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Squamous cell carcinomas (SCCs) are aggressive malignancies. Previous report demonstrated that master transcription factors (TFs) TP63 and SOX2 exhibited overlapping genomic occupancy in SCCs. However, functional consequence of their frequent co-localization at super-enhancers remains incompletely understood. Here, epigenomic profilings of different types of SCCs reveal that TP63 and SOX2 cooperatively and lineage-specifically regulate long non-coding RNA (lncRNA) CCAT1 expression, through activation of its super-enhancers and promoter. Silencing of CCAT1 substantially reduces cellular growth both in vitro and in vivo, phenotyping the effect of inhibiting either TP63 or SOX2. ChIRP analysis shows that CCAT1 forms a complex with TP63 and SOX2, which regulates EGFR expression by binding to the super-enhancers of EGFR , thereby activating both MEK/ERK1/2 and PI3K/AKT signaling pathways. These results together identify a SCC-specific DNA/RNA/protein complex which activates TP63/SOX2-CCAT1-EGFR cascade and promotes SCC tumorigenesis, advancing our understanding of transcription dysregulation in cancer biology mediated by master TFs and super-enhancers. Master regulator transcription factors TP63 and SOX2 have been reported to overlap in genomic occupancy in squamous cell carcinomas (SCCs). Here, the authors demonstrate that TP63 and SOX2 promote co-operatively long non-coding RNA CCAT1 expression through activating its super-enhancer, and CCAT1 forms a complex with TP63 and SOX2, which regulates EGFR super-enhancers and enhances both the MEK/ERK1/2 and PI3K/AKT signaling pathways in SCC.

The COVID-19 pandemic has impacted surgical training nationwide. Our former curricula will likely not return, and training will need to adapt, so we are able to graduate residents of the same caliber as prior to the pandemic. A survey evaluating perceptions of changes made in surgical training was conducted on surgery residents and attendings. Disaster medicine training has become more relevant and 85% residents and 75% attendings agreed it should be incorporated into the curriculum. Safety of family was the most significant concern of residents. Virtual curriculum was perceived to be acceptable by 82% residents and only 22% attendings (p < 0.01). Residents (37%) were less concerned than attendings (61%) of falling behind on their overall training (p = 0.04). Both groups agreed operative skills would be adversely affected (56%vs72%; p = 0.37). To maintain an effective surgical curriculum, programs will need to implement new educational components to better prepare residents to become surgeons of the future. •Comprehensive assessment of the curriculum changes made during the pandemic.•Disaster medicine training, well-being, and concern for families became relevant.•Attendings perceive the pandemic has had adverse effects on training.•New educational methods will need to be incorporated to train residents adequately.

Lobectomy may unnecessarily resect healthy lung parenchyma in Stage 1A non-small cell lung cancers (NSCLC). Segmentectomies may provide a lung-sparing option. VATS segmentectomies can be technically challenging; robotics may have features that provide advantages in performing segmentectomies. We describe the association of the robot on national trends in segmentectomies. The National Cancer Database (2010–2017) was queried for patients with Stage 1A NSCLC who underwent lobectomies and segmentectomies. The proportion of segmentectomies vs. lobectomies and the proportion of robotic vs. VATS segmentectomies was calculated annually. The proportion of segmentectomies increased compared to lobectomies for all surgical approaches but remained constant for minimally-invasive approaches. The proportion of robotic segmentectomies increased over the years compared to VATS segmentectomies. Descriptive statistics are reported as numbers and proportions. Trends in the proportions of lobectomies and segmentectomies were compared using Chi-squared test for categorical variables and unpaired t-test for independent means. A p-value of <0.05 was considered statistically significant. Statistical analysis was performed using SPSS Statistics Software version 24 (IBM Corp, Armonk, NY). We demonstrate an increasing trend and proportion of robotic segmentectomies being performed in comparison to VATS segmentectomies. The robotic platform may facilitate the performance of more segmentectomies for early-stage NSCLC.Statistical Analysis [Display omitted] •The proportion of segmentectomies compared to lobectomies has greatly increased.•Segmentectomy was performed in older patients compared to the lobectomy group.•Patients receiving a MIS approach for segmentectomy significantly increased.•The proportion of robotic compared to VATS segmentectomies has greatly increased.•Robotic segmentectomies have increased in prevalence for stage 1A NSCLC.

