Successful decannulation of patients with traumatic spinal cord injury: A scoping review.

Context: Patients with spinal cord injury (SCI) often require tracheostomy as an immediate life-saving measure. Successful decannulation, or removal of the tracheostomy, improves patient quality of life, function, and physical appearance and is considered an important rehabilitative milestone for SCI patients.Objective: We sought to synthesize the existing published literature on SCI patients undergoing decannulation.Methods: Ovid MEDLINE, Embase, Web of Science, CINAHL, and Cochrane Central Register of Controlled Trials were systematically searched through July 2, 2019 using appropriate keywords and MeSH terms pertaining to tracheostomy and SCI. Searches were human-subject only without language restrictions. Published literature discussing the outcomes of SCI patients who underwent decannulation were screened using inclusion/exclusion criteria determined a priori and reviewed.Results: Twenty-six publications were eligible for review and synthesis out of 1,493 unique articles. Over half of the studies were retrospective case series or reports. The research was nearly all published within the fields of physical medicine and rehabilitation, neurology, and pulmonary/critical care. Three themes emerged from review: (1) interdisciplinary or multidisciplinary tracheostomy team management to optimize decannulation processes, (2) non-invasive intermittent positive-pressure ventilatory support instead of tracheostomy-based ventilator support, and (3) wide variation in the reporting of post-decannulation clinical outcomes.Conclusion: Published research lacks a consistent taxonomy for reporting post-decannulation outcomes in SCI patients. Non-invasive ventilation research could benefit many SCI patients but has been studied in depth primarily by a single authorship group. Further investigation into the socioeconomic and fiscal impact on tracheostomies on SCI patients is warranted.

Inactive full-length p53 mutants lacking dominant wild-type p53 inhibition highlight loss of heterozygosity as an important aspect of p53 status in human cancers.

Over 1000 different mutants of the tumor suppressor protein p53 with one amino acid change in the core domain have been reported in human cancers. In mouse knock-in models, two frequent mutants displayed loss of wild-type (wt) p53 function, inhibition of wt p53 and wt p53-independent gain of function. The remaining mutants have been systematically characterized for loss of wt p53 function, but not other phenotypes. We report the concomitant assessment of loss of function and interference with wt p53 using URA3-based p53 yeast and confirmatory mammalian assays. We studied 76 mutants representing 54% of over 15 000 reported missense core domain mutations. The majority showed the expected complete loss of wt p53 function and dominant p53 inhibition. A few infrequent p53 mutants had wt p53-like activity. Remarkably, one-third showed no interference with wt p53 despite loss of wt p53 function at 37 degrees C. Half of this group consisted of temperature-sensitive p53 mutants, but the other half was surprisingly made up of mutants with complete loss of wt p53 function. Our findings illustrate the diverse behavior of p53 mutants and mechanisms of malignant transformation by p53 mutants. The identification of full-length p53 mutants without dominant inhibition of wt p53 highlights the importance of determining the status of the wt p53 allele in human cancers, in particular in the context of clinical studies. In the case of p53 mutants with no or weak dominant p53 inhibition, presence of the wt allele may indicate a good prognosis cancer, whereas loss of heterozygosity may spell an aggressive, therapy-resistant cancer.

A global suppressor motif for p53 cancer mutants.

The transcription factor and tumor suppressor protein p53 is frequently inactivated in human cancers. In many cases, p53 gene mutations result in high levels of inactive, full-length p53 protein with one amino acid change in the core domain that recognizes p53 DNA-binding sites. The ability to endow function to mutated p53 proteins would dramatically improve cancer therapy, because it would reactivate a central apoptotic pathway. By using genetic strategies and p53 assays in yeast and mammalian cells, we identified a global suppressor motif involving codons 235, 239, and 240. These intragenic suppressor mutations, either alone or in combination, restored function to 16 of 30 of the most common p53 cancer mutants tested. The 235-239-240 suppressor motif establishes that manipulation of a small region of the core domain is sufficient to activate a large number of p53 cancer mutants. Understanding the structural basis of the rescue mechanism will allow the pursuit of small compounds able to achieve a similar stabilization of p53 cancer mutants.