Regulation of Cyclooxygenase-2 Expression by the Translational Silencer TIA-1

The cyclooxygenase-2 (COX-2) enzyme catalyzes the rate-limiting step of prostaglandin formation in inflammatory states, and COX-2 overexpression plays a key role in carcinogenesis. To understand the mechanisms regulating COX-2 expression, we examined its posttranscriptional regulation mediated through the AU-rich element (ARE) within the COX-2 mRNA 3′-untranslated region (3′UTR). RNA binding studies, performed to identify ARE-binding regulatory factors, demonstrated binding of the translational repressor protein TIA-1 to COX-2 mRNA. The significance of TIA-1-mediated regulation of COX-2 expression was observed in TIA-1 null fibroblasts that produced significantly more COX-2 protein than wild-type fibroblasts. However, TIA-1 deficiency did not alter COX-2 transcription or mRNA turnover. Colon cancer cells demonstrated to overexpress COX-2 through increased polysome association with COX-2 mRNA also showed defective TIA-1 binding both in vitro and in vivo. These findings implicate that TIA-1 functions as a translational silencer of COX-2 expression and support the hypothesis that dysregulated RNA-binding of TIA-1 promotes COX-2 expression in neoplasia

An Essential Mesenchymal Function for miR-143/145 in Intestinal Epithelial Regeneration

SummaryDownregulation of the miR-143/145 microRNA (miRNA) cluster has been repeatedly reported in colon cancer and other epithelial tumors. In addition, overexpression of these miRNAs inhibits tumorigenesis, leading to broad consensus that they function as cell-autonomous epithelial tumor suppressors. We generated mice with deletion of miR-143/145 to investigate the functions of these miRNAs in intestinal physiology and disease in vivo. Although intestinal development proceeded normally in the absence of these miRNAs, epithelial regeneration after injury was dramatically impaired. Surprisingly, we found that miR-143/145 are expressed and function exclusively within the mesenchymal compartment of intestine. Defective epithelial regeneration in miR-143/145-deficient mice resulted from the dysfunction of smooth muscle and myofibroblasts and was associated with derepression of the miR-143 target Igfbp5, which impaired IGF signaling after epithelial injury. These results provide important insights into the regulation of epithelial wound healing and argue against a cell-autonomous tumor suppressor role for miR-143/145 in colon cancer

How Low Can We Go?: Comparing Long-term Oncologic Outcomes for APR and LAR in Very Low Rectal Cancer

Management of very low rectal cancer is one of the most challenging issues faced by colorectal surgeons. For tumors in the mid and upper rectum, procedures can be done to resect the cancer while maintaining continence, a major determinant of post-operative quality of life. In the low rectum, however, to optimize oncologic outcomes, many surgeons feel compelled to pursue abdominoperineal (APR) over low anterior resection (LAR), a sphincter-preserving procedure. It was hypothesized that after robust adjustment, procedure choice will not be associated with a difference in disease-free survival in the resection of tumors in the low rectum. To analyze this, the US Rectal Cancer Collaborative Database, a comprehensive, multi-center dataset obtained from six institutions between 2010 and 2016, was queried. Patients undergoing TME resection for Stage I-III very low rectal cancers (involvement) were selected for this study. Patients were categorized by procedure- LAR vs APR. Primary outcome was five-year disease-free survival. Secondary outcomes included overall survival, recurrence, length of stay, and complications. An adjusted analysis was performed to account for all known potential confounders. 431 patients with very low rectal cancer treated by either APR or LAR were identified. 154 (35.7%) underwent APR. The overall recurrence rate was 19.6%. Median follow-up time was 42.5 months. An analysis adjusted for age, gender, BMI, ASA class, and pathologic stage observed no difference in disease free survival between operative types (HR=0.90, 95% CI [0.53-1.52], p=0.70). Similarly, secondary outcomes demonstrated no significant difference between operation types, including length of stay (Beta: 0.04, Std. error = 0.25, p = 0.54), overall survival (HR=1.29, 95% CI [0.71-2.32], p=0.39), or complications (OR = 1.53, 95% CI [0.94 - 2.50], p=0.09). In this analysis, no significant difference in disease-free survival or overall survival was observed between patients undergoing APR or LAR for very low rectal cancer. This comprehensive study supports the treatment of very low rectal cancer, less than 5cm from the anorectal ring with no sphincter involvement, by either abdominal perineal or low anterior resection. Further studies may focus on patient-reported and quality of life outcomes which may influence decision-making

Rare Hepatic Arterial Anatomic Variants in Patients Requiring Pancreatoduodenectomy and Review of the Literature

Normal hepatic arterial anatomy occurs in approximately 50–80% of cases; for the remaining cases, multiple variations have been described. Knowledge of these anomalies is especially important in hepatobiliary and pancreatic surgery in order to avoid unnecessary complications. We describe two cases of patients undergoing pancreatoduodenectomy for abnormalities in the head of the pancreas. Preoperative contrast-enhanced cross-sectional imaging demonstrated relevant, rare hepatic arterial variants: (1) a completely replaced hepatic arterial system with a gastroduodenal artery (GDA) arising directly from the celiac axis and (2) a replaced right hepatic artery originating from the superior mesenteric artery and traveling anterior to the pancreatic uncinate process and head. These findings were confirmed during pancreatoduodenectomy. Both of these variants have been rarely described with an incidence of <1.0%. In the present paper, we describe the hepatic arterial anomalies commonly encountered and clarify the important details associated with these variants as they pertain to pancreatoduodenectomy