Cellular plasticity contributes to intra-tumoral heterogeneity and phenotype switching, which enable adaptation to metastatic microenvironments and resistance to therapies. Mechanisms underlying tumor cell plasticity remain poorly understood. SOX10, a neural crest lineage transcription factor, is heterogeneously expressed in melanomas. Loss of SOX10 reduces proliferation, leads to invasive properties, including the expression of mesenchymal genes and extracellular matrix, and promotes tolerance to BRAF and/or MEK inhibitors. We identify the class of cellular inhibitor of apoptosis protein-1/2 (cIAP1/2) inhibitors as inducing cell death selectively in SOX10-deficient cells. Targeted therapy selects for SOX10 knockout cells underscoring their drug tolerant properties. Combining cIAP1/2 inhibitor with BRAF/MEK inhibitors delays the onset of acquired resistance in melanomas in vivo. These data suggest that SOX10 mediates phenotypic switching in cutaneous melanoma to produce a targeted inhibitor tolerant state that is likely a prelude to the acquisition of resistance. Furthermore, we provide a therapeutic strategy to selectively eliminate SOX10-deficient cells.

Pets, Health, China, Natural experiment,

We thank the surgeons and research assistants who contributed patients and data from the following institutions constituting the Ampullary Carcinoma Study Group and Pancreas Fistula Study Group:

Some controversy surrounds the postoperative feeding regimen utilized in patients who undergo esophagectomy. Variation in practices during the perioperative period exists including the type of nutrition started, the delivery route, and its timing. Adequate nutrition is essential for this patient population as these patients often present with weight loss and have altered eating patterns after surgery, which can affect their ability to regain or maintain weight. Methods of feeding after an esophagectomy include total parenteral nutrition, nasoduodenal/nasojejunal tube feeding, jejunostomy tube feeding, and oral feeding. Recent evidence suggests that early oral feeding is associated with shorter LOS, faster return of bowel function, and improved quality of life. Enhanced recovery pathways after surgery pathways after esophagectomy with a component of early oral feeding also seem to be safe, feasible, and cost-effective, albeit with limited data. However, data on anastomotic leaks is mixed, and some studies suggest that the incidence of leaks may be higher with early oral feeding. This risk of anastomotic leak with early feeding may be heavily modulated by surgical approach. No definitive data is currently available to definitively answer this question, and further studies should look at how these early feeding regimens vary by surgical technique. This review aims to discuss the existing literature on the optimal route and timing of feeding after esophagectomy.