ABSTRACT
Abstract: The tumor suppressor protein p53, a transcription factor playing a key role in cancer prevention, interacts with DNA as its primary means of determining cell fate in the event of DNA damage. When it becomes mutated, it opens damaged cells to the possibility of reproducing unchecked, which can lead to formation of cancerous tumors. Despite its critical role, therapies at the molecular level to restore p53 native function remain elusive, due to its complex nature. Nevertheless, considerable information has been amassed, and new means of investigating the problem have become available. Objectives: We consider structural, biophysical, and bioinformatic insights and their implications for the role of direct and indirect readout and how they contribute to binding site recognition, particularly those of low consensus. We then pivot to consider advances in computational approaches to drug discovery. Materials and methods: We have conducted a review of recent literature pertinent to the p53 protein. Results: Considerable literature corroborates the idea that p53 is a complex allosteric protein that discriminates its binding sites not only via consensus sequence through direct H-bond contacts, but also a complex combination of factors involving the flexibility of the binding site. New computational methods have emerged capable of capturing such information, which can then be utilized as input to machine learning algorithms towards the goal of more intelligent and efficient de novo allosteric drug design. Conclusions: Recent improvements in machine learning coupled with graph theory and sector analysis hold promise for advances to more intelligently design allosteric effectors that may be able to restore native p53-DNA binding activity to mutant proteins. Clinical relevance: The ideas brought to light by this review constitute a significant advance that can be applied to ongoing biophysical studies of drugs for p53, paving the way for the continued development of new methodologies for allosteric drugs. Our discoveries hold promise to provide molecular therapeutics which restore p53 native activity, thereby offering new insights for cancer therapies. Graphical Abstract: Structural representation of the p53 DBD (PDBID 1TUP). DNA consensus sequence is shown in gray, and the protein is shown in blue. Red beads indicate hotspot residue mutations, green beads represent DNA interacting residues, and yellow beads represent both.
ABSTRACT
PURPOSE OF REVIEW: To provide updated guidance for the medication treatment of acute agitation in the setting of psychosis or mania on inpatient psychiatric units. RECENT FINDINGS: This topic presented challenges: studies are sparse, tend to be under-powered, and are difficult to compare. Though there have been few recent studies, there have been several recent meta-analyses, Cochrane reviews, and published guidelines that sift through the primarily older evidence as well as more recent trials. The reviewers often do not agree on what seems to have the best evidence for efficacy and safety. SUMMARY: We conclude that the best approach is to summarize in some detail the evidence for each possible treatment and the interpretations published recently on each of those treatments, and then present recommendations for medication management in tiered rankings, based on the authors' qualitative review of the data and opinions. For oral treatment, the first-tier options are (alphabetically) haloperidol with lorazepam, lorazepam alone, and olanzapine. The second tier includes haloperidol with promethazine, loxapine inhaler, and risperidone alone. Tier 3 includes asenapine and quetiapine. For intramuscular treatment, the first-tier includes haloperidol plus promethazine, and olanzapine alone, and the second-tier includes haloperidol with lorazepam, and lorazepam alone.