Novel insights into the role of translesion synthesis polymerase in DNA incorporation and bypass of 5-fluorouracil in colorectal cancer.

5-Fluorouracil (5-FU) is the first-line chemotherapeutic agent in colorectal cancer, and resistance to 5-FU easily emerges. One of the mechanisms of drug action and resistance of 5-FU is through DNA incorporation. Our quantitative reverse-transcription PCR data showed that one of the translesion synthesis (TLS) DNA polymerases, DNA polymerase η (polη), was upregulated within 72 h upon 5-FU administration at 1 and 10 µM, indicating that polη is one of the first responding polymerases, and the only TLS polymerase, upon the 5-FU treatment to incorporate 5-FU into DNA. Our kinetic studies revealed that 5-fluoro-2'-deoxyuridine triphosphate (5FdUTP) was incorporated across dA 41 and 28 times more efficiently than across dG and across inosine, respectively, by polη indicating that the mutagenicity of 5-FU incorporation is higher in the presence of inosine and that DNA lesions could lead to more mutagenic incorporation of 5-FU. Our polη crystal structures complexed with DNA and 5FdUTP revealed that dA:5FdUTP base pair is like dA:dTTP in the active site of polη, while 5FdUTP adopted 4-enol tautomer in the base pairs with dG and HX increasing the insertion efficiency compared to dG:dTTP for the incorrect insertions. These studies confirm that polη engages in the DNA incorporation and bypass of 5-FU.

Indoxyl sulfate, not P-cresyl sulfate, is associated with advanced glycation end products in patients on long-term hemodialysis.

BACKGROUND/AIMS: Advanced glycation end products (AGEs) are pro-inflammatory and pro-oxidative compounds that play a critical role in endothelial dysfunction and atherosclerosis. Protein-bound uremic toxins, indoxyl sulfate (IS) and p-cresyl sulfate (PCS), inhibit endothelial function. We explored the association of IS and PCS with AGEs in a hemodialysis (HD) cohort. METHODS: This study was a cross-sectional study that recruited 129 stable patients on maintenance HD in a single medical center from July 1 to July 15, 2011. Serum levels of total and free IS, PCS and AGEs were measured concurrently. General laboratory results and patient background were also investigated. RESULTS: Serum levels of AGEs were associated with total IS (r = 2.7, p < 0.01) but not total PCS (r = 0.01, NS), free IS (r = 0.11, NS) or free PCS (r = 0.04, NS) using Pearson's analysis. Multiple linear regression analysis showed that total IS was significantly related to AGEs (ß = 0.296, p < 0.01), free IS (ß = 0.502, p < 0.01) and creatinine (ß = 0.294, p < 0.01). Serum AGEs levels were also independently correlated with diabetes status (ß = 0.250, p = 0.01) and total IS (ß = 0.341, p < 0.01) concentrations after adjusting for other confounding variables. Moreover, patients with diabetes had higher serum AGEs levels than patients without diabetes (p < 0.01). CONCLUSIONS: These findings suggest that serum levels of total IS were associated with AGEs levels, which may participate in the process of atherosclerosis.

Chemical ablation of recurrent and persistent secondary hyperparathyroidism after subtotal parathyroidectomy.

BACKGROUND: Despite preoperative localization or intraoperative parathyroid hormone, monitoring increased the operative successful rate, recurrent, and persistent secondary hyperparathyroidism are still unavoidable after parathyroidectomy or reoperation. We present our experience of using percutaneous ethanol injection therapy (PEIT) in treating these patients. PURPOSE: To conduct a prospective study of 49 patients with recurrent and persistent hyperparathyroidism using PEIT after subtotal parathyroidectomy or reoperative failure. PATIENTS AND METHODS: From January 2001 to August 2009, 49 patients with recurrent or persistent 2HPT after subtotal parathyroidectomy received PEIT. All dialysis patients were divided into 2 groups: recurrent group (n = 28) and persistent group (n = 21). Before PEIT, every patient received sestamibi-(99m)Tc scintigraphy (MIBI scanning), neck ultrasonography (US), bone scanning (T-score and Z-score), and parathyroid function testing. We compared the responses to PEIT treatment in the recurrent and persistent groups with the following parameters: treatment success rate, improvement in bone density, concurrence in diagnosis between US and MIBI scanning and complications. RESULTS: Treatment success was defined as intact PTH < 300 pg/mL; recurrent group is 25 of 28 (89.3%) and persistent group is 20 of 21 (95.2%) (P = 0.694). There was no difference in success rate statistically. T-score in recurrent group before PEIT was -1.2 ± 0.9 and after treatment was -0.6 ± 0.6 (P = 0.004), which is statistically significant. In the persistent group, T-score before PEIT was -1.2 ± 1.0 and after treatment was -0.8 ± 0.6 (P = 0.101). There was no significant difference. For consistence between neck US and MIBI scanning were concordant in the recurrent group in 20 of 28 (71.4%); in persistent group, it was 14 of 21 (66.6%) (P = 0.245); there was no significant difference. Regarding the complications, only hypocalcemia was significantly more common in the recurrent group. Hypocalcemia occurred in 14 of 28 patients in the recurrent group and 6 of 21 in the persistent group (P = 0.022). CONCLUSIONS: Regardless of which group patient was in, PEIT can achieve satisfying result when parathyroid masses were detected by US. Subtotal parathyroidectomy plus PEIT was probably the best combination for treatment of secondary hyperparathyroidism.

Hepatic portal venous gas.

BACKGROUND: Hepatic portal venous gas is an unusual entity associated with a variety of abdominal catastrophes. There is usually a grave prognosis when hepatic portal venous gas is associated with ischemic bowel disease. We reported a 57-year-old man with hepatic portal venous gas associated with extensive infarction of the jejunum and a concomitant perforation at a site in the terminal ileum leading to two operations performed 24 hours apart. Progressive ischemia and infarction after the initial laparotomy resulted in massive resection of the small bowel. METHODS: A follow-up abdominal radiography showed progressive dilatation of the small intestine and thickening of the bowel wall. Computed tomography of the abdomen showed pneumatosis intestinalis and gas collection within the intrahepatic and extrahepatic portal vein and superior mesenteric vein and free gas in the peritoneal cavity. RESULTS: At surgery, a long segment of ischemic change of the jejunum with focal necrosis and one perforation in the terminal ileum with no relation to the ischemic area was discovered. These two areas were resected respectively, and anastomosis was performed. Extensive necrosis of the residual bowel was found on the second-look operation performed 24 hours later, and subsequent resection of involved bowel was performed, resulting in a short-bowel condition. CONCLUSIONS: When hepatic portal venous gas associated with ischemic bowel disease is encountered, coexistence of other abdominal condition with no relation to ischemic segment should be considered.