Weidong Tong

Upregulation of MicroRNA-107 induces proliferation in human gastric cancer cells by targeting the transcription factor FOXO1

MicroRNA‐107 (miR‐107) has been demonstrated to regulate proliferation and apoptosis in many types of cancers. Nevertheless, its biological function in gastric cancer remains largely unexplored. Here, we found that the expression level of miR‐107 was increased in gastric cancer in comparison with the adjacent normal tissues. The enforced expression of miR‐107 was able to promote cell proliferation in NCI‐N87 and AGS cells, while miR‐107 antisense oligonucleotides (antisense miR‐107) blocked cell proliferation. At the molecular level, our results further revealed that expression of FOXO1 was negatively regulated by miR‐107. Therefore, the data reported here demonstrate that miR‐107 is an important regulator in gastric cancer, which will contribute to a better understanding of the important mis‐regulated miRNAs in gastric cancer.

Lubiprostone Is Effective in the Treatment of Chronic Idiopathic Constipation and Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE To evaluate the efficacy and safety of lubiprostone in the treatment of chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C). PATIENTS AND METHODS We performed a literature search of the MEDLINE, Cochrane, Google Scholar, and ClinicalTrials.gov databases (from January 1, 2005, through January 31, 2015). Relevant studies meeting the inclusion criteria were manually searched by 2 independent reviewers. Efficacy outcomes evaluated at 1 week, 1 month, and 3 months of intervention were weekly frequency of spontaneous bowel movements, severity of constipation, consistency of stools, degree of abdominal pain/discomfort, degree of straining, and abdominal bloating. RESULTS Of 246 studies identified, data from 9 trials comprising 1468 patients (63.6%) in the lubiprostone group and 841 (36.4%) in the placebo group were analyzed. We found that lubiprostone treatment significantly improved the severity of constipation, stool consistency, abdominal pain, degree of straining, and abdominal bloating at 1 week (P≤.03) and 1 month (P≤.004), except for abdominal pain at 1 month, which was similar to that when treated with placebo (P=.21). At 3 months, except for abdominal bloating (P=.03), there was no difference between lubiprostone and placebo groups in all other outcomes (P≥.05). Adverse effects such as nausea, vomiting, and diarrhea were common (incidence rate, 2.4%-75%); however, the incidence of serious adverse effects was low (<5%) and was mostly unrelated to lubiprostone treatment. CONCLUSION Lubiprostone is a safe and efficacious drug for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation, with limited adverse effects in 3 months of follow-up.

Exogenous stem cell factor improves interstitial cells of Cajal restoration after blockade of c-kit signaling pathway.

Abstract Objective. Interstitial cells of Cajal (ICC) have been endowed with considerable intrinsic plasticity. Blockade of the c-kit signaling pathway results in the shift of ICC towards a smooth muscle-like phenotype. Little is known about stem cell factor (SCF), the ligand of c-kit, and the role it plays in the process of restoration. The aim of this study was to determine whether exogenous SCF can promote ICC replenishment following the blockade of c-kit signaling. Material and methods. Neutralizing anti-c-kit monoclonal antibody (ACK2) was administered to mice for 8 days after birth. Jejunal muscle strips were cultured up to 7 days. Electrical rhythmic changes were monitored and ICC were examined by immunohistochemistry. Expression of c-kit mRNA was detected by reverse transcriptase-polymerase chain reaction, and expression of Kit protein was detected by Western blot. Results. When c-kit receptors were blocked, ICC nearly disappeared from the jejunum accompanied by the loss of electrical slow waves. By day 7, after in vitro culture with SCF (100 ng/ml), the amplitude of muscle strip slow waves was restored to 0.19 ± 0.07 mV (p < 0.05), whereas the frequency recovered to 13.7 ± 3.32/min (p < 0.01). Furthermore, labeling for c-kit+ cells in the myenteric plexus increased and c-kit mRNA and protein expression were up-regulated compared to that of non-treatment with SCF. Conclusions. The c-kit signaling pathway, activated by SCF, is the critical pathway associated with the control of ICC survival and proliferation. The restoration of ICC number and jejunal electrical rhythm, resulting from blockade of the c-kit signaling pathway, could be facilitated by local SCF administration.

The -1082A>G polymorphism in promoter region of interleukin-10 and risk of digestive cancer: a meta-analysis

The -1082A>G polymorphism is located in promoter region of interleukin-10 (IL-10) and it could affect the production of IL-10. Numerous studies have investigated the association between IL-10 -1082A>G and risk of digestive cancer. However, the conclusion is still inconsistent. Here, we have performed a meta-analysis and systematic review to determine the association between the IL-10 -1082A>G and susceptibility to digestive cancer. In this meta-analysis, we identified 40 eligible studies, involving 7195 patients of digestive cancer and 11755 controls. By pooling all eligible studies, we found the variant -1082G allele significantly increased risk of digestive cancer (G vs. A: OR = 1.181, 95% CI: 1.057–1.319). Further stratified analysis was performed to evaluate the influence of cancer types, ethnicities, study design, sample size and Hardy–Weinberg equilibrium. Stratified analysis suggested that, the -1082A>G polymorphism was only associated with increased risk for gastric cancer (G vs. A: OR = 1.281, 95% CI: 1.102–1.488) and in Asian population (G vs. A: OR = 1.399, 95% CI: 1.188–1.646). No significant publication bias was detected. Based on 40 studies and 18950 participants, we found the variant IL-10 -1082G allele significantly increased susceptibility to digestive cancer, especially for gastric cancer and in Asian population.

