Nuclear activation of Wnt/β-catenin signaling is required for cell proliferation in inflammation and cancer. Studies from our group indicate that β-catenin activation in colitis and colorectal cancer (CRC) correlates with increased nuclear levels of β-catenin phosphorylated at serine 552 (pβ-Cat552). Biochemical analysis of nuclear extracts from cancer biopsies revealed the existence of low molecular weight (LMW) pβ-Cat552, increased to the exclusion of full size (FS) forms of β-catenin. LMW β-catenin lacks both termini, leaving residues in the armadillo repeat intact. Further experiments showed that TCF4 predominantly binds LMW pβ-Cat552 in the nucleus of inflamed and cancerous cells. Nuclear chromatin bound localization of LMW pβ-Cat552 was blocked in cells by inhibition of proteasomal chymotrypsin-like activity but not by other protease inhibitors. K48 polyubiquitinated FS and LMW β-catenin were increased by treatment with bortezomib. Overexpressed in vitro double truncated β-catenin increased transcriptional activity, cell proliferation and growth of tumor xenografts compared to FS β-catenin. Serine 552-> alanin substitution abrogated K48 polyubiquitination, β-catenin nuclear translocation and tumor xenograft growth. These data suggest that a novel proteasome-dependent posttranslational modification of β-catenin enhances transcriptional activation. Discovery of this pathway may be helpful in the development of diagnostic and therapeutic tools in colitis and cancer.
Parastomal hernias (PHs) frequently complicate enterostomy creation. Decision for PH repair (PHR) is driven by patient symptoms due to the frequency of complications and recurrences. The European Hernia Society (EHS) PH classification is based on the PH defect size and the presence/ absence of concomitant incisional hernia. The aim of this study was to evaluate PHR outcomes based on EHS classification. An Institutional Review Board–approved retrospective review of a prospective database between 2009 and 2017 was performed. Patient demographics, enterostomy type, EHS classification, operative technique, and clinical outcomes (postoperative complications, 30-day readmission, and PH recurrence) were obtained. Cases were analyzed by EHS classifications I and II (SmallPH) versus III and IV (LargePH). Sixty-two patients underwent PHR (35: SmallPH, 27: LargePH). Patient groups (SmallPH vs LargePH) were similar based on American Society of Anesthesiologists Class III and obesity. Hernia recurrence was seen in 26 per cent of repairs with no difference between groups. The median recurrence-free survival was 3.9 years. There was no difference in superficial SSI, deep SSI, nonwound complications, or readmission between SmallPH and LargePH. Both small and large PHs experience similar outcomes after repair. Strategies to improve outcomes should be developed and implemented universally across all EHS PH classes.
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