Structural implications of the DFD-in domain in computer-aided molecular design of MAP kinase interacting kinase 2 inhibitors.

Protein translation is a key process on cell development and proliferation that is often deregulated in cancer. MAP kinase interacting kinases 1 and 2(Mnk1/2) play a pivotal role in regulating the capdependent translation through phosphorylation ofeIF4E transcription factor. Thus, Mnk1/2 targeting have been proposed as a novel therapeutic strategy that would minimize side-effects in contrast to other therapies. For this reason, there is a growing interestin designing in silico new Mnk1/2 inhibitors which demands from reliable structural models. Interestingly,the catalytic domain of Mnk proteins are characterized by a DFD motif instead of the characteristicDFG motif of other kinases. However, Mnk2 structural models described in literature are DFG mutated and do not contain the activation loop. Molecular design techniques have been applied to obtain a structural model of the full wild type Mnk2 protein including the activation loop. The effect of the loop on the interaction mechanism of well-known ligands has been evaluated. Obtained results suggest that the presence of the activation loop is determinant for the correct prediction of the active site and it is essential for the design of new inhibitors

5-Amino-6,7,8,9-Tetrahydrobenzo[b][1,8]Naphthyridin-2(1H)-One: The first Example of a new Family of HuperTacrines for Alzheimer's Disease Therapy

In this communication we have described the synthesis of 2-amino-6-oxo-1,6-dihydropyridine-3-carbonitrile (4), and the preparation of 5-amino-6,7,8,9-tetrahydrobenzo[b][1,8]naphthyridin-2(1H)-one (3 a), a non-hepatotoxic, antioxidant agent, showing moderate, but selective human acetylcholinesterase inhibition.JMC thanks MINECO (SAF2012-33304), and Universidad Camilo José Cela (MULTIMOL 2013–20) for supportPeer Reviewe

Risk factors and rate of recurrence after Mohs surgery in basal cell and squamous cell carcinomas: a nationwide prospective cohort (REGESMOHS, Spanish Registry of Mohs Surgery)

Randomized studies to assess the efficacy of Mohs micrographic surgery in basal cell and squamous cell carcinomas are limited by methodological and ethical issues and a lack of long follow-up periods. This study presents the "real-life" results of a nationwide 7-years cohort on basal cell carcinoma and squamous cell carcinoma treated with Mohs micrographic surgery. A prospective cohort was conducted in 22 Spanish centres (from July 2013 to February 2020) and a multivariate analysis, including characteristics of patients, tumours, surgeries and follow-up, was performed. A total of 4,402 patients followed up for 12,111 patient-years for basal cell carcinoma, and 371 patients with 915 patient-years of follow-up for squamous cell carcinoma were recruited. Risk factors for recurrence included age, non-primary tumours and more stages or unfinished surgeries for both tumours, and immunosuppression for squamous cell carcinoma. Incidence rates of recurrence were 1.3 per 100 person-years for basal cell carcinoma (95% confidence interval 1.1-1.5) and 4.5 for squamous cell carcinoma (95% confidence interval 3.3-6.1), being constant over time (0-5 years). In conclusion, follow-up strategies should be equally intense for at least the first 5 years, with special attention paid to squamous cell carcinoma (especially in immunosuppressed patients), elderly patients, non-primary tumours, and those procedures requiring more stages, or unfinished surgeries