The Role of 5-HT3 and 5-HT4 Receptors in the Adaptive Mechanism of Colonic Transit Following the Parasympathetic Denervation in Rats

BACKGROUND Clinical studies show that disturbed colonic motility induced by extrinsic nerves damage is restored over time. We studied whether 5-HT3 and 5HT4 receptors are involved in mediating the adaptive mechanisms following parasympathetic denervation. METHODS Parasympathetic denervation of the entire colon was achieved by bilateral pelvic nerve transection and truncal vagotomy in rats. Colonic transit was measured by calculating the geometric center (GC) of 51Cr distribution. Expression of 5-HT3 and 5HT4 receptor mRNA was determined by real time RT-PCR. RESULTS Parasympathetic denervation caused a significant delay in colonic transit (GC=4.36) at postoperative day (POD) 1, compared with sham operation (GC=6.31). Delayed transit was gradually restored by POD 7 (GC=5.99) after the denervation. Restored colonic transit was antagonized by the administration of 5-HT3 and 5HT4 receptors antagonists at POD 7. 5-HT3 and 5HT4 receptors mRNA expression were significantly increased in the mucosal/submucosal layer at POD 3 or POD 7, whereas no significant difference was observed in the longitudinal muscle layers adherent with the myenteric plexus (LMMP). CONCLUSIONS It is suggested that up-regulation of 5-HT3 and 5-HT4 receptors expression in the mucosal/submucosal layer is involved to restore the delayed transit after the parasympathetic denervation in rats.

IGFBP-3 Gene Methylation in Primary Tumor Predicts Recurrence of Stage II Colorectal Cancers

Objectives:To evaluate the influence of IGFBP-3 methylation on recurrence in patients with stage II colorectal cancer (CRC) from 2 independent cohorts. Background:The relationship between IGFBP-3 methylation in primary tumors (PTs) or lymph nodes (LNs) and risk of recurrence in patients with stage II CRC treated with surgery alone is unknown. Methods:IGFBP-3 methylation of DNA from 115 PTs and 1641 LNs in patients with stage II CRC from 2 independent cohorts was analyzed. Forty patients developed recurrence, whereas 75 matched patients remained recurrence free for more than 2 years after surgery. Cox proportional hazard models were used to calculate hazard ratios (HRs) of recurrence, adjusted for patient and tumor characteristics. Results:Methylation of IGFBP-3 in PTs was identified to be significantly associated with risk of recurrence in the training set. The signature was tested in a validation set and classified 40.7% of patients as high risk. Five-year recurrence-free survival rates were 76.4% and 58.3% for low- and high-risk patients, respectively, with an HR of 2.21 (95% confidence interval, 1.04–4.68; P = 0.039). In multivariate analysis, the signature remained the most significant prognostic factor, with an HR of 2.40 (95% confidence interval, 1.10–5.25; P = 0.029). A combined analysis of 1641 LNs from the 2 sets identified IGFBP-3 methylation in LNs was not associated with risk of recurrence. Conclusions:Detection of IGFBP-3 methylation in PTs, but not in LNs, provides a powerful tool for the identification of patients with stage II CRC at high risk of recurrence.

Opioid receptors and associated regulator of G protein signaling are involved in the cathartic colon of rats

A cathartic colon is characteristic of slow transit constipation (STC), which can result following the long-term use of irritant laxatives. In the present study, the involvement of three opioid receptor subtypes (μ, MOR; δ, DOR; and κ, KOR), regulator of G protein signaling 4 (RGS-4) and β-arrestin-2 were investigated in the cathartic colon of rats. A rat model of a cathartic colon was established by feeding the animals with phenolphthalein, while normal rats were used as a control. The mRNA and protein expression levels of the opioid receptors, RGS-4 and β-arrestin-2 were detected in the rat colon using semi-quantitative reverse transcription polymerase chain reaction and western blot analysis, respectively. The rat model of a cathartic colon was successfully established using the phenolphthalein stimulus, and was shown to result in shrunken myenteric neurons and loose muscle fibers in the intestinal wall. The mRNA and protein expression levels of the three opioid receptor subtypes, RGS-4 and β-arrestin-2 were significantly higher in the cathartic colon group when compared with the levels in the normal control group (all P<0.01). With regard to the protein expression levels, MOR protein increased 2.4 fold, DOR expression increased 1.5 fold, KOR levels increased 1.5 fold, RGS-4 protein increased 3.5 fold and β-arrestin-2 expression increased 2.0 fold. Therefore, the expression levels of opioid receptors were found to increase in the cathartic colons of the rats, indicating that opioid receptors and downstream RGS-4 and β-arrestin-2 signaling may play an important role in the pathogenesis of STC.