Gastroesophageal reflux disease (GERD) is commonly reported on esophagram (UGI) studies. The correlation of findings suggestive of GERD on UGI with pH monitoring and high-resolution esophageal manometry (HRM) studies is unclear. We investigate the correlation between reflux on UGI with the findings on pH studies and HRM. Subjects completed a symptom questionnaire before their scheduled study. Data from pH and HRM studies were compared with findings of the UGI. Sixty-five patients were evaluated. Reflux was reported on UGI in 19 of 65 (29.2%). Thirty-six patients had both UGI and pH studies; 22 of 36 (61.1%) had reflux on pH studies. UGI had a false-negative finding in 11 of 20 (55%) with no radiographic evidence of reflux. There was a false-positive finding in five of 16 (31.2%) patients on UGI. There was concordance in 11 of 36 (30.5%). Sixty-three patients had both UGI and HRM; there was positive concordance in eight of 63 (12.7%). Using pH monitoring as the gold standard for GERD, sensitivity was 0.50, specificity 0.64, positive predictive value 0.68, and negative predictive value 0.45 for reflux on UGI. The correlation between reflux reported on UGI and 24-hour pH monitoring is poor. Esophagram (UGI) should be reserved for defining structural defects in the esophagus and not reflux.

Malignant pleural effusions (MPE) are commonly managed with either pleural catheter (PC) or talc pleurodesis (TP). The aim of this study was to compare survival in MPE patients treated with either PC or TP. A retrospective review of our cancer center database was performed. Patients with metastatic cancer and MPE were analyzed. Demographic and clinical data were tabulated and compared. A total of 238 patients with MPE treated by either PC or TP were included. Of these, 79 patients comprised the PC group and 159 the TP group. PC had a higher incidence of advanced disease (stage III or IV) at initial diagnosis compared with TP (70.9% vs 57.2%, P = 0.05). TP had a longer postprocedure length of stay compared with PC (7.1 vs 5.0 days, P = 0.02); however, overall length of stay was similar (9.7 vs 11.1 days, P = 0.34). Read-missions were significantly lower in TP (11.9% vs 22.8%, P = 0.04). Mean survival was higher in TP compared with PC (18.7 vs 4.1 months, P < 0.001). Patients with metastatic cancer and MPE treated with TP had significantly higher survival compared with PC. This is likely related to a greater disease burden in PC, as 70 per cent of patients in this group had stage III or IV disease on initial presentation.

Decompressive craniectomy in the treatment of severe traumatic brain injury (TBI) is controversial. We conducted a retrospective review of prospectively collected data on all patients requiring surgery for TBI from 1995 through 2001 at Cedars-Sinai Medical Center. Patients were separated into two groups: Group A, craniectomy, and Group B, craniotomy. We had 120 patients; 24 (20%) had craniectomy and 96 (80%) had craniotomy. There were no significant differences in demographics or Injury Severity Scores. The craniectomy group had significantly more TBI as evidenced by more frequently collapsed basilar cisterns on CT scan (P = 0.0001). There was no significant difference in actuarial survival between the groups: 52.8 per cent in the craniectomy group and 79.2 per cent in the craniotomy group (P = 0.08). Calculated mortality for craniectomy was 37.5 per cent versus 18.8 per cent for craniotomy (P = NS). We found four preoperative findings to be significant predictors of mortality: 1) Glasgow Coma Scale score, 2) Injury Severity Score, 3) Simplified Acute Physiology Score, and 4) Acute Physiology and Chronic Health Evaluation II. The type of surgery was not found to be a significant predictor of death even when adjusted for severity of injury. Craniectomy may be helpful for patients with TBI associated with preoperative CT scan evidence of basilar cistern collapse. This is evidenced by similar survival rates between the two groups despite clinical evidence of greater TBI among craniectomy patients.

