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Carbon Starvation Metabolically Regulates Chromatin for Transcriptome Rewiring
(2022-05) Hsieh, Wen-Chuan; Conrad, Nicholas; Kraus, W. Lee; Orth, Kim; Tu, Benjamin
Cells robustly rewire their transcriptomes to survive under stress conditions. Yet, how does such reprogramming of gene expression occur? Under favorable nutrient conditions, acetyl-CoA normally promotes histone acetylation to activate genes required for cell growth. However, glucose starvation significantly reduces the availability of acetyl-CoA. And it is unclear how such a change impacts genome-wide histone acetylation and gene expression. In this study, I set up a robust glucose starvation model in budding yeast to discover a mechanism by which cells preserve acetyl-CoA, a key intermediate in energy metabolism, in order to sustain histone acetylation for gene activation even under stress conditions. I demonstrate a dramatic redistribution of histone acetylation upon glucose starvation. Mechanistically, I determined that a major histone deacetylase (HDAC) releases acetyl groups from histones at growth-promoting genes, which can subsequently be used to acetylate histones at a distinctive set of stress-responsive genes. Strikingly, bioinformatic analysis revealed these genes to be required for gluconeogenic and fat metabolism, which are metabolic pathways that generate acetyl-CoA for oxidation and ATP synthesis. Genetic deletion of histone modifiers mediating this reallocation, including the key HDAC or histone acetyltransferase (HAT), disrupts proper transcriptome rewiring for survival. Given the importance of acetate for recycling the acetyl- group, I next characterize acetyl-CoA synthetases (Acs), metabolic enzymes that convert acetate to acetyl-CoA. I demonstrate that Acs2 is required for maintaining global histone acetylation, yet its nuclear localization appears to be dispensable for such regulation. I observe that the catalytic activity of Acs2 governs the intracellular acetyl-CoA level and global histone acetylation amounts. Compromising its activity leads to up-regulation of ergosterol biosynthetic pathways in addition to gluconeogenic and fat metabolism genes upon glucose starvation. In summary, I reveal an unexpected switch in the specificity of histone acetylation to promote pathways that generate acetyl-CoA for oxidation when acetyl-CoA is limiting. I have elucidated how transcriptome rewiring is driven by reallocation of histone acetylation. My findings present a mechanism by which cells recycle acetyl groups to differentially acetylate histones for activation of key genes required for metabolism and survival.
Improving Intra-Operative Parathyroid Hormone Result Times at the University Hospitals
(2022-05) Wang, Virginia Y.; Reed, W. Gary; Nwariaku, Fiemu; Holt, Shelby A.
Intra-operative parathyroid hormone (ioPTH) levels are the current gold standard for assessing completeness of resection in parathyroidectomy surgery. Due to the time-sensitive nature of these results, delays in processing ioPTH samples lead to non-value-added time (NVAT) in the operating room, which generates unnecessary financial burdens and potential safety hazards for both patients and the hospital system. Baseline analysis of data from 191 parathyroidectomy cases performed by the UT Southwestern Endocrine Surgery Group at Clements University Hospital (CUH) and the Outpatient Surgery Center (OSC) between September 2020 and April 2021 identified a statistically significant delay in the sample-to-lab interval time in cases at the OSC (mean of 27 minutes) compared to cases at CUH (mean of 8 minutes). The need for a lab courier at the OSC is likely a major contributor to this NVAT, as the OSC does not have an in-house lab. Though altering the lab infrastructure to make in-house ioPTH processing at the OSC would be the most effective way to equalize the delay, it was also infeasible within the time constraints of this project given the depth of high-level decision-making this would necessitate. I chose to focus instead on optimizing parathyroidectomy case preparation. I worked with CUH OR nursing clinical leads to modify the Epic template text of surgeon preference cards, which OR nursing staff use to prepare for cases. Analysis of pre- and post-change data from 43 parathyroidectomy cases performed in February and March of 2022 at CUH revealed post-change special cause variation in both the sample-to-lab and lab-to-result interval times. Moving forward, many other interventions are available to continue to improve team communication and knowledge sharing and protocolize contingency plans; further work also remains to be done to address logistical constraints at the OSC on an institutional level.
