Villosol reverses 5-FU resistance in colorectal cancer by inhibiting the CDKN2A gene regulated TP53-PI3K/Akt signaling axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Patrinia villosa (Juss.) (PV) is the drug of choice in traditional Chinese medicine for the treatment of colorectal cancer (CRC) and has achieved reliable efficacy in clinic. Villosol is the active ingredient in PV. However, the molecular mechanism by which Villosol reverses chemoresistance in CRC remains unclear. AIM OF THE STUDY: Analysis of the molecular mechanism by which Villosol, the active ingredient of PV, reverses CRC/5-FU resistance through modulation of the CDKN2A gene was validated by network pharmacology techniques and experiments. MATERIALS AND METHODS: We identified CDKN2A as a gene associated with 5-FU resistance through gene chip analysis. Next, we conducted a series of functional analyses in cell lines, animal samples, and xenograft models to investigate the role, clinical significance, and abnormal regulatory mechanisms of CDKN2A in 5-FU resistance in CRC. In addition, we screened and obtained a raw ingredient called Villosol, which targets CDKN2A, and investigated its pharmacological effects. RESULTS: Analysis of CRC cells and animal samples showed that the upregulation of CDKN2A expression was strongly associated with 5-FU resistance. CRC cells overexpressing CDKN2A showed reduced sensitivity to 5-FU and enhanced tumor biology in vitro. Inhibition of aberrant activation of CDKN2A enhances the expression of TP53. Mechanistically, overexpression of CDKN2A activates the PI3K/Akt pathway and induces resistance to 5-FU. Villosol inhibited CDKN2A, and CRC/5-FU cells regained sensitivity to 5-FU. Villosol effectively reverses 5-FU resistance through the CDKN2A-TP53-PI3K/Akt axis. CONCLUSION: Changes in CDKN2A gene expression can be used to predict the response of CRC patients to 5-FU therapy. Additionally, inhibiting CDKN2A activation with Villosol may present a new approach to overcoming 5-FU resistance in clinical settings.

Adenoma miss rate determined by very shortly repeated colonoscopy: Retrospective analysis of data from a single tertiary medical center in China.

Adenoma miss rate (AMR) has been calculated in several tandem colonoscopy studies, but it costs overmuch to carry out a clinical trial.We aimed to put forward AMR by taking advantage of retrospective data, and to judge the comparability between AMRs from prospective and retrospective data.Data of the patients accepting repeated colonoscopies during January to September 2016 was retrospectively collected and analyzed. Information was recorded, including bowel preparation quality of the first colonoscopy, size, location, histology and whether missed within the first colonoscopy of each single adenoma. AMR was compared by different risk factors through χ test and multivariable logistic regression.Around 267 adenomas were detected during 309 pairs of repeated colonoscopies, of which 66 were missed during the first colonoscopies. AMRs of the lesions small in size, nonadvanced in histology, in poor bowel preparation context and located in the proximal colon, were significantly higher than the opposite ones, and old age and male were related to adenoma missing (P < .05). In multivariable logistic regression analysis, adenoma-related factors (diminutive in size, poor bowel preparation and located in ascending colon, transverse colon or sigmoid colon), and patient-related factors (older than 60 years, male and poor bowel preparation) were found to be independently associated with missing adenomas (P < .05).AMR of retrospective data is comparable to that of tandem studies. Several risk factors influence AMR dramatically, which should be paid attention to.

A long-term follow-up study on the prognosis of endoscopic submucosal dissection for colorectal laterally spreading tumors.

BACKGROUND AND AIMS: Colorectal laterally spreading tumors (LSTs) are divided into homogeneous (LST-G-H), nodular mixed (LST-G-M), flat elevated (LST-NG-F), and pseudodepressed (LST-NG-PD) subtypes. We hypothesized that based on the rates of advanced histology, the recurrence rates of the LST-NG-PD and LST-G-M groups may be higher than those of the other subgroups. METHODS: Endoscopic submucosal dissection (ESD) was performed in 156 patients with a total of 177 LSTs. The clinicopathological features and long-term prognosis of ESD according to specific subtype were investigated. RESULTS: LSTs were most commonly found in the rectum, and the highest percentage of rectal lesions was observed in the LST-G-M group (71.1% vs overall 55.4%, P = .032). The LST-G-M lesions were larger (60 ± 22 mm vs 40 ± 33 mm, P = .034) than the LST-G-H lesions. The LST-G-M group also demonstrated more high-grade intraepithelial neoplasias (32.2% vs 10.8%, P = .003) and submucosal carcinomas (13.6% vs 1.5%, P = .010) compared with the LST-G-H group. The LST-NG-PD group exhibited the highest incidence of submucosally invasive cancer (16.7%). The overall perforation rate was 2.3%. The perforation rate in the LST-NG group was higher than that in the LST-G group (5.7% vs 0.8%, P = .047). All recurrences (7.7%) were found by colonoscopy without any detection of cancers, and no difference was found among the subtypes. CONCLUSIONS: No significant differences were observed among subgroups with 44.4 ± 16.3 months of follow-up. Considering that all recurrences were discovered by colonoscopy and most could be cured by repeated ESD, the LSTs of all subgroups require more intensive follow-up compared with smaller adenomatous lesions.

Detection and miss rates of autofluorescence imaging of adenomatous and polypoid lesions during colonoscopy: a systematic review and meta-analysis.

BACKGROUND AND STUDY AIMS: Autofluorescence imaging (AFI) is an endoscopic imaging technique used to increase the detection of premalignant gastrointestinal lesions, and it has gradually become popular in recent years. This meta-analysis was performed to examine whether AFI provides greater efficacy in the detection of adenomatous and polypoid lesions and can even prevent the failure to detect a single adenoma or polyp. The aim of the study was to systematically review the efficacy of AFI in increasing detection rates and decreasing miss rates. METHODS: Pertinent articles were identified through a search of databases up to December 2013 that included patients who had undergone two same-day colonoscopies (AFI and white light endoscopy [WLE]), followed by polypectomy. Fixed and random effects models were used to detect significant differences between AFI and WLE in regard to adenoma detection rate (ADR), polyp detection rate (PDR), adenoma miss rate (AMR), polyp miss rate (PMR), and procedural time. RESULTS: A total of 1199 patients from six eligible studies met the inclusion criteria. No significant differences were found in ADR (odds ratio [OR] 1.01; 95 % confidence interval [95 %CI] 0.74 - 1.37), PDR (OR 0.86; 95 %CI 0.57 - 1.30), or advanced ADR (OR 1.22; 95 %CI 0.69 - 2.17). The AMR (OR 0.62; 95 %CI 0.44 - 0.86) and PMR (OR 0.64; 95 %CI 0.48 - 0.85) by AFI were significantly lower than those by WLE. The procedural time of AFI was significantly longer than that of WLE (mean 8.00 minutes; 95 %CI 1.59 - 14.41). Subgroup meta-analysis for the other characteristics was not performed because of insufficiency of the primary data. CONCLUSIONS: AFI decreases AMR and PMR significantly compared with WLE but does not improve ADR or PDR. AMR and PMR may be decreased by using AFI in flat and small lesions or when less experienced endoscopists perform the procedure.