Driver Gene Alterations in Malignant Progression of Gastric Cancer.

The identification of driver genes is of great importance in modern medical research. It is also an essential factor in the development of individualization and has a positive effect on understanding the causes of cancer. Gene mutations are the primary cause of the outcomes of the process of tumorigenesis. Driver genes can be used as therapeutic targets for tumor-specific mutation-dependent overexpression. This study sought to identify mutation-based driver genes in gastric cancer (GC) by applying comprehensive gene expression and copy number analysis. Multiplatform analysis was used to identify four major genomic subtypes of GC. The most prominent cancer-related variations observed in this cohort were TTN mutations (found in 56% of tumors), followed by TP53 (51%), MUC16 (7%), and LRP1B (6%) mutations. In our analysis, mutation characteristics were mainly related to the DNA mismatch repair system. In addition, 34 candidate driver oncogenes were identified in GC. Further research identified six GC-related driver genes associated with the levels of immune infiltration of different immune cells and the majority of immune markers. Our mutation-based study of driver oncogenes identified potential drug targets in GC.

Inhibition of GKN2 Attenuates Acute Gastric Lesions Through the NLRP3 Inflammasome.

Objective: Acute gastric lesions are commonly seen in critically ill patients in the intensive care unit and can result in significant upper gastrointestinal bleeding. However, the signaling mechanisms that regulate this severe disease are still unclear. In this study, we explored the involvement of gastrokine 2 (GKN2) in the development of acute gastric lesions in mice. Approach: We measured the degree of injury using the water immersion restraint stress mouse model. Inflammatory cells and factors were analyzed after gastric lesion induction. The luciferase reporter assay was used to detect the transcription activity of nuclear receptor subfamily 3 group C member 1 (NR3C1) in regulation of GKN2. We also detected the downstream pathway of GKN2 in gastric lesions. Results: The results showed that GKN2 could aggravate stress-induced gastric lesions and gastric mucosal cell death. Moreover, the gastric lesion promoted by GKN2 was gastric acid independent. GKN2 could recruit neutrophils and promote the release of inflammatory factors to contribute to inflammation. NR3C1, activated by cortisol under stress, could act as a transcription factor to upregulate the expression of GKN2. Innovation: This study elucidates the process of gastric lesion at a molecular level and explores the possible contender biomarkers for diagnosis and drug targets in wound healing of gastric lesions. Conclusion: In conclusion, GKN2, which was upregulated by cortisol, aggravated the gastric lesion through activation of the inflammasome and inflammatory reaction.

Effects of SW033291 on the myogenesis of muscle-derived stem cells and muscle regeneration.

BACKGROUND: The unmet medical needs in repairing large muscle defects promote the development of tissue regeneration strategy. The use of bioactive molecules in combination with biomaterial scaffold has become an area of great interest. SW033291, a small-molecule inhibitor targeting 15-hydroxyprostaglandin dehydrogenase (15-PDGH) and subsequently elevating the production of prostaglandin E2 (PGE2), has been proved to accelerate the recovery and potentiate the regeneration of multiple tissues including the bone, liver, and colon. The limited understanding of the potential therapeutic effects on myogenesis motivated us to investigate the role of SW033291 in regulating muscle-derived stem cell (MDSC) myogenic differentiation and MDSC-mediated muscle regeneration. METHODS: The characteristics of rat MDSCs, including cell-specific markers and myogenic differentiation potential, were determined. MDSCs were incubated with SW033291 to evaluate PGE2 production and cytotoxicity. The effects of SW033291 on MDSC myogenic differentiation were assessed by quantitative real-time polymerase chain reaction (qPCR), western blot, and immunocytochemistry. The fibrin gel containing MDSCs and SW033291 was used for muscle regeneration in a tibialis anterior muscle defect model. RESULTS: Our data demonstrated that MDSCs were well-tolerated to SW033291 and treatment with SW033291 significantly promoted the production of PGE2 by MDSCs. In vitro analysis showed that SW033291 enhanced the myogenic differentiation and myotube formation by upregulating a series of myogenic markers. Additionally, the activation of PI3K/Akt pathway was involved in the mechanism underlying these promotive effects. Then, in situ casting of fibrin gel containing MDSCs and SW033291 was used to repair the tibialis anterior muscle defect; the addition of SW033291 significantly promoted myofiber formation within the defect region with mild immune response, less fibrosis, and sufficient vascularization. CONCLUSION: SW033291 acted as a positive regulator of MDSC myogenic differentiation, and incorporating the compound with MDSCs in fibrin gel could serve as an effective method to repair large skeletal muscle defects.