Neonatal colon perforation due to anorectal malformations: Can it be avoided?

Anorectal malformations (ARM) are common anomalies in neonates. Diagnostic and therapeutic delays in the management of ARM may lead to colonic perforation, and even death. Physical examination of the perineum is often sufficient to diagnose ARM in neonates. Notwithstanding, delayed diagnosis of ARM has become increasingly familiar to surgeons, as evidenced by the number of recent publications on this topic in the literature. In this commentary, we discuss spontaneous colonic perforation due to delayed diagnosis of ARM in neonates, and highlight the importance of early diagnosis in assuring good outcomes with surgical management. At this point, a thorough examination of the perineum during the initial newborn assessment is mandatory, particularly in those patients presenting with abdominal signs or symptoms.

Adenovirus-mediated stem cell leukemia gene transfer induces rescue of interstitial cells of Cajal in ICC-loss mice

ObjectiveInteraction of c-Kit and its ligand stem cell factor (SCF) is necessary for appropriate development and survival of interstitial cells of Cajal (ICC) in the intestine. Blockade of c-Kit will cause ICC loss in vivo. Stem cell leukemia (SCL) gene acts as a positive regulator of upstream transcription of c-Kit expression. This study aimed to explore whether the restoration of c-Kit expression promoted by SCL gene transfer could rescue ICC in vivo.Materials and methodsA modified ICC-loss mouse model was created by continual administration of anti-c-Kit antibody (ACK2) to obtain a steady status of ICC loss, and a recombinant adenovirus vector containing SCL gene (Ad-SCL) was designed to rescue ICC in these mice. Western blot analysis and immunofluorescence labeling assays were performed to analyze the SCL and c-Kit expression in vitro and in vivo. The distribution and configuration of ICC were observed with immunohistochemistry and electromicroscope.ResultsWestern blot analysis and immunofluorescence labeling assays showed that SCL gene was successfully delivered to cultured HeLa and ICC cells in vitro. Moreover, significantly increased c-Kit expression could be detected in the colon of Ad-SCL-infected ICC-loss mice. Furthermore, rescue of the ICC network and ICC with typical ultrastructural features could be detected in Ad-SCL-infected ICC-loss mice at day 37.ConclusionsAd-SCL was able to enhance c-Kit expression, reactivate the c-Kit/SCF pathway, and rescue ICC in ICC-loss mice. Since loss and defects of ICC are associated with many human gut motility disorders, Ad-SCL may be of potential use in gene therapy of these patients.

Response to the Comment on: Effects of Laparoscopic Roux-en-Y Gastric Bypass for Type 2 Diabetes Mellitus: Comparison of BMI > 30 and < 30 kg/m2

We would like to thank you for responding to our recently published article, BEffects of Laparoscopic Roux-en-Y Gastric Bypass for Type 2 Diabetes Mellitus: Comparison of BMI > 30 and < 30 kg/m^ [1]. We appreciate your interest in our work, and we welcomed these comments. We agree that bariatric surgery should be very carefully selected for overweight individuals (BMI of between 25 and 29) without diabetes. However, for overweight patients with T2DM, it is quite different. During the past decade, bariatric surgery has been explored for the treatment of T2DM patients with low body mass index (BMI), particularly in Asia. As you mentioned, many studies have reported usefulness of gastric bypass surgery in non-obese diabetic patients [2–4]. Bariatric surgery for low BMI T2DM patients is mainly to prevent diabetes related complications rather than mortality. Lots of studies revealed that RYGB is a safe and effective procedure in treating T2DM with low BMI [2–14]. Moreover, Asian population is given priority with abdominal obesity; therefore, the Chinese guidelines for diabetes surgery decreased the BMI to 27.5 kg/m. In our group, we do have a small number of patients whose BMI were below 27.5 kg/m. And those patients underwent bariatric surgery before Chinese guidelines were published. Fortunately, their surgical outcome is positive and the T2DM remission is about 64% postoperative 1 year according to Chinese guidelines (HbA1c< 6.5). We believe the quality of life for these patients should be better. The author points out that some patients in our study are in the early period of diabetes and they are so young. We reviewed our original data, there are two younger patients (25 and 27 years old) with BMI 37.2 and 48.2 kg/m, respectively. They both were morbid obesity and chose RYGB surgery not only to control high glycemic but to reduce weight. I agree with the author point that longer follow-up (more than 5 year) should be done to observe the long-termmortality for those patients after bariatric surgery. The surgery risks are associated with the surgeon’s experience and skills. Every obesity surgeon should be authorized and get the qualification to perform surgery for patients with diabetes based on the consensus or guidelines. We agree that the surgical therapy of diabetes is not the priority for patients. The preoperative evaluation should be completed by a multidisciplinary team seriously and surgical indications should be controlled strictly. Some studies have reported that metabolic surgery could be a cost-effective treatment for patients with T2DM and morbid obesity [15, 16]. We are looking forward to the further research of the cost-effective analysis about metabolic surgery for low BMI T2DM.