MutS functions as a clamp loader by positioning MutL on the DNA during mismatch repair.

Highly conserved MutS and MutL homologs operate as protein dimers in mismatch repair (MMR). MutS recognizes mismatched nucleotides forming ATP-bound sliding clamps, which subsequently load MutL sliding clamps that coordinate MMR excision. Several MMR models envision static MutS-MutL complexes bound to mismatched DNA via a positively charged cleft (PCC) located on the MutL N-terminal domains (NTD). We show MutL-DNA binding is undetectable in physiological conditions. Instead, MutS sliding clamps exploit the PCC to position a MutL NTD on the DNA backbone, likely enabling diffusion-mediated wrapping of the remaining MutL domains around the DNA. The resulting MutL sliding clamp enhances MutH endonuclease and UvrD helicase activities on the DNA, which also engage the PCC during strand-specific incision/excision. These MutS clamp-loader progressions are significantly different from the replication clamp-loaders that attach the polymerase processivity factors ß-clamp/PCNA to DNA, highlighting the breadth of mechanisms for stably linking crucial genome maintenance proteins onto DNA.

A Competing Endogenous RNA Network Reveals Novel Potential lncRNA, miRNA, and mRNA Biomarkers in the Prognosis of Human Colon Adenocarcinoma.

BACKGROUND: Accumulating evidence indicated that long noncoding RNAs (lncRNAs) have a wide range of biological functions and may play significant roles in tumorigenesis and progression. However, the understanding of its functions and related competitive endogenous RNAs (ceRNAs) networks is much less than that of protein-coding genes, particularly in colon adenocarcinoma. METHODS: We comprehensively analyzed the sequencing data of protein-coding and noncoding RNAs in colon adenocarcinoma patients from The Cancer Genome Atlas (TCGA) database. Next, we constructed colon adenocarcinoma-specific ceRNA network and evaluated the effect of these RNAs on overall survival (OS) for colon adenocarcinoma patients. RESULTS: Totally, 1138 differentially expressed lncRNAs (DElncRNAs), 245 microRNAs (DEmiRNAs), and 2081 mRNAs (DEmRNAs) were identified using a threshold of |log2FoldChange| >2.0 and adjusted P-value < 0.01. Subsequently, a colon adenocarcinoma-specific ceRNA network was successfully established with133 DElncRNAs, 29 DEmiRNAs, and 55 DEmRNAs. Among ceRNA network, seven DElncRNAs (AL590483.1, AP004609.1, ARHGEF26-AS1, HOX transcript antisense RNA (HOTAIR), ITCH-IT1, KCNQ1OT1, and LINC00491), four DEmiRNAs (hsa-mir-143, hsa-mir-183, hsa-mir-216a, and hsa-mir-424), and six DEmRNAs (FJX1, TPM2, ULBP2, PDCD4, PLAU, and SERPINE1) significantly correlated with OS (all P-value < 0.05). Notably, several interactions were highlighted in the ceRNA network, such as "KCNQ1OT1-hsa-mir-183-PDCD4", "KCNQ1OT1-hsa-mir-424-TPM2", "HOTAIR-hsa-mir-143-SERPINE1", and "ARHGEF26-AS1-hsa-mir-143-SERPINE1". CONCLUSIONS: These findings reveal several molecules might be novel important prognostic factors and potential treatment targets for colon adenocarcinoma. In addition, these observations contribute to a more comprehensive understanding of lncRNA-related ceRNA network and provide novel strategies for subsequent functional studies of lncRNAs in colon adenocarcinoma.

A propensity score-matched comparison of laparoscopic distal versus total gastrectomy for middle-third advanced gastric cancer.

BACKGROUND: The optimal resection extent for middle-third advanced gastric cancer (AGC) still remains controversial. This study aimed to assess the long-term oncologic outcomes of laparoscopy-assisted distal gastrectomy (LADG) versus laparoscopy-assisted total gastrectomy (LATG) for middle-third AGC. METHODS: A retrospective cohort study was conducted using data from 464 patients who underwent LADG or LATG between September 2007 and March 2013. Propensity score matching (PSM) were used for reducing the confounding effects to compare the long-term oncologic outcomes between two groups. Cox regression analysis was performed to clarify the prognostic factors. RESULTS: After PSM was performed, a well-balanced cohort of 376 patients (188 LADG and 188 LATG) was further analyzed. Of interest, the LADG group had a significantly shorter operative time (244.6 ±â€¯28.0 vs. 259.1 ±â€¯30.1, P < 0.0001), less operative blood loss (142.9 ±â€¯50.9 vs. 157.8 ±â€¯54.1, P = 0.006), earlier day of first flatus (2.6 ±â€¯0.8 vs. 2.9 ±â€¯0.9, P = 0.014), fewer number of retrieved lymph nodes (36.5 ±â€¯7.9 vs. 41.4 ±â€¯9.8, P < 0.0001), and shorter postoperative hospital stay (9.7 ±â€¯1.3 vs. 10.7 ±â€¯1.4, P < 0.0001) than the LATG group. However, no significant differences were observed in days of eating liquid diet (P = 0.626) and days of eating soft diet (P = 0.353). The incidence of overall and severe postoperative complications (Clavien-Dindo grade ≥ IIIa) following the LADG group were significantly fewer than the LATG group (overall, 24.5% vs. 34.6%, P = 0.032; severe, 4.8% vs. 11.2%, P = 0.022). In addition, the LADG group had significantly more favorable overall survival (OS) and disease-free survival (DFS) rates than the LATG group (5-year OS rate, 55.6% vs. 41.8%, P = 0.002; 5-year DFS rate, 45.9% vs. 32.8%, P < 0.001). In multivariate analyses, resection extent was not an independent prognostic factor for OS and DFS. CONCLUSIONS: This PSM cohort analysis has indicated LADG with D2 lymphadenectomy appeared to be safe and reasonable option for patients with middle-third AGC in general. LADG could contribute to improved survival.

