Herniation of the cecum, terminal ileum, and ascending colon through the epiploic foramen is an uncommon presentation of an internal hernia. An 82-year-old female presented with a small bowel obstruction; Computed Tomography (CT) imaging showed a herniation of the terminal ileum, cecum, and ascending colon through the foramen of Winslow into the lesser sac, with cecal volvulus. Prompt surgical treatment included laparotomy and reduction of the hernia, followed by an extended right hemicolectomy with primary anastomosis and functional closure of the epiploic foramen. This report reviews the natural history and management of this rare pathology.
Introduction: Mutant GOF p53 is an epigenetic regulator which promotes oncogenesis. Many cancers with a GOF mutation accumulate cholesterol and inhibition of cholesterol synthesis with statin treatment reverses some of the pro-oncogenic properties of GOF p53. Our central hypothesis is that lipid raft signaling is altered by cholesterol accumulation in cells expressing a GOF p53. To address the role of cholesterol in promoting oncogenesis, we use the SW13 cell line bearing a GOF p53 (H193Y). This cell line has two epigenetically distinct cell subtypes that differentially express genes coding for GPI anchors, cholesterol biosynthesis, and sphingolipids, all of which are components of lipid rafts. In addition, the SW13 subtypes have different oncogenic profiles. The SW13(Vim-) subtype has an epithelial morphology and is highly proliferative. The SW13(Vim+) subtype has a mesenchymal-like phenotype and a higher metastatic potential. When treated with histone deacetylase inhibitors (HDACi), SW13(Vim-) appear to adopt a SW13(Vim+) phenotype. Therefore, we treat with HDACi to control the subtype conversion and shRNA to knock-down GOF p53 expression. This experimental approach allows the composition of raft fraction to be correlated to GOF p53 expression and oncogenic properties of each SW13 subtype, with and without p53 expression. Methods: Proliferation rate, MMP expression, and migration of SW13(Vim-), SW13(Vim+), shRNA SW13(Vim-), and shRNA SW13(Vim+) were quantitated by EdU assays and in situ zymography respectively. We have isolated lipid raft fractions by the detergent-resistant enrichment technique from SW13 cells of each subtype, with and without GOF p53 expression knock-down by shRNA. Proteins by mass spectrometry analysis. Fluorescent cholesterol assays and p53 western blots were used to quantify cholesterol levels and p53 protein expression, respectively. Results: Data suggest that there is a shift from planar rafts in the SW13(Vim-) to caveolar rafts in the SW13(Vim+) line. Although the contribution of GOF p53 to this shift is under study, evidence suggests that raft composition is altered in the shRNA lines, in which GOF p53 has been knocked down by ~90%. In addition, p53 knock-down increases the proliferation rate in SW13(Vim-) (p = 0.01) but does not affect SW13(Vim+). In contrast, p53 knock-down decreases MMP activity in SW13(Vim+) (p = 0.05) but not SW13(Vim-). Conclusions: Our data support the hypothesis that lipid raft signaling is significantly altered between the epigenetically distinct SW13 subtypes and that these differences may correlate to oncogenic potential. In addition, statin treatment, which reverses some of the pro-oncogenic properties of GOF p53, may do so, at least in part, by altering lipid raft composition and signaling. Citation Format: Jacob Moore, Margaux Baatz, Luis Espejo, Kathryn J. Leyva, Elizabeth E. Hull. Differential lipid raft composition correlates with altered oncogenic properties in the SW13 cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4295.
Introduction: Most p53 mutations occur in the DNA binding domain, resulting not only in a loss of WT p53 function but also in the gain of additional onocogenic properties such as increased cellular proliferation and metastasis. Two newly developed pharmaceuticals, NSC 319726 and SCH 529074, refold mutant p53 to a WT conformation, reduce cell proliferation, decrease aggregate formation, and represent a novel therapeutic approach. Another approach to regulating p53 activity is through acetylation. This post-translational modification leads to an activating conformational change in WT p53, but it is unclear how acetylation affects mutant p53. Two histone deacetylase inhibitors (HDACi), MS275 (Entinostat) and FK228 (Romidepsin), are promising chemotherapeutics that increase acetylation of many proteins. In this study, we ask if treatment with these HDACi leads to refolding of mutant p53, reduction of proliferation, and p53 transcription factor activity. Methods: R175H, H193Y, R248Q, and R273H constructs were transfected into a p53-null cell line. Inducible p53 expression in stable subclones was quantitated by immunofluorescence, western blot, and ELISA. Proliferation was measured by incorporation of EdU after treatment with FK228, MS275, NSC 319726, and SCH 529074. Refolding of p53 was determined before and after treatment using the conformational antibodies pAb240 and pAb1620, which bind to unfolded and folded p53, respectively. Functionality of the R175H mutant p53 was assessed by measuring the ability of p53 to bind its response element. Results: We focused on the R175H conformational p53 mutation as had a higher rate of cellular proliferation measured by EdU incorporation compared to the other mutants (p< 0.05). As expected, NSC 319726 treatment reduces R175H proliferation (p< 0.0001) and promotes refolding into the WT p53 conformation (p< 0.05) while no difference was detected with the broad spectrum mutant p53 reactivator SCH 529074. The HDAC inhibitors MS275 and FK228 reduce R175H proliferation (p< 0.0001) and MS275 appears to promote refolding into the WT p53 conformation while FK228 does not. When compared to control, transcription factor activity increased 3.8-fold with NSC 319726 treatment (p < 0.05), 6.0-fold with MS275 treatment (p< 0.0001), and 4.6-fold with FK228 treatment (p<0.01). Results suggest that HDACi may activate mutant p53 and that MS275 may do so by restoring WT conformation. Conclusion: The HDAC inhibitor MS275 reactivates R175H mutant p53 as measured by increased transcription factor activity apparently through refolding, as determined by pAb1620 binding following treatment. These results imply a novel mode of action for HDACi. Clinically this suggests that MS275 may be able to restore WT p53 tumor suppressor activity. Citation Format: Margaux Baatz, Brianna Flores, Jacob Moore, Kathryn J. Leyva, Elizabeth E. Hull. Refolding & restoring function to mutant p53: HDAC inhibitor MS275 partially restores activity to R175H mutant p53 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-093.
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