Zhining Fan

C-Myc-activated long noncoding RNA CCAT1 promotes colon cancer cell proliferation and invasion

Recently, more and more evidence are rapidly accumulating that long noncoding RNAs (lncRNAs) are involved in human tumorigenesis and misregulated in many cancers, including colon cancer. LncRNA could regulate essential pathways that contribute to tumor initiation and progression with their tissue specificity, which indicates that lncRNA would be valuable biomarkers and therapeutic targets. Colon cancer-associated transcript 1 (CCAT1) is a 2628 nucleotide-lncRNA and located in the vicinity of a well-known transcription factor c-Myc. CCAT1 has been found to be upregulated in many cancers, including gastric carcinoma and colonic adenoma-carcinoma. However, its roles in colon cancer are still not well documented and need to be investigated. In this study, we aim to investigate the prognostic value and biological function of CCAT1 and discover which factors may contribute to the deregulation of CCAT1 in colon cancer. Our results revealed that CCAT1 was significantly overexpressed in colon cancer tissues when compared with normal tissues, and its increased expression was correlated with patients’ clinical stage, lymph nodes metastasis, and survival time after surgery. Moreover, c-Myc could promote CCAT1 transcription by directly binding to its promoter region, and upregulation of CCAT1 expression in colon cancer cells promoted cell proliferation and invasion. These data suggest that c-Myc-activated lncRNA CCAT1 expression contribute to colon cancer tumorigenesis and the metastatic process and could predict the clinical outcome of colon cancer and be a potential target for lncRNA direct therapy.

Derlin-1 is overexpressed in human colon cancer and promotes cancer cell proliferation

Derlin-1 is overexpressed in many types of solid tumors and plays an important role in cancer progression. However, the expression pattern and functions of Derlin-1 in human colon cancer are not fully understood. In the present study, we examined Derlin-1 expression in colon cancer cell lines and human tissues and investigated its role in colon cancer. We found that Derlin-1 expression was increased significantly in colon cancer tissues and its overexpression correlated with the tumor differentiation, Dukes stage, invasion, lymph node metastasis, distant metastasis, and poor overall survival. The silencing of Derlin-1 by shRNA led to the growth inhibition of colon cancer cells, which were associated with the promotion of apoptosis. Furthermore, Derlin-1 silencing significantly inhibited the activation of the PI3K/AKT signaling pathway. Taken together, our results showed that Derlin-1 is overexpressed in colon cancer and promotes proliferation of colon cancer cells. Derlin-1 may be a potential therapeutic target for the treatment of colon cancer.

Relief of diabetes by duodenal‑jejunal bypass sleeve implantation in the high‑fat diet and streptozotocin‑induced diabetic rat model is associated with an increase in GLP‑1 levels and the number of GLP‑1‑positive cells

A recently invented duodenal-jejunal bypass sleeve (DJBS) implanted in the duodenum and proximal jejunum has exhibited good glycemic control in diabetes mellitus. However, the specific mechanism by which DJBS placement induces the remission of diabetes is not well known. Previous studies have indicated that changes in the pattern of gut hormone secretion may play a role. The aim of the present study was to explore the role of intestinal L cells and the production of glucagon-like peptide-1 (GLP-1) by these cells in DJBS implantation-induced glycemic control in diabetic rats. A DJBS was placed in the proximal small intestine of rats with diabetes induced by a high-fat diet and low-dose streptozotocin (STZ), and the effects of the DJBS on the remission of diabetes and the GLP-1 levels of plasma and intestinal tissues were investigated 12 weeks after DJBS placement. The number of intestinal GLP-1 positive cells was also counted. When the DJBS had been in place for 12 weeks, the plasma glucose level of the DJBS-implanted rats decreased significantly from 23.33±1.56 mmol/l prior to surgery to 7.70±0.84 mmol/l and the diabetes mellitus was relieved completely; however, diabetic control rats and diabetic rats subjected to sham surgery did not show any improvement. Parallel with the remission of diabetes, the plasma and distal ileum GLP-1 levels of rats in the DJBS implantation group were also higher than those of rats in the diabetic control and sham surgery groups. The number of GLP-1-positive cells in the distal ileum was also higher in the DJBS implantation group than in the diabetic control and sham surgery groups (31.0±2.6 vs. 23.5±4.4 vs. 23.0±3.2 respectively; P<0.01). DJBS implantation effectively led to the remission of diabetes in rats with diabetes induced by a high-fat diet and low-dose STZ when implanted for 12 weeks. The remission of diabetes may be associated with the increase in the number of L cells and elevation of GLP-1 levels induced by DJBS implantation.