Identification of key genes and associated pathways in KIT/PDGFRA wild­type gastrointestinal stromal tumors through bioinformatics analysis.

Gastrointestinal stromal tumors (GISTs) are the most common type of mesenchymal tumor in the gastrointestinal tract. The present study aimed to identify the potential candidate biomarkers that may be involved in the pathogenesis and progression of v­kit Hardy­Zuckerman 4 feline sarcoma viral oncogene homolog (KIT)/platelet­derived growth factor receptor α (PDGFRA) wild­type GISTs. A joint bioinformatics analysis was performed to identify the differentially expressed genes (DEGs) in wild­type GIST samples compared with KIT/PDGFRA mutant GIST samples. Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of DEGs was conducted using Database for Annotation, Visualization and Integrated Discovery and KEGG Orthology­Based Annotation System (KOBAS) online tools, respectively. Protein­protein interaction (PPI) networks of the DEGs were constructed using Search Tool for the Retrieval of Interacting Genes online tool and Cytoscape, and divided into sub­networks using the Molecular Complex Detection (MCODE) plug­in. Furthermore, enrichment analysis of DEGs in the modules was analyzed with KOBAS. In total, 546 DEGs were identified, including 238 upregulated genes primarily enriched in 'cell adhesion', 'biological adhesion', 'cell­cell signaling', 'PI3K­Akt signaling pathway' and 'ECM­receptor interaction', while the 308 downregulated genes were predominantly involved in 'inflammatory response', 'sterol metabolic process' and 'fatty acid metabolic process', 'small GTPase mediated signal transduction', 'cAMP signaling pathway' and 'proteoglycans in cancer'. A total of 25 hub genes were obtained and four modules were mined from the PPI network, and sub­networks also revealed these genes were primarily involved in significant pathways, including 'PI3K­Akt signaling pathway', 'proteoglycans in cancer', 'pathways in cancer', 'Rap1 signaling pathway', 'ECM­receptor interaction', 'phospholipase D signaling pathway', 'ras signaling pathway' and 'cGMP­PKG signaling pathway'. These results suggested that several key hub DEGs may serve as potential candidate biomarkers for wild­type GISTs, including phosphatidylinositol­4,5­bisphosphate 3­kinase, catalytic subunit γ, insulin like growth factor 1 receptor, hepatocyte growth factor, thrombospondin 1, Erb­B2 receptor tyrosine kinase 2 and matrix metallopeptidase 2. However, further experiments are required to confirm these results.

Robotic versus conventional laparoscopic gastrectomy for gastric cancer: A retrospective cohort study.

BACKGROUND: Robot-assisted gastrectomy (RAG), as an alternative minimally invasive surgical technique, is gradually being used for the treatment of gastric cancer (GC). This study aimed to assess the feasibility and safety of RAG over conventional Laparoscopy-assisted gastrectomy (LAG) for the treatment of GC. METHODS: We retrospectively analyzed all procedures (RAG and LAG) performed by one surgeon between 31 January 2017 and 1 December 2017. The short-term of surgical outcomes were compared between two groups and further subgroup analyses were performed. RESULTS: One hundred patients were enrolled in the RAG group and 135 in the LAG group. The demograghics and clinicopathologic characteristics are well matched between two groups. The RAG group had shorter postoperative hospital stay (11 (interquartile range 9-13) vs. 12 (10-14) day; p < 0.0001), earlier day of first flatus (2 (2-3) vs. 3 (2.3-3) day; p < 0.0001), and larger lymph nodes dissection (40.9 ±â€¯13.1 vs. 35.4 ±â€¯15.8; p = 0.004). Of interest, mean numbers of retrieved lymph nodes from station 6 (p = 0.002), 7 (p = 0.032), 10 (p = 0.025), 11p (p = 0.036), and 14v (p = 0.038) in RAG was significantly larger than LAG. However, no significant differences between two groups were observed in operative time (p = 0.136), operative blood loss (p = 0.434), days of eating liquid diet (p = 0.889), and postoperative complications (p = 0.752). In subgroup analyses, the similar results were observed. CONCLUSIONS: RAG for the treatment of GC is a safe and feasible procedure and beneficial for postoperative recovery of GC patients. However, further studies are needed to evaluate long-term and oncologic outcomes of RAG.

