Melanoma is one of the most highly mutated cancer types. To identify functional drivers of melanoma, we searched for cross-species conserved mutations utilizing a mouse melanoma model driven by loss of PTEN and CDKN2A, and identified mutations in Kras, Erbb3, and Ptpn11. PTPN11 encodes the SHP2 protein tyrosine phosphatase that activates the RAS/RAF/MAPK pathway. Although PTPN11 is an oncogene in leukemia, lung, and breast cancers, its roles in melanoma are not clear. In this study, we found that PTPN11 is frequently activated in human melanoma specimens and cell lines and is required for full RAS/RAF/MAPK signaling activation in BRAF wild-type (either NRAS mutant or wild-type) melanoma cells. PTPN11 played oncogenic roles in melanoma by driving anchorage-independent colony formation and tumor growth. In Pten-and Cdkn2a-null mice, tet-inducible and melanocytespecific PTPN11 E76K expression significantly enhanced mela-noma tumorigenesis. Melanoma cells derived from this mouse model showed doxycycline-dependent tumor growth in nude mice. Silencing PTPN11 E76K expression by doxycycline withdrawal caused regression of established tumors by induction of apoptosis and senescence, and suppression of proliferation. Moreover, the PTPN11 inhibitor (SHP099) also caused regression of NRAS Q61K -mutant melanoma. Using a quantitative tyrosine phosphoproteomics approach, we identified GSK3a/ b as one of the key substrates that were differentially tyrosinephosphorylated in these experiments modulating PTPN11. This study demonstrates that PTPN11 plays oncogenic roles in melanoma and regulates RAS and GSK3b signaling pathways.Implications: This study identifies PTPN11 as an oncogenic driver and a novel and actionable therapeutic target for BRAF wild-type melanoma.
Background:
Enteral nutrition is commonly initiated 24 hours after percutaneous endoscopic gastrostomy (PEG) in children. Adult studies report safe refeeding within 1 to 6 hours of PEG, and these findings have been cautiously applied to children. Comparative studies assessing early versus next-day refeeding in children are currently lacking. This study evaluates feeding tolerance and complications following early versus next-day refeeding in children.
Methods:
This is a single-center, pre-post study. In June 2015 our clinical practice changed to begin refeeding within 6 hours of PEG. Children receiving early refeeding from December 2015 to August 2017 were included. A retrospective cohort from February 2013 to April 2015 was used for comparison.
Results:
Forty-six children received early refeeding after PEG and 37 received next-day refeeding. Gender distribution was similar in the 2 groups. Early refeeding patients were slightly older (3.5 vs 2.2 years) and heavier (15.5 vs 11.5 kg) at PEG placement compared to next-day refeeding patients. Early refeeding patients experienced greater postprocedural nausea and/or vomiting (19% vs 8%, P < 0.001) and leakage, irritation, and infection around the stoma (19% vs 0.0%, P < 0.001). Compared to early refeeders, next-day refeeding patients experienced higher occurrence of fever (35% vs 13%, P = 0.021), longer nutritional disruption (24.6 vs 3.7 hours, P < 0.001), and longer length of stay (51 vs 27 hours; P < 0.001). One next-day refeeding patient experienced peritonitis. One early refeeding patient experienced cellulitis requiring hospitalization and a second experienced gastrostomy tube migration into the peritoneal cavity requiring removal.
Conclusion:
Early refeeders experienced higher rates of postprocedural nausea or vomiting and irritation, leakage, or infection around the stoma; but experienced lower rates of postoperative fever. Early refeeding resulted in reduced nutritional interruption and hospital length of stay.
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