The UT Southwestern Perioperative Optimization of Senior Health Program: Impact on Postoperative Delirium After Spine Surgery
(2022-05) Pernik, Mark Nicholas; Bagley, Carlos; Aoun, Salah; Adogwa, Owoicho
BACKGROUND: Delirium is a common complication in geriatric patients who often have multiple underlying risk factors after surgery or hospitalizations. Delirium is most effectively prevented prophylactically, as treatment of delirium may not shorten the duration or severity of delirium. Several investigations of pharmacological prophylaxis have shown minimal effect, whereas many non-pharmacological interventions have been shown to reduce the incidence of delirium. Multicomponent nonpharmacologic interventions can be effective in preventing delirium; however, implementation of preventative measures and programs are variable in perioperative care. OBJECTIVE: The aim of our study was to assess whether the Perioperative Optimization of Senior Health Program (POSH) reduced the incidence of postoperative delirium in geriatric patients undergoing elective spine surgery. METHODS: The POSH program is an interdisciplinary perioperative program involving geriatrics, surgery, and anesthesia. Preoperatively, patients enrolled in POSH (n=147) were referred for a geriatric assessment and optimization for surgery. Intraoperatively, patients underwent an individualized geriatric anesthesia protocol. Patients were co-managed postoperatively by the primary surgical team and the geriatrics consult service. POSH patients were retrospectively compared to a matched historical control group (n=177) treated with standard care. Outcomes included post-operative delirium, provider recognition of delirium, ICU and hospital LOS, initiation of walking postoperatively, and readmission. RESULTS: Patients enrolled in the POSH program were significantly older (75.5 vs. 71.5 years; p<0.001), had more comorbidities (8.0 vs. 6.6; p<0.001), and were more likely to undergo pelvic fixation (36.1% vs. 17.5%; p<0.001). The incidence of postoperative delirium was lower in POSH group compared to historical controls, although not statistically significant (11.6% vs. 19.2%; p=0.065). Delirium was significantly lower in patients who underwent complex spine surgery (≥4 levels of vertebral fusion; N=106) in the POSH group (11.7% vs. 28.9%, p=0.03). There was a 3-fold increase in the recognition of postoperative delirium by providers after program implementation, (76.5% vs. 23.5%; p=0.001). CONCLUSION: Interdisciplinary care for high-risk geriatric patients undergoing elective spine surgery may reduce the incidence of postoperative delirium and increase provider recognition of delirium. The benefit may be greater for those undergoing larger procedures.
Decreased Emergency Department Utilization by Lower Socioeconomic Status Population as a Result of the COVID-19 Pandemic
(2022-05) Plumber, Arifa; Chang, Mary; Marshall, Amanda L.; Idris, Ahamed H.
BACKGROUND: The SARS-CoV-2 (virus which causes COVID-19) pandemic has resulted in lower emergency department (ED) volumes. It precipitated business and school closures along with the implementation of physical distancing measures, which culminated in a Shelter-in-Place Order (SIPO) issued for a major urban area county in March 2020. OBJECTIVE: The objective of this study was to determine the effect of the COVID-19 pandemic on access to health care by patients of different socioeconomic status by examining differences in ED volume by zip code stratified by the SocioNeeds Index, a measure of socioeconomic need correlated with poor health outcomes. Our hypothesis was that decrease in patient visits due to the SIPO was not uniform across Dallas County but was based on socioeconomic need and proximity to Parkland's ED. METHODS: This retrospective chart review examines whether there was a quantitative change in patient visits to an urban, tertiary county hospital (Parkland or PMH) ED from 2019-2020 by zip code. The inclusion criterion was any ED visit from a patient with a zip code within Dallas County, and the exclusion criterion was any blank, alphanumeric, or PO box zip codes including zip codes located outside of Dallas County. The SocioNeeds Index, which rates each zip code by demographic factors relative to others in the county, was used as a proxy for the socioeconomic status of residents of each zip code. We mapped daily patient visits by zip code for four phases: Phase 1 