7 (USP7, HAUSP) has become an attractive target in drug discovery due to the role it plays in modulating Mdm2 levels and consequently p53. Increasing interest in USP7 is emerging due to its potential involvement in oncogenic pathways as well as possible roles in both metabolic and immune disorders in addition to viral infections. Potent, novel, and selective inhibitors of USP7 have been developed using both rational and structure-guided design enabled by high-resolution cocrystallography. Initial hits were identified via fragment-based screening, scaffold-hopping, and hybridization exercises. Two distinct subseries are described along with associated structure–activity relationship trends, as are initial efforts aimed at developing compounds suitable for <i>in vivo</i> experiments. Overall, these discoveries will enable further research into the wider biological role of USP7

Diagnosis and treatment of faecal incontinence: Consensus statement of the Italian Society of Colorectal Surgery and the Italian Association of Hospital Gastroenterologists

Faecal incontinence is a common and disturbing condition, which leads to impaired quality of life and huge social and economic costs. Although recent studies have identified novel diagnostic modalities and therapeutic options, the best diagnostic and therapeutic approach is not yet completely known and shared among experts in this field.The Italian Society of Colorectal Surgery and the Italian Association of Hospital Gastroenterologists selected a pool of experts to constitute a joint committee on the basis of their experience in treating pelvic floor disorders. The aim was to develop a position paper on the diagnostic and therapeutic aspects of faecal incontinence, to provide practical recommendations for a cost-effective diagnostic work-up and a tailored treatment strategy. The recommendations were defined and graded on the basis of levels of evidence in accordance with the criteria of the Oxford Centre for Evidence-Based Medicine, and were based on currently published scientific evidence. Each statement was drafted through constant communication and evaluation conducted both online and during face-to-face working meetings. A brief recommendation at the end of each paragraph allows clinicians to find concise responses to each diagnostic and therapeutic issue