Dysregulation of the Ras oncogene in development causes developmental disorders, "Rasopathies," whereas mutational activation or amplification of Ras in differentiated tissues causes cancer. Rabex-5 (also called RabGEF1) inhibits Ras by promoting Ras mono-and di-ubiquitination. We report here that Rabex-5-mediated Ras ubiquitination requires Ras Tyrosine 4 (Y4), a site of known phosphorylation. Ras substitution mutants insensitive to Y4 phosphorylation did not undergo Rabex-5-mediated ubiquitination in cells and exhibited Ras gain-of-function phenotypes in vivo. Ras Y4 phosphomimic substitution increased Rabex-5mediated ubiquitination in cells. Y4 phosphomimic substitution in oncogenic Ras blocked the morphological phenotypes associated with oncogenic Ras in vivo dependent on the presence of Rabex-5. We developed polyclonal antibodies raised against an N-terminal Ras peptide phosphorylated at Y4. These anti-phospho-Y4 antibodies showed dramatic recognition of recombinant wild-type Ras and Ras G12V proteins when incubated with JAK2 or SRC kinases but not of Ras Y4F or Ras Y4F,G12V recombinant proteins suggesting that JAK2 and SRC could promote phosphorylation of Ras proteins at Y4 in vitro. Anti-phospho-Y4 antibodies also showed recognition of Ras G12V protein, but not wild-type Ras, when incubated with EGFR. A role for JAK2, SRC, and EGFR (kinases with well-known roles to activate signaling through Ras), to promote Ras Y4 phosphorylation could represent a feedback mechanism to limit Ras activation and thus establish Ras homeostasis. Notably, rare variants of Ras at Y4 have been found in cerebellar glioblastomas. Therefore, our work identifies a physiologically relevant Ras ubiquitination signal and highlights a requirement for Y4 for Ras inhibition by Rabex-5 to maintain Ras pathway homeostasis and to prevent tissue transformation.
Study Design Retrospective database study. Objectives The goal of this study was to assess the influence of weekend admission on patients undergoing elective thoracolumbar spinal fusion by investigating hospital readmission outcomes and analyzing differences in demographics, comorbidities, and postoperative factors. Methods The 2016-2018 Nationwide Readmission Database was used to identify adult patients who underwent elective thoracolumbar spinal fusion. The sample was divided into weekday and weekend admission patients. Demographics, comorbidities, complications, and discharge status data were compiled. The primary outcomes were 30-day and 90-day readmission. Univariate logistic regression analyzed the relationship between weekday or weekend admission and 30- or 90-day readmission, and multivariate regression determined the impact of covariates. Results 177,847 patients were identified in total, with 176,842 in the weekday cohort and 1005 in the weekend cohort. Multivariate regression analysis found that 30-day readmissions were significantly greater for the weekend cohort after adjusting for sex, age, Medicare or Medicaid status, and comorbidity status (OR 2.00, 95% CI: 1.60-2.48; P < .001), and 90-day readmissions were also greater for the weekend cohort after adjustment (OR 2.01, 95% CI: 1.68-2.40, P < .001). Conclusions Patients undergoing elective thoracolumbar spinal fusion surgery who are initially admitted on weekends are more likely to experience hospital readmission. These patients have increased incidence of deep vein thrombosis, postoperative infection, and non-routine discharge status. These factors are potential areas of focus for reducing the impact of the “weekend effect” and improving outcomes for elective thoracolumbar spinal fusion.
Objective: Subsidence following anterior cervical discectomy and fusion (ACDF) may lead to disruptions of cervical alignment and lordosis. The purpose of this study was to evaluate the effect of subsidence on segmental, regional, and global lordosis.Methods: This was a retrospective cohort study performed between 2016–2021 at a single institution. All measurements were performed using lateral cervical radiographs at the immediate postoperative period and at final follow-up greater than 6 months after surgery. Associations between subsidence and segmental lordosis, total fused lordosis, C2–7 lordosis, and cervical sagittal vertical alignment change were determined using Pearson correlation and multivariate logistic regression analyses.Results: One hundred thirty-one patients and 244 levels were included in the study. There were 41 one-level fusions, 67 two-level fusions, and 23 three-level fusions. The median follow-up time was 366 days (interquartile range, 239–566 days). Segmental subsidence was significantly negatively associated with segmental lordosis change in the Pearson (r = -0.154, p = 0.016) and multivariate analyses (beta = -3.78; 95% confidence interval, -7.15 to -0.42; p = 0.028) but no associations between segmental or total fused subsidence and any other measures of cervical alignment were observed.Conclusion: We found that subsidence is associated with segmental lordosis loss 6 months following ACDF. Surgeons should minimize subsidence to prevent long-term clinical symptoms associated with poor cervical alignment.
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