Mesh repair of sacrococcygeal hernia via a combined laparoscopic and sacrococcygeal approach: A case report.

BACKGROUND: Sacrococcygeal hernia is a very rare condition that is usually secondary to sacrococcygectomy, and its ideal treatment regimen is unclear. Herein, we report a case of sacrococcygeal hernia occurring in a patient who had no history of sacrococcygeal operation, present the operative procedures of mesh repair via a combined laparoscopic and sacrococcygeal approach that has not been described, and discuss our experience in diagnosis and treatment with a review of the literature. CASE SUMMARY: A 54-year-old woman who chiefly complained of a 10-year history of a reversible bulge in her right sacrococcygeal region was admitted to our hospital. The physical examination revealed a bulge in the right sacrococcygeal region upon standing, which disappeared in the prone position but relapsed when performing the Valsalva manoeuvre. Computed tomography displayed an abnormality in the structure of the tissues between the midline of the sacrococcygeal region and the right gluteus muscle. The patient was diagnosed with sacrococcygeal hernia and received hernia repair with mesh through a combined laparoscopic and sacrococcygeal approach. On laparoscopy, the rectum was dissected posterolaterally, and a defect was identified in the right anterior sacrococcygeal region through which part of the rectum protruded. This was followed by the placement of a self-gripping polyester mesh via a sacrococcygeal approach. There were no postoperative complications. The patient was discharged on postoperative day 7 and was followed for more than 6 mo with no recurrence. CONCLUSION: Laparoscopic mesh repair is recommended as a priority of surgical options for sacrococcygeal hernias, while choosing a self-gripping mesh can help avoid the risk of presacral vessel injury by reducing suture fixation.

GKN2 promotes oxidative stress-induced gastric cancer cell apoptosis via the Hsc70 pathway.

BACKGROUND: The GKN2 is a secretory protein, whose levels decrease in gastric cancer. The present study aimed to investigate the expression, function and mechanism of action of GKN2 in gastric cancer. METHODS: Molecular biology assays were performed to elucidate the function and underlying mechanisms of GKN2 in gastric cancer under stress-induced condition in vivo and in vitro. Clinical specimens were used to assess the correlation of GKN2 and prognosis. RESULTS: We found that overexpression of GKN2 significantly enhanced apoptosis and growth arrest in vitro. GKN2 expression increased in gastric cancer cells exposed to hydrogen peroxide and promoted reactive oxygen species-induced mitochondrial dysfunction and resulted in increased cell apoptosis via inhibition of NF-κB signaling pathway and activation of JNK signaling pathway through the direct interaction of GKN2 with Hsc70. Trefoil factor 1 might contribute to the tumor suppressing effects of GKN2. MiR-216a downregulated GKN2 expression. GKN2 also inhibited xenograft tumor growth and was an independent and significant prognostic factor for patients with gastric cancer treated with oxaliplatin. CONCLUSIONS: Taken together, our data indicate that GKN2 may increase sensitivity of GC cells to the drugs which increase ROS levels in tumors. Inhibition of the interaction between GKN2 and Hsc70 could attenuate the effects induced by GKN2. GKN2 overexpression could be used to determine the subgroup of patients to obtain the more favorable outcome of oxaliplatin treatment and may be used as biomarker of the prognosis of this cancer.

Author Correction: 5-Hydroxymethylcytosine signatures in circulating cell-free DNA as diagnostic biomarkers for human cancers.

In the initial published version of this article, there was a mistake in the P value for the correlation between gene-expression changes and 5 hmC changes in tumors. The correct P value should be same as the P value shown in Fig. S6A: 9.8 × 10-6 (mistakenly shown as "9.8 × 106" in the main text). This correction does not affect the description of results or the conclusions of this study, since the range of P value is between 0 and 1.

A five-miRNA signature predicts survival in gastric cancer using bioinformatics analysis.

