Post-Cesarean Opioid Use after Implementation of Enhanced Recovery after Surgery Protocol.

OBJECTIVE: This study aimed to evaluate whether implementation of an enhanced recovery after surgery (ERAS) protocol is associated with lower maternal opioid use after cesarean delivery (CD). STUDY DESIGN: We performed a pre- and postimplementation (PRE and POST, respectively) study of an ERAS protocol for cesarean deliveries. ERAS is a multimodal, multidisciplinary perioperative approach. The four pillars of our protocol include education, pain management, nutrition, and early ambulation. Patients were counseled by their outpatient providers and given an educational booklet. Pain management included gabapentin and acetaminophen immediately prior to spinal anesthesia. Postoperatively patients received scheduled acetaminophen and ibuprofen. Oxycodone was initiated as needed 24 hours after spinal analgesia. Preoperative diet consisted of clear carbohydrate drink consumed 2 hours prior to scheduled operative time with advancement as tolerated immediately postoperation. Women with a body mass index (BMI) <40 kg/m2 and scheduled CD were eligible for ERAS. PRE patients were randomly selected from repeat cesarean deliveries (RCDs) at a single site from October 2017 to September 2018, BMI <40 kg/m2, without trial of labor. The POST cohort included women who participated in ERAS from October 2018 to June 2019. PRE and POST demographic and clinical characteristics were compared. Primary outcome was total postoperative morphine milligram equivalents (MMEs). Secondary outcomes included length of stay (LOS) and maximum postoperative day 2 (POD2) pain score. RESULTS: All women in PRE (n = 70) had RCD compared with 66.2% (49/74) in POST. Median total postoperative MMEs were 140.0 (interquartile range [IQR]: 87.5-182.5) in PRE compared with 0.0 (IQR: 0.0-72.5) in POST (p < 0.001). Median LOS in PRE was 4.02 days (IQR: 3.26-4.27) compared with 2.37 days (IQR: 2.21-3.26) in POST (p < 0.001). Mean maximum POD2 pain score was 5.28 (standard deviation [SD] = 1.86) in PRE compared with 4.67 (SD = 1.63) in POST (p = 0.04). CONCLUSION: ERAS protocol was associated with decreased postoperative opioid use, shorter LOS, and decreased pain after CD. KEY POINTS: · ERAS protocol was associated with decreased postoperative opioid use after CD.. · ERAS protocol was associated with shorter length of stay after CD.. · ERAS protocol was associated with decreased postoperative pain after CD..

APT2 Inhibition Restores Scribble Localization and S-Palmitoylation in Snail-Transformed Cells.

The multidomain scaffolding protein Scribble (Scrib) organizes key signaling complexes to specify basolateral cell polarity and suppress aberrant growth. In many human cancers, genetically normal Scrib mislocalizes from cell-cell junctions to the cytosol, correlating with enhanced growth signaling and malignancy. Here we confirm that expression of the epithelial-to-mesenchymal transcription factor (EMT-TF) Snail in benign epithelial cells leads to Scrib displacement from the plasma membrane, mimicking the mislocalization observed in aggressive cancers. Upon further examination, Snail promotes a transcriptional program that targets genes in the palmitoylation cycle, repressing many protein acyl transferases and elevating expression and activity of protein acyl thioesterase 2 (APT2). APT2 isoform-selective inhibition or knockdown rescued Scrib membrane localization and palmitoylation while attenuating MEK activation. Overall, inhibiting APT2 restores balance to the Scrib palmitoylation cycle, promoting membrane re-localization and growth attenuation. These findings emphasize the importance of S-palmitoylation as a post-translational gatekeeper of cell polarity-mediated tumor suppression.

Correlated S-palmitoylation profiling of Snail-induced epithelial to mesenchymal transition.

Epithelial cells form spatially-organized adhesion complexes that establish polarity gradients, regulate cell proliferation, and direct wound healing. As cells accumulate oncogenic mutations, these key tumor suppression mechanisms are disrupted, eliminating many adhesion complexes and bypassing contact inhibition. The transcription factor Snail is often expressed in malignant cancers, where it promotes transcriptional reprogramming to drive epithelial-mesenchymal transition (EMT) and establishes a more invasive state. S-Palmitoylation describes the fatty-acyl post-translational modification of cysteine residues in proteins, and is required for membrane anchoring, trafficking, localization and function of hundreds of proteins involved in cell growth, polarity, and signaling. Since Snail-expression disrupts apico-basolateral cell polarity, we asked if Snail-dependent transformation induces proteome-wide changes in S-palmitoylation. MCF10A breast cancer cells were retrovirally transduced with Snail and correlated proteome-wide changes in protein abundance and S-palmitoylation were profiled by using stable isotope labeling in cell culture with amino acid (SILAC) mass spectrometry. This analysis identified increased levels of proteins involved in migration, glycolysis, and cell junction remodeling, and decreased levels of proteins involved in cell adhesion. Overall, protein S-palmitoylation is highly correlated with protein abundance, yet for a subset of proteins, this correlation is uncoupled. These findings suggest that Snail-overexpression affects the S-palmitoylation cycle of some proteins, which may participate in cell polarity and tumor suppression.