Silver-nanoparticle-coated biliary stent inhibits bacterial adhesion in bacterial cholangitis in swine

BACKGROUNDnOne of the major limitations of biliary stents is the stent occlusion, which is closely related to the over-growth of bacteria. This study aimed to evaluate the feasibility of a novel silver-nanoparticle-coated polyurethane (Ag/PU) stent in bacterial cholangitis model in swine.nnnMETHODSnAg/PU was designed by coating silver nanoparticles on polyurethane (PU) stent. Twenty-four healthy pigs with bacterial cholangitis using Ag/PU and PU stents were randomly divided into an Ag/PU stent group (n=12) and a PU stent group (n=12), respectively. The stents were inserted by standard endoscopic retrograde cholangiopancreatography. Laboratory assay was performed for white blood cell (WBC) count, alanine aminotransferase (ALT), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) at baseline time, 8 hours, 1, 2, 3, and 7 days after stent placements. The segment of bile duct containing the stent was examined histologically ex vivo. Implanted biliary stents were examined by a scan electron microscope. The amount of silver release was also measured in vitro.nnnRESULTSnThe number of inflammatory cells and level of ALT, IL-1beta and TNF-alpha were significantly lower in the Ag/PU stent group than in the PU stent group. Hyperplasia of the mucosa was more severe in the PU stent group than in the Ag/PU stent group. In contrast to the biofilm of bacteria on the PU stent, fewer bacteria adhered to the Ag/PU stent.nnnCONCLUSIONSnPU biliary stents modified with silver nanoparticles are able to alleviate the inflammation of pigs with bacterial cholangitis. Silver-nanoparticle-coated stents are resistant to bacterial adhesion.

Effect of a paclitaxel-eluting metallic stent on rabbit esophagus

The use of self-expanding metallic stents (SEMS) is the current treatment of choice for malignant gastrointestinal obstructions. A paclitaxel-eluting metallic SEMS (PEMS) may have an antitumor effect on esophageal tissue. PEMS with 10% paclitaxel or conventional SEMS were inserted into the lower esophagus of rabbits. Following the insertion of the stents for 1, 2, 4 and 6 weeks, the rabbits were sacrificed and the status of the stent insertion was examined, as well as any macroscopic or microscopic mucosal changes in the esophageal tissue. All the rabbits survived until death without any complications. No migration following stent insertion occurred. The number of cases with proximal obstruction increased in a time-dependent manner, and no significant difference was observed between the two groups. Gross histological examination showed similar tissue reaction to the stents at 1, 2 and 4 weeks, and inflammatory cell infiltrating was higher in the SEMS group at 1 and 2 weeks. However, inflammatory cell infiltration was markedly higher in the PEMS group at 4 and 6 weeks. Food-intake and weight were similar in the two groups. The results of the present study demonstrated that PEMS may serve as a safe alternative treatment strategy for esophageal obstruction. Furthermore, PEMS may inhibit the tumor growth of the esophageal wall through inflammatory infiltration and targeted drug delivery. A tumor model will be required in the future for evaluating the prognosis of patients with advanced esophageal carcinoma.

The effect of paclitaxel-eluting covered metal stents versus covered metal stents in a rabbit esophageal squamous carcinoma model.

