Discovering potential WRN inhibitors from natural product database through computational methods.

Microsatellite instability (MSI) is a relatively common feature associated with multiple cancers, and Werner syndrome (WRN) ATP-dependent helicase has been recognized as a novel target for treating MSI cancers, such as colorectal cancer. A small-molecule inhibitor targeting WRN would be a promising strategy for treating colorectal cancer with high MSI expression. In this study, we employed a computer-assisted drug discovery strategy to screen over 30,000 natural product molecules. By using a combination of docking, ligand efficiency, Molecular Mechanics/Generalized Born Surface Area (MM/GBSA), and thermodynamic integration (TI) calculations, we identified MOL008980, MOL010740, MOL011832, T4743, TN1166, and TNP-002173 as potential WRN inhibitors. Subsequent molecular dynamics simulation revealed that these screened natural products possessed better binding dynamic characteristics than ATP substrate and were capable of inhibiting the dynamic process of WRN, making them potential strong ATP competitive inhibitors. In conclusion, our computational approach revealed potential WRN inhibitors from a natural product database, providing a theoretical basis for future research.

An ileal gastrointestinal stromal tumor misdiagnosed as pelvic metastases from rectal cancer: a case report.

With the advancement of imaging and pathological diagnostic methods, it is not uncommon to see synchronous gastrointestinal stromal tumors (GIST) and other primary cancers, the most common of which are synchronous gastric cancer and gastric GIST. However, synchronous advanced rectal cancer and high-risk GIST in the terminal ileum are extremely rare, and they are easily misdiagnosed as rectal cancer with pelvic metastases due to their special location near iliac vessels. Herein, we report a 55-year-old Chinese woman with rectal cancer. Preoperative imaging revealed a middle and lower rectal lesion with a right pelvic mass (considered possible metastasis from rectal cancer). Through multidisciplinary discussions, we suspected the possibility of rectal cancer synchronous with a GIST in the terminal ileum. Intraoperative exploration by laparoscopy revealed a terminal ileal mass with pelvic adhesion, a rectal mass with plasma membrane depression, and no abdominal or liver metastases. Laparoscopic radical proctectomy (DIXON) plus partial small bowel resection plus prophylactic loop ileostomy was performed, and the pathological report confirmed the coexistence of advanced rectal cancer and a high-risk ileal GIST. The patient was treated with the chemotherapy (CAPEOX regimen) plus targeted therapy(imatinib) after surgery, and no abnormalities were observed on the follow-up examination. Synchronous rectal cancer and ileal GIST are rare and easily misdiagnosed as a rectal cancer with pelvic metastases, and careful preoperative imaging analysis and prompt laparoscopic exploration are required to determine the diagnosis and prolong patient survival.

Expression changes of Tim-3 as one of supplementary indicators for monitoring prognosis of liver pathological changes in chronic HBV infection.

PURPOSE: This study was designed to analyze the liver tissue changes among the CHB patients who received treatment for at least 6 months and follow-up for at least 1 year, together with the correlation between the different disease condition and serum markers. METHODS: One-hundred and eighty-five CHB patients underwent antiviral therapy for at least 6 months were enrolled. In the 12-month follow-up, ultrasonography-guided biopsy was performed. The patients were grouped based on the serum markers and pathological changes in liver tissues. Then we determined the serum markers, virological tests and Tim-3 expression among these groups. RESULTS: Antiviral therapy significantly reduced liver inflammation indicators and serum Tim-3 level. However, the fibrosis process of liver tissue was not changed, and there are still disputes on the serum marker and hepatic lesion outcomes. Under normal liver function or negative hepatitis B e antigen (HBeAg) of CHB patients, there might be consensus between Tim-3 change and liver pathological outcome. According to the liver tissue inflammation and fibrosis conditions, Tim-3 was positively correlated with liver function indices. Besides, it was also related to fibrosis stage and inflammation grade. CONCLUSION: There were inconsistent changes between serum markers and liver tissue conditions after anti-viral therapy. Tim-3 expression was more suitable to indicate the changes of liver inflammatory and fibrosis response to some extent than ALT and AST. It may serve as a certain indicator to predict the CHB prognosis, which could be used as one of the monitoring indicators in liver pathological changes of chronic HBV infection, especially in monitoring liver tissue inflammation.

Overexpression of human telomerase reverse transcriptase C-terminal polypeptide sensitizes HeLa cells to 5-fluorouracil­induced growth inhibition and apoptosis.

5­Fluorouracil (5­FU) is a commonly used anti­tumor chemotherapeutic drug for cervical carcinoma. However, increased drug resistance may occur following several cycles of 5­FU­based chemotherapy. Novel strategies of gene therapy for enhancing the sensitivity of cancer cells to 5­FU chemotherapy have been intensively explored. Human telomerase reverse transcriptase (hTERT)C27 is a newly constructed hTERT C­terminal polypeptide that is capable of promoting chromosome end­to­end fusion during anaphase and inducing telomere dysfunction. In the present study, the effects of hTERTC27 overexpression on 5­FU­induced proliferation inhibition and apoptosis were observed. HeLa cells were cultured and transfected with the constructed pcDNA3.1 or pcDNA3.1­hTERTC27 vectors. Expression of hTERTC27 was detected using western blot analysis and was assessed using MTT assays and flow cytometry. The results demonstrated that overexpressed hTERTC27 increased the sensitivity of the HeLa cells to 5­FU and significantly inhibited HeLa cell proliferation with 5­FU treatment. In addition, hTERTC27 overexpression evidently promoted the 5­FU­induced apoptosis by increasing the expression of activated caspase­3 and ­9 and by downregulating the expression of B­cell lymphoma 2. The results suggest that hTERTC27 overexpression is a potential clinical strategy for enhancing the antitumor effect of 5­FU chemotherapy in the treatment of cervical carcinoma.

Early growth response protein-1 promoter-mediated synergistic antitumor effect of hTERTC27 gene therapy and 5-Flurorouracil on nasopharyngeal carcinoma.

hTERTC27 is a newly constructed polypeptide that can induce telomere dysfunction. To study the synergistic antitumor effects of the hTERTC27 polypeptide driven by the early growth response protein-1 (Egr-1) promoter and chemotherapeutic 5-flurorouracil (5-FU) on nasopharyngeal carcinoma, a series of in vitro and in vivo experiments were performed. The results showed that hTERTC27 expression was significantly increased up to 7.21-folds by the 5-FU-activated Egr-1 promoter in C666-1 cells. Overexpressed hTERTC27 made the cells more sensitive to 5-FU, and additionally, inhibited cell proliferation about 20.41%. Combinational therapy of overexpressed hTERTC27 driven by the 5-FU-activated Egr-1 promoter and 5-FU synergistically inhibited cell proliferation and promoted apoptosis of C666-1 cells for about 4.75-fold and 1.76-fold in comparison with a sole therapy of hTERTC27 or 5-FU in vitro. In vivo experiments showed that overexpressed hTERTC27 driven by 5-FU-activated Egr-1 promoter and 5-FU synergistically reduced tumor volume, tumor weight, and local infiltration, which may be relative to tumor cell apoptosis. These results suggest that combinational therapy of overexpressed hTERTC27, which is driven by the 5-FU-activated Egr-1 promoter, and 5-FU may provide a novel approach to treat nasopharyngeal cancer.