Secretory Phospholipase A2 IIa Mediates Expression of Growth Factor Receptors in Esophageal Adenocarcinoma.

BACKGROUND: Receptor tyrosine kinases of the epidermal growth factor receptor (EGFR) family such as human epidermal receptor-2 (HER2) are involved in the development and progression of esophageal adenocarcinoma (EAC). Prior studies have demonstrated that group IIa secretory phospholipase A2 (sPLA2 IIa) can function as a ligand for the EGFR family of receptors and lead to an increase in receptor signaling. AIMS: We hypothesized that sPLA2 IIa inhibition downregulates the expression of EGFR and HER-2 in EAC and through this mechanism decreases proliferation in EAC. METHODS: Normal human esophageal epithelium, Barrett's esophagus (BE), and EAC tissue samples were assayed for baseline expression of EGFR, HER-2, and sPLA2 IIa. sPLA2 IIa was attenuated via inhibitor or lentiviral knockdown in esophageal cell lines, and cells were assayed for EGFR and HER2 expression as well as proliferation. FLO1 EAC cells were injected into the flank of nude mice. After randomization, mice received daily group IIA sPLA2 inhibitor or a control solution, and tumor volume was measured with calipers. RESULTS: sPLA2 IIa, EGFR, and HER2 expression increased across the spectrum of normal esophageal epithelium to EAC. sPLA2 IIa inhibition and knockdown decreased the expression of HER-2 and EGFR and proliferation. Mice treated with sPLA2 IIa inhibitor had smaller tumors than controls. CONCLUSIONS: sPLA2 IIa inhibition decreases EGFR and HER2 expression and lowers proliferation of human EAC. The discovery of sPLA2 IIa inhibition's ability to attenuate growth factor receptor signaling underscores the exciting potential of sPLA2 IIa inhibitors as therapeutics in the treatment of EAC.

Wnt Signaling Mediates Pro-Fibrogenic Activity in Human Aortic Valve Interstitial Cells.

BACKGROUND: Proinflammatory activation of toll-like receptor-4 (TLR4) drives phenotypic changes in aortic valve interstitial cells (AVICs) and produces a fibrogenic phenotype that mediates valvular fibrosis and contributes to aortic stenosis. Prior work identified upregulated Wnt signaling in AVICs taken from valves affected by aortic stenosis. Our purpose was to determine the contribution of Wnt signaling to TLR4-dependent fibrogenic activity in isolated human AVICs. METHODS: Human AVICs were isolated from hearts explanted for cardiac transplantation (N = 4). To test whether Wnt signaling contributed to TLR4-dependent fibrogenic activity, AVICs were treated with Wnt inhibitor (Dkk1) prior to TLR4 activation (LPS) and fibrogenic markers assessed. To determine the mediator of TLR4-to-Wnt signaling, expression of the key Wnt ligand, Wnt3a, was assessed after TLR4 activation and neutralizing antibodies confirmed the identity of the mediator. Fibrogenic activity was assessed after AVICs were treated with recombinant Wnt3a. Statistics were by analysis of variance (P < .05). RESULTS: TLR4 activation upregulated in vitro collagen deposition, type IV collagen and MMP2 expression, and Dkk1 inhibited these responses (P < .05). Expression of Wnt3a was upregulated after TLR4 activation (P < .05). Anti-Wnt3a neutralizing antibodies abrogated TLR4-dependent type IV collagen and MMP2 expression (P < .05). Wnt3a upregulated type IV collagen and MMP2 expression independent of TLR4 activation (P < .05). CONCLUSIONS: This study found that TLR4-dependent fibrogenic activity was mediated through Wnt signaling. The mediator of profibrogenic TLR4-to-Wnt signaling was a key Wnt ligand, Wnt3a. The abrogation of TLR4-induced fibrogenic activity in human AVICs by Wnt blockade illustrates a potential therapeutic role for Wnt inhibition in treatment and/or prevention of aortic stenosis.

A Comparison of Frailty Measures at Listing to Predict Outcomes After Lung Transplantation.

BACKGROUND: Sarcopenia may be an important predictive factor of outcomes after lung transplantation (LTx). Serum albumin and the 6-minute walk distance (6MWD) have been shown to be a marker of LTx outcomes. We measured sarcopenia, albumin, and 6MWD in a cohort of LTx patients and analyzed the utility of these as markers of outcomes for LTx patients. METHODS: We retrospectively identified LTx recipients from 2013-2018 at our institution who underwent computed tomographic imaging during their listing evaluation. From that image, we measured skeletal muscle cross-sectional surface area at the third lumbar vertebral level, and sarcopenia was diagnosed by established cutoffs. Associations between sarcopenia, albumin, 6MWD, and survival, and hospital length of stay, complications, readmissions, and discharge destination were evaluated. RESULTS: Sarcopenia was found in 72% (95 of 132) of patients, 18% (24 of 131) of patients were hypoalbuminemic, and 41% had a low 6MWD. Survival was not associated with presence of sarcopenia (hazard ratio [HR], 1.06; 95% confidence interval [CI], 0.46-2.42) or low 6MWD (HR, 0.86; 95% CI, 0.410-1.83). Hospital length of stay, complications, readmissions, and discharge destination were not influenced by sarcopenia or 6MWD. In contrast, hypoalbuminemia was independently associated with decreased survival (HR, 2.25; 95% CI, 1.04-4.85) and a higher grade of postoperative complications (P = .04). CONCLUSIONS: Sarcopenia is prevalent in LTx patients. Neither sarcopenia nor 6MWD predicted mortality or short-term outcomes after LTx. This is in contrast to albumin levels, which were inversely associated with survival and complications. Albumin shows promise as an important predictor of mortality and short-term outcomes after LTx.

Meta-Analysis of Surgeon Burnout Syndrome and Specialty Differences.

OBJECTIVE: Surgeon burnout compromises the quality of life of physicians and the delivery of care to patients. Burnout rates and interpretation of the Maslach Burnout Inventory (MBI) complicates the interpretation of surgeon burnout. The purpose of this study is to apply a standardized interpretation of severe surgeon burnout termed, "burnout syndrome" to analyze inherent variation within surgical specialties. DESIGN: A systematic literature search was performed using MEDLINE, PsycINFO, and EMBASE to identify studies reporting MBI data by surgical specialty. Data extraction was performed to isolate surgeon specific data. SETTING: A meta-analysis was performed. RESULTS: A total of 16 cross-sectional studies were included in this meta-analysis, totaling 3581 subjects. A random effects model approximated burnout syndrome at 3.0% (95% CI: 2.0%-5.0%; I2 = 78.1%). Subscale analysis of emotional exhaustion, depersonalization, and personal accomplishment indicated subscale burnout in 30.0% (CI: 25.0%-36.0%; I2 = 93.2%), 34.0% (CI: 25.0%-43.0%; I2 = 96.9%), and 25.0% (CI: 18.0%-32.0%; I2 = 96.5%) of surgeons, respectively. Significant differences (p < 0.001) in MBI subscale scoring existed among surgical specialties. CONCLUSIONS: Approximately 3% of surgeons suffer from extreme forms of burnout termed "burnout syndrome," although surgeon burnout may occur in up to 34% of surgeons, characterized by high burnout in 1 of 3 subscales. Surgical specialties have significantly different rates of burnout subscales. Future burnout studies should target the specialty-specific level to understand inherent differences in an effort to better understand methods of improving surgeon burnout.