Abnormal expression of miRNAs is critical for gastric cancer progression. Here, we aimed to identify the differential expression of miRNAs in normal and cancerous gastric tissues and build a nomogram for effectively predicting the survival of patients with gastric cancer. We used high-throughput miRNA data in The Cancer Genome Atlas (TCGA) database for this study. The discriminative capabilities and predictive accuracy of the nomogram depended on the calibration curve and concordance index (C-index), and comparisons were made between the nomogram and current gastric cancer staging systems. Data of 87 patients collected from TCGA as bootstrap resamples were used to validate the results. In total, 129 miRNAs were differential expressed, of which, prognostic function was associated with five miRNAs using Kaplan-Meier analysis. Functional enrichment analysis showed that the target genes of these miRNAs were involved in various cancer-related pathways. Age, metastasis, lymph node status, T stage and the five-miRNA signature were selected as independent survival variables, in the nomogram for primary cohort multivariate analysis. According to the survival probability calibration curve, the nomogram predictions were consistent with the actual observations. The survival predicting nomogram showed a C-index of 0.72 (95% CI, 0.64 to 0.78), which was significantly higher than the C-index of the American Joint Committee on Cancer (AJCC) seventh edition (0.60; P < 0.001). We suggest that the proposed nomogram could be used to accurately predict the prognosis of patients with gastric cancer.

MicroRNA­495 regulates human gastric cancer cell apoptosis and migration through Akt and mTOR signaling.

In the present study, we investigated the expression and cellular distribution of microRNA­495 (miR­495) in human gastric cancer. Prominent downregulation of miR­495 activation was evident in patients with gastric cancer. Cell viability and Annexin V/PI apoptosis assays were used to assess cell proliferation and apoptosis. Then, western blot analysis was used to assess cyclin D1, PI3K, p­Akt and p­mTOR protein expression. Overexpression of miR­495 significantly inhibited cell proliferation, and promoted cell apoptosis of gastric cancer cells. Overexpression of miR­495 also promoted caspase­3/­9 and Bax protein expression, and suppressed cyclin D1 protein expression and the PI3K/Akt/mTOR pathway in gastric cancer cells. Downregulation of miR­495 increased cell proliferation and inhibited cell apoptosis of gastric cancer cells through activation of the PI3K/Akt/mTOR pathway. The PI3K inhibitor, was used to suppress the PI3K/Akt/mTOR pathway, inhibit cell proliferation, promote cell apoptosis, promote caspase­3/­9 and Bax protein expression, and suppress cyclin D1 protein expression of gastric cancer cells through miR­495 inhibition. In conclusion, miR­495 is an important regulator of human gastric cancer cells and may contribute to cell apoptosis through the PI3K/Akt/mTOR/Bax­caspase­3/­9 and cyclin D1 pathway.

Global transcriptome­wide analysis of the function of GDDR in acute gastric lesions.

Acute gastric lesions induced by stress are frequent occurrences in medical establishments. The gastric dramatic downrelated gene (GDDR) is a secreted protein, which is abundantly expressed in normal gastric epithelia and is significantly decreased in gastric cancer. In our previous study, it was found that GDDR aggravated stress­induced acute gastric lesions. However, the role of GDDR in acute gastric lesions remains to be fully elucidated. In the present study, RNA sequencing was performed in order to examine the gene expression profile regulated by GDDR in acute gastric lesions. The dataset comprised four stomach samples from wild-type (WT) mice and four stomach samples from GDDR­knockout mice. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to analyze the differentially-expressed genes (DEGs). Weighted correlation network analysis was used to identify clusters of highly correlated genes. Cytoscape was used to construct a protein­protein interaction network (PPI) of the DEGs. Based on the GO analysis, the upregulated DEGs were distinctly enriched in muscle contraction and response to wounding; and the downregulated DEGs were significantly enriched in the regulation of nitrogen compound metabolic process and regulation of RNA metabolic process. The results of the KEGG pathway analysis showed that the upregulated DEGs were enriched in ECM­receptor interaction and the signaling pathway of cGMP­PKG, and the downregulated DEGs were enriched in the renin­angiotensin system and glycerolipid metabolism. The co­expression network revealed a group of genes, which were associated with increased wound healing in the WT mice. Significant pathways were identified through the PPI network, including negative regulation of the signaling pathway of glucocorticoid receptor, regulation of cellular stress response, and regulation of hormone secretion. In conclusion, the present study improves current understanding of the molecular mechanism underlying acute gastric lesions and may assist in the treatment of gastric lesions.