Short-term efficacy of laparoscopy-assisted vs open radical gastrectomy in gastric cancer.

AIM: To investigate the short-term benefits of laparoscopic radical gastrectomy (LARG) and open radical gastrectomy (ORG) in patients with gastric cancer. METHODS: A total of 400 patients with gastric cancer aged ≤ 65 years who were treated at General Hospital of Lanzhou Military Region were enrolled. Among these, 200 patients underwent LARG between October 2008 and August 2012 (LARG group); and 200 patients underwent ORG between March 2000 and September 2008 (ORG group). The short-term therapeutic benefits between the two groups were analyzed. RESULTS: The LARG procedure offered significantly better benefits to the patients compared to the ORG procedure, including less intraoperative blood loss (103.1 ± 19.5 mL vs 163.0 ± 32.9 mL, P < 0.0001), shorter postoperative hospital stay (6.8 ± 1.2 d vs 9.5 ± 1.6 d, P < 0.0001), less frequent occurrence of postoperative complications (6.5% vs 13.5%, P = 0.02), shorter time to mobilization (1.0 ± 0.3 vs 3.3 ± 0.4 d, P < 0.0001), shorter time to bowel opening (3.3 ± 0.7 d vs 4.5 ± 0.7 d, P < 0.0001), and shorter time to normal diet (3.0 ± 0.4 vs d 3.8 ± 0.5 d, P < 0.0001). However, LARG required a longer time to complete than the ORG procedure (192.3 ± 20.9 min vs 180.0 ± 26.9 min, P < 0.0001). CONCLUSION: Compared to ORG, LARG is safer, more effective, and less invasive for treating gastric cancer, with better short-term efficacy.

Clinical importance of surgical treatment of low rectal carcinoma in anus-preserving procedure--an analysis of 86 cases.

We investigated the methods and experiences of an anus-preserving procedure in curative resection of low rectal carcinoma. Eighty-six patients with low rectal carcinoma underwent Dixon's procedure with device assistance. Patients were then observed for the effects of operation. The operation was successful in all patients. Pathologic examination of specimens revealed negative margins. Complications such as anastomotic leakage were found in 7 cases. All patients recovered well. Device assistance may contribute to the successful performance of anus-preserving procedure in low rectal carcinoma. Whether the anus can be preserved or not depends on the accurate measurement of the distal length of the rectum. A meticulous hemostasis and avoidance of tension on the stoma are key measures for avoiding anastomotic leakage.

[Experimentation and investigation of the effects of TNF and the acceptor expression in renal early trauma with extraneous adrenomedullin].

OBJECTIVE: To investigate the effects of TNF-alpha, TNF-beta and the acceptor expression about mechanical renal trauma with extraneous ADM. METHODS: There were 104 healthy adult plain grade Wistar rat, randomly divided into four groups:8 in the group of control, 32 in the group of trauma, 32 in the group injected ADM before trauma, 32 in the group injected ADM post trauma. The experimental model of rat kidney with mechanical trauma was prepared by striking the area of rat skin reflecting by kidney with free dropping ferrous hammer in the last three groups. ADM (0.1 nmol/kg) administrated by intraperitoneal injection at 10 minutes before trauma or post trauma respectively in injected groups. All rats were executed by drawing-out all the blood in their hearts. Renal tissue was investigated to study positive expression of TNF-alpha, TNF-beta, TNFR after SABC stained. RESULTS: TNF-alpha expression:the TNF-alpha expression of trauma group was more positive than it of control group in the wound early time. The expression of group injected post trauma was less than it of trauma group at 1 h (P < 0.01). The expression of group injected before trauma was less than it of trauma group at 6 h (P < 0.05) TNF-beta expression: the TNF-beta expression of trauma group was less than it of control group at 1 h and 6 h (P < 0.05). The TNF-beta expression of group injected post trauma was more positive than it of trauma group at the same time of 1 h and 6 h (P < 0.01). TNFR expression: the TNFR expression of trauma group was less than it of control group at 6 h (P < 0.01). The TNFR expression of group injected before trauma was more positive than it of trauma group in the at the same time of 1 h and 6 h (P < 0.01). CONCLUSIONS: The TNFR can regulate the TNF-alpha and the TNF-beta in dynamic balancing. The regulation of TNFR is main to TNF-alpha. What the TNF-beta participated in renal trauma mainly is the anti-damage process. ADM can reduce the expression of TNF-alpha. ADM increases the expression of TNF-beta and TNFR.