was the three months preceding the first COVID-19 case's announcement in Dallas, Phase 2 began with the first COVID case, Phase 3 encompassed when the SIPO was in effect for Dallas County, and Phase 4 comprised the three months following the expiration of the SIPO. We compared this data to records over the same time period from the previous year to control for seasonal variation in the absence of a pandemic. RESULTS: There were 275,756 ED patient visits included in this study. We identified a statistically significant decrease in ED visits among patients from all zip codes during the pandemic: 24% between Phase 1 and 4 (p<0.0001) in 2020. Additionally, there was a decrease in visits after the first case in Dallas: Phase 2 (-14%, p<0.0001), Phase 3 (-41%, p<0.0001) and Phase 4 (-25%, p<0.0001) when compared to 2019 but an increase in visits (36%, p< 0.0001) in 2020 once the SIPO expired. Zip codes with highest SNI ranks (highest needs communities) were found to have greater reductions in visits during the SIPO and more sluggish recoveries after the expiration of the SIPO in comparison to those zip codes with the lowest needs. An examination of the geographic distribution of self-reported zip codes indicated that most communities in Dallas County saw a reduction in patient visits over Phases 2 and 3 (especially zip codes further from the ED) and an increase in visits during Phase 4 although not to pre-pandemic values. These changes, however, were not uniform across the county and were tied to socioeconomic factors and proximity of residence to PMH. CONCLUSION: Our hypothesis was supported by the results obtained: a significant decrease in ED visits was observed during the pandemic relative to a non-pandemic year among patients in most zip codes except those with the highest socioeconomic status, suggesting that the threat of the virus and SIPO deterred patients disproportionately from the higher socioeconomic needs communities from accessing healthcare. These results could have implications for future pandemic public health messaging and targeted outreach to communities with barriers to healthcare access.
HPV-Positive and HPV-Negative Vulvar Squamous Cell Carcinoma Are Biologically, but Not Clinically, Distinct
(2022-05) Kolitz, Elysha Megan; Wang, Richard; Mauskar, Melissa M.; Hosler, Gregory A.
BACKGROUND: Vulvar squamous cell carcinoma (VSCC) pathogenesis is traditionally defined by the presence or absence of human papillomavirus (HPV), but the definition of these groups and their molecular characteristics remains ambiguous across studies. OBJECTIVE: The hypothesis of this project was that HPV-positive and HPV-negative VSCC are distinct diagnoses with unique biomarkers and clinically distinct behaviors. The objective was to determine the clinical and biologic relevance of these two groups in VSCC. METHODS: A retrospective cohort analysis of 36 patients with invasive VSCC was performed where HPV status was determined using RNA in situ hybridization (ISH) and polymerase chain reaction (PCR). Clinical annotation, p16 immunohistochemistry (IHC), programmed death ligand-1 (PD-L1) IHC, HPV16 circular E7 RNA (circE7) detection, and RNA-sequencing (RNA-seq) of the cases was performed. RESULTS: A combination of ISH and PCR identified 20 cases (55.6%) as HPV-positive. HPV-status did not impact overall survival (HR: 1.36, 95% CI: 0.307 to 6.037, p=0.6857) or progression-free survival (HR: 1.12, 95% CI: 0.388 to 3.22, p=0.8367), and no significant clinical differences were found between the groups. PD-L1 expression did not correlate with HPV status, but increased expression of PD-L1 correlated with worse overall survival. Transcriptomic analyses (n=23) revealed distinct groups, defined by HPV status, with multiple differentially expressed genes previously implicated in HPV-induced cancers. HPV-positive tumors showed higher global expression of endogenous circular RNAs (circRNAs), including several circRNAs that have previously been implicated in the pathogenesis of other cancers. CONCLUSIONS: In summary, this retrospective cohort analysis did not detect clinical differences between HPV-positive and HPV-negative cases or an association with biomarkers, PD-L1 and circE7. The transcriptomic analysis of VSCC confirmed the biological distinction between these two groups in VSCC and suggested specific diagnostic and therapeutic targets for future studies, including several circRNAs.