5-Hydroxymethylcytosine signatures in circulating cell-free DNA as diagnostic biomarkers for human cancers.

DNA modifications such as 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are epigenetic marks known to affect global gene expression in mammals. Given their prevalence in the human genome, close correlation with gene expression and high chemical stability, these DNA epigenetic marks could serve as ideal biomarkers for cancer diagnosis. Taking advantage of a highly sensitive and selective chemical labeling technology, we report here the genome-wide profiling of 5hmC in circulating cell-free DNA (cfDNA) and in genomic DNA (gDNA) of paired tumor and adjacent tissues collected from a cohort of 260 patients recently diagnosed with colorectal, gastric, pancreatic, liver or thyroid cancer and normal tissues from 90 healthy individuals. 5hmC was mainly distributed in transcriptionally active regions coincident with open chromatin and permissive histone modifications. Robust cancer-associated 5hmC signatures were identified in cfDNA that were characteristic for specific cancer types. 5hmC-based biomarkers of circulating cfDNA were highly predictive of colorectal and gastric cancers and were superior to conventional biomarkers and comparable to 5hmC biomarkers from tissue biopsies. Thus, this new strategy could lead to the development of effective, minimally invasive methods for diagnosis and prognosis of cancer from the analyses of blood samples.

Non-curative surgery for patients with gastric cancer with local peritoneal metastasis: A retrospective cohort study.

The role of non-curative surgery for patients with M1 gastric cancer (GC) is controversial. This study aimed to evaluate the efficacy of non-curative resectional surgery for patients with GC with local peritoneal metastasis.We reviewed the medical records of 47 patients with GC with local peritoneal metastasis, which was found by laparotomy or laparoscopy. The patients were divided into 2 groups: those who underwent gastric resection (n = 29), and a non-resection group who did not (n = 18). The clinical characteristics, postoperative complications, mortality, palliative intervention, and long-term outcomes of the 2 groups were compared.Complications occurred more frequently in the resection group than in non-resection group (P = 0.017). There was no postoperative mortality or reoperation in either group. Palliative intervention was performed in 9 (31%) patients in resection group and 16 (88.9%) patients in non-resection group (P < 0.001). The intervention interval and hospital-free time were significant longer in resection group than in non-resection group (P < 0.001, P < 0.001). The Kaplan-Meier survival curves revealed that resection group had longer survival than non-resection group (P < 0.001).Non-curative resectional surgery helps prolong survival time and improve the quality of life for patients with GC with local peritoneal metastasis.

Surgical strategy for gastric cancer patients with liver cirrhosis: a retrospective cohort study.

INTRODUCTION: Recent studies have shown that radical gastrectomy with extended lymphadenectomy is feasible in gastric cancer patients with liver cirrhosis, but in those studies the main proportion was Child-Pugh class A patients. It is still difficult to choose reasonable surgical strategies for gastric cancer patients with cirrhosis, especially for Child-Pugh class B patients. METHODS: We reviewed the medical records of patients with liver cirrhosis who had undergone radical gastrectomy between January 2001 and December 2012. The clinical characteristics, postoperative complications, mortality and long-term outcomes in the 58 patients were investigated. RESULTS: Severe complications and postoperative mortality occurred more frequently in class B patients than in class A patients (P < 0.05). In patients with class A and B, the complications and mortality rate was 37.5% and 4.2% in D1 lymph node dissection group and 71.9% and 25% in D2 lymph node dissection group, respectively. Kaplan-Meier survival analysis showed longer survival for class A patients than for class B patients (P < 0.05). For class B patients with advanced gastric cancer, D2 lymph node dissection could not provide a longer survival than D1 lymph node dissection (P = 0.282). CONCLUSION: Radical operation with D1 or D2 lymph node dissection can be tolerated in class A gastric cancer patients. D1 lymph node dissection is recommended in class B patients, and radical gastrectomy is very dangerous, even fatal for class C patients.