Graft coronary arteriosclerosis (GCA) is the leading cause of long-term mortality after heart transplantation (HTx). The goal of this study was to demonstrate that inhibition of immune-mediated injury by cyclosporine (CsA) protects the allograft from GCA. ACI-to-Lewis rat allografts were disparate in major and nonmajor histocompatibility loci. Isografts (Lewis-Lewis) were controls. Treatment groups received either olive oil or CsA at 2.5, 5, 10, or 20 mg/kg/day for 3 months. Histology (elastin) and immunohistochemistry using monoclonal antibodies to CD4, CD8, CD45R, RT1B, CD11b/c, CD25, and α-actin was performed to examine the epicardial and intramyocardial coronary arteries. Computerized image morphometry was utilized to measure intimal and medial thickness and area. Rats receiving olive oil or CsA at 2.5 mg/kg/day had severe rejection and no graft survival. CsA at 5 mg/kg/day resulted in less severe rejection with significant intimal and medial proliferation (P < 0.001). CsA at 10–20 mg/kg/day paralleled Lewis-Lewis isograft outcomes and inhibited arteriosclerotic vascular changes in the allograft (P < 0.001). Perivascular T-helper cells and macrophages were a characteristic finding with low-dose CsA but rare with higher CsA doses. In this new model of accelerated GCA in rats, immune-mediated antigen-dependent vasculopathy as a result of inadequate immunosuppresion is fundamental in the development of GCA, which appeared equally in epicardial arteries and intramyocardial arterioles. CsA prevents GCA in a dose-dependent fashion in the rat allograft.

Tissue fibrosis is a common pathological outcome of chronic disease that markedly impairs organ function leading to morbidity and mortality. In the lung, idiopathic pulmonary fibrosis (IPF) is an insidious and fatal interstitial lung disease associated with declining pulmonary function. Here, we show that alveolar type 2 (AT2) stem cells isolated from IPF lung tissue exhibit characteristic transcriptomic features of cellular senescence. We used conditional loss of Sin3a in adult mouse AT2 cells to initiate a program of p53-dependent cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis. We establish that senescence rather than loss of epithelial stem cells serves as a proximal driver of Tgf-beta; activation and progressive fibrosis and show that either genetic or pharmacologic interventions targeting p53 activation, senescence, or downstream Tgf-beta activation, block fibrogenesis. Footnotes * We have corrected and updated reference list.

Early postoperative ambulation is vital to minimizing length of stay (LOS), but few hospitals objectively measure ambulation to predict outcomes. Wearable activity monitors have the potential to transform assessment of postoperative ambulation, but key implementation data, including whether digitally monitored step count can identify patients at risk for poor efficiency outcomes, are lacking. To define the distribution of digitally measured daily step counts after major inpatient surgical procedures, to assess the accuracy of physician assessment and ordering of ambulation, and to quantify the association of digitally measured step count with LOS. Prospective cohort study at Cedars-Sinai Medical Center, an urban tertiary referral center. Participants were patients undergoing 8 inpatient operations (lung lobectomy, gastric bypass, hip replacement, robotic cystectomy, open colectomy, abdominal hysterectomy, sleeve gastrectomy, and laparoscopic colectomy) from July 11, 2016, to August 30, 2017. Use of activity monitors to measure daily postoperative step count. Operation-specific daily step count, daily step count by physician orders and assessment, and a prolonged LOS (>70th percentile for each operation). Among 100 patients (53% female), the mean (SD) age was 53 (18) years, and the median LOS was 4 days (interquartile range, 3-6 days). There was a statistically significant increase in daily step count with successive postoperative days in aggregate (r = 0.55; 95% bootstrapped CI, 0.47-0.62; P < .001) and across individual operations. Ninety-five percent (356 of 373) of daily ambulation orders were \"ambulate with assistance,\" although daily step counts ranged from 0 to 7698 steps (0-5.5 km) under this order. Physician estimation of ambulation was predictive of the median step count (r = 0.66; 95% bootstrapped CI, 0.59-0.72; P < .001), although there was substantial variation within each assessment category. For example, daily step counts ranged from 0 to 1803 steps (0-1.3 km) in the \"out of bed to chair\" category. Higher step count on postoperative day 1 was associated with lower odds of prolonged LOS from 0 to 1000 steps (odds ratio [OR], 0.63; 95% CI, 0.45-0.84; P = .003), with no further decrease in odds after 1000 steps (OR, 0.99; 95% CI, 0.75-1.30; P = .80). In this study, digitally measured step count up to 1000 steps on postoperative day 1 was associated with lower probability of a prolonged LOS. Wearable activity monitors improved the accuracy of assessment of daily step count over the current standard of care, providing an opportunity to identify patients at risk for poor efficiency outcomes.