Background The use of self-expanding metallic stents (SEMSs) is the current treatment of choice for malignant gastrointestinal obstructions. However, these stents can promote only drainage and have no antitumor effect. Some studies have reported that drug-eluting SEMSs may have tumor inhibition potential. The aim of this study was to evaluate the efficiency and safety of paclitaxel-eluting SEMSs (PEMSs) in rabbit esophageal cancer models. Materials and methods A PEMS was covered with a paclitaxel-incorporated membrane, in which the concentration of paclitaxel was 10% (wt/vol). The rabbit models were created endoscopically. Then, a PEMS or SEMS was endoscopically inserted into the rabbit esophagus. Two weeks after stent placement, the rabbits were sacrificed, and we evaluated the tumor volume, area of the wall defect, area of the tumor under endoscopic ultrasound (EUS) before and after stent placement, status of the proximal esophageal obstruction, tumor metastasis food-intake and weight loss. Results A total of 26 rabbits received stent insertion and survived until sacrifice, and migration occurred in 4 cases, 3 in SEMS group and 1 in PEMS group. For the remaining 22 rabbits, at the sacrificed time, the average tumor volume was 7.00±4.30 cm3 in the SEMS group and 0.94±1.51 cm3 in the PEMS group (P<0.05). The area of the esophageal wall defect was 0.70±0.63 cm2 in the SEMS group and 0.17±0.16 cm2 in the PEMS group (P<0.05). The tumor area under EUS was 4.40±1.47 cm2 in the SEMS group and 1.30±1.06 cm2 in the PEMS group (P<0.05). At the time of stent placement, tumor area under EUS was comparable in the two groups. Other indices did not significantly differ between the two groups. Conclusions SEMS and PEMS are both safe and effective to relieve dysphagia in rabbit esophageal cancer models. A PEMS can serve as an alternative tool for advanced esophageal cancer that may inhibit tumor growth by serving as a drug sustained-release platform. Clinical trials of the stent are warranted in the future.

Effect of Age on Survival Outcome in Operated and Non-Operated Patients with Colon Cancer: A Population-Based Study.

Objective To know the effect of age on survival outcome in operated and non-operated patients with colon cancer. Methods From the Surveillance, Epidemiology, and End Results database, we identified 123,356 patients with colon cancer who were diagnosed between 1996 and 2005, grouped them as older or younger than 40 years and analyzed their 5-year cancer-specific survival (CSS) data, along with some risk factors, using Kaplan–Meier methods and multivariable Cox regression models. Results The younger group had significantly higher pathological grades (P<0.001), more mucinous and signet-ring histology (P<0.001), advanced AJCC stage (P<0.001), and were more likely to undergo surgery (P<0.001). For surgically treated patients, age did not significantly affect 5-year CSS (younger: 66.7%; older: 67.3%; P = 0.86). Further analysis showed that age was an independent prognostic factor in stage I–IV disease (stage I: P = 0.001; P<0.001 for stages II–IV, in both uni- and multivariate analyses), but not for patients with unknown disease stage (P = 0.52). For non-surgically treated patients, age significantly affected 5-year CSS (younger: 16.2%; older: 12.9%; P<0.001) in univariate analysis; and was an independent prognostic factor (P<0.001) in multivariate analysis. Conclusion The CSS rate for younger CC patients was at least as high as for older patients, although they presented with higher proportions of unfavorable factors and more advanced disease.

Endoscopic closure of a colonic defect using a novel endoloop system via a single-channel endoscope

Successful closure of postoperative defects is essential for endoscopic resection of early neoplasms. The endoscopic pursestring suture (EPSS) using a double-channel colonoscope has been shown to be safe and effective. This method involves the interaction of the endoloop and the metal clips through two separate endoscope channels [1]. However, single-channel colonoscopes aremore popular in clinical practice because of their longer length, more flexible operation, and cheaper price, especially when used in the right colon. We report on a novel endoloop system that was innovatively applied via a single-channel endoscope. A 70-year-old man was referred to our center with a 9-month history of increasing defecation. Endoscopic examination with biopsy and histopathology revealed a nongranular type of laterally spreading tumor with moderate atypical hyperplasia in the ileocecal junction. Endoscopic submucosal dissection was performed for en bloc resection. The large defect (2.5×2.0cm) was completely closed by EPSS via a single-channel colonoscope (CF Q260; Olympus, Tokyo, Japan), as follows. As an independent device, the nylon loop (Loop-30; LeCamp, Changzhou, China) was first delivered and positioned around the defect. Multiple clips were then applied to fix the endoloop in place. The loop was tightened by grasping the tail with a hook and pulling backward to close the defect (● Fig.1,● Video 1). The entire procedure was completed via the single channel. The closing process took 8 minutes. The patient was discharged 2 days after the operation without any adverse events. Lua et al. [2] described their experience of closing a mucosal defect in the stomach using a single-channel gastroscope. To our knowledge, the current case is the

Endoscopic retrieval followed by compression hemostasis using a Sengstaken–Blakemore tube to manage a foreign body with suspected aortic injury

A 44-year-old woman presented with unremitting chest pain after a fish meal. A fishbone had been stuck in her esophagus overnight. A local endoscopist had tried to remove it but had failed. Contrast-enhanced computed tomography (● Fig.1) confirmed that there was a high density line shadow in the esophagus just below the tracheal bifurcation. The fishbone had pierced the esophageal wall andwas close to thedescending aortic adventitia, and possible aortic injury was strongly suspected. Standard cardiovascular surgery was planned, but was refused by the woman and her relatives because of the potentiallymassive surgical trauma. With written informed consent, an innovative endoscopic strategy involving multidisciplinary cooperation was successfully employed (● Video1). Using endoscopic imaging, only the tip of the fishbone could be observed, 28cm from the incisors (● Fig.2). Grasping forceps were introduced and the 2.2cmlong fishbone was successfully retrieved (● Fig.3). Then fresh blood immediately spurted out. After flushing with normal saline, a Sengstaken–Blakemore tube (SBT) was immediately inserted. The gastric balloon was placed accurately over the mucosal wound, inflated with 100mL of gas, and adjusted for local compression Fig.1 Contrast-enhanced computed tomography scan of a 44-year-old woman with a fishbone stuck in her esophagus. The fishbone had pierced the esophageal wall and was close to the descending aorta (arrow).

FOXO1, a Potential Therapeutic Target, Regulates Autophagic Flux, Oxidative Stress, Mitochondrial Dysfunction, and Apoptosis in Human Cholangiocarcinoma QBC939 Cells

Background/Aims: Autophagy is an evolutionarily conserved catabolic mechanism to maintain energy homeostasis and to remove damaged cellular components, which plays an important role in the survival of various cells. Inhibiting autophagy is often applied as a new strategy to halt the growth of cancer cells. Methods: The effect of FOXO1 gene on cellular function and apoptosis and its underlying mechanisms were investigated in cultured QBC939 cells by the methylthiazoletetrazolium (MTT) assay, western blot, DCFDA mitochondrial membrane potential, and ATP content measurement. FOXO1 siRNA was applied to down-regulate FOXO1 expression in QBC939 cells. Results: Here we reported that FOXO1, acetylation of FOXO1 (Ac-FOXO1) and the following interaction between Ac-FOXO1 and Atg7 regulated the basal and serum starvation (SS)-induced autophagy as evidenced by light chain 3 (LC3) accumulation and p62 degration. Either treatment with FOXO1 siRNA or resveratrol, a sirt1 agonist, inhibited autophagic flux, resulting in oxidative stress, mitochondrial dysfunction (MtD) and apoptosis in QBC939 cells, which were attenuated by enhancing autophagy with rapamycin. On the contrary, inhibiting autophagic flux with 3-MA worsened all these effects in QBC939 cells. Conclusions: Taken together, our study for the first time identified FOXO1 as a potential therapeutic target to cure against human cholangiocarcinoma via regulation of autophagy, oxidative stress and MtD.